July 2013 - The Endocrine Society

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Memory Loss and Other Side EffectsFuel the Statin Debate

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EndocrinE newsJULY 2013 ThE LEaDINg MagazINE FOR ENDOCRINOLOgISTS

Please see Important Safety Information, including Boxed Warning regarding osteosarcoma, and Brief Summary on following pages. See Full User Manual that accompanies the delivery device.

INDICATIONS AND USAGE• FORTEO is indicated for the treatment of postmenopausal women with osteoporosis at high risk for fracture, to increase bone mass

in men with primary or hypogonadal osteoporosis at high risk for fracture, and for the treatment of men and women with osteoporosis associated with sustained, systemic glucocorticoid therapy (daily dosage equivalent to 5 mg or greater of prednisone) at high risk for fracture

• High risk for fracture is de� ned as a history of osteoporotic fracture, multiple risk factors for fracture, or patients who have failed or are intolerant to other available osteoporosis therapy

FORTEO is administered as a 20-microgram once-daily dose and is available in a 2.4-mL pre� lled delivery device for subcutaneous injection over 28 days.

WARNING: POTENTIAL RISK OF OSTEOSARCOMASee the Important Safety Information for Complete Boxed Warning.

• In rats, teriparatide caused an increase in the incidence of osteosarcoma, a malignant bone tumor.• Because of the uncertain relevance of the rat osteosarcoma � nding to humans, prescribe FORTEO only for patients for

whom potential bene� ts outweigh potential risk.• FORTEO should not be prescribed for patients at increased baseline risk for osteosarcoma (eg, those with Paget’s disease

of bone or unexplained elevations of alkaline phosphatase, pediatric and young adult patients with open epiphyses, or prior external beam or implant radiation therapy involving the skeleton).

FORTEO has the anabolic action to help form new bone1

• FORTEO is not a bisphosphonate; FORTEO is not an antiresorptive1-3

• FORTEO is the only FDA-approved anabolic agent for osteoporosis

• FORTEO strengthens bone by forming new bone on cortical and trabecular surfaces and increasing skeletal mass2

The FORTEO Co-pay Card helps limit your eligible patients’ out-of-pocket costs to $50/month*

• Patients are eligible for up to 24 months of therapy

• Offer is subject to eligibility; other restrictions or limitations may apply

*This offer may be terminated, rescinded, revoked, or amended by Lilly USA, LLC at any time without notice. Patient should provide the card to his/her pharmacist, along with a valid prescription from the physician.

CONSIDER FORTEO TO HELP REDUCE THE RISK OF FRACTURE AND HELP FORM NEW BONE

FOR PATIENTS WITH OSTEOPOROSIS AT HIGH RISK FOR ANOTHER FRACTURE ONE OSTEOPOROTIC

FRACTURE MAY LEAD TO ANOTHER

KJob Number: 15913Revision No: 0Date: 10/30/12

YMC152_33474 SS


YMC152_33474

INDICATIONS AND USAGE• FORTEO is indicated for the treatment of postmenopausal women with osteoporosis at high risk for fracture, to increase bone mass in men

with primary or hypogonadal osteoporosis at high risk for fracture, and for the treatment of men and women with osteoporosis associated with sustained, systemic glucocorticoid therapy (daily dosage equivalent to 5 mg or greater of prednisone) at high risk for fracture



IMPORTANT SAFETY INFORMATION

WARNING: POTENTIAL RISK OF OSTEOSARCOMAIn male and female rats, teriparatide caused an increase in the incidence of osteosarcoma (a malignant bone tumor) that was dependent on dose and treatment duration. The effect was observed at systemic exposures to teriparatide ranging from 3 to 60 times the exposure in humans given a 20-mcg dose. Because of the uncertain relevance of the rat osteosarcoma � nding to humans, prescribe FORTEO® (teriparatide [rDNA origin] injection) only for patients for whom the potential bene� ts are considered to outweigh the potential risk. FORTEO should not be prescribed for patients who are at increased baseline risk for osteosarcoma (including those with Paget’s disease of bone or unexplained elevations of alkaline phosphatase, pediatric and young adult patients with open epiphyses, or prior external beam or implant radiation therapy involving the skeleton).

CONTRAINDICATIONSHypersensitivity to teriparatide or to any of its excipients. Reactions have included angioedema and anaphylaxis.

WARNINGS AND PRECAUTIONSThe following categories of patients have increased baseline risk of osteosarcoma and therefore should not be treated with FORTEO: Paget’s disease of bone, pediatric populations and young adults with open epiphyses, or prior external beam or implant radiation therapy.

Patients should be encouraged to enroll in the voluntary FORTEO Patient Registry, which is designed to collect information about any potential risk of osteosarcoma in patients who have taken FORTEO. Enrollment information can be obtained by calling 1-866-382-6813, or by visiting www.forteoregistry.rti.org.

Cases of bone tumor and osteosarcoma have been reported rarely in people taking FORTEO in the post-marketing period. The causality to FORTEO use is unclear.

The safety and ef� cacy of FORTEO have not been evaluated beyond 2 years of treatment. The use of FORTEO for more than 2 years during a patient’s lifetime is, therefore, not recommended.

Patients with the following conditions also should not receive FORTEO: bone metastases or a history of skeletal malignancies, metabolic bone diseases other than osteoporosis, or hypercalcemic disorders.

FORTEO may increase serum calcium, urinary calcium, and serum uric acid.

Use with caution in patients with active or recent urolithiasis because of risk of exacerbation. If active urolithiasis or pre-existing hypercalciuria are suspected, measurement of urinary calcium excretion should be considered.

Transient orthostatic hypotension may occur with initial doses of FORTEO. In short-term clinical pharmacology studies, transient episodes of symptomatic orthostatic hypotension were observed in 5% of patients. FORTEO should be administered initially under circumstances where the patient can sit or lie down if symptoms of orthostatic hypotension occur.

Patients receiving digoxin should use FORTEO with caution because FORTEO may transiently increase serum calcium and hypercalcemia may predispose patients to digitalis toxicity.

ADVERSE REACTIONSThe most common adverse reactions in clinical trials include: arthralgia (10.1% FORTEO vs. 8.4% placebo), pain (21.3% FORTEO vs. 20.5% placebo), and nausea (8.5% FORTEO vs. 6.7% placebo). Other adverse reactions include: dizziness, leg cramps, joint aches, and injection site reactions.

USE IN PREGNANCY/NURSING MOTHERSFORTEO should be used during pregnancy only if the potential bene� t justi� es the potential risk to the fetus. Based on animal studies, FORTEO may cause fetal harm.

It is not known whether teriparatide is excreted in human milk. Breastfeeding mothers should discontinue nursing or FORTEO, taking into account the importance of treatment to the mother.

INSTRUCTIONS FOR FORTEO USEFORTEO is provided as a � xed-dose, pre� lled delivery device that can be used for up to 28 days, including the � rst injection. The delivery device contains 28 daily doses of 20 mcg each. Do not transfer the contents of the delivery device into a syringe. The FORTEO Delivery Device should be stored under refrigeration at 36° to 46° F (2° to 8° C) at all times. Do not use FORTEO if it has been frozen.

TE HCP ISI 24SEP2012

For more safety information, please see Brief Summary of Prescribing Information, including Boxed Warning regarding osteosarcoma, on following pages. See Full User Manual that accompanies the delivery device.References: 1. Riggs BL, Par� tt AM. J Bone Miner Res. 2005;20:177‐184. 2. FORTEO Prescribing Information. 3. National Osteoporosis Foundation. Osteoporosis medicines: what you need to know. Available at: http://www.nof.org/aboutosteoporosis/managingandtreating/medicinesneedtoknow. Accessed September 19, 2012.

TE-80859 1012. Printed in USA. ©Lilly USA, LLC 2012. All rights reserved. FORTEO is a registered trademark of Eli Lilly and Company.


YMC152_33474

INDICATIONS AND USAGE• FORTEO is indicated for the treatment of postmenopausal women with osteoporosis at high risk for fracture, to increase bone mass in men

with primary or hypogonadal osteoporosis at high risk for fracture, and for the treatment of men and women with osteoporosis associated with sustained, systemic glucocorticoid therapy (daily dosage equivalent to 5 mg or greater of prednisone) at high risk for fracture



IMPORTANT SAFETY INFORMATION

WARNING: POTENTIAL RISK OF OSTEOSARCOMAIn male and female rats, teriparatide caused an increase in the incidence of osteosarcoma (a malignant bone tumor) that was dependent on dose and treatment duration. The effect was observed at systemic exposures to teriparatide ranging from 3 to 60 times the exposure in humans given a 20-mcg dose. Because of the uncertain relevance of the rat osteosarcoma � nding to humans, prescribe FORTEO® (teriparatide [rDNA origin] injection) only for patients for whom the potential bene� ts are considered to outweigh the potential risk. FORTEO should not be prescribed for patients who are at increased baseline risk for osteosarcoma (including those with Paget’s disease of bone or unexplained elevations of alkaline phosphatase, pediatric and young adult patients with open epiphyses, or prior external beam or implant radiation therapy involving the skeleton).

CONTRAINDICATIONSHypersensitivity to teriparatide or to any of its excipients. Reactions have included angioedema and anaphylaxis.

WARNINGS AND PRECAUTIONSThe following categories of patients have increased baseline risk of osteosarcoma and therefore should not be treated with FORTEO: Paget’s disease of bone, pediatric populations and young adults with open epiphyses, or prior external beam or implant radiation therapy.

Patients should be encouraged to enroll in the voluntary FORTEO Patient Registry, which is designed to collect information about any potential risk of osteosarcoma in patients who have taken FORTEO. Enrollment information can be obtained by calling 1-866-382-6813, or by visiting www.forteoregistry.rti.org.

Cases of bone tumor and osteosarcoma have been reported rarely in people taking FORTEO in the post-marketing period. The causality to FORTEO use is unclear.

The safety and ef� cacy of FORTEO have not been evaluated beyond 2 years of treatment. The use of FORTEO for more than 2 years during a patient’s lifetime is, therefore, not recommended.

Patients with the following conditions also should not receive FORTEO: bone metastases or a history of skeletal malignancies, metabolic bone diseases other than osteoporosis, or hypercalcemic disorders.

FORTEO may increase serum calcium, urinary calcium, and serum uric acid.

Use with caution in patients with active or recent urolithiasis because of risk of exacerbation. If active urolithiasis or pre-existing hypercalciuria are suspected, measurement of urinary calcium excretion should be considered.

Transient orthostatic hypotension may occur with initial doses of FORTEO. In short-term clinical pharmacology studies, transient episodes of symptomatic orthostatic hypotension were observed in 5% of patients. FORTEO should be administered initially under circumstances where the patient can sit or lie down if symptoms of orthostatic hypotension occur.

Patients receiving digoxin should use FORTEO with caution because FORTEO may transiently increase serum calcium and hypercalcemia may predispose patients to digitalis toxicity.

ADVERSE REACTIONSThe most common adverse reactions in clinical trials include: arthralgia (10.1% FORTEO vs. 8.4% placebo), pain (21.3% FORTEO vs. 20.5% placebo), and nausea (8.5% FORTEO vs. 6.7% placebo). Other adverse reactions include: dizziness, leg cramps, joint aches, and injection site reactions.

USE IN PREGNANCY/NURSING MOTHERSFORTEO should be used during pregnancy only if the potential bene� t justi� es the potential risk to the fetus. Based on animal studies, FORTEO may cause fetal harm.

It is not known whether teriparatide is excreted in human milk. Breastfeeding mothers should discontinue nursing or FORTEO, taking into account the importance of treatment to the mother.

INSTRUCTIONS FOR FORTEO USEFORTEO is provided as a � xed-dose, pre� lled delivery device that can be used for up to 28 days, including the � rst injection. The delivery device contains 28 daily doses of 20 mcg each. Do not transfer the contents of the delivery device into a syringe. The FORTEO Delivery Device should be stored under refrigeration at 36° to 46° F (2° to 8° C) at all times. Do not use FORTEO if it has been frozen.

TE HCP ISI 24SEP2012

For more safety information, please see Brief Summary of Prescribing Information, including Boxed Warning regarding osteosarcoma, on following pages. See Full User Manual that accompanies the delivery device.References: 1. Riggs BL, Par� tt AM. J Bone Miner Res. 2005;20:177‐184. 2. FORTEO Prescribing Information. 3. National Osteoporosis Foundation. Osteoporosis medicines: what you need to know. Available at: http://www.nof.org/aboutosteoporosis/managingandtreating/medicinesneedtoknow. Accessed September 19, 2012.

TE-80859 1012. Printed in USA. ©Lilly USA, LLC 2012. All rights reserved. FORTEO is a registered trademark of Eli Lilly and Company.

BWJob Number: 15913Revision No: 0Date: 10/31/12

152_33474

7.125 x 9.875

FORTEO® (teriparatide [rDNA origin] 20 mcg for injection) PA097FSAM01 FORTEO® (teriparatide [rDNA origin] 20 mcg for injection) PA097FSAM01

FORTEO TE HCP BS 28JUN2012 PA097FSAM01 BRF SUMMARY 7.125 X 9.875 PRINTER VERSION page 1 of 2

FORTEO® (teriparatide [rDNA origin] 20 mcg for injection)Brief Summary Consult the package insert for complete prescribing information.

WARNING: POTENTIAL RISK OF OSTEOSARCOMAIn male and female rats, teriparatide caused an increase in the incidence of osteosarcoma (a malignant bone tumor) that was dependent on dose and treatment duration. The effect was observed at systemic exposures to teriparatide ranging from 3 to 60 times the exposure in humans given a 20-mcg dose. Because of the uncertain relevance of the rat osteosarcoma finding to humans, prescribe FORTEO® only for patients for whom the potential benefits are considered to outweigh the potential risk. FORTEO should not be prescribed for patients who are at increased baseline risk for osteosarcoma (including those with Paget’s disease of bone or unexplained elevations of alkaline phosphatase, pediatric and young adult patients with open epiphyses, or prior external beam or implant radiation therapy involving the skeleton).

INDICATIONS AND USAGEFORTEO is indicated: for the treatment of postmenopausal women with

osteoporosis at high risk for fracture; to increase bone mass in men with primary or hypogonadal osteoporosis at high risk for fracture; for the treatment of men and women with osteoporosis associated with sustained, systemic glucocorticoid therapy at high risk for fracture. High risk for fracture is defined as a history of osteoporotic fracture, multiple risk factors for fracture, or patients who have failed or are intolerant to other available osteoporosis therapy.

CONTRAINDICATIONSDo not use FORTEO in patients with Hypersensitivity to teriparatide or to any

of its excipients. Reactions have included angioedema and anaphylaxis.

WARNINGS AND PRECAUTIONSOsteosarcoma In male and female rats, teriparatide caused an increase in

the incidence of osteosarcoma (a malignant bone tumor) that was dependent on dose and treatment duration. FORTEO should not be prescribed for patients at increased baseline risk of osteosarcoma. These include Paget’s disease of bone (unexplained elevations of alkaline phosphatase may indicate Paget’s disease of bone); pediatric and young adult patients with open epiphyses; prior external beam or implant radiation therapy involving the skeleton. Patients should be encouraged to enroll in the voluntary FORTEO Patient Registry, which is designed to collect information about any potential risk of osteosarcoma in patients who have taken FORTEO. Enrollment information can be obtained by calling 1-866-382-6813, or by visiting www.forteoregistry.rti.org. Treatment Duration The safety and efficacy of FORTEO have not been evaluated beyond 2 years of treatment. Consequently, use of the drug for more than 2 years during a patients’ lifetime is not recommended. Bone Metastases and Skeletal Malignancies Patients with bone metastases or a history of skeletal malignancies should not be treated with FORTEO. Metabolic Bone Diseases Patients with metabolic bone diseases other than osteoporosis should not be treated with FORTEO. Hypercalcemia and Hypercalcemic Disorders FORTEO has not been studied in patients with pre-existing hypercalcemia. These patients should not be treated with FORTEO because of the possibility of exacerbating hypercalcemia. Patients known to have an underlying hypercalcemic disorder, such as primary hyperparathyroidism, should not be treated with FORTEO. Urolithiasis or Pre-existing Hypercalciuria In clinical trials, the frequency of urolithiasis was similar in patients treated with FORTEO and placebo. However, FORTEO has not been studied in patients with active urolithiasis. If active urolithiasis or pre-existing hypercalciuria are suspected, measurement of urinary calcium excretion should be considered. FORTEO should be used with caution in patients with active or recent urolithiasis because of the potential to exacerbate this condition. Orthostatic Hypotension FORTEO should be administered initially under circumstances in which the patient can sit or lie down if symptoms of orthostatic hypotension occur. In short-term clinical pharmacology studies with teriparatide, transient episodes of symptomatic orthostatic hypotension were observed in 5% of patients. Typically, an event began within 4 hours of dosing and spontaneously resolved within a few minutes to a few hours. When transient orthostatic hypotension occurred, it happened within the first several doses, it was relieved by placing the person in a reclining position, and

it did not preclude continued treatment. Drug Interactions Hypercalcemia may predispose patients to digitalis toxicity. Because FORTEO transiently increases serum calcium, patients receiving digoxin should use FORTEO with caution.

ADVERSE REACTIONSClinical Trials Experience Because clinical studies are conducted under

widely varying conditions, adverse reaction rates observed in the clinical studies of a drug cannot be directly compared to rates in the clinical studies of another drug and may not reflect the rates observed in practice. Treatment of Osteoporosis in Men and Postmenopausal Women The safety of FORTEO in the treatment of osteoporosis in men and postmenopausal women was assessed in two randomized, double-blind, placebo controlled trials of 1382 patients (21% men, 79% women) aged 28 to 86 years (mean 67 years). The median durations of the trials were 11 months for men and 19 months for women, with 691 patients exposed to FORTEO and 691 patients to placebo. All patients received 1000 mg of calcium plus at least 400 IU of vitamin D supplementation per day. The incidence of all cause mortality was 1% in the FORTEO group and 1% in the placebo group. The incidence of serious adverse events was 16% in FORTEO patients and 19% in placebo patients. Early discontinuation due to adverse events occurred in 7% of FORTEO patients and 6% of placebo patients. Percentage of Patients with Adverse Events Reported by at Least 2% of FORTEO-Treated Patients and in More FORTEO-Treated Patients than Placebo-Treated Patients from the Two Principal Osteoporosis Trials in Women and Men Adverse Events are Shown Without Attribution of Causality(FORTEO, N=691, Placebo, N=691): Body as a Whole: Pain (21.3%, 20.5%), Headache (7.5%, 7.4%), Asthenia (8.7%, 6.8%), Neck Pain (3.0%, 2.7%); Cardiovascular: Hypertension (7.1%, 6.8%), Angina Pectoris (2.5%, 1.6%), Syncope (2.6%, 1.4%); Digestive System: Nausea (8.5%, 6.7%), Constipation (5.4%, 4.5%), Diarrhea (5.1%, 4.6%), Dyspepsia (5.2%, 4.1%), Vomiting (3.0%, 2.3%), Gastrointestional disorder (2.3%, 2.0%), Tooth disorder (2.0%, 1.3%); Musculoskeletal: Arthralgia (10.1%, 8.4%), Leg cramps (2.6%, 1.3%); Nervous System: Dizziness (8.0%, 5.4%), Depression (4.1%, 2.7%) Insomnia (4.3%, 3.6%), Vertigo (3.8%, 2.7%); Respiratory System: Rhinitis (9.6%, 8.8%), Cough increased (6.4%, 5.5%), Pharyngitis (5.5%, 4.8%), Dyspepsia (3.6%, 2.6%), Pneumonia (3.9%, 3.3%); Skin and Appendages: Rash (4.9%, 4.5%), Sweating (2.2%, 1.7%). Immunogenicity In the clinical trial, antibodies that cross-reacted with teriparatide were detected in 3% of women (15/541) receiving FORTEO. Generally, antibodies were first detected following 12 months of treatment and diminished after withdrawal of therapy. There was no evidence of hypersensitivity reactions or allergic reactions among these patients. Antibody formation did not appear to have effects on serum calcium, or on bone mineral density (BMD) response. Laboratory Findings Serum Calcium: FORTEO transiently increased serum calcium, with the maximal effect observed at approximately 4 to 6 hours post-dose. Serum calcium measured at least 16 hours post-dose was not different from pretreatment levels. In clinical trials, the frequency of at least 1 episode of transient hypercalcemia in the 4 to 6 hours after FORTEO administration was increased from 2% of women and none of the men treated with placebo to 11% of women and 6% of men treated with FORTEO. The number of patients treated with FORTEO whose transient hypercalcemia was verified on consecutive measurements was 3% of women and 1% of men. Urinary Calcium: FORTEO increased urinary calcium excretion, but the frequency of hypercalciuria in clinical trials was similar for patients treated with FORTEO and placebo. Serum Uric Acid: FORTEO increased serum uric acid concentrations. In clinical trials, 3% of FORTEO patients had serum uric acid concentrations above the upper limit of normal compared with 1% of placebo patients. However, the hyperuricemia did not result in an increase in gout, arthralgia, or urolithiasis. Renal Function: No clinically important adverse renal effects were observed in clinical studies. Assessments included creatinine clearance; measurements of blood urea nitrogen (BUN), creatinine, and electrolytes in serum; urine specific gravity and pH; and examination of urine sediment. Studies in Men and Women with Glucocorticoid-Induced Osteoporosis The safety of FORTEO in the treatment of men and women with glucocorticoid-induced osteoporosis was assessed in a randomized, double-blind, active-controlled trial of 428 patients (19% men, 81% women) aged 22 to 89 years (mean 57 years) treated with ≥ 5mg per day prednisone or equivalent for a minimum of 3 months. The duration of the trial was 18 months with 214 patients exposed to FORTEO and 214 patients exposed to oral daily bisphosphonate (active control). All patients received 1000 mg of calcium plus 800 IU of vitamin D supplementation per day. The incidence of all cause mortality was 4% in the FORTEO group and 6% in the active

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BWJob Number: 15913Revision No: 0Date: 10/31/12

FORTEO® (teriparatide [rDNA origin] 20 mcg for injection) PA097FSAM01 FORTEO® (teriparatide [rDNA origin] 20 mcg for injection) PA097FSAM01

FORTEO TE HCP BS 28JUN2012 PA097FSAM01 BRF SUMMARY 7.125 X 9.875 PRINTER VERSION page 2 of 2

control group. The incidence of serious adverse events was 21% in FORTEO patients and 18% in active control patients, and included pneumonia (3% FORTEO, 1% active control). Early discontinuation because of adverse events occurred in 15% of FORTEO patients and 12%fiof active control patients, and included dizziness (2% FORTEO, 0% active control). Adverse events reported at a higher incidence in the FORTEO group and with at least a 2% difference in FORTEO-treated patients compared with active control-treated patients were: nausea (14%, 7%), gastritis (7%,fi 3%), pneumonia (6%, 3%), dyspnea (6%, 3%), insomnia (5%, 1%), anxiety (4%, 1%), and herpes zoster (3%, 1%), respectively. Postmarketing Experience: The following adverse reactions have been identifled during postapproval use of FORTEO. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Osteosarcoma: Cases of bone tumor and osteosarcoma have been reported rarely in the postmarketing period. The causality to FORTEO use is unclear. Long term osteosarcoma surveillance studies are ongoing. Hypercalcemia: Hypercalcemia greater than 13.0 mg/dL has been reported with FORTEO use. Adverse events reported since market introduction that were temporally (but not necessarily causally) related to FORTEO therapy include the following: Allergic Reactions: Anaphylactic reactions, drug hypersensitivity, angioedema, urticaria; Investigations: Hyperuricemia; Respiratory System: Acute dyspnea, chest pain; Musculoskeletal: Muscle spasms of the leg or back; Other: Injection site reactions including injection site pain, swelling and bruising; oro-facial edema.

