Pharmacology Updates. Quang T Nguyen, FACP, FACE, FTOS 11/18/17

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1 Pharmacology Updates Quang T Nguyen, FACP, FACE, FTOS 11/18/17

2 14 Classes of Drugs Available for the Treatment of Type 2 DM in the USA ### Class A1c Reduction Hypoglycemia Weight Change Dosing (times/day) 01 Metformin No Neutral-Loss GLP-1 agonists No Loss 1-2, QW Injected 03 DPP-IV inhibitors No Neutral 1, QW 04 SGLT2 inhibitors No Loss 1 05 Sulfonylureas Yes Gain Repaglinide Yes Gain 3 07 Nateglinide Rare Gain 3 08 Bromocriptine No Neutral 1 09 Bile acid sequestrant 0.5 No Neutral α-glucosidase inhibitor No Neutral 3 11 Thiazolidinediones No Gain 1 12 Amylin mimetics No Loss 3, Injected 13 Insulin, rapid-acting Yes Gain 1-4, Injected 14 Insulin, long-acting Yes Gain 1-2, Injected

3 Diabetes Care 2012;35: Choosing the Appropriate Therapy Glucose monitoring? Side effects? Ease of use? Cost? Contraindications? Effectiveness? Extra glycemic effects? Can I lose weight?

4 Characteristics of an Ideal Anti-Hyperglycemic Agent Effective gets patients to goal Well-tolerated and safe Durable effects over years Oral, once daily/weekly therapy Weight loss Lowers blood pressure Reduces microvascular and macrovascular disease

5 Complementary Mechanisms of Action of Current Diabetes Medications Insulin Sulfonylureas Megltinides TZDs Islet b-cell Impaired Insulin Secretion GLP-1 Islet a-cell RA DPP-4 inhibitors Pramlintide GLP-1 RA DPP-4 inhibitors Decreased Incretin Effect Insulin TZDs Increased Lipolysis SGLT-2 inhibitors Increased Glucagon Secretion Metformin Insulin TZD GLP-1RA Bromocriptine GLP-1 RA Increased Hepatic Glucose Production Neurotransmitter Dysfunction Diabetes 2009;58: Increased Glucose Resorption Insulin TZDs Decreased Glucose Uptake

6 Endocr Pract 2016;22 (No. 1) QUESTIONS?

7 Metformin Should be considered cornerstone (1 st line treatment) o if not contraindicated for patients with type 2 DM Low hypoglycemia risk Reduces LDL-C and triglycerides o increases HDL-C Reduces blood pressure Decreases all-cause mortality May decrease cancer risk May increase longevity!

8 Rationale Approach to Prescribing Metformin in the Setting of Chronic Kidney Disease JAMA 2014;312: ; patients with renal problems 2 April 8, 2016 FDA-Metformin safe for some

9 Metformin IR vs ER/XR vs Glumetza

10 RIOMET

11 DPP-IV Inhibitors Januvia Janumet Janumet XR (GLUMETZA) Tradjenta Jentadueto (BID, IR) Jentadueto XR Onglyza Kombiglyze XR Nesina Kazano (IR)

12 DPP-IV Inhibitors Prolong GLP-1 (glucose-dependent insulin secretion, glucagon blocking, delay gastric emptying-satiety) Weight loss A1c: 0.5-1%

13 GLP-1 Receptor Agonists Exenatide (Byetta) Lixisenatide (Lyxumia) Liraglutide (Victoza) Dulaglutide (Trulicity) Exenatide ER (Bydureon) Albiglutide (Tanzeum) Semaglutide (oral and subcutaneous)

14 GLP-1 Actions Increase insulin secretion in a glucose-dependent manner Decrease glucagon secretion from pancreas Increases B-cell mass, increase insulin secretion Decrease food intake by increasing satiety Promote insulin sensitivity A1c: 1-1.5%

15 Plasma Insulin ( U/mL) Plasma Insulin Responses to Oral and Intravenous Glucose: Incretin Effect (GLP-1) Normal Weight: Non-Diabetic Subjects 90 Oral Glucose Intravenous Glucose Time (min) Data from: Perley M, et al. J Clin Invest 1967; 46:

16 The GLP-1 Receptor Agonist Class: Pharmacokinetic Properties GLP-1 Receptor Agonist Short-acting (<24 hours) Long-acting ( 24 hours) Exenatide BID Lixisenatide QDay Liraglutide QDay Dulaglutide QWeek Albiglutide QWeek Semaglutide QWeek Exenatide QWeek Byetta. Summary of Product Characteristics 1 ; Lyxumia. Summary of Product Characteristics 2 ; Victoza. Summary of Product Characteristics 3 ; Diabetes Obes Metab 2011;13: ; Diabetes Obes Metab 2009;11: ; J Clin Endo Metab 2008;93: ; Novo Nordisk. Data on file; 8. Clin Pharmacokinet 2011;50:

