Disclosure New Drugs for Diabetes: No conflict of interest to - PDF document

Disclosure New Drugs for Diabetes: No conflict of interest to disclose Which Ones, For Which Patients? Primary Care Medicine: Principles and Practice Lisa Kroon, PharmD, CDE Chair and Professor of Clinical Pharmacy UCSF School of Pharmacy Learning Objectives Medication Treatment Options To 2000  Insulin (human and analogs)  Describe the mechanism of action and unique characteristics of the various (new) classes of  Sulfonylureas (1950’s) medications used in type 2 diabetes that are  Biguanides (metformin; 12/94) recommended as 2 nd line agents.  Discuss contraindications, precautions for use, and  Alpha-glucosidase inhibitors (Acarbose 9/95) side effect profiles of these medications.  Meglitinides (Repaglinide 12/97; Nateglinide 12/00)  Select among the classes of medications to develop  Thiazolidinediones (Rosiglitazone 5/99; Pioglitazone 7/99) appropriate and effective medication regimens to improve glycemic control for an individual patient. 1

Diabetes-Related Complications among U.S. Adults Medication Treatment Options with and without Diagnosed Diabetes (1990–2010) Since 2005  Amylin (pramlintide)  Glucagon-like peptide receptors agonists (GLP-1 RAs)  Dipeptidyl peptidase-4 inhibitors (DPP-4 inhibitors)  Bile acid sequestrants (colesevelam)  Dopamine agonist (bromocriptine)  Sodium-glucose cotransporter- 2 inhibitors (SGLT-2 inhibitors) Gregg EW et al. N Engl J Med 2014;370:1514-1523 . DCCT: Cumulative Incidence of First UKPDS-10 year Follow-Up Occurrence of Nonfatal Myocardial Infarction, Glucose Control Stroke, or Death from Cardiovascular Disease Holman RR et al. NEJM 2008;359:1577 [UKPDS 80] 3,277 patients (of 4,209) entered post-trial monitoring; seen annually for 5 years Mean Glycated Hemoglobin: Difference between conventional and control groups lost within 1 year after study ended 57% ↓ risk The Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications (DCCT/EDIC) Study Research Group. N Engl J Med 2005;353:2643-2653. 2

Antihyperglycem ic Therapy in Type 2 Diabetes UKPDS-10 year Follow-Up Clinical Outcomes Outcome SFU and Insulin Groups Metformin Group Relative Risk (p-value) Relative Risk (p- value) Any DM-related endpoint ↓ 9% (0.04) ↓ 21% (0.01) MI ↓ 15% (0.01) ↓ 33% (0.005) Microvascular disease ↓ 24% (0.001) ↓ 16% (0.31) Death from any cause ↓ 13% (0.007) ↓ 27% (0.002) “Legacy Effect” Across studies to date, tight glycemic control consistently ↓ RR of nonfatal MI by 15%. Holman RR et al. NEJM 2008;359:1577 [UKPDS 80] Rodriguez-Gutierrez R, Montori RM. Circ Cardiovasc Qual Outcomes; 2016 Sep;9(5):504-12. doi: 10.1161/CIRCOUTCOMES.116.002901. Epub 2016 Aug 23 ADA. 7. Approaches to Glycemic Treatment. Diabetes Care 2015; 38(suppl 1): S43. Figure 7.1; adapted with ADA. Standards of Medical Care-2016. Diabetes Care 2016;39;Suppl 1 permission from Inzucchi SE, et al. Diabetes Care, 2015; 38: 140-149 Tailored Approach to the Management of Glycemic Goals Hyperglycemia  HbA1c < 7.0% (mean PG  150-160 mg/dl)  Pre-prandial PG 80-130 mg/dl  Post-prandial PG <180 mg/dl  Individualization is key:  Tighter targets (<6.5%) – short duration of diabetes, long life expectancy, no significant CVD  Looser targets (<8.0%) – long-standing diabetes, limited life expectancy, advanced micro/macro complications, comorbidities, hypoglycemia prone, etc. Avoidance of hypoglycemia ADA. 5. Glycemic Targets. Diabetes Care 2016;39(Suppl 1):S43 . Diabetes Care, Diabetologia. 19 April 2012 [Epub ahead of print] 3

Why Metformin as 1 st Line? Case Study  Demonstrated long-term impact on macrovasular  MK, a 52 year old male, was diagnosed with type 2 complications diabetes. [A1C 8.1%; LDL-C 66;TG 148;HDL-C 53; BMI  Stimulates AMP-activated protein kinase, which  hepatic 32; BP136/80]. Other medical problems include glucose output hypertension (on HCTZ 25 mg daily, benazepril 40 mg  Inhibits mitochondrial respiratory chain, causing shift daily) and dyslipidemia (on atorvastatin 40 mg daily). towards anaerobic metabolism (lactate is by-product) resulting in  energy for gluconeogenesis He was started on metformin and over the next 2  +CV effects:  TG,  LDL-C,  HDL-C; improves endothelial function months, the metformin is titrated to 1000 mg BID. His A1C is now 7.1%.  Other effects: ? anticancer properties  SE: GI (diarrhea, nausea, anorexia, metallic taste), lactic  What is your assessment of his glycemic control? Is he at goal? acidosis, vit B 12 deficiency  No weight gain; no hypoglycemia (except when used in combo therapy)  Affordable Advancing to Dual Therapy Case Study, cont’d  It is now 2 years later and MK still is taking metformin 1000 mg po BID.  Labs: A1C 8.2% (was as low as 6.5% 1 year after starting metformin); eGFR 80;LFT’s wnl; BMI 28.  What is your assessment?  What is his A1C goal? Combination Therapy:  What do you recommend? Combine Agents with Different Mechanisms of Action ADA. 7. Approaches to Glycemic Treatment. Diabetes Care 2015; 38(suppl 1): S43. Figure 7.1; adapted with permission from Inzucchi SE, et al. Diabetes Care, 2015; 38: 140-149 4