USE IN SPECIFIC POPULATIONSPregnancy Category C. There are no adequate and well-controlled studies

of FORTEO in pregnant women. In animal studies, teriparatide increased skeletal deviations and variations in mouse offspring at doses more than 60fitimes the equivalent human dose and produced mild growth retardation and reduced motor activity in rat offspring at doses more than 120 times the equivalent human dose. FORTEO should be used during pregnancy only if the potential beneflt justifles the potential risk to the fetus. In animal studies, pregnant mice received teriparatide during organogenesis at subcutaneous doses 8 to 267fitimes the human dose. At doses ≥ 60 times the human dose, the fetuses showed an increased incidence of skeletal deviations or variations (interrupted rib, extra vertebra or rib). When pregnant rats received subcutaneous teriparatide during organogenesis at doses 16fi to 540 times the human dose, the fetuses showed no abnormal flndings. In a perinatal/postnatal study, pregnant rats received subcutaneous teriparatide from organogenesis through lactation. Mild growth retardation in female offspring at doses ≥120 times the human dose (based on surface area, mcg/m2). Mild growth retardation in male offspring and reduced motor activity in both male and female offspring occurred at maternal doses 540fi times the human dose. There were no developmental or reproductive effects in mice or rats at doses 8 or 16 times the human dose, respectively. Exposure multiples were normalized based on body surface area (mcg/m2). Actual animal doses: mice (30 to 1000 mcg/kg/day); rats (30 to 1000fimcg/kg/day). Nursing Mothers: It is not known whether teriparatide is excreted in human milk. Because of the potential for tumorigenicity shown for teriparatide in animal studies, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of thefi drug to the mother. Pediatric Use: The safety and efflcacy of FORTEO have not been established in any pediatric population. FORTEO should not be prescribed in patients at an increased baseline risk of osteosarcoma which include pediatric and young adult patients with open epiphyses. Therefore, FORTEO is not indicated for use in pediatric or young adult patients with open epiphyses. Geriatric Use: Of the patients receiving FORTEO in the osteoporosis trial of 1637fipostmenopausal women, 75%fiwere 65fiyears of age and over and 23% were 75 years of age and over. Of the patients receiving FORTEO in the osteoporosis trial of 437 men, 39%fiwere 65fiyears of age and over and 13%fiwere 75 years of age and over. No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identifled differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out. Hepatic Impairment: No studies have been performed infi patients with hepatic impairment. Renal Impairment: In 5 patients with severe renal impairment (CrCl<30 mL/min), the AUC and T1/2 of teriparatide were increased by 73% and 77%, respectively. Maximum serum concentration of teriparatide was not increased.

OVERDOSAGEIncidents of overdose in humans have not been reported in clinical trials.

Teriparatide has been administered in single doses of up to 100fimcg and in repeated doses of up to 60 mcg/day for 6 weeks. The effects of overdose that might be expected include a delayed hypercalcemic effect and risk of orthostatic hypotension. Nausea, vomiting, dizziness, and headache might also occur. In postmarketing spontaneous reports, there have been cases of medication errors in which the entire contents (up to 800 mcg) of the FORTEO delivery device (pen) have been administered as a single dose. Transient events reported have included nausea, weakness/lethargy and hypotension. In some cases, no adverse events occurred as a result of the overdose. No fatalities associated with overdose have been reported. Overdose Management There is no speciflc antidote for teriparatide. Treatment of suspected overdose should include discontinuation of FORTEO, monitoring of serum calcium and phosphorus, and implementation of appropriate supportive measures, such as hydration.

DOSAGE FORMS AND STRENGTHSMulti-dose prefllled delivery device (pen) for subcutaneous injection

containing 28 daily doses of 20 mcg.

PATIENT COUNSELING INFORMATIONPatients should read the FDA-approved Medication Guide and delivery

device (pen) User Manual before starting therapy with FORTEO and re-read them each time the prescription is renewed. Patients need to understand and follow the instructions in the FORTEO delivery device User Manual. Failure to do so may result in inaccurate dosing.

06/15/2012

PLEASE SEE FULL PRESCRIBING INFORMATION OR WWW.FORTEOHCP.COM FOR ADDITIONAL INFORMATION.

Literature revised: March 21, 2012

Marketed by: Lilly USA, LLCIndianapolis, IN 46285, USA

www.forteo.comCopyright © 2002, 2012, Eli Lilly and Company.

All rights reserved.PA097FSAM01Rx only.

TE HCP BS 28JUN2012 PA097FSAM01

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CoVer Story

statins: rap sheet or Bum rap?By Terri D'ArrigoCholesterol-lowering drugs are taken by more than 20 million Americans, but the fears of possible side effects have sounded an alarm among patients and doctors. How do you see beyond the hype and the hysteria?

Price GougingBy Kelly HorvathBaby boomers are seeing an increase in longevity. And so are the chronic ailments that afflict them, most notably diabetes. Diabetes costs will total almost $250 billion annually. Before this staggering economic burden finally topples the healthcare industry, the key to curtailing costs lies in one simple word: Prevention.

Gaping Holes seen in electronic record securityBy Eric SeaborgElectronic health records could be a tempting target for hackers because the software is vulnerable, but workers’ habits can be even worse. It’s time for your practice to adopt a culture of security awareness.

Hormone Health Network Fact sheet:Goiter: Symptoms, Causes & Treatments Your Patients Need to Know

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Scan this QR code with your smartphone or mobile device for Endocrine News Online.

DePArTMeNTs

8 President’s Viewpoint Introducing Teresa K. Woodruff, PhD

9 editor’s Page New editor highlights July issue

10 Trends & Insights News from the latest research

20 Laboratory Notes Diamonds may hold the key to extending the life of a sperm

23 Practice Resources Pediatric Self-Assessment Program: What is causing a toddler’s sudden illness?

26 research Roundup Studies in the Society journals

27 inTouch Society & member news

40 Classifieds Job opportunities

JULY 2013 CONTENTS

www.endocrine.org

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The Endocrine Society is pleased to welcome its

president for 2013–2014, Teresa K. Woodruff, PhD, who took office June 19. Woodruff is a leading expert in reproductive endocrinology and vice chair for research in the Department of Obstetrics and Gynecology at the Feinberg School of Medicine at Northwestern University. She coined the term “oncofertility” to describe her work researching female reproductive health and infertility and translating her findings to the clinical care of women who will lose their fertility due to cancer treatments. She has co-edited three books on the subject, detailing everything from procedural guidelines and best practices to the ethical, religious, economical, and legal implications of preserving fertility in cancer patients.

She also advocates for gender specificity in clinical tri-als in order to reach a better understanding of the effects that medicine has on women, and she founded the Wom-en’s Health Research Institute at Northwestern University to develop programs to better serve women’s health. She has served on The Endocrine Society Council and has been recognized nationally, receiv-ing numerous awards and honors for her work.

Woodruff succeeds Wil-liam F. Young Jr. MD, MSc, as the Society continues its rotation of presidents who represent its core constituencies: basic researchers, clinical researchers, and clinical practitioners. “It was a tremendous honor to be selected by my peers to lead this organization for a short period of time,” she says. “As volunteer members, we all contribute to the health of our field, and I look forward to serving with the leadership and committee members.”

Woodruff joined The Endocrine Society 25 years ago, influenced by her mentors at Northwestern University, Kelly Mayo and Neena Schwartz, who also both served as presidents of the Society. “I'm somewhat homozygous for the endocrine science phenotype,” she says.

One of her first experiences as a Society member

was in New Orleans in 1988, where she admits she was a little star struck, presenting a paper on the cloning of the subunits for the hormone inhibin and showing how they were regulated during the reproductive cycle of the rodent “in front of a packed room of endocrinology super luminaries — folks that I had read about but never met.”

She says she was inspired by Society members almost immediately, discovering new avenues and con-cepts in member impact and value. “My first committee was on membership,” she recalls. “Gwen Childs was the chair [of the Membership Committee] and a real activist. I imprinted on her way of thinking outside the box.”

Now that she’s something of a super luminary her-self, Woodruff plans to inspire Society members in the coming year, describing her goals of developing a new look for the Society, including a new logo that “refreshes the way we present ourselves to the world,” as well as cre-ating a tagline “that has momentum and expresses our goals and our values.”

But it’s not just about aesthetics; she plans to intro-duce even more tangible member benefits, including new awards categories that reward members for their achievements, accelerating the careers of the newest society members, and creating a new program called

“Leap” that represents the most innovative science and the best scientists in endocri-nology. “Reward, Accelerate, Leap,” Woodruff says, “our bold new awards program that increases the visibility of people and ideas.”

Woodruff hopes these fresh approaches translate to new tactics and implemen-tation plans for tackling the “grand global challenges” in endocrinology, including the colliding epidemics of obe-sity and diabetes, the increasing health risks of endocrine disruptors, the fulcrum between global population expan-sion and personal reproductive needs, and the support of endocrine science in a low-no- resource environment.

“We have to be a society about solutions,” she says. “We have to invest in next-generation innovators and advocate for them with funding agencies and govern-ments around the globe.”

—Derek Bagley is associate editor of Endocrine News

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vIEWPoINTPRESIDENT’S

introducing the New President: TeresA K. WooDruFF, PhD

eN

Teresa K. Woodruff, PhD

“We have to be a society about solutions,”

she says. “We have to invest in next generation innovators and advocate for them with

funding agencies and governments around the globe.”

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Another ENDO has passed and as I’m sure you noticed if you made it to San Francisco, it was

a roaring success, with attendance records being broken almost every single day. The sessions were nothing short of amazing in terms of the amount of information that was shared. For me, it was a great opportunity to meet so many of you in person, and I can assure you that I returned to the East Coast with more than my fair share of story ideas and sources for a dozen years’ worth of Endocrine News!

And speaking of timely information, this issue is loaded with stories about topics currently in the fore-front of our national consciousness. On page 14, Terri D’Arrigo delves into the controversies surrounding statins, those cholesterol-lowering drugs that are prescribed to over 20 million of us. These drugs are being blamed for a litany of side effects including memory loss and diabetes. Physicians are now determining whether these alleged “wonder drugs” are as wonderful as first thought. Are the possible side effects worth it? In many cases it simply boils down to what’s worse, a heart attack or diabetes? Rest assured, this is an issue that won’t be going away any time soon.

As the baby boomer population lives longer, the incidence of chronic maladies is also on the rise. None is more prevalent than dia-betes, with an estimated 22 million people suffering from it in 2012. To no one’s surprise, the financial burden of this disease is almost $250 billion, according to a study by the American Diabetes Association. In “Price Gouging” on page 17, Kelly Horvath comes to the realization that the solution to stop these spiraling costs rests with the physician as well as with the patient. The old adage about “an ounce of prevention” has never been more relevant.

Apparently diamonds aren’t just a girl’s best friend anymore; they’re also a sperm’s. Former Endocrine News associate editor Jacque-line Ruttiman writes about research that shows how diamond-coated petri dishes improve the survival rate for sperm used in IVF proce-dures, thus increasing the success rates for parents-to-be (page 20). Of course, the addition of diamonds to the mix is only going to increase an already costly procedure, but hopefully it will reduce the number of procedures, thereby lowering costs in the long run.

Be sure to let me know what you think of the topics we’re covering this month. Your thoughts and opinions and any feedback you want to offer are vital in ensuring the continued success and future growth of Endocrine News. You can always find me at [email protected]. I look forward to hearing from you.

Mark A. NewmanManaging Editor, Endocrine News

ThE LEaDINg MagazINE FOR ENDOCRINOLOgISTS

JULY 2013

President: Teresa K. Woodruff, [email protected]

President-Elect: Richard J. Santen, [email protected]

Past President: William F. Young Jr., [email protected]

Secretary-Treasurer: Kenneth h. hupart, [email protected]

Executive Director & CEO: Scott [email protected]

Senior Director of Publications: Eleanore [email protected]

Director of Publications: Douglas [email protected]

Managing Editor: Mark a. Newman [email protected]

Production Manager/Art Director: Cynthia [email protected]

Associate Editor: Derek [email protected]

Prepress & Printing: Cenveo Publishing Serviceswww.cadmus.com

PAGEEDITOR’S

Endocrine News is a registered trademark owned by The Endocrine Society

Endocrine News informs and engages the global endocrine community by delivering timely, accurate, and trusted content covering the

practice, research, and profession of endocrinology.

The mission of The Endocrine Society is to advance excellence in endocrinology and promote its

essential and integrative role in scientific discovery, medical practice, and human health.

Endocrine News® is published 12 times a year by The Endocrine Society, 8401 Connecticut Ave.,

Suite 900, Chevy Chase, MD 20815 Phone 301-941-0200 • Fax 301-941-0259

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newsenDocrine

Mark A. Newman,Managing Editor

eN

& INSIGHTSTRENDS

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Group Clinics Improve Outcomes, KeeP CosTs DoWN

With chronic diseases such as diabetes requiring constant management and never-ending medical bills, group medical clinics (GMCs) have been shown to be effec-tive at managing diabetes. Are they also cost effective?

George L. Jackson, PhD, MHA, at the Durham Center for Health Services Research in Primary Care in North Carolina, and his team of scientists recently studied 239 people with poorly controlled diabetes receiving either usual care or attending GMCs every two months for one year. GMC atten-dance included education and structured interactions among the up to eight group members, and the care team comprised registered nurses, certified diabetes educa-tors, pharmacists, and general internists. Diabetes in the GMC group was more successfully managed, with lower systolic blood pressure and cholesterol levels. In their follow-up paper, to be published soon in the Journal of the American Medical

Association: Internal Medicine, the research-ers report that having better controlled disease, the GMC group required fewer emergency room and primary care visits, thereby offsetting the annual $460 GMC fee. Moreover, GMC participants reported greater satisfaction with the group experience than with conventional one- on-one care.The researchers conclude that cost-effective and clinically beneficial GMCs could be the new face of long-term care for certain chronic diseases in the United States.

— Kelly Horvath

PAiD DieTers Lose More Weight

With obesity contributing to “presenteeism,” a lack of pro-ductivity while at work due to health problems, employ-ers are looking for ways to combat this costly problem. A new study shows that one way they could save money is by paying their employees to lose weight.

Jeffrey Kullgren, MD, MS, MPH, at the University of Michigan, and his team of

researchers divided 105 obese dieters (body mass index 30–40 kg/m2) into three groups: a control group given links to an online weight-loss network to participate in monthly weigh-ins; a second group who were additionally offered a monthly $100 incentive to meet their individual weight-loss goal; and a third, who were subdivided into groups of five to split $500 among only those group members who met their goals (thus building in the possibility of a bigger payout if not all five met goals). In their paper, to be published soon in the Annals of Internal Medicine, the researchers report that

the third group lost on average 4.4 kg more weight than the non-incentivized control group and 3.2 kg more than the individually incentivized group after 24 weeks of dieting. However, 12 weeks post-incentive, the individual-incentive group had kept off an average of 2.7 kg more weight than the group-incentive group.The researchers conclude that the prospect of a bigger cash reward among the group-incentive participants was the strongest motivator to lose weight. Maintaining that loss over the long term might also be more success-ful if the incentive plan is likewise continued.

— Kelly Horvath

sTATiNs oFTeN PresCriBeD with No Likely Benefit

Statins cost the healthcare system more than $20 billion a year and may be overprescribed to patients who are not at high risk for coronary heart disease (CHD).

Michael E. Johansen, MD, at the University of Michi-gan, Ann Arbor, and his team of scientists anony-mously surveyed 202 family and internal medicine and cardiology physicians on their treatment choices in six clinical vignettes, each concerning a hypothetical patient ranging from age 40 to 75 years with various baseline risk factors for hyperlipidemia (e.g., high “bad” cholesterol or blood pressure level, diabetes, smoking), but none with existing CHD. In their paper, to be published soon in the Journal of the American Medical Associa-tion: Internal Medicine, the researchers report that most physicians (70%) would have prescribed a statin to even the patients with very low risk for devel-oping CHD anytime soon yet fewer than half would have prescribed a statin for the diabetic patient who may have benefited most. The researchers conclude that physicians prescribe statins almost reflexively, focusing solely on cholesterol levels and without adequately weighing the risk–benefit ratio. Lifestyle modification (e.g., quitting smoking, eating well, and exercising) is most effective in many patients with high cholesterol but no other CHD risk factors, they add.

— Kelly Horvath

Couples who take longer to conceive may be at higher risk of having children born with mild neurological problems, accord-ing to new research.

Babies born through in vitro fertilization (IVF) have an increased risk of being born prematurely or having a low birth weight, possibly leading to a developmental disor-der. But what has been previously linked to the IVF treatments, the developmental problems actually may be connected to what initially caused the couples’ infertility.

In an article appearing in Archives of Dis-ease in Childhood: Fetal & Neonatal edition, researchers from The Netherlands exam-ined 209 two-year-old children who were born to subfertile parents. The couples had taken between 1.6 and 13.2 years to conceive. More than half of the couples had undergone IVF.

The study, led by Jorien Seggers of the University of Groningen, assessed the children’s neurological development by testing their movement, muscle tone, reflexes, gross and fine motor function, and hand-eye coordination. Results showed that minor neurological dysfunction (MND) was present in 16 children (7.7%). In the children with MND, couples took an average of 4.1 years to become pregnant compared with an average of 2.8 years in couples with children born without MND. Taking longer to get pregnant was linked with a 30% higher risk of having a baby with MND. — Glenda Fauntleroy

GuT MiCroBiATA Important for Healthy Metabolism

For years, scientists have wondered why roux-en-Y gastric bypass (RYGB), the most widely done form of gastric bypass surgery, results not only in rapid weight loss but also in an even faster return to normal glucose metabolism, suggesting that the latter effect is not due strictly to decreased caloric intake or absorption. A new study tests whether the changes RYGB causes in the makeup of gut microbes accounts for the additional effects.

Doctors Lee Kaplan, MD, PhD, at the Harvard Medi-cal School, Massachusetts, and Peter Turnbaugh, PhD, at Harvard’s Center for Systems Biology, and their team of researchers divided 23 mice into an RYGB group, a sham surgery group, and a sham sur-gery coupled with caloric restriction group, analyzing their fecal samples before

surgery and then weekly for 12 weeks. In their paper, published in Science Trans-lational Medicine, the researchers report increases in proteobacteria and verruco-microbia and a decrease in firmicutes in the RYGB and the dieting groups, with more dramatic and rapid changes among the RYGB group. When proteobac-teria and verrucomicrobia were transferred to mice guts in the sham surgery group, rapid weight loss resulted.The researchers conclude that the changes in gut bacteria account for the metabolic benefits seen after RYGB, possibly by increas-ing levels of short-chain fatty acids, which speed up metabolism. Manipulating the gut microbiota without sur-gery could be a potential new therapy to address obesity in humans, they add.

