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What’s New in the Treatment of Diabetes Celia Levesque RN, MSN, CNS-BC, NP-C, CDE, BC-ADM. If you want a copy of the slides, email: clevesqu@mdanderson.org Objectives • Discuss the American Diabetes Association 2015 recommendations for mgt of DM • Set appropriate glycemic targets • Discuss recommended therapeutic lifestyle changes to aid in the mgt of diabetes • Prescribe an effective medication regimen to meet glycemic targets • Manage common co-morbid diabetes complications US Statistics 2014 • 29.1 million or 9.3% have DM • 21 million diagnosed • 8.1 million undiagnosed • 1.7 million new cases in 2012 • Prediabetes: 86 million in 2012 US Statistics: 2012: Youth • Diabetes in Youth: total of 208,000 (0.25%) • Annual incidence 2008-2009 • T1DM: 18,436 • T2DM: 5,089 • Children born in the year 2000+: % developing DM in their lifetime • 1 in 3 children of all races except Hispanic • 1 in 2 Hispanic children US Statistics: 2012 Complications • Hypoglycemia: 282,000 ED visits in 2011 • Hypertension: 71% of adults age > 18 • Dyslipidemia: 65% of adults age > 18 • CVD Death Rates: 2003-2006 1.7 x higher in adults with diabetes • MI Rates: 2010: 1.8 x higher in adults with diabetes • CVA: in 2010: 1.5 x higher in adults with diabetes • Blindness/eye disease: 2005-2008: 4.2 million with retinopathy age > 40 • CKD: in 2011: DM listed as primary cause in 44% of new cases of kidney failure • Dialysis: in 2011 total of 228,924 cases with 49,677 of them new cases • Amputations: in 2010 ~ 73,000 in age > 20 due to DM (60% of all amputations)

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Diagnosis of Pre DM & DM Normal Pre Diabetes Diabetes Fasting BG 65-99 g/dL 100-125 /dL >125 mg/dL 2 hr PP < 140 mg/dL 140-199 mg/dL >199 mg/dL HbA1c < 5.7% 5.7-6.4% >6.4% Testing in Asymptomatic People • Adults BMI > 25 (> 23 in Asian Americans) WHO HAVE 1+ RISK FACTORS o Physical inactivity o First-degree relative with diabetes o High-risk race o Giving birth to baby > 9# or previous GDM o HTN o HDL <35 and/or triglyceride > 250 o PCOS o HbA1c > 5.7% or IFG on previous test o Other clinical conditions associated with insulin resistance: ie acanthosis nigricans, severe obesity • If tests are normal, repeat testing every 3 years at minimum • Those with prediabetes, treat CVD risk factors • Test in children and adolescents who are overweight or obese who have 2+ risk factors for diabetes • There is no screening for type 1 diabetes Classifications of DM • Type 1 DM • Type 2 DM • Other specific types of DM due to other causes o genetic defects in b-cell function o genetic defects in insulin action o diseases of the exocrine pancreas ie cystic fibrosis o drug- or chemical-induced • Gestational DM Initial Evaluation & Management • Perform a comprehensive diabetes evaluation • Classify diabetes • Detect diabetes complications • Review previous treatment plan • Formulate a management plan • Referral for specialty services if needed (ie ophthalmology, podiatry, etc) • Provide a basis for continuing care

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History of Diabetes • Age and characteristics of onset • Eating patterns/nutrition history • Presence of comorbidities including diabetes complications • Diabetes self-care skills • Current DM meds • Recent home BG test results / A1c • Hypoglycemia: frequency, symptoms, ability to self treat Physical Exam • Ht, wt, BMI • BP including orthostatic measurements if indicated • Fundoscopic by trained person • Thyroid palpation • Skin: acanthosis nigricans, and injection sites • Comprehensive foot exam Laboratory • A1c if accurate • Fasting lipid profile within past 1 year • Liver function tests • Urine albumin excretion with spot urine albumin-to-creatinine ratio • Serum creatinine and calculated GFR • TSH in pts w T1DM, dyslipidemia, or female > age 50 Referrals • Eye care • Family planning • Diabetes education • Dentist • Mental health professional

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Nutrition Goals • Promote healthy eating patterns • To attain BG, BP, and lipid goals • Achieve and maintain body weight goals • Delay or prevent diabetes complications • Individualized plan: no ideal % of macronutrients • CHO: vegetables, fruits, whole grains, legumes and dairy carbohydrate better • 14 gm fiber per 1000 calories • Mediterranean-style monounsaturated fatty acids • For T1DM: using insulin to carb ratio results in improved glycemic control • For T2DM: simple meal plan Exercise • Reduce sedentary time to < 90 minutes spent sitting • 150 min/wk mod intensity aerobic exercise over at least 3 d/wk • 2 d/wk: resistance training • Exercise does not improve HbA1c in T1DM but still important to do • Exercise improves HbA1c in T2DM and prediabetes • Routine screening for CAD is not recommended: use clinical judgement Psychological assessment • Depression screening (esp. in > 65 yo) • Diabetes-related distress • Anxiety • Eating disorders • Cognitive impairment Immunizations • All routine vaccines as general populations • Annual influenza in all > 6 m • Pneumococcal polysaccharide vaccine 23 (PPSV23) in pts w DM > 2 yr • Adults > 65 should receive both PPSV23 and PCV13 o If not previous received pneumococcal vaccine: give PCV13 first followed by PPSV23 6-12 months after PCV13 (do not co-administer, minimum interval bet is 8 wks) • Hepatitis B to unvaccinated patients Testing: HbA1c • HbA1c at least 2 x year who have stable glycemic control • HbA1c quarterly whose tx has changed or are not meeting goal • Use point-of-care for those already diagnosed if possible

