PowerPoint Presentation - 20 mcg QD -0.28 to 1.21 kg QD = once daily. 3/22/2017 8 Drucker DJ, et al....
Transcript of PowerPoint Presentation - 20 mcg QD -0.28 to 1.21 kg QD = once daily. 3/22/2017 8 Drucker DJ, et al....
3/22/2017
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Type 2 Diabetes – Pathophysiology and Pharmacology Review
Joshua J. Neumiller, PharmD, CDE, FASCP
Vice Chair & Associate Professor,
Department of Pharmacotherapy
Washington State University
Spokane, WA
This educational activity is sponsored by Postgraduate Healthcare Education, LLC (PHE) and supported by an educational grant from Boehringer Ingelheim Pharmaceuticals Inc. and Lilly USA, LLC.
Accreditation Statement
PHARMACY
Postgraduate Healthcare Education, LLC is accredited by the Accreditation Council for Pharmacy Education as a provider of continuing pharmacy education.
UAN: 0430-0000-17-014-L01-P
0430-0000-17-014-H01-P
Credits: 1.0 hour (0.10 ceu)
Type of Activity: Knowledge
Media: Internet
New Horizons in Diabetes Care: Reducing Cardiovascular Risks Through Advances in
PharmacotherapyThis valuable and engaging 3-part webinar series was designed to inform and educate pharmacists in all practice settings who are involved in the care of patients with T2DM, bridging the gap of learning about the new classes of medications for T2DM, including their pathophysiologic basis of action across the continuum of care for patients with T2DM, while keeping in mind the cardiovascular safety of these glucose-lowering medications.
Attend one, two, or all three webinars and gain confidence in applying the results of recent studies to clinical practice.
Part 1 - “Type 2 Diabetes—Pathophysiology and Pharmacology Review”
Wednesday, March 22, 2017 at 1:00 PM EDT
Part 2 – “Intensifying Therapy after Basal Insulin Optimization in Type 2 Diabetes—Options for Targeting Postprandial Control”
Thursday, March 30, 2017 at 1:00 PM EDT
Part 3 – “Cardiovascular Outcome Trials (CVOTs): Practical Considerations for your Type 2 Diabetes Patients”
Wednesday, April 5, 2017 at 1:00 PM EDT
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Disclosures to Participants
Conflicts of Interest and Financial Relationships
Presenter and Program Chair:
Joshua J. Neumiller, PharmD, CDE, FASCP
• Advisory Board/Consultant: Eli Lilly & Boehringer Ingelheim
• Research Grant Support to WSU: Novo Nordisk
Content Reviewer:
Tricia Russell, PharmD, BCPS, CDE has nothing to disclose.
Learning Objectives
After completing this webinar, participants will be able to:
1. Describe the clinical pharmacology of the dipeptidyl peptidase-4 (DPP-4) inhibitors, glucagon-like peptide-1 (GLP-1) receptor agonists, and sodium-glucose cotransporter-2 (SGLT-2) inhibitors
2. Understand the concept of implementing combination pharmacotherapy by addressing complementary pathophysiologic targets
3. Describe the role of DPP-4 inhibitors, GLP-1 receptor agonists, and SGLT-2 inhibitors as monotherapy and in combination with other medications for the treatment of type 2 diabetes (T2DM)
Normal Regulation of Glucose Homeostasis
Glucose output Glucose uptake
Glucagon(α-cell)
Insulin(β-cell)
Pancreas
Liver Muscle
Porte D Jr, Kahn SE. Clin Invest Med. 1995;18(4):247-254.Kahn CR, Saltiel AR. Joslin’s Diabetes Mellitus. 14th ed. Lippincott Williams & Wilkins; 2005:145-168.
Normal blood glucose
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Glucose output Glucose uptake
Glucagon(α-cell)
Insulin(β-cell)
Pancreas
Liver
Hyperglycemia
Muscle
Islet cell dysfunction
Del Prato S, MarchettiP. Horm Metab Res. 2004;36(11-12):775-781.Porte D Jr, Kahn SE. Clin Invest Med. 1995;18(4):247-254.Kahn CR, Saltiel AR. Joslin’s Diabetes Mellitus. 14th ed. Lippincott Williams & Wilkins; 2005:145-168.
Dysregulation of Glucose Homeostasis in T2DM
*
* Reduced effect of insulin indicating insulin resistance
T2DM
Years from diagnosis 0 5-10 -5 10 15
Pre-diabetes
OnsetDiagnosis
Insulin secretion
Insulin resistance
Postprandial glucose (PPG)
Macrovascular complications
Fasting glucose (FPG)Microvascular complications
Ramlo-Halsted BA, Edelman SV. Prim Care. 1999;26(4):771-789.Nathan DM. N Engl J Med. 2002;347(17):1342-1349.