— Kelly Horvath

FisH oiL LeNGTHeNs LiFesPAN Among Older Adults

Eating fish and seafood, foods that are unique in containing long-chain polyunsaturated omega-3 fatty acids, can improve cardiovascular and brain health. A new study examines for the first time whether these benefits might help us live longer.

Darius Mozafarrian, MD, DrPH, at the Harvard School of Public Health, Massachusetts, and his team of researchers ana-lyzed blood level data of three types of omega-3 fatty acid from 2,692 healthy U.S. adults ages 69–79 years who participated in the National Heart, Lung, and Blood Institute’s 1992–2008 Cardiovascular Health Study. In their paper, to be published soon in the Annals of Internal Medicine, the researchers report that docosahexaenoic acid lowered risk of coronary heart disease (CHD) death by 40%, eicosapentae-

noic acid lowered risk of nonfatal heart attack, and docosapentaenoic acid lowered risk of stroke death. Although none of the three omega-3 acids was strongly related to reducing noncardiovascular causes of death, those participants with the highest circulating levels of all three types had an overall 27% lower risk of mortality due to all causes.The researchers say that the biggest benefit comes from increasing fish intake to about two servings a week. The gain is well worth it—on average, this amount increased lifespan by 2.2 years.

— Kelly Horvath

LoNGer CoNCePTioN Time Leads to More Neurological Issues

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Sources: WebMD, CDC, Scientific American, Annals of Internal Medicine

About Statins FastFACTS

MORE THAN 20 MILLION U.S. STATIN USERS

1 in 4 Americans

takes cholesterol-

lowering statins.

300Side effects

linked to statins

6 out of 100,000 patients on statins suffered from rhabdomyolysis, which causes permanent muscle death.

6 out of 100,000 patients on statins suffered from rhabdomyolysis, which causes permanent muscle death.

Approximately 130 people need to take statins for a year to prevent just one unwanted health outcome.

500 people have to take statins to prevent a single death.

130:1

500:1

Approximately 130 people need to take statins for a year to prevent just one unwanted health outcome.

500 people have to take statins to prevent a single death.

Adolescent Bariatric Surgeries Decline While oBesiTy rATes soArWith childhood obesity at an all-time high — one in three kids is over-weight or obese — effective strate-gies to combat this epidemic and its comorbid diseases are vital. Is ado-lescent bariatric surgery one such strategy?

Deirdre C. Kelleher, MD, at the Children’s National Medical Center, Washing-ton, D.C., and her team of scientists

retrospectively analyzed data from the Healthcare Cost and Utiliza-tion Project Kids’ Inpatient Database for the decade 2000–2009 to determine rate of bariatric surgery in adolescents (ages 10–19 years) and characterize related trends. In their paper, to be published soon in the Journal of the American Medical Association: Pediat-rics, the research-

ers report that procedure rates increased consid-erably during the first three years ( from 328 to 987) but subsequently plateaued. Type of procedure, length of hospital stay, and complication rates also changed: Minimally invasive (i.e., laparoscopic) procedures are now more likely to be done than open pro-cedures, reducing both hospital stay and complications.

The researchers also found that males and younger adolescents are less likely to undergo the surgery than females age 17 years and older with private insurance. Those with low socio-economic status and on Medicaid are also in the minority. Their data underscore the dispar-ity between obesity rates and use of low-risk, minimally invasive bariatric surgery that could improve or even save many lives.

— Kelly Horvath

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Not backiNg dowN from this fight.

Jay T, PH.D.PrinciPal scienTisT ProTein TecHnologies

Cardiovascular

© 2013 Amgen Inc. All rights reserved. Not for Reproduction. 74741-R1-V1

Biotechnology vs cardiovascular Disease. The fight is on.

For the scientists at Amgen, that fight is personal. With millions suffering a cardiac event each year, we are never far from being touched by cardiovascular disease ourselves—be it a family member’s health issue, a friend’s, or our own. As we use the power of biotechnology to pioneer new therapeutics, we are determined to alter the course of this global epidemic. Because behind the statistics is one vital thing: the lives of people we know.

STATINS:are the side effects from cholesterol-lowering drugs worth the risk?

Cover STORy

By Terri D’Arrigo

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When the Food and Drug Administration (FDA)

announced labeling changes to cholesterol-lowering statins in February of last year, the media were quick to sound the alarm. Headlines proclaimed that statins raise the risk of diabetes and cause memory loss. Debate arose about side effects and whether statins, taken by more than 20 million Americans, were overprescribed. Suddenly, an entire class of wonder drugs wasn’t so wonderful anymore.

But more recent evidence sug-gests that the there’s more to the statin story. Analyses of three major trials — including one the FDA cited in its warnings about dia-betes — revealed that increased rates of diabetes in statin users depended on whether they already had risks for the disease before starting the drugs. Another study demonstrated that not only were statins well-tolerated in patients who had previously stopped taking them because of side effects, but that reports of memory problems in particu-lar were rare. Yet this news did not garner as much attention in the mainstream consumer media.

What gives?“A lot of media attention focuses on things that create sensation,” said Anne Carol Goldberg, MD, FACP, associate professor of medicine at the Washington University School of Medicine in St. Louis. “But what physicians have to do is educate patients on the reality, which is that these drugs

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save lives, particularly among people at high risk for cardiovascular disease.”

Goldberg said she encoun-ters resistance to statins among her patients, in part because of what they hear anecdotally or in the news. “Peo-ple are afraid of them and think they cause bad effects. I will show patients figures from the Cholesterol Treat-ment Trialists Collaboration [CTT] and explain what we actually see in terms of benefits,” she said.

The CTT is a group of physicians and researchers in the United Kingdom who conduct periodic meta-analyses

large randomized trials of lipid-lowering treatments. In the November 13, 2010, issue of The Lancet, the CTT published a meta-analysis, of 26 randomized trials involving more than 169,000 participants

wherein they found that reducing LDL cholesterol by 38 to 77 mg/dl via statins

reduces the risk of vascular events such as heart attack, coronary revascular-ization, and stroke by 40% to 50%. More

recently, in the August 11, 2012, issue of The Lancet, the CTT published a meta-analysis of

27 randomized trials involving more than 174,000 patients, which revealed that even low-risk patients

who would not normally be considered for statin therapy derive as much risk reduction for vascular

events from statins as high-risk patients do.

Diabetes riskThe labeling for statins now includes a warning that there

have been reports of increased blood glucose and A1c measurements in people who take the drugs. Among its reasons for the warning, the FDA cited findings from the Justification for the Use of Statins in Primary Prevention: An Intervention Trial Evaluating Rosuvastatin (JUPITER) trial, which noted a 27% increase in investigator-reported diabetes in patients who took rosuvastatin compared to those who took placebo.

In light of the warnings, JUPITER researchers fur-ther analyzed data from the trial’s 17,603 participants to

weigh the benefits of statins against the risk of diabetes. As noted in the August 11, 2012, issue of The Lancet, they found a 28% increase in diabetes among statin users who already had one or more major risk factor for the disease. The team also learned that 134 vascular events or deaths were avoided for every 54 new diagnoses of diabetes, lead-ing them to conclude that the cardiovascular benefits of statin therapy exceed the risk of developing diabetes.

A more recent analysis of data from two other stud-ies with a combined 15,056 participants, Treating to New Targets (TNT) and Incremental Decrease in Endpoints Through Aggressive Lipid Lowering (IDEAL), yielded sim-ilar results. In this analysis, published in the January 15, 2013, issue of the Journal of the American College of Cardiol-ogy, researchers compared 80 mg/day of atorvastatin with 10 mg/day atorvastatin or 20–40 mg/day of simvastatin to assess vascular benefits and diabetes risk. They saw a 24%

increase in high-dose participants who already had two to four diabetes risk factors, and no increased diabetes in high-dose participants with no or only one risk factor for diabetes, compared to low-dose participants. Yet com-pared to low doses, the higher dose reduced the number of cardiovascular events in patients regardless of how many diabetes risk factors they had.

It boils down to severity, said David Waters, MD, pro-fessor emeritus at the University of California — San Fran-cisco and lead investigator in the TNT/IDEAL analysis. “If you think about diabetes and cardiovascular disease, the two really aren’t equivalent. Developing diabetes is bad, but having a heart attack or stroke and dying is worse.”

Although diabetes itself raises the risk of cardiovas-cular disease, populations at risk for both tend to overlap, Waters said. “These are people with high blood pressure, higher than normal fasting glucose, high BMI, and [bad] family histories. Either way, they’re going to benefit from statin therapy.”

AT-A-GLANCE:• In2012theFDAannouncedlabelingchangestocholesterol-loweringstatinstoincludewarningsaboutdiabetesriskandmemoryloss.

• AnalysesoftheJUPITER,TNT,andIDEALtrialsrevealedthatincreasedratesofdiabetesinstatinusersdependedonwhethertheyalreadyhadrisksforthediseasebeforestartingthedrugs.

• AstudypublishedthisyearintheAnnals of Internal Medicinesuggeststhatmemorylossfromstatinsisrareandthatstatinsarewell-tolerated.

“…Physicians have to… educate patients on the reality,

which is that these drugs save lives, particularly among people at high risk

for cardiovascular disease.” — Anne Carol Goldberg, MD, FACP, associate professor of

medicine at the Washington University School of Medicine in St. Louis.

Like Goldberg, Waters has patients who hesitate to take statins. He addresses their concerns by empha-sizing risk minimization. “Say a patient has a high BMI. They’ll say they’re afraid taking a statin will give them diabetes. But if they lose weight, they can cut their risk of developing diabetes right there.”

Waters has a bone to pick with what he sees as a bias against statins. “A lot of other drugs out there increase the risk of diabe-

tes, like beta blockers, diuretics, HIV drugs, and steroids, but people rarely want to talk about that. They say they don’t want to take a statin because they’re against big bad drug companies, so they’ll take niacin instead. Well, niacin doubles your risk of getting diabetes.”

The Question of side effectsStatin labeling now includes a warning that cognitive effects such as memory loss and confusion have been reported in people who take the drugs. The FDA based its warning on reports received through its Adverse Event Reporting System (AERS), where clinicians and patients voluntarily report what they feel to be side effects of the drugs, and noted that the reports generally described people in their 50s or older who experienced noticeable, if poorly defined, memory loss or impairment that disap-peared when they stopped taking statins.

However, a study by researchers in the April 2, 2013, Annals of Internal Medicine suggests that memory loss from statin use may actually be rather rare. In the study, which was designed to ascertain the reasons for statin discontin-uation and the role of statin-related events in routine care settings over eight years, memory loss was reported in only .06% of participants, or less than 1 in 1,000.

Among the 107,835 participants in the study, 18,778 patients, or 17.4%, had documented statin-related side effects. Muscle pain was the most common side effect, experienced by 4.71% of patients in the study overall. Of those who had side effects, 11,124 stopped taking statins.

Then 6,579 began taking statins again. The drugs were well-tolerated the second time around for these patients, as 92.2% of them were still taking statins a year after resum-ing therapy.

Alexander Turchin, MD, MS, associate physi-cian at Brigham and Wom-en’s Hospital, assistant professor of medicine at

Harvard Medical School in Boston, and the senior author of the study, acknowledges that there is a discrepancy between clinical trials’ reported rates of adverse reactions such as muscle pain and what physicians are observing anecdotally in routine care. “If you talk to doctors on the front lines and their patients, you’re constantly hearing about these reac-tions,” he said. “But in the clinical trials, their incidence is similar between statin and placebo arms.”

This could be for a number of reasons, he said. “Clini-cal trial participants who pass eligibility criteria tend to be healthier overall. On the other hand many of the symp-toms that are reported as attributable to statins are not very specific, such as muscle pain. Sometimes the symp-toms are specific to an individual statin or a higher dose. Other times the symptoms might not be from statins at all, but another underlying condition. We think our data implies a range of explanations.”

Turchin added that the older age of many statin users can make it difficult to root out whether their memory loss is actually from statins. “Older patients are at higher risk for vascular dementia from multiple strokes and for the onset of Alzheimer’s disease. This can paint a mixed picture both clinically and pathologically. It’s not an easy diagnosis to make.”

William James Howard, MD, MACP, director of Med-Star Washington Hospital Center’s Lipid Clinic and Lipid Consultation services in Washington, D.C., cautioned against awareness of potential side effects becoming a self-fulfilling prophecy. “One of the problems is that we have created a monster,” he said. “Most people get some muscle or joint pain as they get older, and they tend to ignore it.

But if it’s in the back of your mind because you’ve been warned about it in commercials and the news, if you have muscle pain, you’ll think, ‘Oh, it’s the statin,’ when really it might be because you’re 60 and 60-year-olds tend to have a few aches and pains.”

Howard counters the power of suggestion by having patients keep a diary for a few days before starting statin therapy. They record whether, where, and when they have pain or other symptoms so that both physician and patients know what kinds of issues already existed before starting the statin.

The sheer number of people who take statins makes compiling statistics tricky, Howard said. “If you have mil-lions of people on any drug, you will have associations with anything imaginable, whether it’s memory loss, insomnia, peripheral neuropathy, and so on. But that doesn’t mean there’s a cause-and-effect relationship,” he said. “As we move forward with the research, we really need to separate out causation versus association.”

And so the statin story will continue to unfold.—D’Arrigo is a health and science writer based in Holbrook, N.Y.,

and a regular contributor to Endocrine News16

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eN

STaTINS avaILaBLE IN ThE U.S. Atorvastatin (Lipitor) Fluvastatin (Lescol) Lovastatin (Mevacor, Altoprev) Pravastatin (Pravachol) Rosuvastatin Calcium (Crestor) Simvastatin (Zocor)

COMBINaTION MEDICaTIONSThaT INCLUDE a STaTIN Atorvastatin and amlodipine (Caduet) Lovastatin and niacin (Advicor) Simvastatin and ezetimibe (Vytorin)

Source: The American Heart Association

“Developing diabetes is bad, but having a heart attack or stroke

and dying is worse.” — David Waters, MD, professor emeritus

at the University of California — San Francisco

In 2011,

Americans

spent…

$7.7B

$4.4B

AstraZeneca

CRESTOR

Pfizer

Lipitor

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By Kelly Horvath

An aging baby boom population coupled with increas-ing human longevity has combined to dramatically

increase incidence of chronic disease, particularly diabetes. Increasing by 5 million in just five years, 22.3 million people were living with diabetes in 2012.

The economic burden of diabetes grows even faster than its incidence. Diabetes costs, both direct and indirect, will total around $245 billion for 2012, according to the April 2013 Scientific Statement by the American Diabetes Asso-ciation (ADA), “Economic Costs of Diabetes in the U.S. in 2012.” This staggering figure reflects a five-year increase in diabetes costs greater than the overall cost of medical care as a whole (which holds true even after adjusting for infla-tion). The ADA last undertook an economic burden study in 2007; at that time, diabetes costs were $174 billion. (Other costs not included in the ADA figure include undiagnosed diabetes, which is estimated to cost another $18 billion; pre-diabetes, another $25 billion; and unknown hidden costs, such as those incurred by nonpaid caregivers or by family members living with diabetes patients.)

Direct and indirect CostsOf the $245 billion, direct costs command the larger share at $176 billion, and indirect costs come in around $69 bil-lion. Direct costs include emergency room care, hospital inpatient days, nursing/residential facil-ity use, ambulance services, ambulatory visits, hospice care, podiatry, prescrip-tion medications, diabetic supplies, and other equipment and supplies, whereas indirect costs are associated with productivity loss from a combina-tion of absenteeism (workdays missed due to health conditions), presentee-ism (reduced work productivity while at work due to health conditions), reduced

AT-A-GLANCE:• TheADA’sestimatedcostsofdiagnoseddiabeteshaverisen41%,up$71billionfrom$174billionin2007to$245billionin2012.

• Despiteoverallhospitalinpatientcostshavingdecreasedfrom50%to43%,inpatienthospitalcostsforpatientswithdiabetesincreased—from$58billionin2007to$76billionin2012.

• Diabetespreventionmeasuresarethebestwaytolowertheseastronomiccostsinthefuture,saytheADAandothers.

workforce participation among those with chronic disability, and

the productivity lost from prema-ture mortality. Direct and indirect costs

break down by age group as well, with most (59%) direct costs attributable to patients

ages 65 years and older, whereas 88% of indirect costs derive from those younger than age 65 years.

Not surprisingly, the disease costs substantially more (study findings show from two to eight times higher) when it is poorly controlled and/or associated

with complications. Diabetes-related conditions accounting for most of the overall direct costs include

heart and renal failure; heart disease, such as conduction disorders, cardiac dysrhythmias, hypertension, myocardial infarction, and chronic ischemic heart disease; cataracts; cellulitis; urinary tract infections; and poor general health.

These conditions combine to increase annual medi-cal expenditures for people with diabetes by 2.3 times over those without the disease. In fact, according to the ADA, “More than one in 10 healthcare dollars in the U.S. are spent directly on diabetes and its complications, and more than one in five healthcare dollars in the U.S. goes to the care of people with diagnosed diabetes.” Notably, hospital inpatient care is the largest piece of this spending, having risen to 48% ( from $58 billion in 2007 to $76 billion in 2012), despite over-all hospital inpatient care costs having decreased: of total direct medical costs, inpatient care dropped from 50% to 43% in the same five-year period.

How and why costs have skyrocketed by 41% in five years to $245 billion seems to have less to do with specific economic factors (i.e., treatment costs rising) than with sheer disease predominance, according to the ADA. Diabe-tes prevalence reflects changing demographics (i.e., older adults show a greater prevalence, and the numbers of older adults are increasing both as baby boomers age and people live longer in general); increases in risk factors, especially obesity; decreasing mortality (i.e., people are living longer with disease due to improved treatments), and better dis-ease detection. Some say that if incidence continues to bur-geon, one in three people will be diagnosed with diabetes by 2050. Matt Petersen, managing director, Medical Infor-mation and Professional Engagement of the ADA, says, “I believe the key observation to make is that the increased cost from 2007 to 2012 is primarily a result of increased prevalence of diagnosed diabetes. One might think that the availability of new and often expensive medications would have contributed to that increased cost, but in fact the

Feature STORy

Spiraling diabetes-related costs

demand redoubled prevention efforts

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proportion of the cost attributable to anti-diabetic agents remained flat during that time.”

Despite the availability of several new diabetes medi-cations and despite double the use of such agents, overall pharmacy costs stayed more or less constant over a 10-year period at 12% of diabetes medical spending in 2012. Inter-estingly, prescriptions to treat diabetes complications cost significantly more than did prescriptions to treat diabetes — at 18% and 12%, respectively.

reducing CostsEveryone agrees that this steadily increasing economic bur-den is overwhelming the U.S. healthcare system. Medicare currently shoulders the costs incurred by 14 million people living with diabetes — almost half of the diagnosed popula-tion. Among Medicare, Medicaid, and military programs, in fact, the U.S. federal government pays for 62% of diabetes-related costs. U.S. federal gov-ernment 2014 budget proposals to reduce this outlay include shifting more costs to wealthier Medicare recipients and cutting about $350 billion from providers and recipients. Opponents fear that such sweeping changes would limit care access for the biggest and most needy populations — low-income, older, and disabled diabetes patients — as well as cause an over-all regression in public health. Other measures, such as the program hosted by the Centers for Medicare and Medicaid that allows patients to mail order their diabetes-related medications and equipment from suppliers who competi-tively bid to participate (commonly known by the acronym DMEPOS), saved only $202 million in 2011.

The dilemma presented by these current and pro-posed measures (i.e., effectively reducing care access on the one hand and not saving enough money on the other) leaves many asking, how, then, do we pay this ever-

increasing bill? In the healthcare sector, however, many say we are approaching the issue from the wrong angle. We should not be looking at how to pay the bill so much as how to prevent the cost from being incurred.

“If the primary driver of the increased costs is increased prevalence, it’s a compelling argument that we should be looking at primary prevention of type 2 diabetes as the most important strategy for containing the costs,” says Petersen. “And prevention of course would not only reduce economic costs, but would also bring the quality-of-life benefits that would come from preventing diabetes in the first place.” Hospital inpatient care is the largest piece of the cost pie (one day is estimated to cost $5,000), but preventing diabe-tes (or even effectively controlling it) would directly mitigate that expenditure by negating the trip to the hospital.

Thus, the answer to at least part of this problem is self-evident, say physicians and researchers, and is also

long backed up by findings from the 2002 Diabetes Prevention Program (DPP). If 95%–98% of diabetes is type 2, and if the risk of developing type 2 diabetes is dramatically increased by obesity, then we need lifestyle interven-

tions targeting obesity to prevent diabetes from developing and thereby stanch the increase in the diabetes base popu-lation, which some say is growing by 5,000 people a day.

“We feel prevention is paramount for reducing the future cost of the condition,” says Kelly L. Close, president of Close Concerns, a diabetes awareness organization, and editor-in-chief of diaTribe, an online diabetes news jour-nal. For the other part of the problem, that is, those already diagnosed with diabetes, the answer is optimizing care, she says, adding, “We would like to move away from the ‘treat to failure’ model that so many patients get caught in and move toward new therapies. For example, exploration of annual use of continuous glucose monitoring so that poor manage-ment doesn’t escalate.”