Incretin-Based Therapies DPP ‐ 4 Inhibitors SFUs/Glinides GLP ‐ 1 Rec. Agonists  Gut hormones released postprandially GLP ‐ 1 Rec. Agonists  2 main gut incretins  Glucose-dependent insulinotropic polypeptide (GIP) • Released by K cells in duodenum Acarbose  Glucagon-like peptide-1 (GLP-1) Miglitol • Released by L cells in small intestines • Levels are diminished in type 2 DM post-meal; t 1/2 <2 minutes  Rapidly degraded by dipeptidyl peptidase IV (DPP-IV) • GLP-1 analogs (injectable) • DPP-IV inhibitors (oral, daily) TZDs Metformin http://professional.diabetes.org/ImageBank.aspx “Incretin Effect” in Healthy Subjects Actions of GLP-1 Oral Glucose GLP-1: Secreted upon the Intravenous (IV) Glucose ingestion of food Promotes satiety and * inhibits appetite 200 2.0 * Plasma Glucose (mg/dL) * C-peptide (nmol/L) Alpha cells: 1.5 Incretin Effect *  Postprandial * glucagon secretion * 100 1.0 Liver: *  Glucagon reduces hepatic 0.5 Beta cells: glucose output - Enhances glucose-dependent insulin secretion 0 0.0 Stomach: -  Beta cell mass -  apoptosis Slows gastric emptying 0 60 120 180 0 60 120 180 Time (min) Time (min) Flint A, et al. J Clin Invest . 1998;101:515-520; Data from Larsson H, et al . Acta Physiol Scand. 1997;160:413-422 Nauck MA, et al. J Clin Endocrinol Metab . 1986;63:492-498 Nauck MA, et al. Diabetologia . 1996;39:1546-1553; Data from Drucker DJ. Diabete s. 1998;47:159-169 5

Postprandial Plasma Levels of Exenatide GLP-1 RAs: Comparisons Exceeded Physiologic Levels of GLP-1 Baseline Exenatide Lixisenatide Liraglutide Exenatide XR Albiglutide Dulaglutide Exenatide 75 75 (Byetta) (Adlyxin) (Victoza) (Bydureon) (Tanzeum) (Trulicity) Sitagliptin 2-h Postprandial Plasma GLP-1 (pM) FDA 2005 Pending 2010 2012 2014 2014 Approved (NDA 63.8 2-h Plasma Exenatide (pM) 09.25.15) 50 50 Glucose PPG PPG FPG/PPG FPG>PPG FPG>PPG FPG>PPG profile target 25 25 Admin Twice daily Once daily Once daily Once Once Once weekly weekly weekly 15.1 Delivery Multi-use Multi-use Multi-use Single-use Single-use Single-use pen pen pen pen* pen* pen 7.9 7.2 0 0 Renal <30 not rec; No dosage No dosage <30 not rec; No dosage No dosage dosing 30-50 use adjustment adjustment 30-50 use adjustment adjustment Plasma Exenatide Plasma GLP-1 caution caution Patients with T2D; Evaluable population, n = 61 for all treatment groups; Mean ± SE * Requires reconstitution 2-wk post-treatment concentration data; DeFronzo RA, et al. Curr Med Res Opin 2008; 24:2943-2952 GLP-1 RAs: Nausea Comparison of GLP-1 RAs (A1C) While nausea declines after 3 weeks, it persists in some patients. Pratley R et al. Int J Clin Pract 2011;65:397-407 Trujillo J. Therapeutic Advances in Endocrinology & Metabolism. 2015;6:19-28. 6

DPP-4 Inhibitors: Comparisons Comparison of GLP-1 RAs (Weight) Sitagliptin Saxagliptin Linagliptin Alogliptin (Januvia) (Onglyza) (Tradjenta) (Nesina) FDA 2006 2009 2011 2013 Approved Dosing frequency 100 mg daily 5 mg daily 5 mg daily 25 mg daily Efficacy ↓ 0.6% ↓ 0.7% ↓ 0.4% ↓ 0.8% ( ↓ A1C) monotherapy Efficacy ↓ 0.7% ↓ 1.2% ↓ 0.7% ↓ 0.9% ( ↓ A1C) combination therapy Renal dosing (ml/min) 50 mg daily 2.5 mg daily No dosage 12.5 mg (30-60) (30-50) (<50)* adjustment 6.25 mg (<30) 25 mg (<30) Trujillo J. Therapeutic Advances in Endocrinology & Metabolism. 2015;6:19-28. Baetta R. Drugs 2011;71:1441-67. * Also DDI with CYP3A4/5 GLP -1 RAs vs. DPP-4 Inhibitors Incretin Agents: Safety Issues (not head-to-head)  Thyroid cancer and neoplasia  Thyroid C-cell tumors in rodent models  CI/not recommended for use in patients with personal or family history of MTC (medullary thyroid cancer) or MEN 2  Black box warning for liraglutide, exenatide XR, albiglutide, dulaglutide  Pancreas  In pancreata of age-matched organ donors, DM treated with incretins had ~40% ↑ pancrea � c mass (exocrine cell proliferation and dysplasia (intraepithelial neoplasia). [ Butler et al. Diabetes. 2013]  Pancreatitis Aroda VR et al. Clinical Therapeutics. 2012 7