Natural History of T2DM
Pathophysiologic Defects in T2DM
DeFronzo RA. Diabetes. 2009;58(4):773-795.
Decreased incretin effect
Neurotransmitterdysfunction
Islet b-cellImpairedinsulin
secretion
Decreased glucose uptake
Islet a-cellIncreased
glucagonsecretion
Increased lipolysis
Increased glucose reabsorption
Increasedhepaticglucose
production
Hyperglycemia
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Select Antihyperglycemic Pharmacotherapy Options
Insulin
• Prandial insulin
• Insulin lispro
• Insulin aspart
• Insulin glulisine
• Insulin human inhaled
• Regular human insulin
• Basal insulin
• Insulin NPH
• Insulin detemir
• Insulin glargine U-100
• Insulin glargine U-300
• Insulin degludec
Oral medications
• Biguanides
• Sulfonylureas
• Meglitinides
• Thiazolidinediones
• a-Glucosidase inhibitors (AGIs)
• DPP-4 inhibitors
• SGLT-2 inhibitors
Non-insulin injectable agents
• GLP-1 receptor agonists
• Amylin mimetic
Cornell S, Dorsey VJ. Postgrad Med. 2012;124(4):84-94.
American Diabetes Association Standards of Medical Care in Diabetes. Approaches to glycemic treatment.
Diabetes Care. 2017;40(Suppl 1):S64-S74.
Pathophysiologic Defects in T2DM
DeFronzo RA. Diabetes. 2009;58(4):773-795.
Decreased incretin effect
Neurotransmitterdysfunction
Islet b-cellImpairedinsulin
secretion
Decreased glucose uptake
Islet a-cellIncreased
glucagonsecretion
Increased lipolysis
Increased glucose reabsorption
Increasedhepatic glucose
production
Hyperglycemia
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Nauck M, et al. Diabetologia. 1986;29(1):46-52.
The Incretin Effect
Oral glucose load
Intravenous glucose infusion
Time (min)
Insu
lin (
mU
/L)
80
60
40
20
0
18060 1200
Time (min)
Insu
lin (
mU
/L)
80
60
40
20
0
18060 1200
Incretineffect
Control subjects (n = 8) People with T2DM (n = 14)
Endogenous GLP-1: Effects in Humans
GLP-1 is secreted fromL-cells of the jejunum
and ileum
GLP-1 then…
• Stimulates glucose-dependent insulin secretion
• Suppresses glucagonsecretion
• Slows gastric emptying• Increases satiety
After food ingestion…
Drucker DJ. Curr Pharm Des. 2001;7(14):1399-1412. Drucker DJ. Mol Endocrinol. 2003;17(2):161-171.
Drucker DJ. Cell Metab. 2006;3(3):153-165.
Pharmacological Strategies to Augment the Incretin Effect
• GLP-1 secretion is impaired in T2DM• Natural GLP-1 has an extremely short half-life
Add GLP-1 analogues with longer half-life:
Exenatide (Byetta)
Liraglutide (Victoza)
Lixisenatide (Adlyxin)
Once-weekly Exenatide (Bydureon)
Albiglutide (Tanzeum)
Dulaglutide (Trulicity)
Block DPP-4 to slow the enzymatic degradation of GLP-1:
Sitagliptin (Januvia)
Saxagliptin (Onglyza)
Linagliptin (Tradjenta)
Alogliptin (Nesina)
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Neumiller JJ. Med Clin North Am. 2015;99(1):107-129.
Comparison of Incretin-based Therapies
Select clinical properties of DPP-4 inhibitors and GLP-1 receptor agonists
DPP-4 inhibitors GLP-1 receptor agonists
Slow gastric emptying No Yes
Effect on postprandial hyperglycemia
Yes Yes (variable)
Effect on weight Weight neutral Weight loss
Route of administration Oral Subcutaneous injection
Associated with hypoglycemia when used as monotherapy
No No
Comparison of DPP-4 Inhibitors Currently Available in the United States (U.S.)