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Comparison of HbA1c to Average Blood glucose

HbA1c% Average Blood

Glucose 6 126 7 154 8 183 9 212

10 240 11 269 12 298

Converting HbA1c to Average Blood Glucose: Math Formula § Estimated Average Glucose = 28.3 x HbA1c – 43.9 § Example: HbA1c = 7% § 28.3 x 7 – 43.9 = 154.2 Nathan, D et al. Translating the A1c Assay into estimated average glucose values. Diabetes Care 2008; 31: 1473-8. A1c Targets

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HbA1c Goal HbA1c Consider in the following < 7% § Most non-pregnant pts < 6.5% § If can be achieved without significant hypoglycemia, short duration DM,

long life expectancy, no significant CVD < 8% § History of severe hypoglycemia,

§ Limited life expectancy, § Advanced microvascular or macrovascular complications, § Extensive comorbid conditions, § Those with long-standing DM in whom the general goal is difficult to attain despite DSME, appropriate glucose monitoring, and effective doses of multiple glucose-lowering agents including insulin

Causes of Inaccurate HbA1c

• Factors that affect erythrocytes o Blood loss o Hemolysis o Hemoglobin variants (ie if HbA1 is not 99%)

• In patients with insulin deficiency and wide swings in BG, HbA1c alone is not the best measure – combine SB with HbA1c • Elderly patients may have a 1% increase in HbA1c with the same blood glucose levels, so not overly manage the elderly based on HbA1c levels. Manage the elderly based on home blood

glucose values. Benefit of Each 1% Drop in A1c UKPDS. Lancet 1998; 352: 837-853.

• Diabetes related deaths: 25% • Microvascular complications: 35% • Decrease in MI: 18% • Decrease in all-cause mortality: 7%

Testing: SMBG

• If intensive insulin mgt: o Before eating and occasionally PP and hs o Exercise o Symptoms of hypoglycemia and after tx hypoglycemia o Before critical tasks (ie driving)

• If on oral agents: o Insufficient evidence to whether it should be done and how often

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Diabetes Medications

Medication Class Route Year HbA1c % reduced Alpha-glucosidase inhibitor PO 1995 0.5-0.8 Amylin analog SC 2005 0.6 Biguanide PO 1995 1.5 Bile acid sequestrin PO 2008 0.5 with metformin Dopamine agonist PO 2009 0.5-0.9 DPP-4 inhibitors PO 2006 0.5-0.8 GLP-1 Receptor Antagonist SC 2005 0.6 Insulin SC 1921 > 2.5 Meglitinides PO 1997 1-1.5 SGLT2 inhibitor PO 2013 0.91-1.16 Sulfonylurea PO 1946 1.5 Thiazolidinedione PO 1999 0.8-1.0 Patient / Disease Features to consider prior to choosing a diabetes medication regimen

• Risk of hypoglycemia • Disease duration • Life expectancy • Important comorbidities • Established vascular complications • Patient attitude and expected treatment efforts • Resources and support

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Biguanide

Mechanism of Action

Activates AMP-kinase, improves insulin resistance indirectly, reduces hepatic glucose production

Lowers HbA1c

1.5%

Type of Diabetes

2

Main Benefits

Decreases blood glucose without causing hypoglycemia or weight gain, low cost

Common adverse effects

Nausea, vomiting, diarrhea, flatulence, low serum B12. May cause ovulation in anovulatory and premenopausal PCOS patients

Cautious Use

Malnourished, debilitation, infection-induced stress, fever, trauma, elderly

Contraindications

BLACK BOX WARNING: lactic acidosis is a rare but potentially severe consequence of therapy with metformin. Do not use or discontinue in those with unstable, acute CHF who are at risk of hypoperfusion and hypoxemia, renal dysfunction (creatinine > 1.4 in women, and > 1.5 in men, dehydration, sepsis, surgery, tests involving the injection of dye, hepatic disease, excessive or chronic alcohol consumption, hypersensitivity, metabolic acidosis, diabetic ketoacidosis

Cost

Generic: on $4 list

Pregnancy Category B

Name

Dose Available mg

Usual Start Dose mg

Max Dose mg

Metformin (Glucophage)

500, 850, 1000 500 bid or 850 qd Max Dose: 2550 qd; Contra: renal/hepatic disease

Metformin Ext-rel (Glucophage XR, Fortamet, Glumetza)

500, 750 500 bid or 850 qd Max dose: 2500; Contra in renal/hepatic disease

Metformin Oral Solution (Riomet)

100/ml 500 bid or 850 qd Max Dose: 2550 qd; Contra in renal/hepatic disease

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Sulfonylureas

Mechanism of Action

Closes KATP channels on β-cell on plasma membranes causing insulin secretion

Lowers HbA1c

1.5%

Type of Diabetes

2

Main Benefits

Can be used as monotherapy or in combination with other oral agents (with the exception of glinides) or with insulin

Common adverse effects

Hypoglycemia, weight gain

Cautious Use

Impaired renal and hepatic function, adrenal or pituitary insufficiency, elderly, malnourished