The Endocrine Society is fully in agreement that pre-vention is paramount and urges the federal government to likewise recognize this necessity. The Society's director of government and public affairs Stephanie Kutler says, “The Society has been working with members of Congress to secure full funding for the [DPP], and the new [ADA] data have helped to illustrate the urgency of our message. These costs will continue to grow unless we do something to pre-vent more people from developing diabetes, and the proven way to do that is through primary prevention programs like the DPP. But Congress and the Administration must make this a priority and fully fund the program.”

Investing in new drugs and technology as well as in public health programs on diabetes prevention seems to be the consensus among the healthcare sector. “More research into new prevention programs and treatments and cures” should also be a priority, adds Kutler. Perhaps legislators will realize that a twist on the old quote might apply here: “You must spend money to save money.”

—Horvath is a freelance writter in Baltimore, and a regular contributor to Endocrine News

“We would like to move away from the ‘treat to failure’ model that so many patients get caught in and move toward new therapies.”

— Kelly Close, president, Close Concerns; editor, diaTribe

Direct Costs Indirect Costs

$176B $69BDirect Costs$176 Billion• emergencyroomcare• hospitalinpatientdays• nursing/residential facility use • ambulanceservices• ambulatoryvisits• hospicecare• podiatry• prescriptionmedications• diabeticsupplies• otherequipment and supplies

Indirect Costs$69 BillionProductivity loss from a combination of: • absenteeism• presenteeism• reducedworkforce

participation among those with chronic disability

• theproductivity lost from premature mortality

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LABORATORY NoTES

Diamond-coated petri dishes protect sperm, thus improving IVF success rates. In vitro fertilization

(IVF) already carries a hefty price tag—and the procedure may get costlier. A new method using nanocrystalline dia-monds to carpet the bottom of petri dishes might ensure better survival and performance of sperm, improving IVF success, suggests a recent study in the Online Proceedings Library of the Materials Research Society.

“Our finding is likely to change the world of the petri dish,” explains Andrei Sommer, PhD, a materials scientist at Ulm University in Germany and the study’s lead author.

The average IVF cycle in the United States costs $12,400, according to the American Society of Reproduc-tive Medicine. Because its success rate remains rather low, at about 30%, couples often undergo multiple treatment rounds before they successfully conceive. “Poor sperm per-formance” is a common problem, which typically requires actual injection of sperm into an egg. Yet for decades a part of the solution was right in front of the reproductive endo-crinologists’ eyes: the petri dish.

The majority of IVF clinics—about 99.9%—use disposable petri dishes made from polystyrene plastic. When cell medium is applied to these dishes, the surface softens, as verified by a material harness-measuring device called a nanoindenter. The liquefied surface facilitates the formation of reactive oxygen species (ROS) that is toxic to cells, including sperm, oocytes, and embryos.

Searching for ways to get around this problem, Sommer remembered the title of an American Chemical Soci-ety press release on his previous work titled, “Diamonds may have been life’s best friend on pri-mordial Earth,” which suggested that the surface of natu-ral diamonds might have provided the right conditions for life-creating chemical reactions. For his research, the title served as a “guiding light sentence” and stimulated the inclusion of nanodiamond-coated petri dishes.

Sommer’s team applied fresh sperm samples, at about 4.1 million/mL — lower than the typical male sperm con-

centration of 20–200 million/mL — onto four different types of petri dishes: polystyrene, quartz glass, sandblasted quartz glass coated with nanodiamonds, and quartz glass coated with nanodiamonds. After 42 hours at 37 degrees Celsius, about 20% more sperm survived in the pricey petri dishes, specifically the nanodiamond-coated plain and sandblasted quartz dishes, than the bargain polystyrene ones; the plain quartz containers without the diamond dusting yielded about 10% better viability than the polystyrene dishes.

The 42-hour time point could be important because, in IVF, after about 40 hours, the eggs are examined to see

if they have become fertilized by the sperm and are forming embryos. The embryos are then

placed in the woman’s uterus, thus bypass-ing the fallopian tubes, and hopefully

ensuring pregnancy.“During conventional IVF, sperm

cells and oocytes both contact the bottom of the petri dish before the zygote is formed. These hours, and subsequent days prior to the transfer

of the embryo into the recipient, are critical,” said Sommer, who added that

sperm, while sensitive to ROS, are more robust to them than oocytes and embryos.Bradley Anawalt, MD, chief of medicine

at the University of Washington Medical Center and specialist in male reproductive physiology, who was not involved in the study, described the work as “a relatively simple and straightforward study that asks a simple ques-tion no one has asked before.”

He added that this research backs up prior findings that infertile men are exposed to ROS in their testicles and includes speculation that antioxidant therapies might

DiAMoNDs in the rough

THeDiAMoND-CoATeD

PeTri DisHes are not only sperm

and egg’s best friend. They could also aid in culturing stem cells and cancer cells.

By Jacqueline Ruttimann Oberst

A new method using nanocrystalline diamonds to car-pet the bottom of petri dishes might ensure better sur-vival and performance of sperm, improving IVF success. However, since the average cost for an IVF procedure is already over $12,000, the addition of diamonds to the process will only increase that price tag.

help these men. Given that banked sperm are often fro-zen in polystyrene containers, Anawalt posits that it is possible these containers could also affect the long-term viability of these frozen sperm.

Richard Rawlins, PhD, IVF laboratory director at Rush-Copley Center for Reproductive Health in Aurora, IL., men-tioned that ROS scavengers are typically added to culture media to soak up any ROS in the dishes, yet perhaps these chemicals are not enough. He also called the study “a novel application of engineering helping out biology.”

Sommer’s group plans on testing the plates to see if it has any effect on sperm morphology and motility. They also want to ensure that the diamond coatings are biologi-cally and chemically inert and do not release other toxic chemicals of their own.

The diamond-coated petri dishes are not only sperm and egg’s best friend. They could also aid in culturing stem cells and cancer cells, suggested Sommer, whose lab pre-viously reported greater growth success of P19 mouse embryonic carcinoma cells on the diamond-dusted quartz petri dishes’ substrates.

Although these dishes could theoretically be reused through sterilization techniques such as autoclaving, Sommer correctly points out that “neither the IVF com-munity nor the patients will accept making babies in ‘used’ petri dishes.”

If Sommer’s future research continues to indicate that these plates show promise, companies could start manu-facturing these dishes in the next couple of years. And IVF clinics that purchase these dishes would somehow trans-fer the costs to the patients.

—Ruttimann Oberst, PhD, is a freelance writer in Bethesda, MD and a regular contributor to Endocrine News

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Finding new ways to reimburse physicians is a critical next step in reforming America’s healthcare system.

Since 2002, physicians have faced potentially devastating payment cuts that have resulted from the flawed payment formula known as the sustainable growth rate (SGR). In 1997, the SGR was mandated by Congress in an attempt to stabilize federal spending and to balance the budget. Each year, target expenditures are established that take into account things like changes to physician service fees and the number of Medicare beneficiaries. If actual expen-ditures exceed that target, cuts to physician payments the subsequent year must take place to offset the difference.

While Congress typically passes short-term legisla-tive patches to avoid these cuts, this approach to Medi-care reimbursement is untenable. This year, physicians can expect to receive a 25% cut in Medicare payments if Congress fails to act. And in order to provide a perma-nent solution, Congress must find $139 billion.

Because of the high price tag and the general divisiveness in Congress, an alternative approach to reimbursing physicians has not been given serious thought — until recently. Earlier this year, the House committees on Energy & Commerce and Ways & Means released a framework for reforming the Medicare payment system. Much like the trend toward patient-centered care, pay-ing America’s physicians may also be moving toward an individualized approach.

The current congressio-nal proposals promise to give physicians a variety of reim-bursement options, rather than taking a one-size-fits-all approach to replacing the SGR. Enabling physi-cians to choose how they get paid is a fresh take on a system that has long been shack-led by formulaic considerations rather than improving the quality of patient care.

So how would this proposal work? First Congress

must decide the payment models from which physicians can select. Once these options have been decided, physi-cians would receive stable payments for several years to give them time to decide which option would work best for their practice. Physicians can continue to be paid under the fee-for-service (FFS) system or they can choose to participate in an alternative payment model that utilizes team-based care to streamline healthcare delivery. The FFS system will also see some changes during this time to integrate quality and performance measures so that future payment updates can take these considerations into account.

Throughout this process, the committees have engaged key stakeholders, like The Endocrine Soci-ety, to ensure the alternative payment models that are selected can benefit all specialties. The Society has long advocated for payment reform to better account for the

undervaluation of the evaluation and management ser-vices that endocrinologists most often provide. The

Society has also been supportive of both the SGR repeal and for physicians to be able to select a

reimbursement option that is most suitable for their practice.

In comments to the committees regarding this framework, the Soci-

ety has stressed the importance of working with physician organi-

zations to ensure that there are relevant quality mea-sures for all physicians. The Society also believes that providing flexibility during the selection process of an alternative payment model is a critical step in incentiv-izing physicians to try out new mechanisms for reim-bursement. Comments on implementation, EHR

adoption, clinical improve-ment activities, alternative payment models, and resource utilization were also included in the com-ment letter, which can be found at www.endocrine.org/advocacy/legislative/letters.

Replacing the SgR: a Physician-centered approach?

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ADVOCACY WATCH

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PRACTICE rESoUrCES

Atwo-year-old boy is admitted to the hospital for spitting up and poor feeding. He was reportedly healthy until the

week of this hospital admission, although his slow growth and lack of weight gain have been a consistent problem for which no definite diagnosis has been given. He was born after a full-term pregnancy to a 24-year-old primigravida woman. Gestation was complicated by early oligohydram-nios and relatively poor weight gain, but the birth weight was 3,770 g (68th percentile) and birth length was 50.8 cm (62nd percentile). Although vaginal delivery was attempted, the use of forceps was unsuccessful and cesarean delivery was necessary after a difficult and prolonged labor. There were no other complications, and two days after delivery, the newborn was discharged with his mother.

There is no family history of disease, the child is not taking any medications, and he has not been exposed to any unknown substances. On physical examination, weight is below the fifth percentile and height is at the 10th percentile. He has no dysmorphic features, but he is dehydrated, pale, and lethargic. He has no trauma or rashes. He has normal male genitalia with bilaterally descended testes. An X-ray of the abdomen shows cal-cifications that are thought to represent kidney stones. Abdominal CT is shown.

Laboratory test results:

Sodium = 114 mEq/L (136-142 mEq/L) Potassium = 7.2 mEq/L (3.5-5.0 mEq/L) ACTH = 2,500 pg/mL (10-60 pg/mL) Cortisol = 1.2 μg/dL (AM serum cortisol,

10-20 μg/dL) 17-Hydroxyprogesterone = 35 ng/dL

(AM 17-hydroxyprogesterone 60-300 ng/dL) Plasma renin activity = 86 ng/mL per h

(0.6-4.3 ng/mL per h)

Which one of the following diagnoses is most consis-tent with the biochemical profile and CT image of this patient?

A Allgrove syndromeB Familial glucocorticoid deficiencyC Congenital adrenocortical hyperplasia D Adrenal hemorrhageE Congenital HIV infection and adrenal insufficiency

A ToDDLer’s suDDeN iLLNess: A Case study from Pediatric esAP

answer on page 30

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Drawing on the expertise of leading pediatric endocrinologists, the Pediatric Endocrine Self-Assessment Program 2013-2014 (Pediatric ESAPTM) is designed to provide pediatric endocrinologists and fellows with a comprehensive tool for knowledge self-assessment. A unique product line, which includes two interactive online modules and the complete reference book, Pediatric ESAP is the essential study guide for those in the process of maintaining or obtaining certification. With content based on all areas of the American Board of Pediatrics’ exam blueprint, each online module contains 50 clinical case vignettes and includes extensive follow-up discussion and reference materials to help learners integrate new knowledge into performance. Enabling you to benchmark yourself against peers, Pediatric ESAP is a key resource to prepare for the American Board of Pediatrics’ exam and meet Maintenance of Certification (MOC requirements).

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Computer-based medical records hold promise for improving treatment and efficiency, but experts

say they are open to attack from hackers, malware, and even nosy employees.

The electronic health record (EHR) pro-grams certified for use in medical practices and hospitals are far from secure, but the behavior of many practitioners exacerbates the risks.

“In terms of security management, the healthcare industry is particularly bad,” said Avi Rubin, PhD, professor of computer science at Johns Hopkins University and technical director of its Information Security Institute.

Software ProblemsStudies have found EHR software surprisingly vulnerable to potential hackers. A research team that examined a pair of EHR systems found very basic vulnerabilities, said team leader Laurie Williams, PhD, a computer science profes-sor at North Carolina State University. The programs were open to “almost beginner level security attacks.”

Williams said that these vulnerabilities are not unusual compared with other kinds of software, but are troubling because the records contain such sensitive and personal information. Williams said that if credit card information is breached, a user can close an account and get a new credit card. “But with health records, if some-

one’s private information gets out, you can’t with-draw that knowledge,” she said.

Potential problems range from identity theft from the release of information such as Social Security numbers to tampering with records themselves. “You could possibly change some-one’s blood type and then they’d get a transfusion of the wrong type,” she said.

EHR software users are at the mercy of the software developers and government regulators because they must buy a certified system, and Williams and Rubin agreed that the certification process has not paid adequate atten-tion to security. They said that practitioners should pres-sure vendors and government regulators to make security a higher priority.

GAPINGHOLES Seen in Electronic Record Security By Eric Seaborg

“... with health records, if someone’s private information gets out,

you can’t withdraw that knowledge.” — Laurie Williams, computer science professor,

North Carolina State University

People ProblemsRubin toured hospitals to observe their practices and was appalled to find a general disregard for computer secu-rity. He often saw passwords posted on computers by sticky notes. In one hospital, a nurse had the job of typing a physician’s password into computers so the physician would not time out, which left the machines unattended and unprotected most of the time. The common practice of distributing to patients disks containing their X-rays—and executable programs for reading them—is dangerous because practitioners have no idea what is really on them when patients walk in with them. The disks could contain malware that could infect whole systems.

Williams noted that in the interest of making the tran-sition to electronic records easier, some practices have been tempted to take shortcuts such as having a single

log-in ID for doctors and another for nurses, rather than having individual user IDs. “If they do that, they will have no way to trace who did what. So to use the blood example again, they should be able to go back and see who changed the blood type,” Williams said.

Tips for ImprovementApparently, hackers have not set their sights on the medi-cal establishment in a big way yet—most healthcare secu-rity breaches have resulted from mistakes such as the loss or theft of laptops. Rubin recommended engaging a secu-rity professional as a consultant or in-house in the case of larger institutions.

—Seaborg is a freelance writer in Charlottesville, VA, and a regular contributor to Endocrine News

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Great ideas are only useful when you share them, so consider publishing your book with Endocrine press: Endocrine Society’s newly revamped book publishing program.

We are currently soliciting book proposals that provide important and cutting-edge information on a range of issues related to endocrinology.

We are particularly interested in books with scopes and subject matter relative to the Endocrine Society’s mission of advancing excellence in endocrinology to promotes its essential and integrative role in scientific discovery, medical practice, and human health.

Key topics of interest include the following:

• Adrenal • Bone & Calcium• Cardio Metabolic• Diabetes • Lipids & Obesity • Neuroendocrinology• Pediatric Endocrinology • Pituitary• Reproductive• Thyroid

endocrine Press An Imprint of the Endocrine Society

SPECIAL CALL FOR MANUSCRIPTS ON HealtH Disparities in enDocrine DisorDers

Submit a book proposal or pitch your own topic by contacting Maxine Aldred at [email protected]. For more information about Endocrine Press, please visit

http://www.endocrine.org/endocrine-press.

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Durazo-Arvizu, and Stephen H. Schneider These results suggest that if PTH is suppressed at a lower serum 25OHD in the obese com-pared to the entire population, the lower average 25OHD concentra-tions in the obese may not have the same physiological significance as in the general population.

Approach to Testing Growth Hormone (GH) Secretion in Obese Subjects Vera Popovic GH stimula-tion tests should be avoided in obese subjects with very low pretest probability.

The following studies, among others, will be published in Endocrine Society journals. Before print, they are edited and posted online in each journal’s Early Release section. You can access the journals at www.endocrine.org.

Hypoglycemia and Diabetes: A Report of a Workgroup of the American Diabetes Associa-tion and The Endocrine Society Elizabeth R. Seaquist, John

Anderson, Belinda Childs, Philip Cryer, Samuel Dagogo-Jack, Lisa Fish, Simon R. Heller, Henry Rodriguez, James Rosenzweig, and Robert Vigersky The workgroup reconfirmed previous definitions of hypoglycemia in diabetes, reviewed the implications of hypoglycemia on both short- and long-term outcomes, considered the implica-tions of hypoglycemia on treatment outcomes, presented strategies to prevent hypoglycemia, and identified knowledge gaps that should be addressed by future research.

Clinical Outcomes and Molecular Profile of Differentiated Thyroid Cancers with Radioiodine-Avid Distant Metastases M.M. Sabra, J.M. Dominguez, R.K. Grewal, S.M. Larson, R.A. Ghossein, R.M. Tuttle, and J.A. Fagin RAIA metastatic FCDTC are overrepresented with RAS mutations, whereas RAI refractory metastatic thyroid cancers are enriched with BRAF mutations.

Approach to the Patient With Hypogonadotropic Hypogonadism Letícia Ferreira, Gontijo Silveira, and Ana Claudia Latronico The precise and early diagnosis of HH can prevent negative physical and psychological sequelae, preserve normal peak bone mass, and restore the fertility in affected patients.

The Effect of Obesity on the Relation-ship Between Serum Parathyroid Hormone and 25-Hydroxyvitamin D in Women Sue A. Shapses, Esther J. Lee, Deeptha Sukumar, Ramon

RESEARCH roUNDUP

Estrogen-Related Receptor γ (ERRγ) Regulates Oxygen-Dependent Expression of Voltage-gated Potassium (K+) Channels and Tissue Kallikrein

during Human Trophoblast Differentiation Yanmin Luo, Premlata Kumar, and Carole R. Mendelson ERRγ mediates O2-dependent expression of genes involved in human trophoblast differentiation, function, and vascular homeostasis.

Increased Bone Mass in Mice Lacking the Adipokine Apelin Lalita Wattanach-anya, Wei-Dar Lu, Ramendra K. Kundu, Liping Wang, Marcia J.

Abbott, Dylan O'Carroll, Thomas Quertermous, and Robert A. Nissenson The increased bone mass in mice lacking apelin suggested complex direct and paracrine/endocrine effects of apelin on bone, possibly via modulating insulin sensitivity. These results indicate that apelin functions as a physi-ologically significant antianabolic factor in bone in vivo.

Renal Protective Effects of Toll-like Receptor 4 Signaling Blockade in Type 2 Diabetic Mice J.J. Cha, Y.Y. Hyun, M.H. Lee, J.E. Kim, D.H. Nam, H.K. Song, Y.S. Kang, J.E. Lee, H.W. Kim, J.Y. Han, and D.R. Cha GIT27 treatment improves insulin resistance and protects against the renal injury that occurs in type 2 diabetic nephropathy through both metabolic and antiglomeruloscle-rotic mechanisms, which suggests that TLR pathway inhibition might play a direct protective role in diabetic kidney disease.

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cAMP-Responsive Element Binding Protein: A Vital Link in Embryonic Hormonal Adaptation Maria Schindler, Sünje Fischer, René Thieme, Bernd Fischer, and Anne Navarrete Santos Transcription factors CREB and ATFs vitally participate in embryo-maternal cross talk before implantation in a cell lineage-specific manner. Embryonic CREB/ATFs act as insulin/IGF sensors. Lack of insulin is compensated by a CREB-medi-ated adiponectin expression, which may maintain glucose uptake in blastocysts grown in diabetic mothers.

Age Increase of Estrogen Receptor-α (ERα) in Cortical Astrocytes Impairs Neurotrophic Support in Male and Female Rats Jason M. Arimoto, Angela Wong, Irina Rozovsky, Sharon W. Lin, Todd E. Morgan, and Caleb E. Finch The persisting effects of ovarian acyclicity in vitro are hypothesized to arise from steroidal perturba-tions during ovarian senescence, which suggests that increased astrocyte ERα expression during aging contributes to the E2 desensi-tization of the neuronal responses in both sexes.

InTOUCH

The 2014 Annual Meeting Steering Committee (AMSC) will have the large task of planning the joint 16th Interna-tional Congress of Endocrinology/The Endocrine Society’s 96th Annual Meeting & Expo. President Teresa Woodruff, PhD, will work with the chairs and AMSC members to create an exciting and comprehensive program. The first clinician-in-practice chair, Carol Wysham, MD, PhD, will bring special attention to the interests of the practicing clinician members of the Society.

Introducing tHe 2014 annual Meeting steering coMMittee!