Characteristic Sitagliptin(Januvia)
Saxagliptin(Onglyza)
Linagliptin(Tradjenta)
Alogliptin(Nesina)
Hypoglycemia risk
Low Low Low Low
Initial dose (normal CrCl)
100 mg daily 5 mg daily 5 mg daily 25 mg daily
Dose adjustment for renal impairment
•CrCl < 50 mL/min: 50 mg daily•CrCl ≤ 30 mL/min: 25 mg daily
•CrCl ≤ 50 mL/min: 2.5 mg daily
No adjustment recommended on the basis of renal function
•CrCl < 60 mL/min: 12.5 mg daily•CrCl < 30 mL/min: 6.25 mg daily
Sitagliptin prescribing information, 2009.Saxagliptin prescribing information, 2009.Linagliptinprescribing information, 2012.Alogliptinprescribing information, 2013.
CrCl = creatinine clearance.
Effects of Currently Available DPP-4 Inhibitors
Characteristic Sitagliptin(Januvia)
Saxagliptin(Onglyza)
Linagliptin(Tradjenta)
Alogliptin(Nesina)
Average A1C lowering*
0.65% to 0.79% 0.36% to 0.82% 0.50% to 0.69% 0.47% to 0.85%
Average weight change*
+0.3 to +1.2 kg -0.51 to +1.3 kg +0.33 to +1.1 kg +0.14 to +0.51 kg
Neumiller JJ. Med Clin North Am. 2015;99(1):107-129.Sitagliptin prescribing information, 2009.
Saxagliptin prescribing information, 2009.Linagliptinprescribing information, 2012.Alogliptinprescribing information, 2013.
*PBO-subtracted change from baseline; baseline characteristics of study groups and concomitant medications varied among studies.
A1C = Hemoglobin A1C.
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Key Considerations for the Use of DPP-4 Inhibitors
• Oral administration
• Generally weight neutral
• Side effects:– Headache
– Nasopharyngitis/upper respiratory tract infections
– Generally well tolerated
• Warnings/precautions:– Pancreatitis
– Hypoglycemia (when added to secretagogues or insulin)
– Allergic reactions
– Heart failure? (saxagliptin & alogliptin)
Comparison of A1C Reductions with GLP-1 Receptor Agonists
-2
-1.8
-1.6
-1.4
-1.2
-1
-0.8
-0.6
-0.4
-0.2
0
DURATION-1 DURATION-6DURATION-5 LEAD-6 GetGoal-XAWARD-6AWARD-1 HARMONY-7
Exe
nat
ide
BID
Exe
nat
ide
QW
Exe
nat
ide
BID
Exe
nat
ide
BID
Exe
nat
ide
BID
Exe
nat
ide
QW
Exe
nat
ide
QW
Lira
glu
tid
e
Lira
glu
tid
e
Du
lagl
uti
de
1.5
mg
Du
lagl
uti
de
0.7
5 m
g
Du
lagl
uti
de
1.5
mg
Lira
glu
tid
e
Lira
glu
tid
e
Alb
iglu
tid
e
Lixi
sen
atid
e
Exe
nat
ide
BID
Adapted from Trujillo JM, et al. Ther Adv Endocrinol Metab. 2015;6(1):19-28.; Erratum. 2015;6(3):135-136.Madsbad S. Diabetes Obes Metab. 2016;18(4):317-332.
Change in A1C (%)
Study
BID = twice daily; QW = once weekly.
Adapted from Triplitt C, Solis-Herrera C. Diabetes Educ. 2015;41(suppl 1):32S-46S.
GLP-1 Receptor Agonists: Weight Change Ranges in Phase III Trials
- 0.5 0.0 0.5 1.0 1.5 2.0 2.5 3.0 3.5 4.0 4.5
Weight reduction (kg)
Exenatide 10 µg BID
Exenatide 2 mg QW
Liraglutide 1.2 mg QD
Liraglutide 1.8 mg QD
Dulaglutide 0.75 mg QW
Dulaglutide 1.5 mg QW
Albiglutide 30 mg QW
*
+0.28 to -1.21 kg
-1.30 to -3.03 kg
+0.21 to -2.6 kg
-0.20 to -3.60 kg
+0.30 to -2.6 kg
-2.00 to -3.7 kg
-1.07 to -3.60 kg
Lixisenatide 10 - 20 mcg QD -0.28 to -1.21 kg
QD = once daily.
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Drucker DJ, et al. Lancet. 2008;372(9645):1240-1250.
Comparison of Exenatide Products (30-week Data)
Exenatide extended-release
suspension
Exenatide BID
A1C reduction (%)FPG reduction (mg/dL)PPG reduction (mg/dL)Achievement of A1C < 7%
1.9a
41b
9677%d
1.525
124c
61%Change in body weight (kg) -3.7 -3.6aP = 0.0023; bP < 0.0001; cP = 0.0124; dP = 0.0039 versus comparator.