17 Short- and Long-acting GLP-1 Receptor Agonists Have Different Effects on Glucose GLP-1 Receptor Agonist Short-acting (<24 hours) Long-acting ( 24 hours) FPG PPG FPG PPG Bolus > Basal Basal > Bolus Diabetes Obes Metab 2012;14:675

18 Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Outcome Results (LEADER) Trial Over 9000 DM 2 with risk factors for CVD over up to 5 years (largest and longest trial for Novo to date) Primary end point o composite outcome of first occurrence of 1) cardiovascular death, 2) nonfatal myocardial infarction, or 3) nonfatal stroke The trial met criteria for both non-inferiority and superiority for all three of the end-point components. The drug significantly reduced the risk of heart attack or stroke.

19 Combination of a Basal Insulin with a GLP-1 Agonist is Scientifically Logical Lancet Diabetes Endocrinol 2014;2:

20 Mode of Action of SGLT 2 Inhibitors in the Kidney Expert Opin Drug Metab Toxicol 2014;10:

21 SGLT 2 Inhibitors Canagliflozin (Invokana) + Metformin (Invokamet) INVOKAMET XR (50/500, 50/1000, 150/500, 150/1000) Dapagliflozin (Farxiga) + Metformin (Xigduo XR) XIGDUO XR (5/500, 5/1000, 10/500, 10/1000) Empagliflozin (Jardiance) + Metformin (Synjardy) + Linagliptin (Glyxambi)

22 EMPA -REG 7020 pts (3.1 years)- composite end point 490/4687 (10.5%) (Empa) 282/2333 (12.1%) (Placebo) Empa signficantly lower risk of death from CVD causes (3.7 vs. 5.9%), hospitalization for CHF (2.7 vs. 4.1) and death from any cause (5.7% vs. 8.3%) No differences in MI, stroke 22

23 EMPA-REG Trial Empagliflozin 3-point Major Adverse Cardiovascular Events (MACE) Time to first occurrence of cardiovascular death, nonfatal MI and nonfatal stroke N Engl J Med 2015;373:

24 EMPA-REG Trial Empagliflozin All-Cause Mortality N Engl J Med 2015;373:

25 Sulfonylureas (Glyburide, Glipizide, and Glimepiride) and Meglitinides (Repaglinide and Nateglinide) Sulfonylureas among most widely used drugs for type 2 DM o Stimulate insulin secretion by binding to the ATP-dependent potassium channel o Effective, inexpensive Caveats: Weight gain Hypoglycemia especially in the elderly Major osteoporotic fractures Increased CVD events* Ischemic Preconditioning Premature b-cell exhaustion-no!! * Glimepiride Does NOT increase CVD events compared with metformin

26 Cycloset A Unique Therapeutic Option The Role of a Dopamine Agonist in the Treatment of Type 2 Diabetes

27 Colesevelam Bile acid sequestrant Decrease LDL but raise TG Avoid in patients with TG > 400 mg/dl A1c: 0.5%

28 Alpha-glucosidase Slow the digestion of starches A1c: 0.5%

29 Thiazolidinediones (TZDs) Pioglitazone Rosiglitazone PPAR-gamma Weight gain/edema: Contraindicated in NYHA Class III-IV Beta cell preservation A1c: 1-1.5%

30 Amylinomimetics Pramlintide Amylin= natural peptide secreted with insulin Suppress glucagon secretion, delay gastric emptying, promote satiety Can be used in type 1 or 2 Injections with meals (tid) along with short acting insulins A1c: %

31 Long-Acting Insulin Basal Insulin Human NPH (N) Detemir (Levemir) Glargine (Lantus)/Biosimilar Insulin Glargine o U300 Lantus (Toujeo) o Lixilan (Glargine + Lixisenatide) o Basaglar - USA (BI/Lilly) Abasria-UK Insulin Degludec (Tresiba) o Xultophy (Degludec + Liraglutide)

32 Rapid Acting Insulin Insulin Aspart (Novolog) Lispro (Humalog) Glulisine (Apidra) Inhaled Insulin (Afrezza) HUMULIN R-U 500

33 Premix Insulins Limitation-2 Insulin Changes at Once 70/30 [ ] 75/25 50/50 Newer designer insulins safer and more predictable. Most come in pen injectors which are easy to use and less cumbersome than vials and syringes.

34 Personal Recommendations First Line Therapy: Metformin (XR) or Glumetza Second Line Therapy: GLP-1 s (Byetta, Victoza, Bydureon, Trulicity, Tanzeum) Second Line Therapy: SGLT-2 Inhibitors (Farxiga, Invokana, Jardiance) Third Line Therapy: Flip Flop of the Second Line Drugs Third Line Therapy: DPP-IV inhibitors Fourth Line: TZDs, SU, Insulin 34

35 Questions/Comments?