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Derek Leroith, MD, PhD, ENDO 2014 Chair

Matthew Ringel, MD, PhDClinical Science Chair

Kevin Grove, PhDBasic Science Chair

Carol Wysham, MD, PhDClinician-in-Practice Chair

Richard Eastell, MBBS, MDMichael Levine, MDSteven Smith, MDJane Reusch, MDBernard Robaire, PhDErica Elizabeth Marsh, MDJorma Toppari, MD, PhDNelly Mauras, MDAdrian Lee, PhDLouis Luttrell, MD, PhDJohn Cidlowski, PhD

Kristy Brown, PhDStephanie Lee, MD, PhDGal Omry, MDWiebke Arlt, MD, DSc,

FRCP, FMedSciGregory Brent, MDLaura Calvi, MDCheri Deal, MD, PhDPatricia Elizalde, PhDGhada Fuleihan, MD, MPHAshley Grossman, MD, FRCPAnnette Grueters, MD, PhDRobert Handa, PhDAnthony Hollenberg, MDMalcolm Low, MD, PhDChristopher McCartney, MDRobert Millar, PhDSue Moenter, PhDJohn Newell-Price, MD, PhD, MRCPPere Puigserver, PhD

Elliot Rayfield, MDCharles Roberts, Jr., PhDDonald Simonson, MD, MPH, ScDFrances Sladek, PhDJenny Visser, PhDHumphrey Yao, PhDPhilip Zeitler, MD, PhDDaniel Marks, MD, PhD

In addition, eight members of the International Society for Endocrinol-ogy will be joining the AMSC this year.

Peter Ebling, MBBS,MDTeresa Sir Petermann, MDWeiqing Wang, MDPhilippe Chanson, MD, MSSubhanker Chowdhury, MD, MSMoises Mercado, MDAugustine Ohwovoriole, MD, MSElizabeth Paz-Pacheco, BS, MD

Is there a topic that you would like to learn more about at ENDO?

THe 2014 ANNuAL MeeTiNG sTeeriNG CoMMiTTee

welcomes suggestions for the joint 16th International Congress of Endocrinology/The Endocrine Society’s 96th annual Meeting & Expo

To submit suggestions, visit www.ice-endo2014.org. The deadline to submit suggestions is July 24, 2013.

ReCORD NuMBeRS fOR

ESAP™-ITE 2013This year the Endocrine Self-Assessment Program In-Training (ESAP-ITE) exam was a great success! The Self-Assessment Committee is happy to report that 560 endocrine fellows from 134 training pro-grams worldwide have completed the exam during the month of April. Of those 134 training programs, seven new training programs registered their fellows, including four international programs. “We designed ESAP-ITE to assess fellows’ knowledge across a broad range on endocrinology topics,” says Alan Dalkin, chair of the Self-Assessment Committee. “The exam has become an essential tool for fellowship training program directors domestically, and the addition of SI units to the 2014 exam will increase applicability to international training programs as well.” Learn more about ITE on endoselfassessment.org.

peDiatric esap™ 2013–2014: Increased Benefits to Board Certified Pediatric Endocrinologists

The American Board of Pedi-atrics (ABP) has begun transition-ing toward the new “continuous” Maintenance of Certification (MOC) model, requiring physicians to earn 40 Part 2 MOC points per five-year MOC cycle. To address this increased regulatory need, Pediatric ESAP 2013–2014 has been redesigned and ABP-approved to offer 40 MOC Part 2 points, which is twice the number of MOC Part 2 points offered by its predecessor, Pediatric ESAP 2011–2012. This new offering, developed by the Pediatric Self-Assessment Com-mittee, includes two 50-question interactive modules and a printed book. Learn more about the ben-efits of Pediatric ESAP 2013–2014 on endoselfassessment.org.

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EventCALENDARAugust 7-10: PhilAdelPhiA

sePtember 19-22: milAn, itAly

sePtember 23-27: bArcelonA

sePtember 24-28: new orleAns

ENDOCRINE SOCIETY and HORmONE HEALTH NETwORk Launch New Websites Visit the new websites of The Endocrine Society and the Hormone Health Network for an improved user experience, including new designs and improved layouts, to help you find the information you need, fast.

The Society website, endocrine.org, provides you with all of the tools and information you need to succeed in your work environment. Log on and stay up-to-date on important events; find products, services, and meetings to help advance your work; learn about hot topics in public policy; and more.

Created for patients, backed by the Society’s clinical and scientific expertise, hormone.org is your partner in endocrine patient education. With more than 100 free resources in English and Spanish, hormone.org educates patients and improves communication. Visited by 2 million people a year, The Hormone Health Network gives your patients a better understanding of hormone, health, disease, and treatment. The Network’s goal is to help providers move patients from educated to engaged, creating active partners in their healthcare.

Submit Your Nominations for the 2013 early investigators worksHop Did you know that The Endocrine Society annually hosts a workshop specifically designed to provide young investigators an in-depth introduction into the foundation for building successful careers in research at the Early Investigators Workshop? The two-day workshop offers early career investigators career development talks, small group presentations, and network-ing opportunities with peers and faculty. This year, the Society will hold the Early Investigators Work-shop on October 21–22 in India-napolis, Ind. This workshop is a must-attend for clinical fellows and post-doctoral fellows planning for independent research careers.

Here’s what participants of the 2012 Early Investigators Workshop shared with Endocrine News about their experiences.

Dr. Michael Stitzel, senior post-doctoral fellow at The Johns

Hopkins University School of Medi-cine, was drawn to the workshop by the basic science offerings and sessions focusing on grant writing,

lab management, negotiation, and mock study section: “I was expect-ing two intense days of scientific and professional advice and I was not disappointed. The personal and professional experiences that the faculty advisors shared were enlightening. I left San Francisco with a much better perspective of the “black box” of Study Section and scientific review of grants and with eyes wide open to the chal-lenges and techniques in negotiat-ing for a faculty position.”

He shared additional insights into the workshop’s networking oppor-tunities: “Networking opportunities are usually difficult to facilitate in such a short, two-day workshop,

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PEDIATRICESAP™

PEDIATRIC

ENDOCRINE

SELF-ASSESSMENT

PROGRAM 2013-2014

Module 1 and Module 2

QUESTIONS

ANSWERS

DISCUSSIONS

Endocrine Press

Pediatric ESAP™

2013-2014: Ped

iatric End

ocrine S

elf-Assessm

ent Pro

gram

Founded in 1916, The Endocrine Society

is dedicated to advancing excellence

in endocrinology and promoting its

essential role as an integrative force in

scientific research and medical practice.

ISBN: 978-1-936704-17-0

The Endocrine Society

8401 Connecticut Avenue, Suite 900

Chevy Chase, MD 20815

www.endocrine.org

www.endoselfassessment.org

Drawing on the expertise of leading pediatric endocrinologists, the

Pediatric Endocrine Self-Assessment Program 2013-2014 (Pediatric

ESAPTM) is designed to provide pediatric endocrinologists and fellows with

a comprehensive tool for knowledge self-assessment. A unique product

line, which includes two interactive online modules and the complete

reference book, Pediatric ESAP is the essential study guide for those in

the process of maintaining or obtaining certification. With content based

on all areas of the American Board of Pediatrics’ exam blueprint, each

online module contains 50 clinical case vignettes and includes extensive

follow-up discussion and reference materials to help learners integrate new

knowledge into performance. Enabling you to benchmark yourself against

peers, Pediatric ESAP is a key resource to prepare for the American Board of

Pediatrics’ exam and meet Maintenance of Certification (MOC requirements).

• 100 clinical case vignettes with answers, discussions, and references

• Two interactive online modules and printed reference book

• Earn up to 40 MOC Part 2 points and 32.0 AMA PRA Category 1 Credits™

Job Name: 493952_PED_ESAP

PDF Page: 493952_PED_ESAP_Cover.p1.pdf

Process Plan: Virtual_Proof_MultiPagePDF

Date: 13-05-17

Time: 19:13:59

Operator: ____________________________

PageMark-Color-Comp

❏ OK to proceed

❏ Make corrections and proceed

❏ Make corrections and show another proof

Signed: ___________________ Date: ______

but I felt I the organizers, and particularly the partici-pating faculty, made this a goal. I have found at other meetings that it can be difficult to penetrate the cliques that naturally occur. At this meeting, the faculty did a great job distributing themselves at meals and during the break amongst the trainees. I don’t know if this was a conscious effort, but I did greatly appreciate it! Networking with other fellows who are at the same or similar stages of their careers was an added bonus.”

Dr. Irina Bancos, fellow from Mayo Clinic, shared her perspective on the workshop: “I would highly recommend the Early Investigators Workshop to my colleagues! My advice would be to consider presenting a proposal that is in the early stages of development as it is most likely to be thought-provoking

to attendees. I also believe that first-year fellows would highly benefit from the workshop as this experience is likely to teach a better way to design research and avoid possible mistakes. Insightful and motivating!”

Dr. Justin Gregory, pediatric endo-crine fellow at Vanderbilt University, also joined in the discussion: “I was given some great suggestions for my research after I gave a short presen-tation about what I am doing in the lab right now. One helpful sugges-tion was to look into some surgical

literature that I had not considered looking into that has some applicability for my research in hypoglycemia in T1DM. During some of the talks, the speakers had some great words of advice about how to effectively write research grant proposals. I am applying these as I write my F32 grant application. I also really appreciated the insights shared by the speakers about effective time management and balancing life as a physician and as a spouse and parent.”

Registration for the Early Investigators Workshop is now open to post-doctoral and clinical fellows wish-ing to grow their research knowledge base and develop skills that will help further their research careers. Regis-tration will be open through August 19, 2013. Space for this event is limited so apply today!

For more information, please visit the 2013 Early Investigators Workshop website, www.endocrine.org/awards/ConfTravelGrants/clinical_investigators_workshop/index.cfm.

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CALL FOR NOMINATIONS AND APPLICATIONS FOR EDITOR-IN-CHIEF OF JOURNAL OF CLINICAL

ENDOCRINOLOGY AND mETABOLISm

The Endocrine Society is seeking candidates for the position of Editor-in-Chief of Journal of Endocrinology and Metabolism for a five-year term beginning January 1, 2015. This position requires a dynamic, nationally recognized clinician who has a broad background in the field and is committed to maintaining the journal’s reputation for publishing cutting-edge science. Journal of Clinical Endocrinology and Metabolism provides an international forum for papers enhancing the understanding, diagnosis, and treatment of endocrine and metabolic disorders. It is the world’s leading peer-reviewed journal for endocrine clinical research and cutting edge clinical practice reviews.

RESPONSIBILITIESThe Editor-in-Chief of Journal of Clinical Endocrinology and Metabo-lism receives editorial and administrative support from The Endocrine Society’s Managing Editor and editorial office staff in Chevy Chase, MD, as well as an honorarium. The Editor-in-Chief oversees the peer review process and content development:•SelectinghisorherDeputyEditors,AssociateEditors(6),and

Editorial Board (47)•Providingdirectionforthejournalanditscontentfeaturesand

identifying emerging “hot” areas of importance and soliciting papers for submission

•ParticipatinginmeetingsofthePublicationsCoreCommittee• Participatinginmeetingswiththeeditors-in-chiefoftheSociety’s

other journals

NOMINaTIONSAll members of The Endocrine Society are encouraged to suggest the names of potential candidates by contacting Scott Herman, Group Managing Editor — Associate Director, Publications for The Endocrine Society, at [email protected]. Please submit your suggestions by august 30, 2013.

aPPLICaTIONSApplicants for the position of Editor-in-Chief of Journal of Clinical Endo-crinology and Metabolism should submit the following materials:•Descriptionofqualifications•Statementoutlininghowthecandidateplanstooverseethejournal,

including goals for content, target readership, acceptance criteria, and editorial policy

•ProposedAssociateEditors,areasofexpertise,andprocessforeditorial decision-making

•Discussionofthepresentstatusofthejournal,opportunitiesforgrowth and enhancement, and plans to achieve goals

•Curriculum vitaeApplications are due by September 30, 2013, and should be emailed as PDF attachments to Scott Herman ([email protected]). Please call 301.951.2615 to ensure that your submission has been received. Selected candidates will be contacted by the search committee chair and asked to provide more details. The Publications Core Committee will interview finalists in person at its March 2014 meeting and choose a candidate to recommend to The Endocrine Society Council.

PUBLICaTIONS CORE COMMITTEEThe search process is being undertaken by the Publications Core Com-mittee, and the chair of the search committee is Janet Schlechte, MD. The other members of the committee are: Margaret Shupnik, PhD, Chair; Dennis Baskin, PhD; Joanna Burdette, PhD; Kerri Burnstein, MD; Martin Fassnacht, MD; Sandra Licht, MD; Jeffrey A. Sandler, MD; and Daniel Spratt, MD.

JCEM THE JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM

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The answer is: D. Adrenal hemorrhage

This patient has adrenal calcifications (see arrows) caused by adrenal hemorrhage (Answer D), a well-recognized obstetric complication of the newborn, which is an increasingly rare cause of adrenal insufficiency because of the improvements in care during labor and delivery.

However, it is still an issue, and unless diagnosed and treated early, it can lead to chronic, partially com-pensated adrenal insufficiency or adrenal insufficiency crisis or both. In about half of the reported cases, the bleeds are bilateral and occur at birth. Gradually, the affected glands develop calcifications. Risk factors include large birth weight, hypoxia, septicemia, coagu-lation defects, and thromboembolism. Other causes of adrenal calcifications include tuberculosis; auto-immunity; Wolman disease ( familial xanthomatosis); Niemann-Pick disease; and masses including hemor-rhagic and teratomatous cysts, ganglioneuromas, pheo-chromocytomas, neuroblastomas, and adrenocortical cancer. Adrenal calcification may also be an incidental finding, although then it is also attributed to perinatal adrenal hemorrhage. This patient’s history and pre-sentation are consistent with the cases with adrenal hemorrhage that have been described in the literature, with presentation of adrenal insufficiency not at birth or shortly thereafter, but rather later in the second or third year of life. Typically, these patients compensate for their adrenal dysfunction with high ACTH levels. Partial adrenal insufficiency should be suspected in any infant who has failure to thrive and difficulty feeding, but no primary gastrointestinal disorder. Their condi-tion may decompensate during an infection, a bout of diarrhea, or the course of any other illness, and then they present with severe adrenal insufficiency like the child in this vignette.

Patients with Allgrove syndrome (Answer A) (also known as triple A syndrome) present with alacrima, acha-lasia, and adrenal insufficiency, but they never develop calcifications in their adrenal glands.

Allgrove syndrome and other causes of familial glu-cocorticoid deficiency syndromes (Answer B) also rarely cause mineralocorticoid deficiency.

Congenital adrenocortical hyperplasia (CAH) (Answer C) associated with mineralocorticoid defi-ciency is an unlikely diagnosis in a fully virilized male with low 17-hydroxyprogesterone levels. Although salt-losing 21-hydroxylase deficiency would be consistent with the biochemical profile in this male toddler, the 17-hydroxyprogesterone levels would be expected to be high. Also, CAH is not known to be associated with adrenal gland calcifications.

Finally, congenital HIV infection (Answer E) can cause adrenal insufficiency, but unless it leads to tuberculosis or parasitic infections (i.e., histoplasmosis), it would not be associated with adrenal gland calcifications. These calcifi-cations tend to also be unilateral in patients who develop them secondary to an infection.

question on page 23

PRACTICE rESoUrCES

ANsWerThe Pediatric Endocrine Self-assessment Program (ESaP) Enjoy this case? Access the NEW Pediatric ESAP 2013-2014 by visiting endoselfassessment.org today. Self-assessment products from The Endocrine Society offer CME credits and MOC points. Visit endoselfassessment.org and use the personalized “My Modules” dashboard to manage your CME and MOC needs.

A ToDDLer’s suDDeN iLLNess: A Case study from Pediatric esAP

eN

I0047A_AsizeLaunchAd_M8.indd 1 4/8/13 2:07 PM

Introducing INVOKANATM—the fi rst and only treatment option approved in the United States that reduces the reabsorption of glucose in the kidneys via sodium glucose co-transporter-2 (SGLT2) inhibition1

A1C Reductions as Monotherapy INVOKANATM monotherapy provided statisticallysignifi cant A1C reductions vs placebo at 26 weeks1

A1C Reductions vs Sitagliptin INVOKANATM 300 mg demonstrated greater A1C reductions vs sitagliptin 100 mg, in combination with metformin + a sulfonylurea, at 52 weeks (P<0.05)1

>> Diff erence from sitagliptin†: –0.37%

Incidence of Hypoglycemia Monotherapy over 26 weeks: 100 mg: 3.6%; 300 mg: 3.0%; placebo: 2.6%1

With metformin and a sulfonylurea over 52 weeks: INVOKANATM 300 mg: 43.2%; sitagliptin 100 mg: 40.7%1

>> Insulin and insulin secretagogues are known to cause hypoglycemia. INVOKANA™ can increase the risk of hypoglycemia when combined with insulin or an insulin secretagogue

Convenient Once-Daily Dosing1

>> Recommended starting dose: INVOKANA™ 100 mg

>> Dose can be increased to 300 mg in patients tolerating 100 mg, who have an eGFR of ≥60 mL/min/1.73 m2 and require additional glycemic control

The most common (≥5%) adverse reactions were female genital mycotic infection, urinary tract infection, and increased urination.

References: 1. Invokana [prescribing information]. Titusville, NJ: Janssen Pharmaceuticals, Inc; 2013. 2. Stenlöf K, Cefalu WT, Kim KA, et al. Effi cacy and safety of canaglifl ozin monotherapy in subjects with type 2 diabetes mellitus inadequately controlled with diet and exercise. Diabetes Obes Metab. 2013;15(4):372-382.

Learn more at INVOKANAhcp.com/journal

Eff ect on Weight*Statistically signifi cant weight reductions vs placebo at 26 weeks (P<0.001)1

>> Diff erence from placebo†: 100 mg: –2.2%; 300 mg: –3.3%

Impact on Systolic Blood Pressure (SBP)*Statistically signifi cant SBP lowering vs placebo at 26 weeks (P<0.001)2

>> Diff erence from placebo†:100 mg: –3.7 mm Hg; 300 mg: –5.4 mm Hg

ENVISION NEW POSSIBILITIES

In adults with type 2 diabetes,NOW

AVAILABLE

INVOKANA™ (canaglifl ozin) is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus.

INVOKANA™ is not recommended in patients with type 1 diabetes or for the treatment of diabetic ketoacidosis.

IMPORTANT SAFETY INFORMATIONCONTRAINDICATIONS>> History of a serious hypersensitivity reaction to INVOKANA™.>> Severe renal impairment (eGFR <30 mL/min/1.73 m2), end

stage renal disease, or patients on dialysis.

WARNINGS and PRECAUTIONS>> Hypotension: INVOKANA™ causes intravascular volume

contraction. Symptomatic hypotension can occur after

initiating INVOKANA™, particularly in patients with impaired renal function (eGFR <60 mL/min/1.73 m2), elderly patients, and patients on either diuretics or medications that interfere with the renin-angiotensin-aldosterone system (eg, angiotensin-converting-enzyme [ACE] inhibitors, angiotensin receptor blockers [ARBs]), or patients with low systolic blood pressure. Before initiating INVOKANA™ in patients with one or more of these characteristics, volume status should be assessed and corrected. Monitor for signs and symptoms after initiating therapy.

Please see additional Important Safety Information and Brief Summary of full Prescribing Information on the following pages.

INVOKANATM is not indicated for weight loss or as antihypertensive treatment.

*Prespecifi ed secondary endpoint.

INVOKANATM 300 mg(n=197; mean baseline A1C: 8.01%)

INVOKANATM 100 mg(n=195; mean baseline A1C: 8.06%)

Placebo (n=192; mean baseline A1C: 7.97%)

A1C Change From Baseline With INVOKANA™ Monotherapy1

–0.77

+0.14

–1.03

– 0.91DIFFERENCE FROM

PLACEBO

(95% CI: –1.09, –0.73); P<0.001

– 1.16DIFFERENCE FROM

PLACEBO

(95% CI: –1.34, –0.99); P<0.001

–0.2

–0.4

–0.6

–0.8

–1.0

–1.2

0.2

0

Cha

nge

in A

1C (

%)

fro

m b

asel

ine

(ad

just

ed m

ean)

†Adjusted mean.


WARNINGS and PRECAUTIONS (cont’d)>> Impairment in Renal Function: INVOKANA™ (canagliflozin)

increases serum creatinine and decreases eGFR. Patients with hypovolemia may be more susceptible to these changes. Renal function abnormalities can occur after initiating INVOKANA™. More frequent renal function monitoring is recommended in patients with an eGFR below 60 mL/min/1.73 m2.

>> Hyperkalemia: INVOKANA™ can lead to hyperkalemia. Patients with moderate renal impairment who are taking medications that interfere with potassium excretion, such as potassium-sparing diuretics, or medications that interfere with the renin-angiotensin-aldosterone system are more likely to develop hyperkalemia. Monitor serum potassium levels periodically after initiating INVOKANA™ in patients with impaired renal function and in patients predisposed to hyperkalemia due to medications or other medical conditions.

>> Hypoglycemia With Concomitant Use With Insulin and Insulin Secretagogues: Insulin and insulin secretagogues are known to cause hypoglycemia. INVOKANA™ can increase the risk of hypoglycemia when combined with insulin or an insulin secretagogue. Therefore, a lower dose of insulin or insulin secretagogue may be required to minimize the risk of hypoglycemia when used in combination with INVOKANA™.