Contraindications

Ketoacidosis

Cost

Generic, on $4 list

Pregnancy Category C

Name Dose Available mg Usual Start Dose mg Max Dose mg

Glimepiride (Amaryl)

1, 2, 4 1–2 qd Max Dose: 8

Glipizide (Glucotrol)

5, 10 5 qd Max Dose: 20 qd

Glipizide ext-rel (Glucotrol XL)

5, 10 5 qd Max Dose: 20 qd

Glyburide (Diabeta)

1.25, 2.5, 5 2.5 – 5; 1.25 for elderly Max Dose: 20 qd

Glyburide (Glynase Pres Tab)

1.5, 3, 6 2.5 – 5; 1.25 for elderly Max Dose: 20 qd

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Meglitinides Mechanism of Action

Closes KATP channels on β-cell on plasma membranes causing insulin secretion. Repaglinide is metabolized by the liver enzymes CYP3A4 & CYP2C8. Nateglinide is metabolized by hepatic cytochrome P450 CYP2Cp (70%) and CYP34A (30%)

Lowers HbA1c

1-1.5%

Type of Diabetes

2

Main Benefits

Increases insulin levels for a short period of time compared to sulfonylurea agents. Meglitinides have a lower risk of hypoglycemia compared to sulfonylureas. Good for those who skip meals.

Common adverse effects

Hypoglycemia (less risk compared to sulfonylureas)

Cautious Use

Renal insufficiency, liver disease, use with insulin, adrenal insufficiency, surgery, trauma, elderly, pituitary insufficiency, malnourished

Contraindications

Ketoacidosis, allergy to medication, Type 1 diabetes, used with gemfibrozil results in increased repaglinide plasma concentrations 8-fold and may result in severe hypoglycemia

Cost

Brand name only average $60-100/month

Pregnancy Category C

Name

Dose Available mg

Usual Start Dose mg

Max Dose mg

Nateglinide (Starlix)

60, 120 120 tid; Max Dose: 360 qd; Can start at 60 tid if A1c near target

Repaglinide (Prandin)

0.5, 1, 2 0.5 ac if A1c < 8 Max Dose: 16 qd; Caution hepatic/renal impairment

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Thiazolidinediones

Mechanism of Action

Activates the nuclear transcription factor PPAR- ϒ. Improves target cell response to insulin; decreases hepatic gluconeogenesis. Metabolized to active metabolites by hepatic CYP2C8 & CYP34A

Lowers HbA1c

0.8-1%

Type of Diabetes

2

Main Benefits

Improves blood glucose control without hypoglycemia

Common adverse effects

May causes ovulation in females in some premenopausal anovulatory women, weight gain, edema

Cautious Use

If ALT increases to 3 x UNL, stop treatment, if 1.5-3 x ULN retest weekly until normal or until 3 x UNL and need to discontinue, dyspnea, rapid weight gain, combination with used with insulin or other oral diabetes agents

Contraindications

BLACK BOX WARNING: thiazolidinediones exacerbate CHF in some patients Do not use if NYHA class III or IV heart failure, diabetic ketoacidosis, hypersensitivity, type 1 diabetes, moderate-severe hepatic impairment (ALT > 2.5 UNL)

Cost

Brand name: approximately $100/month for 15; $150/month for 30; $200/month for 45

Pregnancy Category C

Name

Dose Available mg

Usual Start Dose mg

Max Dose mg

Pioglitizone (Actos)

15, 30, 45 15 or 30 qd Max Dose: 45 qd; Conta in Class III or IV HF

Rosiglitizone (Avandia)

2, 4, 8 4 qd or 2 bid Max dose: 8 qd

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Dipeptidyl peptidase 4 inhibitor

Mechanism of Action

Inhibits DPP-4 activity, increasing active incretin (GLP-1, GIP) concentrations. Increases glucose dependent insulin secretion, decreases glucose dependent glucagon secretion; metabolism limited, primarily by CYP3A4

Lowers HbA1c

0.5-0.8%

Type of Diabetes

2

Main Benefits

Improves blood glucose control without risk of hypoglycemia or weight gain

Common adverse effects

Few, comparable to placebo, abdominal pain, diarrhea, nasopharyngitis, nausea headache, URI

Cautious Use

Renal impairment, acute pancreatitis, use with insulin or sulfonylureas

Contraindications

Type 1 diabetes, diabetic ketoacidosis

Cost

Low $200s/month

Name Dose Available mg Usual Start Dose mg Max Dose mg

Sitagliptin Phosphate (Januvia)

25, 50, 100 100 qd 100; Cr Cl 30-50: 50 qd, Cr Cl < 30: 25 qd

Saxagliptin (Onglyza)

2.5, 5 2.5-5 qd

5 Cr Cl < 30: 2.5 qd

Linagliptin (Tradjenta)

5 5 5 No dose adjustments needed

Alogliptin (Nesina)

6.25, 12.5, 25 25 25 Cr Cl 30-59: 12.5 Cr Cl < 30: 6.25

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Alpha-Glucosidase Inhibitors

Mechanism of Action

Inhibits intestinal α-glucosidase. Delays GI absorption of carbohydrate

Lowers HbA1c

0.5-0.8%

Type of Diabetes

2

Main Benefits

Improves postprandial blood glucose. Does not causes hypoglycemia or weight gain

Common adverse effects

Abdominal pain, diarrhea, elevated serum transaminases, flatulence

Cautious Use

Concurrent use with sulfonylureas, If hypoglycemia occurs, treat with oral dextrose not sucrose