Key Considerations for the Use of GLP-1 Receptor Agonists
• Subcutaneous administration
• Can result in weight loss
• Side effects:– Nausea/vomiting
– Injection site reactions
• Contraindications:– Personal/family history of medullary thyroid carcinoma or
multiple endocrine neoplasia type 2 (long-acting products)
• Warnings/precautions:– Pancreatitis
– Hypoglycemia (when added to secretagogues or insulin)
Pathophysiologic Defects in T2DM
DeFronzo RA. Diabetes. 2009;58(4):773-795.
Decreased incretin effect
Neurotransmitterdysfunction
Islet b-cellImpairedinsulin
secretion
Decreased glucose uptake
Islet a-cellIncreased
glucagonsecretion
Increased lipolysis
Increased glucose reabsorption
Increased hepaticglucose
production
Hyperglycemia
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~180 grams of glucose filtered per day
SGLT-2
Virtually no urinary glucose
excretion
SGLT-1
Reabsorption of ~90% of filtered
glucose
Reabsorption of ~10% of filtered
glucose
Renal Glucose Reabsorption Under Normal Conditions
Neumiller JJ, et al. Drugs. 2010;70(4):377-385.
SGLT-2 Inhibition
Glucose
Glomeruli
Blood vessel
SGLT-1
SGLT-2
SGLT-2 inhibitor Urine
SGLT-1
Small intestine
Idris I, Donnelly R. Diabetes Obes Metab. 2009;11(2):79-88.
~90% of filtered glucose is reabsorbed through SGLT-2 transporters in the
early proximal tubule
Inhibition of SGLT-2 transporters in the proximal tubule blocks the reabsorption of filtered glucose,
leading to increased glucose excretion via urine
Canagliflozin versus Glimepiride as Add-on to Metformin: Change in A1C
Cefalu WT, et al. Poster presented at the 73rd Scientific Session of the ADA. June 21-25, 2013; Chicago, IL.CANA = canagliflozin; GLIM = glimepiride.
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Canagliflozin versus Glimepiride as Add-on to Metformin:Change in Weight
Cefalu WT, et al. Poster presented at the 73rd Scientific Session of the ADA. June 21-25, 2013; Chicago, IL.
Comparison of SGLT-2 Inhibitors Currently Available in the U.S.
Characteristic Canagliflozin(Invokana)
Dapagliflozin(Farxiga)
Empagliflozin(Jardiance)
Hypoglycemia risk (as monotherapy)
Low Low Low
Dose 100 mg daily before breakfast; increase to 300
mg daily, if needed
5 mg daily in the morning; increase to 10 mg daily, if
needed
10 mg daily in the morning; increase
to 25 mg, if needed
Effect on weight Weight loss Weight loss Weight loss
Renal Dose Adjustment of SGLT-2 Inhibitors
Canagliflozin prescribing information, 2017.Dapagliflozin prescribing information, 2016.Empagliflozin prescribing information, 2016.
Kohan DE, et al. Kidney Int. 2014;85(4):962-971.
Agent Dosing in CKD stages 3, 4 and 5 (non-dialysis)
Canagliflozin(Invokana)
• eGFR ≥ 60 ml/min/1.73 m2
No dosage adjustment needed• eGFR 45 - 59 ml/min/1.73 m2
Do not exceed 100 mg/day by mouth• eGFR < 45 ml/min/1.73 m2
Do not initiate and discontinue in patients currently receiving drug
Dapagliflozin(Farxiga)
Do not initiate; discontinue with eGFR < 60 mL/min/1.73 m2
Empagliflozin(Jardiance)
• eGFR ≥ 45 ml/min/1.73 m2
No dosage adjustment needed• eGFR < 45 ml/min/1.73 m2
Do not initiate and discontinue in patients currently receiving drug
eGFR = estimated glomerular filtration rate.
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Canagliflozin: Less A1C Reduction with Declining eGFR
Woo V, et al. Poster presented at the 73rd Scientific Session of the ADA. June 21-25, 2013; Chicago, IL.
Key Considerations for the Use of SGLT-2 Inhibitors
• Unique mechanism of action– Have been studied in combination with a variety of other medication classes
• Oral administration
• Low hypoglycemia risk as monotherapy– Caution when used with secretagogues or insulin
• Can result in weight loss and modest decrease in blood pressure
• Side effects:– Genital mycotic infections
– Urinary tract infections
– Orthostasis (especially in elderly, chronic kidney disease, diuretic use)• Watch volume status
– Increased levels of low-density lipoproteins
– Euglycemic diabetic ketoacidosis
American Diabetes Association Standards of Medical Care in Diabetes. Approaches to glycemic treatment.