>> Genital Mycotic Infections: INVOKANA™ increases the risk of genital mycotic infections. Patients with a history of genital mycotic infections and uncircumcised males were more likely to develop genital mycotic infections. Monitor and treat appropriately.

>> Hypersensitivity Reactions: Hypersensitivity reactions (eg, generalized urticaria), some serious, were reported with INVOKANA™ treatment; these reactions generally occurred within hours to days after initiating INVOKANA™. If hypersensitivity reactions occur, discontinue use of INVOKANA™; treat per standard of care and monitor until signs and symptoms resolve.

>> Increases in Low-Density Lipoprotein (LDL-C): Dose-related increases in LDL-C occur with INVOKANA™. Monitor LDL-C and treat per standard of care after initiating INVOKANA™.

>> Macrovascular Outcomes: There have been no clinical studies establishing conclusive evidence of macrovascular risk reduction with INVOKANA™ or any other antidiabetic drug.

DRUG INTERACTIONS>> UGT Enzyme Inducers: Rifampin: Co-administration

of canagliflozin with rifampin, a nonselective inducer of several UGT enzymes, including UGT1A9, UGT2B4, decreased canagliflozin area under the curve (AUC) by 51%. This decrease in exposure to canagliflozin may decrease efficacy. If an inducer of these UGTs (eg, rifampin, phenytoin, phenobarbitol, ritonavir) must be co-administered with INVOKANA™ (canagliflozin), consider increasing the dose to 300 mg once daily if patients are currently tolerating INVOKANA™ 100 mg once daily, have an eGFR greater than 60mL/min/1.73 m2, and require additional glycemic control. Consider other antihyperglycemic therapy in patients with an eGFR of 45 to less than 60 mL/min/1.73 m2 receiving concurrent therapy with a UGT inducer and requiring additional glycemic control.

>> Digoxin: There was an increase in the area AUC and mean peak drug concentration (C

max) of digoxin (20% and 36%,

respectively) when co-administered with INVOKANA™ 300 mg. Patients taking INVOKANA™ with concomitant digoxin should be monitored appropriately.

USE IN SPECIFIC POPULATIONS>> Pregnancy Category C: There are no adequate and well-

controlled studies of INVOKANA™ in pregnant women. Based on results from rat studies, canagliflozin may affect renal development and maturation. In a juvenile rat study, increased kidney weights and renal pelvic and tubular dilatation were evident at ≥0.5 times clinical exposure from a 300-mg dose.

These outcomes occurred with drug exposure during periods of animal development that correspond to the late second and third trimester of human development. During pregnancy, consider appropriate alternative therapies, especially during the second and third trimesters. INVOKANA™ should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

>> Nursing Mothers: It is not known if INVOKANA™ is excreted in human milk. INVOKANA™ is secreted in the milk of lactating rats, reaching levels 1.4 times higher than that in maternal plasma. Data in juvenile rats directly exposed to INVOKANA™ showed risk to the developing kidney (renal pelvic and tubular dilatations) during maturation. Since human kidney maturation occurs in utero and during the first 2 years of life when lactational exposure may occur, there may be risk to the developing

human kidney. Because many drugs are excreted in human milk, and because of the potential for serious adverse reactions in nursing infants from INVOKANA™, a decision should be made whether to discontinue nursing or to discontinue INVOKANA™, taking into account the importance of the drug to the mother.

>> Pediatric Use: Safety and effectiveness of INVOKANA™ in pediatric patients under 18 years of age have not been established.

>> Geriatric Use: Two thousand thirty-four (2034) patients 65 years and older, and 345 patients 75 years and older were exposed to INVOKANA™ in nine clinical studies of INVOKANA™. Patients 65 years and older had a higher incidence of adverse reactions related to reduced intravascular volume with INVOKANA™ (such as hypotension, postural dizziness, orthostatic hypotension, syncope, and dehydration), particularly with the 300-mg daily dose, compared to younger patients; more prominent increase in the incidence was seen in patients who were ≥75 years of age. Smaller reductions in HbA1C with INVOKANA™ relative to placebo were seen in older (65 years and older; -0.61% with INVOKANA™ 100 mg and -0.74% with INVOKANA™ 300 mg relative to placebo) compared to younger patients (-0.72% with INVOKANA™ 100 mg and -0.87% with INVOKANA™ 300 mg relative to placebo).

>> Renal Impairment: The efficacy and safety of INVOKANA™ were evaluated in a study that included patients with moderate renal impairment (eGFR 30 to <50 mL/min/ 1.73 m2). These patients had less overall glycemic efficacy and had a higher occurrence of adverse reactions related to reduced intravascular volume, renal-related adverse reactions, and decreases in eGFR compared to patients with mild renal impairment or normal renal function (eGFR ≥60 mL/min/1.73 m2); patients treated with INVOKANA™ 300 mg were more likely to experience increases in potassium.

The efficacy and safety of INVOKANA™ have not been established in patients with severe renal impairment (eGFR <30 mL/min/1.73 m2), with end-stage renal disease (ESRD), or receiving dialysis. INVOKANA™ is not expected to be effective in these patient populations.

>> Hepatic Impairment: No dosage adjustment is necessary in patients with mild or moderate hepatic impairment. The use of INVOKANA™ has not been studied in patients with severe hepatic impairment and it is therefore not recommended.

OVERDOSAGE>> There were no reports of overdose during the clinical

development program of INVOKANA™ (canagliflozin).

In the event of an overdose, contact the Poison Control Center. It is also reasonable to employ the usual supportive measures, eg, remove unabsorbed material from the gastrointestinal tract, employ clinical monitoring, and institute supportive treatment as dictated by the patient’s clinical status. Canagliflozin was negligibly removed during a 4-hour hemodialysis session. Canagliflozin is not expected to be dialyzable by peritoneal dialysis.

ADVERSE REACTIONS>> The most common (≥5%) adverse reactions were female

genital mycotic infections, urinary tract infections, and increased urination. Adverse reactions in ≥2% of patients were male genital mycotic infections, vulvovaginal pruritis, thirst, nausea, and constipation.

Please see Brief Summary of full Prescribing Information on the following pages.

Canagliflozin is licensed from Mitsubishi Tanabe Pharma Corporation.

Janssen Pharmaceuticals, Inc.

IMPORTANT SAFETY INFORMATION (continued from first page)

© Janssen Pharmaceuticals, Inc. 2013 April 2013 K02CAN13075

K02C

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9


INVOKANA™(canagliflozin) tablets, for oral useBrief Summary of Prescribing Information.IndIcatIons and UsageINVOKANA™ (canagliflozin) is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus [see Clinical Studies (14) in full Prescribing Information].Limitation of Use: INVOKANA is not recommended in patients with type 1 diabetes mellitus or for the treatment of diabetic ketoacidosis.contraIndIcatIons• History of a serious hypersensitivity reaction to INVOKANA [see Warnings

and Precautions].• Severe renal impairment (eGFR less than 30 mL/min/1.73 m2), end stage

renal disease or patients on dialysis [see Warnings and Precautions and Use in Specific Populations].

WarnIngs and PrecaUtIonsHypotension: INVOKANA causes intravascular volume contraction. Symptomatic hypotension can occur after initiating INVOKANA [see Adverse Reactions] particularly in patients with impaired renal function (eGFR less than 60 mL/min/1.73 m2), elderly patients, patients on either diuretics or medications that interfere with the renin-angiotensin-aldosterone system (e.g., angiotensin-converting-enzyme [ACE] inhibitors, angiotensin receptor blockers [ARBs]), or patients with low systolic blood pressure. Before initiating INVOKANA in patients with one or more of these characteristics, volume status should be assessed and corrected. Monitor for signs and symptoms after initiating therapy.Impairment in renal Function: INVOKANA increases serum creatinine and decreases eGFR. Patients with hypovolemia may be more susceptible to these changes. Renal function abnormalities can occur after initiating INVOKANA [see Adverse Reactions]. More frequent renal function monitoring is recommended in patients with an eGFR below 60 mL/min/1.73 m2.Hyperkalemia: INVOKANA can lead to hyperkalemia. Patients with moderate renal impairment who are taking medications that interfere with potassium excretion, such as potassium-sparing diuretics, or medications that interfere with the renin-angiotensin-aldosterone system are more likely to develop hyperkalemia [see Adverse Reactions]. Monitor serum potassium levels periodically after initiating INVOKANA in patients with impaired renal function and in patients predisposed to hyperkalemia due to medications or other medical conditions. Hypoglycemia with concomitant Use with Insulin and Insulin secretagogues: Insulin and insulin secretagogues are known to cause hypoglycemia. INVOKANA can increase the risk of hypoglycemia when combined with insulin or an insulin secretagogue [see Adverse Reactions]. Therefore, a lower dose of insulin or insulin secretagogue may be required to minimize the risk of hypoglycemia when used in combination with INVOKANA.genital Mycotic Infections: INVOKANA increases the risk of genital mycotic infections. Patients with a history of genital mycotic infections and uncircumcised males were more likely to develop genital mycotic infections [see Adverse Reactions]. Monitor and treat appropriately.Hypersensitivity reactions: Hypersensitivity reactions (e.g., generalized urticaria), some serious, were reported with INVOKANA treatment; these reactions generally occurred within hours to days after initiating INVOKANA. If hypersensitivity reactions occur, discontinue use of INVOKANA; treat per standard of care and monitor until signs and symptoms resolve [see Contraindications and Adverse Reactions].Increases in Low-density Lipoprotein (LdL-c): Dose-related increases in LDL-C occur with INVOKANA [see Adverse Reactions]. Monitor LDL-C and treat per standard of care after initiating INVOKANA.Macrovascular outcomes: There have been no clinical studies establishing conclusive evidence of macrovascular risk reduction with INVOKANA or any other antidiabetic drug.adverse reactIonsThe following important adverse reactions are described below and elsewhere in the labeling:• Hypotension [see Warnings and Precautions]• Impairment in Renal Function [see Warnings and Precautions]• Hyperkalemia [see Warnings and Precautions]• Hypoglycemia with Concomitant Use with Insulin and Insulin

Secretagogues [see Warnings and Precautions]• Genital Mycotic Infections [see Warnings and Precautions]• Hypersensitivity Reactions [see Warnings and Precautions]• Increases in Low-Density Lipoprotein (LDL-C) [see Warnings and

Precautions]clinical studies experience: Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to the rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.Pool of Placebo-Controlled Trials: The data in Table 1 is derived from four 26-week placebo-controlled trials. In one trial INVOKANA was used as monotherapy and in three trials INVOKANA was used as add-on therapy [see Clinical Studies (14) in full Prescribing Information]. These data reflect exposure of 1667 patients to INVOKANA and a mean duration of exposure to

INVOKANA of 24 weeks. Patients received INVOKANA 100 mg (N=833), INVOKANA 300 mg (N=834) or placebo (N=646) once daily. The mean age of the population was 56 years and 2% were older than 75 years of age. Fifty percent (50%) of the population was male and 72% were Caucasian, 12% were Asian, and 5% were Black or African American. At baseline the population had diabetes for an average of 7.3 years, had a mean HbA1C of 8.0% and 20% had established microvascular complications of diabetes. Baseline renal function was normal or mildly impaired (mean eGFR 88 mL/min/1.73 m2). Table 1 shows common adverse reactions associated with the use of INVOKANA. These adverse reactions were not present at baseline, occurred more commonly on INVOKANA than on placebo, and occurred in at least 2% of patients treated with either INVOKANA 100 mg or INVOKANA 300 mg. table 1: adverse reactions From Pool of Four 26−Week Placebo-controlled

studies reported in ≥ 2% of InvoKana-treated Patients*

Adverse ReactionPlacebon=646

InvoKana100 mgn=833

InvoKana300 mgn=834

Female genital mycotic infections†

3.2% 10.4% 11.4%

Urinary tract infections‡ 4.0% 5.9% 4.3%Increased urination§ 0.8% 5.3% 4.6%Male genital mycotic infections¶

0.6% 4.2% 3.7%

Vulvovaginal pruritus 0.0% 1.6% 3.0%Thirst# 0.2% 2.8% 2.3%Constipation 0.9% 1.8% 2.3%Nausea 1.5% 2.2% 2.3%

* The four placebo-controlled trials included one monotherapy trial and three add-on combination trials with metformin, metformin and sulfonylurea, or metformin and pioglitazone.

† Female genital mycotic infections include the following adverse reactions: Vulvovaginal candidiasis, Vulvovaginal mycotic infection, Vulvovaginitis, Vaginal infection, Vulvitis, and Genital infection fungal. Percentages calculated with the number of female subjects in each group as denominator: placebo (N=312), INVOKANA 100 mg (N=425), and INVOKANA 300 mg (N=430).

‡ Urinary tract infections includes the following adverse reactions: Urinary tract infection, Cystitis, Kidney infection, and Urosepsis.

§ Increased urination includes the following adverse reactions: Polyuria, Pollakiuria, Urine output increased, Micturition urgency, and Nocturia.

¶ Male genital mycotic infections include the following adverse reactions: Balanitis or Balanoposthitis, Balanitis candida, and Genital infection fungal. Percentages calculated with the number of male subjects in each group as denominator: placebo (N=334), INVOKANA 100 mg (N=408), and INVOKANA 300 mg (N=404).

# Thirst includes the following adverse reactions: Thirst, Dry mouth, and Polydipsia.

Abdominal pain was also more commonly reported in patients taking INVOKANA 100 mg (1.8%), 300 mg (1.7%) than in patients taking placebo (0.8%). Pool of Placebo- and Active-Controlled Trials: The occurrence of adverse reactions was also evaluated in a larger pool of patients participating in placebo- and active-controlled trials.The data combined eight clinical trials [see Clinical Studies (14) in full Prescribing Information] and reflect exposure of 6177 patients to INVOKANA. The mean duration of exposure to INVOKANA was 38 weeks with 1832 individuals exposed to INVOKANA for greater than 50 weeks. Patients received INVOKANA 100 mg (N=3092), INVOKANA 300 mg (N=3085) or comparator (N=3262) once daily. The mean age of the population was 60 years and 5% were older than 75 years of age. Fifty-eight percent (58%) of the population was male and 73% were Caucasian, 16% were Asian, and 4% were Black or African American. At baseline, the population had diabetes for an average of 11 years, had a mean HbA1C of 8.0% and 33% had established microvascular complications of diabetes. Baseline renal function was normal or mildly impaired (mean eGFR 81 mL/min/1.73 m2).The types and frequency of common adverse reactions observed in the pool of eight clinical trials were consistent with those listed in Table 1. In this pool, INVOKANA was also associated with the adverse reactions of fatigue (1.7% with comparator, 2.2% with INVOKANA 100 mg, and 2.0% with INVOKANA 300 mg) and loss of strength or energy (i.e., asthenia) (0.6% with comparator, 0.7% with INVOKANA 100 mg and 1.1% with INVOKANA 300 mg).In the pool of eight clinical trials, the incidence rate of pancreatitis (acute or chronic) was 0.9, 2.7, and 0.9 per 1000 patient-years of exposure to comparator, INVOKANA 100 mg, and INVOKANA 300 mg, respectively.In the pool of eight clinical trials with a longer mean duration of exposure to INVOKANA (68 weeks), the incidence rate of bone fracture was 14.2, 18.7, and 17.6 per 1000 patient years of exposure to comparator, INVOKANA

INVOKANA™ (canagliflozin) tablets


100 mg, and INVOKANA 300 mg, respectively. Upper extremity fractures occurred more commonly on INVOKANA than comparator.In the pool of eight clinical trials, hypersensitivity-related adverse reactions (including erythema, rash, pruritus, urticaria, and angioedema) occurred in 3.0%, 3.8%, and 4.2% of patients receiving comparator, INVOKANA 100 mg and INVOKANA 300 mg, respectively. Five patients experienced serious adverse reactions of hypersensitivity with INVOKANA, which included 4 patients with urticaria and 1 patient with a diffuse rash and urticaria occurring within hours of exposure to INVOKANA. Among these patients, 2 patients discontinued INVOKANA. One patient with urticaria had recurrence when INVOKANA was re-initiated.Photosensitivity-related adverse reactions (including photosensitivity reaction, polymorphic light eruption, and sunburn) occurred in 0.1%, 0.2%, and 0.2% of patients receiving comparator, INVOKANA 100 mg, and INVOKANA 300 mg, respectively.Other adverse reactions occurring more frequently on INVOKANA than on comparator were:Volume Depletion-Related Adverse Reactions: INVOKANA results in an osmotic diuresis, which may lead to reductions in intravascular volume. In clinical studies, treatment with INVOKANA was associated with a dose-dependent increase in the incidence of volume depletion-related adverse reactions (e.g., hypotension, postural dizziness, orthostatic hypotension, syncope, and dehydration). An increased incidence was observed in patients on the 300 mg dose. The three factors associated with the largest increase in volume depletion-related adverse reactions were the use of loop diuretics, moderate renal impairment (eGFR 30 to less than 60 mL/min/1.73 m2) and age 75 years and older (Table 2) [see Dosage and Administration (2.2) in full Prescribing Information, Warnings and Precautions, and Use in Specific Populations].table 2: Proportion of Patients With at Least one volume depletion-related

adverse reactions (Pooled results from 8 clinical trials)

Baseline characteristic

comparator group*

%

InvoKana 100 mg

%

InvoKana 300 mg

%Overall population 1.5% 2.3% 3.4%75 years of age and older† 2.6% 4.9% 8.7%eGFR less than 60 mL/min/1.73 m2† 2.5% 4.7% 8.1%Use of loop diuretic† 4.7% 3.2% 8.8%

* Includes placebo and active-comparator groups† Patients could have more than 1of the listed risk factorsImpairment in Renal Function: INVOKANA is associated with a dose-dependent increase in serum creatinine and a concomitant fall in estimated GFR (Table 3). Patients with moderate renal impairment at baseline had larger mean changes.table 3: changes in serum creatinine and egFr associated with

InvoKana in the Pool of Four Placebo-controlled trials and Moderate renal Impairment trial

Placebon=646

InvoKana 100 mgn=833

InvoKana 300 mgn=834

Pool of Four Placebo-Controlled Trials

BaselineCreatinine (mg/dL) 0.84 0.82 0.82

eGFR (mL/min/1.73 m2) 87.0 88.3 88.8

Week 6 Change

Creatinine (mg/dL) 0.01 0.03 0.05eGFR (mL/min/1.73 m2) -1.6 -3.8 -5.0

End of Treatment Change*

Creatinine (mg/dL) 0.01 0.02 0.03

eGFR (mL/min/1.73 m2) -1.6 -2.3 -3.4

Placebon=90

InvoKana 100 mgn=90

InvoKana 300 mgn=89

Moderate Renal Impairment Trial

Baseline Creatinine (mg/dL) 1.61 1.62 1.63eGFR (mL/min/1.73 m2) 40.1 39.7 38.5

Week 3 Change

Creatinine (mg/dL) 0.03 0.18 0.28eGFR (mL/min/1.73 m2) -0.7 -4.6 -6.2

End of Treatment Change*

Creatinine (mg/dL) 0.07 0.16 0.18

eGFR (mL/min/1.73 m2) -1.5 -3.6 -4.0

* Week 26 in mITT LOCF populationIn the pool of four placebo-controlled trials where patients had normal or mildly impaired baseline renal function, the proportion of patients who experienced at least one event of significant renal function decline, defined as an eGFR below 80 mL/min/1.73 m2 and 30% lower than baseline, was 2.1% with placebo, 2.0% with INVOKANA 100 mg, and 4.1% with INVOKANA 300 mg. At the end of treatment, 0.5% with placebo, 0.7% with INVOKANA 100 mg, and 1.4% with INVOKANA 300 mg had a significant renal function decline.