Contraindications

Hypersensitivity, diabetic ketoacidosis, cirrhosis, inflammatory bowel disease, colonic ulceration, partial intestinal obstruction

Cost

25 mg and 50 mg/month $40-60; 100 mg/month $60-100

Name Dose Available mg Usual Start Dose mg Max Dose mg

Acarbose (Precose)

25, 50, 100 25 tid Max Dose: Adult: 150/d < 60 kg, 300/d > 60 kg

Miglitol (Glyset)

25, 50, 100 25 tid Max Dose: 300

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Sodium-Glucose Co-Transporter 2 (SGLT2)

Mechanism of Action

Inhibits SGLT2 in the proximal nephron. Blocks the reabsorption of glucose by the kidneys which results in increased glucose excretion and lower blood glucose concentrations in patients with type 2 diabetes

Lowers HbA1c

0.8% with the 100 dose 1.03% with the 300 dose

Type of Diabetes

2

Main Benefits

Weight loss, low risk of hypoglycemia

Common adverse effects

Female genital mycotic infections, urinary tract infection, increased urination

Cautious Use

Adrenal insufficiency, balanitis, breast-feeding, children, dehydration, diabetic ketoacidosis, fever, geriatric, hepatic disease, hypercholesterolemia, hypercortisolism, hyperglycemia, hyperkalemia, hyperthyroidism, hypoglycemia, vaginitis, renal impairment, pregnancy, pituitary insufficiency, neonates, malnutrition, infants

Contraindications

Ketoacidosis, dialysis, renal failure, type 1 diabetes

Cost

$290

Pregnancy Category

C

Name Dose Available mg Usual Start Dose mg Max Dose mg

Canaglidlozin (Invokana)

100, 300 100 qd taken before 1st meal of the day eGFR > 45

Max Dose: 300 qd eGFR > 60

Dapagliflozin (Farxiga)

5, 10 5 eGFR > 60 10 eGFR > 60

Empagliflozin (Jardiance)

10, 25 10 eGFR > 45 25 eGFR > 45

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Dopamine Agonist

Mechanism of Action

Activates dopaminergic receptors. Moderates hypothalamic regulation of metabolism. Increases insulin sensitivity. Used as adjust with other diabetes medications.

Lowers HbA1c

03-0.5%

Type of Diabetes 2

Main Benefits

Postprandial g lucose concentrat ions were improved without increasing plasma insul in concentrat ions

Common adverse effects

GI upset, fatigue, dizziness, headache, hypotension, syncope, somnolence, hypoglycemia

Cautious Use

Abrupt discontinuation, acute MI, angina, bipolar disorder, cardiac arrhythmias, cardiac disease, children coronary artery disease, dementia, depression, driving or operating machinery, geriatric, GI bleed, hepatic disease, hypotension, peptic ulcer disease, peripheral vascular disease, pregnancy, pulmonary fibrosis, renal disease, renal impairment, retroperitoneal fibrosis, schizophrenia, surgery

Contraindications

Ketoacidosis, type 1 diabetes, basilar/hemiplegic migraine, breast-feeding, eclampsia, ergot alkaloid hypersensitivity, hypertension, preeclampsia

Cost

$80

Pregnancy Category B

Name Dose Available mg Usual Start Dose mg Max Dose mg

Bromocriptine (Cycloset)

0.8 0.8 qd in the morning within 2 hours of waking, increase the dose by 0.8/d no more frequently than every 1 week

Max Dose: 1.6-4.8 qd

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Bile Acid Sequestrant

Mechanism of Action

Binds with bile acids in the intestine thereby impeding their reabsorption. As the bile acid pool is depleted, the hepatic enzyme, cholesterol 7-alpha-hydroxylase is upregulated, which increases the conversion of cholesterol to bile acids. The mechanism of action for reducing blood glucose is unknown.

Lowers HbA1c

0.5-0.6%

Type of Diabetes

2

Main Benefits

Lowers both HbA1c and LDL

Common adverse effects

Constipation, dyspepsia, nausea, dysphagia

Cautious Use

Biliary obstruction, breast-feeding, children, cholelithiasis, coagulopathy, constipation, dysphagia, gastroparesis, hemorrhoids, ileus, phenylketonuria, pregnancy, surgery, vitamin K deficiency

Contraindications

Ketoacidosis, GI obstruction, hypertriglyceridemia, pancreatitis

Cost

$50-60

Pregnancy Category B, it is not systemically absorbed

Name Dose Available mg Usual Start Dose Max Dose

Colesevelam (Welchol)

625 3 tab bid, or 6 tab qd Max Dose: 7 tab/day

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Combination Oral Agents

Name

Dose Available mg Usual Start Dose mg Max Dose mg

Alogliptin + metformin Kazano

12.5/500; 12.5/1000 12.5/500 25/2000

Alogliptin + pioglitazaone Oseni

12.5/15, 12.5/30; 12.5/45; 25/15; 25/30; 25/45

25/15 25/45

Canagliflozin/metformin Invokamet

50/500, 50/1000, 150/500, 150/1000 150/500 300/2000

Dapagliflozin/metformin Xigduo XR

5/500, 5/1000, 10/500, 10/1000 5/500 5/1000 bid

Empagliflozin/linagliptin Glyxambi

10/5, 25/5 10/5 25/5

Empagliflozin/metformin Synjardy

12.5/500, 12.5/1000, 5/500, 5/1000 5/500 bid 12.5/1000 bid

Glipizide + metformin Metaglip

2.5/250; 2.5/500; 5/500 2.5/250 qd If BG 280-320 mg /dL start 2.5/500 bid

20/2000

Glyburide + metformin Glucovance

1.25/250; 2.5/500; 5/500

1.25/250 qd or bid 20/2500

Linagliptin + metformin Jentadueto

2.5/500; 2.5 850; 2.5/1000 If new to metformin: 2.5/500 bid; previously on metformin: 2.5/current dose of metformin bid