Diabetes Care. 2017;40(Suppl 1):S64-S74.
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Unger J, Parkin CG. Postgrad Med. 2010;122(3):145-157.Cornell S, Dorsey VJ. Postgrad Med. 2012;124(4):84-94.
Comparison of Glucose-lowering Abilities of T2DM Pharmacotherapy Options
MonotherapyRoute of
administration Targets insulin
resistanceTarget glucose:
FPG or PPGA1C reduction*
(%)
Sulfonylurea Oral No Both 1.5 – 2.0
Metformin Oral Yes FPG 1.5
Glitazones Oral Yes Both 1.0 – 1.5
Meglitinides Oral No PPG 0.5 – 2.0
AGIs Oral No PPG 0.5 – 1.0
DPP-4 inhibitors Oral No PPG 0.5 – 0.7
Bile acid sequestrant Oral No PPG 0.4
Dopamine agonists Oral No PPG 0.4
SGLT-2 inhibitors Oral ↓ glucose toxicity Both 0.7 – 1.1
GLP-1 receptor agonists Injectable NoShort-acting – PPGLong-acting – Both
0.8 – 1.5
Amylin analogs Injectable No PPG 0.6
Insulin Injectable ↓ glucose toxicity Basal – FPGBolus – PPG
↓ as much as needed
*A1C reduction data are not from head-to-head comparative studies.
Once FBG is optimized, start addressing PPG excursions:• Add GLP-1 receptor agonist or• Add 1 rapid-acting insulin
injection to largest meal or• Change to premixed insulin
twice daily
American Diabetes Association Standards of Medical Care in Diabetes. Approaches to glycemic treatment.
Diabetes Care. 2017;40(Suppl 1):S64-S74.
GLP-1 Receptor Agonist vs. Bolus Insulin in Patients with T2DM and Optimized Basal Insulin
Diamant M, et al. Diabetes Care. 2014;37(10):2763-2773.
ΔA
1C
(%
)
0-1.5
-1.0
-0.5
0.0
302 18 24
Insulin lispro
Exenatide BID
Weeks since randomization
4 6 8 12
ΔFP
G (
mm
ol/
L)
0-1.0-0.5
0.51.0
302 18 24
Weeks since randomization
4 6 8 12
0.0
Blo
od
glu
cose
(m
mo
l/L)
PreBreakfast
ΔB
od
y w
eigh
t (k
g)
0-3
0
23
302 18 24
Weeks since randomization
4 6 8 12
1
-1-2
Post Pre Post Pre Post 3AMLunch Dinner
bb
bbbbbb
a a a aa
a a a
5
7
9
11
ap < 0.01 for exenatide BID vs. insulin lisprobp < 0.001 for exenatide BID vs. insulin lispro
Exenatide caused more gastrointestinal issues (47% vs. 13%) but fewer non-nocturnal episodes of hypoglycemia (15% vs. 34%) than insulin lispro
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Reprinted with permission from American Association of Clinical Endocrinologists © 2017 AACE. Garber AJ, Abrahamson MJ, Barzilay JI, et al. AACE/ACE comprehensive type 2 diabetes management algorithm 2017. EndocrPract.2017;23: 207-238.
Reprinted with permission from American Association of Clinical Endocrinologists © 2017 AACE. Garber AJ, Abrahamson MJ, Barzilay JI, et al. AACE/ACE comprehensive type 2 diabetes management algorithm 2017. EndocrPract.2017;23: 207-238.
Reprinted with permission from American Association of Clinical Endocrinologists © 2017 AACE. Garber AJ, Abrahamson MJ, Barzilay JI, et al. AACE/ACE comprehensive type 2 diabetes management algorithm 2017. EndocrPract.2017;23: 207-238.
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Don’t Miss the Upcoming Webinars in This Series!
• Intensifying Therapy after Basal Insulin Optimization in Type 2 Diabetes – Options for Targeting Postprandial Control
Presenter: Dr. Susan Cornell
• Cardiovascular Outcome Trials (CVOTs): Practical Considerations for Your Type 2 Diabetes Patients
Presenter: Dr. Curtis Triplitt
Thank you!
Special Thanks:
• Postgraduate Healthcare Education, LLC
• Susan Cornell, PharmD
• Curtis Triplitt, PharmD
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