In a trial carried out in patients with moderate renal impairment with a baseline eGFR of 30 to less than 50 mL/min/1.73 m2 (mean baseline eGFR 39 mL/min/1.73 m2) [see Clinical Studies (14.3) in full Prescribing Information], the proportion of patients who experienced at least one event of significant renal function decline, defined as an eGFR 30% lower than baseline, was 6.9% with placebo, 18% with INVOKANA 100 mg, and 22.5% with INVOKANA 300 mg. At the end of treatment, 4.6% with placebo, 3.4% with INVOKANA 100 mg, and 3.4% with INVOKANA 300 mg had a significant renal function decline. In a pooled population of patients with moderate renal impairment (N=1085) with baseline eGFR of 30 to less than 60 mL/min/1.73 m2 (mean baseline eGFR 48 mL/min/1.73 m2), the overall incidence of these events was lower than in the dedicated trial but a dose-dependent increase in incident episodes of significant renal function decline compared to placebo was still observed.Use of INVOKANA was associated with an increased incidence of renal-related adverse reactions (e.g., increased blood creatinine, decreased glomerular filtration rate, renal impairment, and acute renal failure), particularly in patients with moderate renal impairment.In the pooled analysis of patients with moderate renal impairment, the incidence of renal-related adverse reactions was 3.7% with placebo, 8.9% with INVOKANA 100 mg, and 9.3% with INVOKANA 300 mg. Discontinuations due to renal-related adverse events occurred in 1.0% with placebo, 1.2% with INVOKANA 100 mg, and 1.6% with INVOKANA 300 mg [see Warnings and Precautions].Genital Mycotic Infections: In the pool of four placebo-controlled clinical trials, female genital mycotic infections (e.g., vulvovaginal mycotic infection, vulvovaginal candidiasis, and vulvovaginitis) occurred in 3.2%, 10.4%, and 11.4% of females treated with placebo, INVOKANA 100 mg, and INVOKANA 300 mg, respectively. Patients with a history of genital mycotic infections were more likely to develop genital mycotic infections on INVOKANA. Female patients who developed genital mycotic infections on INVOKANA were more likely to experience recurrence and require treatment with oral or topical antifungal agents and anti-microbial agents [see Warnings and Precautions].In the pool of four placebo-controlled clinical trials, male genital mycotic infections (e.g., candidal balanitis, balanoposthitis) occurred in 0.6%, 4.2%, and 3.7% of males treated with placebo, INVOKANA 100 mg, and INVOKANA 300 mg, respectively. Male genital mycotic infections occurred more commonly in uncircumcised males and in males with a prior history of balanitis or balanoposthitis. Male patients who developed genital mycotic infections on INVOKANA were more likely to experience recurrent infections (22% on INVOKANA versus none on placebo), and require treatment with oral or topical antifungal agents and anti-microbial agents than patients on comparators. In the pooled analysis of 8 controlled trials, phimosis was reported in 0.3% of uncircumcised male patients treated with INVOKANA and 0.2% required circumcision to treat the phimosis [see Warnings and Precautions].Hypoglycemia: In all clinical trials, hypoglycemia was defined as any event regardless of symptoms, where biochemical hypoglycemia was documented (any glucose value below or equal to 70 mg/dL). Severe hypoglycemia was defined as an event consistent with hypoglycemia where the patient required the assistance of another person to recover, lost consciousness, or experienced a seizure (regardless of whether biochemical documentation of a low glucose value was obtained). In individual clinical trials [see Clinical Studies (14) in full Prescribing Information], episodes of hypoglycemia occurred at a higher rate when INVOKANA was co-administered with insulin or sulfonylureas (Table 4) [see Warnings and Precautions].table 4: Incidence of Hypoglycemia* in controlled clinical studiesMonotherapy(26 weeks)

Placebo(n=192)

InvoKana 100 mg(n=195)


Overall [N (%)] 5 (2.6) 7 (3.6) 6 (3.0)In combination with Metformin(26 weeks)

Placebo + Metformin

(n=183)

InvoKana 100 mg + Metformin

(n=368)


(n=367)

Overall [N (%)] 3 (1.6) 16 (4.3) 17 (4.6)Severe [N (%)]† 0 (0) 1 (0.3) 1 (0.3)In combination with Metformin(52 weeks)

glimepiride + Metformin

(n=482)


(n=483)


(n=485)Overall [N (%)] 165 (34.2) 27 (5.6) 24 (4.9)Severe [N (%)]† 15 (3.1) 2 (0.4) 3 (0.6)In combination with sulfonylurea(18 weeks)

Placebo + sulfonylurea

(n=69)

InvoKana 100 mg+ sulfonylurea

(n=74)

InvoKana 300 mg+ sulfonylurea

(n=72)Overall [N (%)] 4 (5.8) 3 (4.1) 9 (12.5)In combination with Metformin + sulfonylurea(26 weeks)

Placebo + Metformin + sulfonylurea

(n=156)


+ sulfonylurea(n=157)

InvoKana 300 mg + Metformin + sulfonylurea

(n=156)Overall [N (%)] 24 (15.4) 43 (27.4) 47 (30.1)Severe [N (%)]† 1 (0.6) 1 (0.6) 0

INVOKANA™ (canagliflozin) tablets INVOKANA™ (canagliflozin) tablets


table 4: Incidence of Hypoglycemia* in controlled clinical studies (continued)

In combination with Metformin + sulfonylurea(52 weeks)

sitagliptin + Metformin + sulfonylurea

(n=378)


(n=377)Overall [N (%)] 154 (40.7) 163 (43.2)Severe [N (%)]† 13 (3.4) 15 (4.0)In combination with Metformin + Pioglitazone(26 weeks)

Placebo + Metformin + Pioglitazone

(n=115)

InvoKana 100 mg + Metformin + Pioglitazone

(n=113)


(n=114)Overall [N (%)] 3 (2.6) 3 (2.7) 6 (5.3)In combination with Insulin(18 weeks)

Placebo(n=565)



Overall [N (%)] 208 (36.8) 279 (49.3) 285 (48.6)Severe [N (%)]† 14 (2.5) 10 (1.8) 16 (2.7)

* Number of patients experiencing at least one event of hypoglycemia based on either biochemically documented episodes or severe hypoglycemic events in the intent-to-treat population

† Severe episodes of hypoglycemia were defined as those where the patient required the assistance of another person to recover, lost consciousness, or experienced a seizure (regardless of whether biochemical documentation of a low glucose value was obtained)

Laboratory Tests: Increases in Serum Potassium: Dose-related, transient mean increases in serum potassium were observed early after initiation of INVOKANA (i.e., within 3 weeks) in a trial of patients with moderate renal impairment [see Clinical Studies (14.3) in full Prescribing Information]. In this trial, increases in serum potassium of greater than 5.4 mEq/L and 15% above baseline occurred in 16.1%, 12.4%, and 27.0% of patients treated with placebo, INVOKANA 100 mg, and INVOKANA 300 mg, respectively. More severe elevations (i.e., equal or greater than 6.5 mEq/L) occurred in 1.1%, 2.2%, and 2.2% of patients treated with placebo, INVOKANA 100 mg, and INVOKANA 300 mg, respectively. In patients with moderate renal impairment, increases in potassium were more commonly seen in those with elevated potassium at baseline and in those using medications that reduce potassium excretion, such as potassium-sparing diuretics, angiotensin-converting-enzyme inhibitors, and angiotensin-receptor blockers [see Warnings and Precautions].Increases in Serum Magnesium: Dose-related increases in serum magnesium were observed early after initiation of INVOKANA (within 6 weeks) and remained elevated throughout treatment. In the pool of four placebo-controlled trials, the mean change in serum magnesium levels was 8.1% and 9.3% with INVOKANA 100 mg and INVOKANA 300 mg, respectively, compared to -0.6% with placebo. In a trial of patients with moderate renal impairment [see Clinical Studies (14.3) in full Prescribing Information], serum magnesium levels increased by 0.2%, 9.2%, and 14.8% with placebo, INVOKANA 100 mg, and INVOKANA 300 mg, respectively.Increases in Serum Phosphate: Dose-related increases in serum phosphate levels were observed with INVOKANA. In the pool of four placebo controlled trials, the mean change in serum phosphate levels were 3.6% and 5.1% with INVOKANA 100 mg and INVOKANA 300 mg, respectively, compared to 1.5% with placebo. In a trial of patients with moderate renal impairment [see Clinical Studies (14.3) in full Prescribing Information], the mean serum phosphate levels increased by 1.2%, 5.0%, and 9.3% with placebo, INVOKANA 100 mg, and INVOKANA 300 mg, respectively.Increases in Low-Density Lipoprotein Cholesterol (LDL-C) and non-High-Density Lipoprotein Cholesterol (non-HDL-C): In the pool of four placebo-controlled trials, dose-related increases in LDL-C with INVOKANA were observed. Mean changes (percent changes) from baseline in LDL-C relative to placebo were 4.4 mg/dL (4.5%) and 8.2 mg/dL (8.0%) with INVOKANA 100 mg and INVOKANA 300 mg, respectively. The mean baseline LDL-C levels were 104 to 110 mg/dL across treatment groups [see Warnings and Precautions].Dose-related increases in non-HDL-C with INVOKANA were observed. Mean changes (percent changes) from baseline in non-HDL-C relative to placebo were 2.1 mg/dL (1.5%) and 5.1 mg/dL (3.6%) with INVOKANA 100 mg and 300 mg, respectively. The mean baseline non-HDL-C levels were 140 to 147 mg/dL across treatment groups.Increases in Hemoglobin: In the pool of four placebo-controlled trials, mean changes (percent changes) from baseline in hemoglobin were -0.18 g/dL (-1.1%) with placebo, 0.47 g/dL (3.5%) with INVOKANA 100 mg, and 0.51 g/dL (3.8%) with INVOKANA 300 mg. The mean baseline hemoglobin value was approximately 14.1 g/dL across treatment groups. At the end of treatment, 0.8%, 4.0%, and 2.7% of patients treated with placebo, INVOKANA 100 mg, and INVOKANA 300 mg, respectively, had hemoglobin above the upper limit of normal.drUg InteractIonsUgt enzyme Inducers: Rifampin: Co-administration of canagliflozin with rifampin, a nonselective inducer of several UGT enzymes, including

UGT1A9, UGT2B4, decreased canagliflozin area under the curve (AUC) by 51%. This decrease in exposure to canagliflozin may decrease efficacy. If an inducer of these UGTs (e.g., rifampin, phenytoin, phenobarbital, ritonavir) must be co-administered with INVOKANA (canagliflozin), consider increasing the dose to 300 mg once daily if patients are currently tolerating INVOKANA 100 mg once daily, have an eGFR greater than 60 mL/min/1.73 m2, and require additional glycemic control. Consider other antihyperglycemic therapy in patients with an eGFR of 45 to less than 60 mL/min/1.73 m2 receiving concurrent therapy with a UGT inducer and require additional glycemic control [see Dosage and Administration (2.3) and Clinical Pharmacology (12.3) in full Prescribing Information].digoxin: There was an increase in the area AUC and mean peak drug concentration (Cmax) of digoxin (20% and 36%, respectively) when co-administered with INVOKANA 300 mg [see Clinical Pharmacology (12.3) in full Prescribing Information]. Patients taking INVOKANA with concomitant digoxin should be monitored appropriately.Use In sPecIFIc PoPULatIonsPregnancy: Teratogenic Effects: Pregnancy Category C: There are no adequate and well-controlled studies of INVOKANA in pregnant women. Based on results from rat studies, canagliflozin may affect renal development and maturation. In a juvenile rat study, increased kidney weights and renal pelvic and tubular dilatation were evident at greater than or equal to 0.5 times clinical exposure from a 300 mg dose [see Nonclinical Toxicology (13.2) in full Prescribing Information].These outcomes occurred with drug exposure during periods of animal development that correspond to the late second and third trimester of human development. During pregnancy, consider appropriate alternative therapies, especially during the second and third trimesters. INVOKANA should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.nursing Mothers: It is not known if INVOKANA is excreted in human milk. INVOKANA is secreted in the milk of lactating rats reaching levels 1.4 times higher than that in maternal plasma. Data in juvenile rats directly exposed to INVOKANA showed risk to the developing kidney (renal pelvic and tubular dilatations) during maturation. Since human kidney maturation occurs in utero and during the first 2 years of life when lactational exposure may occur, there may be risk to the developing human kidney. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from INVOKANA, a decision should be made whether to discontinue nursing or to discontinue INVOKANA, taking into account the importance of the drug to the mother [see Nonclinical Toxicology (13.2) in full Prescribing Information].Pediatric Use: Safety and effectiveness of INVOKANA in pediatric patients under 18 years of age have not been established.geriatric Use: Two thousand thirty-four (2034) patients 65 years and older, and 345 patients 75 years and older were exposed to INVOKANA in nine clinical studies of INVOKANA [see Clinical Studies (14.3) in full Prescribing Information]. Patients 65 years and older had a higher incidence of adverse reactions related to reduced intravascular volume with INVOKANA (such as hypotension, postural dizziness, ortho static hypotension, syncope, and dehydration), particularly with the 300 mg daily dose, compared to younger patients; more prominent increase in the incidence was seen in patients who were 75 years and older [see Dosage and Administration (2.1) in full Prescribing Information and Adverse Reactions]. Smaller reductions in HbA1C with INVOKANA relative to placebo were seen in older (65 years and older; -0.61% with INVOKANA 100 mg and -0.74% with INVOKANA 300 mg relative to placebo) compared to younger patients (-0.72% with INVOKANA 100 mg and -0.87% with INVOKANA 300 mg relative to placebo).renal Impairment: The efficacy and safety of INVOKANA were evaluated in a study that included patients with moderate renal impairment (eGFR 30 to less than 50 mL/min/1.73 m2) [see Clinical Studies (14.3) in full Prescribing Information]. These patients had less overall glycemic efficacy and had a higher occurrence of adverse reactions related to reduced intravascular volume, renal-related adverse reactions, and decreases in eGFR compared to patients with mild renal impairment or normal renal function (eGFR greater than or equal to 60 mL/min/1.73 m2); patients treated with INVOKANA 300 mg were more likely to experience increases in potassium [see Dosage and Administration (2.2) in full Prescribing Information, Warnings and Precautions, and Adverse Reactions].The efficacy and safety of INVOKANA have not been established in patients with severe renal impairment (eGFR less than 30 mL/min/1.73 m2), with ESRD, or receiving dialysis. INVOKANA is not expected to be effective in these patient populations [see Contraindications and Clinical Pharmacology (12.3) in full Prescribing Information].Hepatic Impairment: No dosage adjustment is necessary in patients with mild or moderate hepatic impairment. The use of INVOKANA has not been studied in patients with severe hepatic impairment and is therefore not recommended [see Clinical Pharmacology (12.3) in full Prescribing Information].



overdosageThere were no reports of overdose during the clinical development program of INVOKANA (canagliflozin).In the event of an overdose, contact the Poison Control Center. It is also reasonable to employ the usual supportive measures, e.g., remove unabsorbed material from the gastrointestinal tract, employ clinical monitoring, and institute supportive treatment as dictated by the patient’s clinical status. Canagliflozin was negligibly removed during a 4-hour hemodialysis session. Canagliflozin is not expected to be dialyzable by peritoneal dialysis.PatIent coUnseLIng InForMatIonSee FDA-approved patient labeling (Medication Guide).Instructions: Instruct patients to read the Medication Guide before starting INVOKANA (canagliflozin) therapy and to reread it each time the prescription is renewed.Inform patients of the potential risks and benefits of INVOKANA and of alternative modes of therapy. Also inform patients about the importance of adherence to dietary instructions, regular physical activity, periodic blood glucose monitoring and HbA1C testing, recognition and management of hypoglycemia and hyperglycemia, and assessment for diabetes complications. Advise patients to seek medical advice promptly during periods of stress such as fever, trauma, infection, or surgery, as medication requirements may change.Instruct patients to take INVOKANA only as prescribed. If a dose is missed, advise patients to take it as soon as it is remembered unless it is almost time for the next dose, in which case patients should skip the missed dose and take the medicine at the next regularly scheduled time. Advise patients not to take two doses of INVOKANA at the same time.Inform patients that the most common adverse reactions associated with INVOKANA are genital mycotic infection, urinary tract infection, and increased urination.Inform female patients of child bearing age that the use of INVOKANA during pregnancy has not been studied in humans, and that INVOKANA should only be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Instruct patients to report pregnancies to their physicians as soon as possible.Inform nursing mothers to discontinue INVOKANA or nursing, taking into account the importance of drug to the mother.Laboratory Tests: Due to its mechanism of action, patients taking INVOKANA will test positive for glucose in their urine.Hypotension: Inform patients that symptomatic hypotension may occur with INVOKANA and advise them to contact their doctor if they experience such symptoms [see Warnings and Precautions]. Inform patients that dehydration may increase the risk for hypotension, and to have adequate fluid intake.Genital Mycotic Infections in Females (e.g., Vulvovaginitis): Inform female patients that vaginal yeast infection may occur and provide them with information on the signs and symptoms of vaginal yeast infection. Advise them of treatment options and when to seek medical advice [see Warnings and Precautions].Genital Mycotic Infections in Males (e.g., Balanitis or Balanoposthitis): Inform male patients that yeast infection of penis (e.g., balanitis or balanoposthitis) may occur, especially in uncircumcised males and patients with prior history. Provide them with information on the signs and symptoms of balanitis and balanoposthitis (rash or redness of the glans or foreskin of the penis). Advise them of treatment options and when to seek medical advice [see Warnings and Precautions].Hypersensitivity Reactions: Inform patients that serious hypersensitivity reactions such as urticaria and rash have been reported with INVOKANA. Advise patients to report immediately any signs or symptoms suggesting allergic reaction or angioedema, and to take no more drug until they have consulted prescribing physicians.Urinary Tract Infections: Inform patients of the potential for urinary tract infections. Provide them with information on the symptoms of urinary tract infections. Advise them to seek medical advice if such symptoms occur.Active ingredient made in BelgiumFinished product manufactured by:Janssen Ortho, LLCGurabo, PR 00778Manufactured for:Janssen Pharmaceuticals, Inc.Titusville, NJ 08560Licensed from Mitsubishi Tanabe Pharma Corporation© 2013 Janssen Pharmaceuticals, Inc.10282400K02CAN13080B



table 4: Incidence of Hypoglycemia* in controlled clinical studies (continued)

In combination with Metformin + sulfonylurea(52 weeks)

sitagliptin + Metformin + sulfonylurea

(n=378)


(n=377)Overall [N (%)] 154 (40.7) 163 (43.2)Severe [N (%)]† 13 (3.4) 15 (4.0)In combination with Metformin + Pioglitazone(26 weeks)

Placebo + Metformin + Pioglitazone

(n=115)


(n=113)


(n=114)Overall [N (%)] 3 (2.6) 3 (2.7) 6 (5.3)In combination with Insulin(18 weeks)

Placebo(n=565)



Overall [N (%)] 208 (36.8) 279 (49.3) 285 (48.6)Severe [N (%)]† 14 (2.5) 10 (1.8) 16 (2.7)

* Number of patients experiencing at least one event of hypoglycemia based on either biochemically documented episodes or severe hypoglycemic events in the intent-to-treat population

† Severe episodes of hypoglycemia were defined as those where the patient required the assistance of another person to recover, lost consciousness, or experienced a seizure (regardless of whether biochemical documentation of a low glucose value was obtained)

Laboratory Tests: Increases in Serum Potassium: Dose-related, transient mean increases in serum potassium were observed early after initiation of INVOKANA (i.e., within 3 weeks) in a trial of patients with moderate renal impairment [see Clinical Studies (14.3) in full Prescribing Information]. In this trial, increases in serum potassium of greater than 5.4 mEq/L and 15% above baseline occurred in 16.1%, 12.4%, and 27.0% of patients treated with placebo, INVOKANA 100 mg, and INVOKANA 300 mg, respectively. More severe elevations (i.e., equal or greater than 6.5 mEq/L) occurred in 1.1%, 2.2%, and 2.2% of patients treated with placebo, INVOKANA 100 mg, and INVOKANA 300 mg, respectively. In patients with moderate renal impairment, increases in potassium were more commonly seen in those with elevated potassium at baseline and in those using medications that reduce potassium excretion, such as potassium-sparing diuretics, angiotensin-converting-enzyme inhibitors, and angiotensin-receptor blockers [see Warnings and Precautions].Increases in Serum Magnesium: Dose-related increases in serum magnesium were observed early after initiation of INVOKANA (within 6 weeks) and remained elevated throughout treatment. In the pool of four placebo-controlled trials, the mean change in serum magnesium levels was 8.1% and 9.3% with INVOKANA 100 mg and INVOKANA 300 mg, respectively, compared to -0.6% with placebo. In a trial of patients with moderate renal impairment [see Clinical Studies (14.3) in full Prescribing Information], serum magnesium levels increased by 0.2%, 9.2%, and 14.8% with placebo, INVOKANA 100 mg, and INVOKANA 300 mg, respectively.Increases in Serum Phosphate: Dose-related increases in serum phosphate levels were observed with INVOKANA. In the pool of four placebo controlled trials, the mean change in serum phosphate levels were 3.6% and 5.1% with INVOKANA 100 mg and INVOKANA 300 mg, respectively, compared to 1.5% with placebo. In a trial of patients with moderate renal impairment [see Clinical Studies (14.3) in full Prescribing Information], the mean serum phosphate levels increased by 1.2%, 5.0%, and 9.3% with placebo, INVOKANA 100 mg, and INVOKANA 300 mg, respectively.Increases in Low-Density Lipoprotein Cholesterol (LDL-C) and non-High-Density Lipoprotein Cholesterol (non-HDL-C): In the pool of four placebo-controlled trials, dose-related increases in LDL-C with INVOKANA were observed. Mean changes (percent changes) from baseline in LDL-C relative to placebo were 4.4 mg/dL (4.5%) and 8.2 mg/dL (8.0%) with INVOKANA 100 mg and INVOKANA 300 mg, respectively. The mean baseline LDL-C levels were 104 to 110 mg/dL across treatment groups [see Warnings and Precautions].Dose-related increases in non-HDL-C with INVOKANA were observed. Mean changes (percent changes) from baseline in non-HDL-C relative to placebo were 2.1 mg/dL (1.5%) and 5.1 mg/dL (3.6%) with INVOKANA 100 mg and 300 mg, respectively. The mean baseline non-HDL-C levels were 140 to 147 mg/dL across treatment groups.Increases in Hemoglobin: In the pool of four placebo-controlled trials, mean changes (percent changes) from baseline in hemoglobin were -0.18 g/dL (-1.1%) with placebo, 0.47 g/dL (3.5%) with INVOKANA 100 mg, and 0.51 g/dL (3.8%) with INVOKANA 300 mg. The mean baseline hemoglobin value was approximately 14.1 g/dL across treatment groups. At the end of treatment, 0.8%, 4.0%, and 2.7% of patients treated with placebo, INVOKANA 100 mg, and INVOKANA 300 mg, respectively, had hemoglobin above the upper limit of normal.drUg InteractIonsUgt enzyme Inducers: Rifampin: Co-administration of canagliflozin with rifampin, a nonselective inducer of several UGT enzymes, including