2.5/1000 bid

Pioglitizone + glimepiride Duetact

30/2; 30/4 If on previously start with usual dose. If not, start 30/2 or 30/4 daily

30/4

Pioglitizone + metformin Actoplus Met

15/500, 15/850 15/500 qd or bid; 15/850 qd or bid 45/2550

Pioglitizone + metformin XR Actoplus Met XR

15/500, 15/ 850 15/500 qd or bid; 15/850 qd or bid 45/2550

Repaglinide + metformin PrandiMet

1/500; 2/500 1/500 with meals 10/2500

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Rosiglitizone + glimepiride (Avandaryl)

4/1; 4/2; 4/4 4/1 qd 4 /4

Rosiglitizone + metformin Avandamet

1/500; 2/500; 4/500; 2/1000; 4/1000

2/500 qd or bid 8/2000; Contra in Class III or IV HF

Sitagliptin phosphate + metformin Janumet

50/500; 50/1000 50/500 bid 100/2000

Sitagliptin phosphate + metformin XR Janumet XR

50/500; 50/1000; 100/1000 50/500 bid 100/2000

Sitagliptin + simvastatin Juvisync

50/10; 50/20; 50/40; 100/10; 100/20; 100/40

100/40 qd. If already on simvastatin: 100/current simvastatin dose

100/40

Saxagliptin + metformin XR Kombiglyze XR

5/500; 5/1000; 2.5/1000 Take daily in the evening 5/2000

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GLP-1 Agonists

Mechanism of Action

Activates GLP-2 receptors. Increases glucose dependent insulin secretion. Decreases glucose dependent glucagon secretion. Slows gastric emptying. Increases satiety.

Lowers HbA1c

0.6%

Type of Diabetes

2

Main Benefits

Improves blood glucose control without weight gain, promotes weight loss by decreasing appetite

Common adverse effects

Diarrhea, nausea, vomiting

Cautious Use

Risk for pancreatitis, renal failure

Contraindications

Hypersensitivity, Renal impairment with CrCl < 30 mL/min, do not use liraglutide in patients with a history of or family history of medullary thyroid cancer

Approximate Cost

5 mcg Pen or 10 mcg Pen $300

Name Dosage Available Usual Starting Dose Max Dose Albiglutide (Tanzeum)

30 mg Pen, 50 mg Pen 30 mg weekly 50 mg weekly

Dulaglutidel Trulicity

0.75 mg/5mL Pen, 1.5 mg/5 mL Pen 0.75 mg weekly 1.5 mg weekly

Exenatide (Byetta)

5 mcg Pen, 10 mcg Pen

5 mcg bid 10 mcg bid

Exenatide ext-rel (Bydureon)

2 mg powder for suspension for injection kit or Pen injector

2 mg weekly 2 mg weekly

Liraglutide (Victoza)

18 mcg/3 ml Pen 0.6 mcg daily 1.8 mcg daily

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Amylin Analog / Amylinomimetic

Mechanism of Action

Synthetic analog of the polypeptide pancreatic hormone amylin. Activates amylin receptors. Slows gastric emptying. Suppresses glucagon. Regulates appetite

Lowers HbA1c

0.6%

Type of Diabetes

1 or 2 to be used with prandial insulin (syringe or insulin pump) with a meal containing 30 or more grams of carbohydrate

Main Benefits

Improves postprandial blood glucose control. Some patients, who are overweight, may lose weight. No effects on weight if the patient is normal weight.

Common adverse effects

Nausea, headache, vomiting, anorexia, severe hypoglycemia (not directly caused by pramlintide but by the combination of insulin with pramlintide)

Cautious Use

Patients at high risk of severe hypoglycemia

Contraindications

Hypersensitivity, gastroparesis, HbA1c > 9%, current prokinetic agent usage, hypoglycemia unawareness

Cost

1000 mcg/ml $70.40 per ml or ~ $380 per 2 pens

Name What It Is Action How Given Side Effects Available Forms

Symlin Dose Prescribed

Increment Using u-100 insulin syringe in units

Pramlintide (Symlin)

Synthetic analog of human amylin. Used in those with type 1 and type 2 patients.

Slows gastric emptying, increases satiety, decreases after meal glucagon, decreases postprandial hyperglycemia

Subcutaneous injection 15-120 mcg at meals of 30 grams of carbohydrate or more. Do not mix with insulin.