UGT1A9, UGT2B4, decreased canagliflozin area under the curve (AUC) by 51%. This decrease in exposure to canagliflozin may decrease efficacy. If an inducer of these UGTs (e.g., rifampin, phenytoin, phenobarbital, ritonavir) must be co-administered with INVOKANA (canagliflozin), consider increasing the dose to 300 mg once daily if patients are currently tolerating INVOKANA 100 mg once daily, have an eGFR greater than 60 mL/min/1.73 m2, and require additional glycemic control. Consider other antihyperglycemic therapy in patients with an eGFR of 45 to less than 60 mL/min/1.73 m2 receiving concurrent therapy with a UGT inducer and require additional glycemic control [see Dosage and Administration (2.3) and Clinical Pharmacology (12.3) in full Prescribing Information].digoxin: There was an increase in the area AUC and mean peak drug concentration (Cmax) of digoxin (20% and 36%, respectively) when co-administered with INVOKANA 300 mg [see Clinical Pharmacology (12.3) in full Prescribing Information]. Patients taking INVOKANA with concomitant digoxin should be monitored appropriately.Use In sPecIFIc PoPULatIonsPregnancy: Teratogenic Effects: Pregnancy Category C: There are no adequate and well-controlled studies of INVOKANA in pregnant women. Based on results from rat studies, canagliflozin may affect renal development and maturation. In a juvenile rat study, increased kidney weights and renal pelvic and tubular dilatation were evident at greater than or equal to 0.5 times clinical exposure from a 300 mg dose [see Nonclinical Toxicology (13.2) in full Prescribing Information].These outcomes occurred with drug exposure during periods of animal development that correspond to the late second and third trimester of human development. During pregnancy, consider appropriate alternative therapies, especially during the second and third trimesters. INVOKANA should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.nursing Mothers: It is not known if INVOKANA is excreted in human milk. INVOKANA is secreted in the milk of lactating rats reaching levels 1.4 times higher than that in maternal plasma. Data in juvenile rats directly exposed to INVOKANA showed risk to the developing kidney (renal pelvic and tubular dilatations) during maturation. Since human kidney maturation occurs in utero and during the first 2 years of life when lactational exposure may occur, there may be risk to the developing human kidney. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from INVOKANA, a decision should be made whether to discontinue nursing or to discontinue INVOKANA, taking into account the importance of the drug to the mother [see Nonclinical Toxicology (13.2) in full Prescribing Information].Pediatric Use: Safety and effectiveness of INVOKANA in pediatric patients under 18 years of age have not been established.geriatric Use: Two thousand thirty-four (2034) patients 65 years and older, and 345 patients 75 years and older were exposed to INVOKANA in nine clinical studies of INVOKANA [see Clinical Studies (14.3) in full Prescribing Information]. Patients 65 years and older had a higher incidence of adverse reactions related to reduced intravascular volume with INVOKANA (such as hypotension, postural dizziness, ortho static hypotension, syncope, and dehydration), particularly with the 300 mg daily dose, compared to younger patients; more prominent increase in the incidence was seen in patients who were 75 years and older [see Dosage and Administration (2.1) in full Prescribing Information and Adverse Reactions]. Smaller reductions in HbA1C with INVOKANA relative to placebo were seen in older (65 years and older; -0.61% with INVOKANA 100 mg and -0.74% with INVOKANA 300 mg relative to placebo) compared to younger patients (-0.72% with INVOKANA 100 mg and -0.87% with INVOKANA 300 mg relative to placebo).renal Impairment: The efficacy and safety of INVOKANA were evaluated in a study that included patients with moderate renal impairment (eGFR 30 to less than 50 mL/min/1.73 m2) [see Clinical Studies (14.3) in full Prescribing Information]. These patients had less overall glycemic efficacy and had a higher occurrence of adverse reactions related to reduced intravascular volume, renal-related adverse reactions, and decreases in eGFR compared to patients with mild renal impairment or normal renal function (eGFR greater than or equal to 60 mL/min/1.73 m2); patients treated with INVOKANA 300 mg were more likely to experience increases in potassium [see Dosage and Administration (2.2) in full Prescribing Information, Warnings and Precautions, and Adverse Reactions].The efficacy and safety of INVOKANA have not been established in patients with severe renal impairment (eGFR less than 30 mL/min/1.73 m2), with ESRD, or receiving dialysis. INVOKANA is not expected to be effective in these patient populations [see Contraindications and Clinical Pharmacology (12.3) in full Prescribing Information].Hepatic Impairment: No dosage adjustment is necessary in patients with mild or moderate hepatic impairment. The use of INVOKANA has not been studied in patients with severe hepatic impairment and is therefore not recommended [see Clinical Pharmacology (12.3) in full Prescribing Information].



overdosageThere were no reports of overdose during the clinical development program of INVOKANA (canagliflozin).In the event of an overdose, contact the Poison Control Center. It is also reasonable to employ the usual supportive measures, e.g., remove unabsorbed material from the gastrointestinal tract, employ clinical monitoring, and institute supportive treatment as dictated by the patient’s clinical status. Canagliflozin was negligibly removed during a 4-hour hemodialysis session. Canagliflozin is not expected to be dialyzable by peritoneal dialysis.PatIent coUnseLIng InForMatIonSee FDA-approved patient labeling (Medication Guide).Instructions: Instruct patients to read the Medication Guide before starting INVOKANA (canagliflozin) therapy and to reread it each time the prescription is renewed.Inform patients of the potential risks and benefits of INVOKANA and of alternative modes of therapy. Also inform patients about the importance of adherence to dietary instructions, regular physical activity, periodic blood glucose monitoring and HbA1C testing, recognition and management of hypoglycemia and hyperglycemia, and assessment for diabetes complications. Advise patients to seek medical advice promptly during periods of stress such as fever, trauma, infection, or surgery, as medication requirements may change.Instruct patients to take INVOKANA only as prescribed. If a dose is missed, advise patients to take it as soon as it is remembered unless it is almost time for the next dose, in which case patients should skip the missed dose and take the medicine at the next regularly scheduled time. Advise patients not to take two doses of INVOKANA at the same time.Inform patients that the most common adverse reactions associated with INVOKANA are genital mycotic infection, urinary tract infection, and increased urination.Inform female patients of child bearing age that the use of INVOKANA during pregnancy has not been studied in humans, and that INVOKANA should only be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Instruct patients to report pregnancies to their physicians as soon as possible.Inform nursing mothers to discontinue INVOKANA or nursing, taking into account the importance of drug to the mother.Laboratory Tests: Due to its mechanism of action, patients taking INVOKANA will test positive for glucose in their urine.Hypotension: Inform patients that symptomatic hypotension may occur with INVOKANA and advise them to contact their doctor if they experience such symptoms [see Warnings and Precautions]. Inform patients that dehydration may increase the risk for hypotension, and to have adequate fluid intake.Genital Mycotic Infections in Females (e.g., Vulvovaginitis): Inform female patients that vaginal yeast infection may occur and provide them with information on the signs and symptoms of vaginal yeast infection. Advise them of treatment options and when to seek medical advice [see Warnings and Precautions].Genital Mycotic Infections in Males (e.g., Balanitis or Balanoposthitis): Inform male patients that yeast infection of penis (e.g., balanitis or balanoposthitis) may occur, especially in uncircumcised males and patients with prior history. Provide them with information on the signs and symptoms of balanitis and balanoposthitis (rash or redness of the glans or foreskin of the penis). Advise them of treatment options and when to seek medical advice [see Warnings and Precautions].Hypersensitivity Reactions: Inform patients that serious hypersensitivity reactions such as urticaria and rash have been reported with INVOKANA. Advise patients to report immediately any signs or symptoms suggesting allergic reaction or angioedema, and to take no more drug until they have consulted prescribing physicians.Urinary Tract Infections: Inform patients of the potential for urinary tract infections. Provide them with information on the symptoms of urinary tract infections. Advise them to seek medical advice if such symptoms occur.Active ingredient made in BelgiumFinished product manufactured by:Janssen Ortho, LLCGurabo, PR 00778Manufactured for:Janssen Pharmaceuticals, Inc.Titusville, NJ 08560Licensed from Mitsubishi Tanabe Pharma Corporation© 2013 Janssen Pharmaceuticals, Inc.10282400K02CAN13080B



JCEMJCEMJCEMJCEMJCEMJCEMTHE JOURNAL

OF CLINICAL

ENDOCRINOLOGY

& METABOLISM

MAY 2013 • VoluMe 98 • NuMber 05

www.endo-society.org

5.967Impact Factor2

011

JCEM: 5.967

The Endocrine Society is seeking candidates for the position of Editor-in-Chief of the Journal of Endocrinology & Metabolism (JCEM ) for a 5-year term beginning January 1, 2015. Applicants will have an opportunity to work with an outstanding editorial team to direct the world’s leading peer-reviewed journal for clinical research and practice reviews in endocrinology. All members of The Endocrine Society are encouraged to suggest the names of potential candidates by contacting Scott Herman, Group Managing Editor – Associate Director, Publications for The Endocrine Society, at [email protected]. Please submit your suggestions by August 30, 2013.

For more information, visit www.endocrine.org/jcemeic

Call for Nominations

Visit JCEM Focus to Get the Best Information on

Diabetes and Thyroid

Stay Focused with New Microsites from JCEM

Simply visit jcem.endojournals.org and click Diabetes Focus, Thyroid Focus, or Bone/Calcium Focus to fi nd information relevant to your area of interest.

New microsites from Endocrinology, Endocrine Reviews, and Molecular Endocrinology will also be launching soon.

Focus to Get the Best Information on

Diabetes and Thyroid

If you are interested in submitting classified advertising to Endocrine News,

please contact Christine Whorton at [email protected] or 800-361-3906.

OCHSNER HEALTH SYSTEM in New Orleans is

searching for a BC/BE ENDOCRINOLOGIST to join our staff at Ochsner Baptist Medical Center.

Candidates with experience or directly from training

are welcomed to apply. Areas of interest should include

general endocrine disorders, diabetes, and endocrine

disorders as related to pregnancy. This position is

mainly outpatient based, but will serve a large Ob/Gyn

group with significant inpatient consultation. Salary is

competitive and commensurate with experience and

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Ochsner Baptist Medical Center, with a deep-rooted

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physicians. We have all private rooms, an ICU, 13

operating rooms, and a state-of-the art imaging center.

We are proud to be distinguished by our excellence

in specialty care and high patient satisfaction scores.

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department is staffed by a team of board-certified ER

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The Ochsner Health System comprises 8 hospitals and

more than 38 clinics across southeast Louisiana with

over 1.5 million clinic patient visits annually. Ochsner is

a major provider of graduate medical education with 23

ACGME-accredited residency and fellowship programs,

including our Endocrinology Fellowship Program. Please

visit our Web site at

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New Orleans is a cosmopolitan, historic city with a

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Please email CV to: [email protected], Ref. # ABENDO1 or call 800-488-2240 for more information. EOE.

Sorry, no J-1 visa opportunities available.

ENDOCRINOLOGIST

CLASSIFIEDS

40

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Put the power of The Endocrine Society behind your recruiting efforts and take advantage of our• Free CV Database• Print, Web, and Bulk Advertising• Free Tips/How-To Resources

Christine Whorton, EndoCareers®

[email protected]

wE offEr ThE best pricing andrESulTS you will find anywhErE

www.endocareers.org

cont

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Put the power of The Endocrine Society behind your recruiting efforts and take advantage of our• Free CV Database• Print, Web, and Bulk Advertising• Free Tips/How-To Resources

Christine Whorton, EndoCareers®

[email protected]

wE offEr ThE best pricing andrESulTS you will find anywhErE

www.endocareers.org

cont

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Gundersen Lutheran Medical Center, Inc. | Gundersen Clinic, Ltd.

The Department of Pediatrics at Gundersen Health System based inLa Crosse, Wis, is seeking a part-time board certified/board eligiblePediatric Endocrinologist to join our existing pediatric endocrinolo-gist. A team approach is taken with diabetes patients, which includescertified diabetes nurse educators, nurse clinicians and a nutritionist.

Practice highlights:• Wonderful team of diabetes educators and endocrine nurses• Opportunities for medical education, and clinical research• Services currently offered include care of children with Diabetes

and a wide array of endocrine problems including disorders of growth and puberty, thyroid disease and bone disease

Paula Stoner, Medical Staff [email protected]/medcareersEOE/AA/LEP

A LANDSCAPE OF OPPORTUNITIES

PEDIATRICENDOCRINOLOGIST

La Crosse, Wisconsin

In keeping with the mission to advance excellence in endocrinology, The Endocrine Society is pleased to announce the launch of Endocrine Press. This newly revamped publishing program will offer a wide scope of content, from peer-reviewed journals to scholarly books and other material, in both print and digital formats.

Do You Have an Idea for a Book?A great idea is only useful if you share it. By publishing with Endocrine Press, your knowledge can reach a broad audience of endocrinology professionals and beyond. We’re currently seeking editors, authors, and manuscript ideas.

If you are interested in getting published we can help you get started. Visit www.endocrinepress.org to complete a book proposal form or learn more about the submission process.

Be sure to include the following information in your proposal submission:

• A brief description of the proposed book

• Target audience

• A list of other published works on the same topic and a description of what makes your book unique or different

• Anticipated completion date of the manuscript

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For additional information, please contact: Maxine Aldred, [email protected]

Learn more at www.endocrinepress.org

Announcing Endocrine Press!

• A list of other published works on the same topic and a description of what

Endocrine_Press_Full_wBleed.indd 1 6/4/13 11:19 AM

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What are the symptoms of a goiter?

You can have a goiter but have no symptoms at all, other than having some swelling at the base of your neck. Some people also may have• Tightness in the throat• Coughing • Hoarseness• Trouble swallowing• Trouble breathing

What is a goiter?A goiter is an enlarged thyroid gland. The thyroid gland, located in the front of your neck, makes thyroid hormones. When your thyroid gland is enlarged, it can produce too much, too little, or just enough thyroid hormone.

What do thyroid hormones do?

Thyroid hormones travel from your thyroid gland through the blood to all parts of your body. They control how your body uses food for energy, and help all your organs work well. Thyroid hormones affect your metabolism rate, which means how fast or slow your brain, heart, muscles, liver, and other parts of your body work.

If your metabolism is too fast or too slow, you won’t feel well. For example, if you don’t have enough thyroid hormone and your metabolism slows down, you might feel tired and cold. Or, if you have too much thyroid hormone, you might feel nervous and warm.

DiD you knoW?the most common cause of goiter outside of the U.s. is a lack of iodine in the diet. iodine is a substance in food (iodized salt and seafood) that the thyroid uses to make thyroid hormones. however, a lack of iodine is not common in the U.s. because iodine is added to salt and many foods.

FACT SHeeT

goiter

thyroid gland

FS_TD_Goiter_EN 12-12.indd 1 12/10/12 10:41 AM

43

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What are the symptoms of a goiter?

You can have a goiter but have no symptoms at all, other than having some swelling at the base of your neck. Some people also may have• Tightness in the throat• Coughing • Hoarseness• Trouble swallowing• Trouble breathing

What is a goiter?A goiter is an enlarged thyroid gland. The thyroid gland, located in the front of your neck, makes thyroid hormones. When your thyroid gland is enlarged, it can produce too much, too little, or just enough thyroid hormone.

What do thyroid hormones do?

Thyroid hormones travel from your thyroid gland through the blood to all parts of your body. They control how your body uses food for energy, and help all your organs work well. Thyroid hormones affect your metabolism rate, which means how fast or slow your brain, heart, muscles, liver, and other parts of your body work.

If your metabolism is too fast or too slow, you won’t feel well. For example, if you don’t have enough thyroid hormone and your metabolism slows down, you might feel tired and cold. Or, if you have too much thyroid hormone, you might feel nervous and warm.

DiD you knoW?the most common cause of goiter outside of the U.s. is a lack of iodine in the diet. iodine is a substance in food (iodized salt and seafood) that the thyroid uses to make thyroid hormones. however, a lack of iodine is not common in the U.s. because iodine is added to salt and many foods.

FACT SHeeT

goiter

thyroid gland


www.hormone.orggoiter fact sheet

What caUses a goiter?

In the U.S., the most common causes of swelling are• Hashimoto’s disease (leading to an underactive thyroid)• Graves’ disease (leading to an overactive thyroid)• Nodules (lumps) on one or both sides of the thyroid gland

Less common causes include a hormone made during pregnancy that increases thyroid hormone production, inflammation of the thyroid, or thyroid cancer. A goiter also can be present in a newborn if his or her thyroid gland doesn’t work properly before birth.

What factors increase the risk of a goiter?

Risk factors include• Being a woman• Being over age 40 • Being pregnant or in menopause• Having a family history of autoimmune disease or goiter• Having been exposed to radiation as a child or having had

radiation treatment to your neck or chest • Having a diet low in iodine

Some medicines also increase the risk of goiter.

hoW is a goiter diagnosed?

A goiter is often found during a physical exam when your doctor feels swelling in your neck. Your doctor also may use other tests to

find the cause of the goiter and to see how advanced it is, such as• Hormone tests to show whether your thyroid gland is

underactive or overactive • Antibody tests for Hashimoto’s disease and Graves’ disease• Ultrasound to see the size of your thyroid and whether there

are nodules• A thyroid scan to look at your thyroid, especially if your thyroid

is overactive• Other scans (CT or MRI) of the neck to check your windpipe• A biopsy (using a needle to get a sample of your thyroid for

testing)

What is the treatment for a goiter?

Treatment depends on the cause of the goiter, its size, and your symptoms. If your goiter is small and your thyroid is making normal amounts of thyroid hormone, your doctor might observe the goiter over time instead of starting treatment right away.

Possible treatments include• Medicines for underactive or overactive thyroid • Radioactive iodine for overactive thyroid (to shrink the goiter)

Surgery is rarely used. However, removal of the thyroid gland might be recommended for a large goiter, for one causing breathing or swallowing problems, for nodules, or for thyroid cancer.

Questions to ask your doctor• What is causing my goiter?

• What are my options for treatment?

• What are the risks and benefits of each treatment option?

• how long will i need treatment?

• should i see an endocrinologist for my care?

resoUrces

• Find-an-endocrinologist: www.hormone.org or call 1-800-HORMONE (1-800-467-6663)

• Hormone Health Network information about thyroid disorders: www.hormone.org/Thyroid/overview.cfm

• Mayo Clinic information about goiter: www.mayoclinic.com/health/goiter/DS00217

• MedlinePlus (National Institutes of Health) information about goiter: www.nlm.nih.gov/medlineplus/ency/article/001178.htm

the hormone health network offers free, online resources based on the most advanced clinical and scientific knowledge from the endocrine society (www.endo-society.org). the network’s goal is to move patients from educated to engaged, from informed to active partners in their health care. this fact sheet is also available in spanish at www.hormone.org/Spanish.

editors

Bryan haugen, MDJames hennessey, MDLeonard Wartofsky, MD

January 2013

definitions of thyroid conditionsUnderactive thyroid gland: when the thyroid gland doesn’t make enough thyroid hormone; also called hypothyroidism. When the thyroid is underactive, the body’s metabolism runs too slowly.

overactive thyroid gland: when the thyroid gland makes too much thyroid hormone; also called hyperthyroidism. When the thyroid is overactive, metabolism runs too quickly.

hashimoto’s disease (the most common cause of underactive thyroid): when the immune system attacks and damages the thyroid gland; then the damaged gland no longer makes enough thyroid hormone.

graves’ disease (the most common cause of overactive thyroid): when the immune system attacks the thyroid gland and causes it to make too much thyroid hormone.


*Three studies evaluated meters using the global standard of ≥95% of individual glucose results from 3 test strip lots shall fall within ± 15 mg/dL of the results of the manufacturer’s reference method at glucose concentrations <100 mg/dL and within ± 15% at ≥100 mg/dL. Studies included: Freckmann G, et al. J Diabetes Sci Technol. 2012;6(5):1060-1075.; Baumstark A, et al. J Diabetes Sci Technol. 2012;6(5):1076-1086.; Brazg RL, et al. J Diabetes Sci Technol. 2013;7(1):144-152. Studies funded by grants from Roche Diagnostics.

ACCU-CHEK NANO and ACCU-CHEK AVIVA are trademarks of Roche. © 2013 Roche. 316-52547-0613

Don’t gamble with your patients’ health.24 blood glucose meters failed recent accuracy studies.*

Is theirs one of them?

ACCU-CHEK® meters passed every study, every time. All other major manufacturers had a meter that failed.

Make the switch today.

The recent failure of a large number of blood glucose meters to consistently meet accuracy standards has created growing concern, especially for those using meters to determine how much insulin to dose. Your patients’ health is very important to us. It’s time to switch to an ACCU-CHEK meter today.

For more information, go to accu-chek.com/accurate

July 2013 - The Endocrine Society

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