Hypoglycemia. Decrease premeal insulin dose by 30 – 50%. Anorexia, nausea, vomiting. Titrate doses as tolerated

Amylin: Vial Pen 120 (1000 mcg/ml)

15 mcg 2.5 units

30 mcg 5.0 units

45 mcg 7.5 units

60 mcg 10 units

120 mcg 20 units

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Common 2 Drug Combination Metformin

HbA1c ↓ High Hypo: Low Weight: Neutral or loss Major SE: GI / lactic acidosis Cost: Low

+ SU TZD DPP-4 GLP-1 SGLT2 Insulin HbA1c ↓ High High Medium High Medium Highest Hypo High Moderate Low Low Low Highest Weight Gain Gain Neutral Loss Loss Gain Major SE Hypogly Edema HF Rare GI UTI, mcotic Hypogly Cost Low High High High High Variable Common 3 Drug Combination

Met +

SU +

Met +

TZD +

Met +

DPP-4 +

Met +

GLP-1 +

Met +

SGLT2

Met +

Insulin +

TZD SU/meg SU/meg SU/meg SU/meg TZD DPP-4 DPP-4 TZD TZD DPP4 DPP-4 GLP-1 GLP-1 Insulin Insulin Insulin GLP-1 Insulin Insulin SGLT2 TZD SGLT2 SGLT2 SGLT2

Normal Insulin Secretion ¡ Basal: continuous insulin to compensate for liver glucose ¡ Bolus: surge for food 1st phase: rapid rise in serum insulin levels inhibits glucagon release and therefore liver glucose release 2nd phase: to cover the food ingested

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Insulin U-100

Name Onset Maximum Effect Duration Available Forms Storage

Recommendation Lispro (Humalog)

15 minutes 30-90 min 3 - 5 h Lilly: vial, Prefilled pen, Penfill cartridge, Kwik pen

28 days once in use

Aspart (Novolog)

10 - 20 min 60 - 120 min 3 - 5 h NovoNordisk: Vial, Flexpen, Penfill cartridge

28 days once in use

Glulisine (Apidra)

10 - 20 min 1 – 2 h 3 – 4 h Sanofi-Aventis: Vial, Penfill cartridge (Opticlix)

28 days once in use

Regular (Humulin R, Novolin R, Relion R)

0.5 – 1 h 2 – 3 h 4 – 12 h Lilly: vial 28 days once in use

NPH Humulin N Novolin N Relion N

1.5 – 4 h 4 – 12 h Up to 24 h Lilly: Vial, prefilled pen; NovoNordisk: Vial, Penfill cartridge

Vial 28 days once in use; Pen 14 days once in use

Glargine (Lantus)

1 – 2 h Flat 24 h Sanofi-Aventis: Vial, Penfill cartridge (Opticlix). Solostar pen

28 days once in use

Detemir (Levemir)

0.8 – 2 h 3.2 – 9.3 h (dose dependent)

Up to 24 h NovoNordisk: Vial, Flexpen

Vial and Pen: 42 days once in use

Humalog U-200

• Contains 200 units per milliliter • Comes in a KwikPen containing 600 units per pen, 2 pens per box

Glargine U-300 (Toujeo) • Contains 300 units per milliliter • Comes in a Solostar pen containing 450 units per pen, 3 pens per box

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Humulin R U-500 • May be use in patients with type 1 or type 2 diabetes requiring more than 200 units of insulin per day • Contains 500 units per milliliter • Comes in a 20 milliliter vial containing 10.000 units • The vial is marked with a band of diagonal brown strips to distinguish it from the U-100 vial which has no stripes and has “U-500 highlighted in red • Requires special training: mistakes in drawing up can easily be made. • The Lilly company provides patient education literature helping patients to know how to correctly draw up U-500 Regular insulin • The prescribed dose is expressed in actual units along with corresponding milliliters if using a tuberculin syringe, or corresponding markings if using an insulin syringe

Example:

Units of U-500 Regular insulin Marking on Tuberculin Syringe Marking on U-100 Insulin Syringe 20 0.04 milliliters 4 unit marking 30 0.06 milliliters 6 unit marking 40 0.08 milliliters 8 unit marking 50 0.1 milliliters 10 unit marking 60 0.12 milliliters 12 unit marking 70 0.14 milliliters 14 unit marking

Afrezza Inhalation

• Rapid acting inhaled insulin • Not recommended for those who smoke or have stopped smoking recently • Must get spirometry (FEV1) prior to starting Afrezza • Dosage forms: 4 units blue cartridge, 8 units green cartridge

o 60 – 4 unit cartridges with 2 inhalers: NDC 47918-004-02 o 90 - 4 unit cartridges with 2 inhalers: NDC 47918-004-03 o 90 - 8 unit cartridges with 2 inhalers: NDC 47918-008-03 o 90 – with 60 as 4 unit cartridges and 30 as 8 unit cartridges: NDC 47918-048-12 o 90 – with 30 at 4 unit cartridges and 60 as 8 unit cartridges: NDC 47918-048-21 o 180 – with 90 as 4 unit cartridges and 90 as 8 unit cartridges: NDC 47918-048-33

• Starting dose for insulin naïve: 4 units • Peak: 53 minutes Duration 160 minutes • Care: Refrigerator for unopened sealed foil package until expiration date; Room temperature 59-86 degrees: sealed blister cards + strips: use within 10 days; open strips: use within 3 days • Cartridges should be at room temperature for 10 minutes before use • Has not been studied in pregnant women. Do not use unless the potential benefits outweighs the risk. No major malformations were observed in rat studies • Increases in anti-insulin antibodies compared to subcutaneous injected insulin but the increased antibodies did not reduce efficacy • In patients without chronic lung disease, patients treated with Afrezza had a 40 mL greater decline from baseline in forced expiratory volume in one second (FEV1) compared to patients

with comparator anti-diabetes treatments. The decline occurred in the first 3 months of therapy and persisted over 2 years. • Afrezza causes a small but greater decline in lung function over time. Assess pulmonary function at baseline, at 6 months, and annually thereafter in the absence of pulmonary symptoms.

If the decline is > 20% in FEV1 from baseline, consider discontinuing Afrezza. Consider more frequent monitoring in patients with pulmonary symptoms. • The long-term safety and efficacy of Afrezza in patients with chronic lung disease has not been established. • 27% patients reported cough compared to 5.2%of patients treated with comparator. Cough was the most common reason for discontinuation. • Hypoglycemia is the most common adverse reaction.

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• Contraindications: during episodes of hypoglycemia, chronic lung disease (asthma, COPD), hypersensitivity to regular human insulin or Afrezza, diabetic ketoacidosis, smokers Injected Mealtime insulin Dose Afrezza Dose # of 4 unit blue cartridges # of 8 unit green cartridges Up to 4 units 4 units 1 0 5-8 units 8 units 0 1 9-12 units 12 units 1 1 13-16 units 16 units 0 2 17-20 units 20 units 1 2 21-24 units 24 units 0 3

Combination Insulins Humulin 70/30 70% Isophane Suspension (intermediate acting

insulin) 30% Regular Lilly: vial, prefilled pen Vial: 28 days once in

use, Pen: 10 days once in use

Novolin 70/30 Relion 70/30

70% Isophane Suspension (intermediate acting insulin) 30% Regular

NovoNordisk: Vial, Penfill cartridge

28 days once in use

Humulin 50/50 50% Isophane Suspension (intermediate acting insulin) 50% Regular

Lilly: Vial 28 days once in use

Humalog Mix 75/25 75% Lispro Protamine Suspension (NPL) (intermediate acting) 25% lispro

Lilly: Vial, Disposable Pen Vial: 28 days once in use; Pen 10 days once in use

Humalog Mix 50/50 50% Lispro Protamine Suspension (NPL) (intermediate acting) 50% lispro

Lilly: vial, disposable pen

Novolog Mix 7030 70% Aspart Protamine Suspension (intermediate acting) 30% aspart

NovoNordisk: Vial, Disposable pen (Flexpen), Penfill Cartridge

Vial: 28 days once in use; Pen 14 days once in use

Initiating Insulin in T2DM: ADA Recommendations

• Start: 10 units per day or 0.1-0.2 units / kilogram / day • Adjust by increasing 10-15% or 2-4 units once or twice weekly to reach target fasting blood glucose • For hypoglycemia: determine and address the cause. Decrease dose by 4 units or 10-20%

Initiating Prandial Insulin in T2DM

• Add 1 rapid acting insulin injection before the largest meal • Start: 4 units or 0.1 units per kilogram or 10% basal dose if A1c < 8%. Consider decreasing the basal dose by the same amount. • Adjust by increasing dose by 1-2 units or 10-15% once or twice weekly until blood glucose target is reached • For hypoglycemia: determine and address the cause. Decrease dose by 2-4 units or 10-20%

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Adding > 2 Prandial Insulin Doses in T2DM • Start: 4 units or 0.1 units per kilogram or 10% basal dose if A1c < 8%. Consider decreasing the basal dose by the same amount. • Adjust by increasing dose by 1-2 units or 10-15% once or twice weekly until blood glucose target is reached • For hypoglycemia: determine and address the cause. Decrease dose by 2-4 units or 10-20%

As an Alternative to Basal / Bolus Dosing: Use Premixed insulin twice daily

• Start: Divide current basal dose into 2/3 in am and 1/3 in pm, or ½ in am and ½ in pm • Adjust by increasing the dose by 1-2 units or 10-15% once or twice weekly until the blood glucose is at target • For hypoglycemia: Determine and address cause. Decrease corresponding dose by 2-4 units or 10-20%.

Total Daily Dose Based on Weight

• 0.25 units per kg if: weight < 70 kg, renal failure, hepatic failure, or malnourished • 0.4 units per kg for most patients weighing 70 to 100 kg • 0.6- 0.8 units per kg if on low dose steroid therapy, obese or weight over 100 kg • 0.9 units per kg if on high dose steroids and metformin with 2 BG > 250 mg/dL • 1.2 units per kg if on high dose steroids with 2 BG > 250 mg/dL

Initiating Insulin in T1DM

• Most will use an MDI or insulin pump regimen • Must be willing to perform BG testing ac & hs for MDI or pump therapy • Many will split their basal insulin am/pm • CHO counting with insulin: carb ratio beneficial • If not willing to use intensive insulin therapy then use split/mix insulin at breakfast and supper

Determining Total Daily Dose in T1DM Units/Kg/Day Patient 0.5 Conditioned athlete, honeymoon phase 0.6 Motivated exerciser, woman in 1st phase follicular cycle 0.7 Women in luteal phase or 1st trimester preg, adult mildly ill with virus, child starting puberty 0.8 Women in 2nd trimester preg, adult with severe infection 0.9 Women in 3rd trimester preg, adult with bacterial infection 1.0 Women at term preg, adult with severe bacterial infection or illness, child at peak puberty 1.5-2.0 Child at peak puberty who is ill Percent Basal Vs Bolus

• No steroids: 50% basal, 50% bolus • Low dose steroids less than 40 mg dexamethasone or equivalent: 40% basal, 60% bolus • High dose steroids equal to or greater than 40 mg dexamethasone or equivalent: 25% basal, 75% bolus

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Insulin to CHO ratio • Divide 500 by the total daily dose • Only accurate if the basal insulin and prandial insulin are in a 50%/50% ratio • Example:

o 50 units per day o 500 ÷ 50 = 10 o Start with 1 unit per 10 grams of CHO

Sensitivity Factor / Correction Factor

• The mg/dl that 1 u rapid acting insulin will decrease BG Also called correction factor o Math Formula: 1700 Rule

Total Daily Dose Sensitivity 10 170 20 85 30 56 40 42 50 34 60 28 70 24 80 21 90 18

100 17 Question: How units of rapid / short acting insulin should be given to correct the hyperglycemia?

• SF = 50 • Target BG = 100 mg/dL • Current BG = 250 • 250 – 100 = 150 • 150 ÷ 50 = 3 units

Insulin adjustment

• If the overnight BG is high, raise the basal insulin • If the lunch BG is above target: raise the breakfast fast/short acting • If the supper BG is above target: raise the lunch fast/short acting • If the bedtime BG is above target: raise the supper fast/short acting • If the overnight BG is low, lower the basal insulin • If the lunch BG is below target: lower the breakfast fast/short acting • If the supper BG is below target: lower the lunch fast/short acting • If the bedtime BG is below target: lower the supper fast/short acting

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Putting it all together Ms. Washington is a 65 yo pt w newly dx T2DM,

• BMI 34, Ht 5’ 4”, 200 # / 90.9 kg • HbA1c 8%, no symptoms of hyperglycemia • Creatinine 1.0

o What therapy would you start first? o What would you go to next if monotherapy is unsuccessful? o If insulin: what would the initial regimen?

Mr. Williams is a 25 yo pt w newly dx T1DM 6’, 68.2 kg, BMI 20, he is a motivated exerciser

• HbA1c 12%, with symptoms of hyperglycemia • Creatinine 0.7

• What therapy would you start first?

o Start MDI therapy: 50% basal, 50% bolus o Total daily dose: 68.2 x 0.6 u/kg = 40.92 o 50% Basal = approximately 20 units (May need less basal than bolus because of exercise)

§ May use Detemir or Glargine in 1 or divided doses § May use Glargine U-300 once daily § May use NPH twice daily in am and bedtime, or just at bedtime if using Regular insulin during the day for 3 meals

o 50% Bolus = approximately 20 units § Can start by dividing the total calculated bolus dose by 3 § Can calculate an insulin to carb ratio: 500 ÷ TDD 40 = 12.5 can start with 1 unit per 12 or 13 grams of CHO § Sensitivity / Correction factor

o 1700 ÷ TDD 40 = 42.5 Can round to 40 or 45 Hypertension

• BP goals: < 140/90 • Lower systolic < 130 if possible without undue tx burden • Lower diastolic < 90 if possible without undue tx burden

Hypertension Treatment: BP > 120/80: TLC BP > 140/90: TLC + medication Therapeutic Lifestyle Changes

• DASH-style diet • Reduce sodium • Increase potassium • Moderation of alcohol • Increase physical activity

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Medications for Hypertension in Patients with Diabetes • ACEI or ARB • Thiazide diuretic + ACEI or ARB

Dyslipidemia

• Screen lipids at dx, at 40 yrs, and then every 1-2 yrs

Treatment of Dyslipidemia in Diabetes

• Therapeutic lifestyle changes • BG control if increased triglycerides and/or low HDL • If triglycerides are > 500, evaluate for secondary causes • If DM + CVD: TLC + high-intensity statin • If DM < 40 & 1+ risk fx for CVD: TLC + mod or high intensity statin • If DM 40-75 & No added risk fx for CVD: TLC + mod intensity statin • If DM 40-75 & 1+ risk fx for CVD: TLC + high intensity statin • If DM > 75 & No added risk fx for CVD: TLC + mod intensity statin • If DM > 75 & 1+ risk fx for CVD: TLC + mod or high intensity statin

Recommendations for statins

• Statins + fibrate o This combination associated with increased risk for abnormal transaminase levels, myositis, or rhabdomyolysis o Higher risk if high dose statin and renal disease o Lower risk if combined with fenofibrate compared to gemfibrozil

Age (years) Risk Factors Statin dose Monitoring of lipids

< 40 None CVD risk factors Overt CVD

None Moderate or high High

Annually or PRN to monitor for adherence

40-75 None CVD risk factors Overt CVD

Moderate High High

PRN to monitor for adherence

> 75 None CVD risk factors Overt CVD

Moderate Moderate or high High

PRN to monitor for adherence

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Aspirin • Consider ASA 75-162 mg/d in T1 or T2DM at >10% CV risk

o Most men >50 yrs & women > 60 yrs w 1+ add risk fx § Fam hx CVD § HTN § Smoking § Dyslipidemia § Albuminuria

• Use aspirin if DM + CVD o Use ASA 75-162 mg/d as secondary prevention in DM + CVD o Use clopidogrel 75 mg/d if ASA allergy o Dual antiplatelet tx is reasonable up to a yr after acute coronary syndrome

Coronary heart disease

• Routine screening in asymptomatic patients is not recommended • In known CVD + DM:

o Use ASA and statin if not contraindicated o Consider ACEI o If prior MI: use beta blockers for at least 2 yrs after event o If symptomatic heart failure, do not use TZD o If stable CHF, metformin may be used if renal function good o Don’t use metformin in unstable or hospitalized pts w CHF