Diabetes Update Part 2 of 3 Division of Endocrinology Department of Medicine Wayne State University Medical School Detroit, Michigan

Why the Interest in Incretins ?

Major discussion point: INtestine SeCRETion INsulin

The Incretin Defect in Type 2 Diabetes Insulin Resistance Relative Insulin Deficiency DISCUSSION: Classic understanding of the pathogenesis of type 2 diabetes consists of progressive insulin resistance coupled with gradual deterioration of beta-cell function The literature makes it clear there is another fundamental defect in the pathogenesis of type 2 diabetes: dysregulation of incretin hormones such as GLP-1 The acute effects of incretin hormones play a major role in insulin secretion from the beta cell In fact, the incretin effect accounts for up to 70% of the insulin response to oral glucose intake1 REFERENCE: Holst JJ, Gromada J. Role of incretin hormones in the regulation of insulin secretion in diabetic and nondiabetic humans. Am J Physiol Endocrinol Metab. 2004;287(2):E199-E206. *Note to speakers: This is a graphic that is used in other speaker slide decks. Please note that the title and graphics have been changed slightly to reflect the core message of this deck. Hyperglycemia Type 2 Diabetes Incretin effect accounts for up to 70% of the insulin response to oral glucose intake1 1. Holst JJ, Gromada J. Role of incretin hormones in the regulation of insulin secretion in diabetic and nondiabetic humans. Am J Physiol Endocrinol Metab. 2004;287(2):E199-E206. 4 4

GLP-1 Effects in Humans Understanding the Natural Role of Incretins DISCUSSION POINTS: --Upon food ingestion, GLP-1 is secreted into the circulation from L cells of small intestine. --GLP-1 increases beta-cell response by enhancing glucose-dependent insulin secretion. --GLP-1 decreases beta-cell workload and hence the demand for insulin secretion by: --Regulating the rate of gastric emptying such that meal nutrients are delivered to the small intestine and, in turn, absorbed into the circulation more smoothly, reducing peak nutrient absorption and insulin demand (beta-cell workload) --Decreasing postprandial glucagon secretion from pancreatic alpha cells, which helps to maintain the counterregulatory balance between insulin and glucagon --Reducing postprandial glucagon secretion, GLP-1 has an indirect benefit on beta-cell workload, since decreased glucagon secretion will produce decreased postprandial hepatic glucose output --Having effects on the central nervous system, resulting in increased satiety (sensation of satisfaction with food intake) and a reduction of food intake --By decreasing beta-cell workload and improving beta-cell response, GLP-1 is an important regulator of glucose homeostasis. SLIDE BACKGROUND: --Effect on Beta-cell: Drucker DJ. Diabetes. 1998; 47:159-169 --Effect on Alpha cell: Larsson H, et al. Acta Physiol Scand. 1997; 160:413-422 --Effects on Liver: Larsson H, et al. Acta Physiol Scand. 1997; 160:413-422 --Effects on Stomach: Nauck MA, et al. Diabetologia. 1996; 39:1546-1553 --Effects on CNS: Flint A, et al. J Clin Invest. 1998; 101:515-520

Leveraging the Therapeutic Potential of GLP-1 DISCUSSION POINTS: --The half-life of GLP-1 is less than 2 minutes – meaning a continuous infusion of exogenous GLP-1 would be necessary to overcome the enzymatic degradation of GLP-1 by DPP-IV. --Inhibition of DPP-IV, which would extend the half-life of endogenous GLP-1, is one avenue of research. --Incretin mimetics are compounds that mimic GLP-1’s glucoregulatory effects, but are resistant to DPP-IV degradation. Examples are: --Analogs of the natural GLP-1 molecule. --Exenatide, a naturally occurring incretin mimetic that mimics multiple glucoregulatory effects of GLP-1 and is resistant to DPP-IV enzymatic degradation, is the first FDA-approved incretin mimetic. Exenatide is the active ingredient in BYETTA.

ADA/EASD Consensus Statement Includes a GLP-1 Receptor Agonist STEP 1 At diagnosis: Lifestyle + MET If A1C ≥7% STEP 2 Tier 1: Well-validated core therapies* OR Tier 2: Less well-validated therapies* “If hypoglycemia is particularly undesirable…” and/or “promotion of weight loss is a consideration…” Lifestyle + MET + SFU Lifestyle + MET + basal insulin Lifestyle + MET + GLP-1 receptor agonist† Lifestyle + MET + PIO DISCUSSION: Highlight the updated American Diabetes Association (ADA) consensus treatment algorithm for the treatment of type 2 diabetes and exenatide’s place before basal insulin as a Tier 2 approach An ADA consensus statement represents the authors' collective analysis, evaluation, and opinion at the time of publication and does not represent official association opinion CLICK #1: At diagnosis, recommend lifestyle interventions and check A1C every 3 months until A1C is <7% and then at least every 6 months CLICK #2: Course of therapy should be augmented if A1C ≥7% Consider a Tier 1 or Tier 2 approach, with special consideration to lifestyle+MET+GLP-1 receptor agonist to avoid greater risk of hypoglycemia and if patient is a good candidate for weight loss Lifestyle+MET+basal insulin should be your next treatment before moving to Tier 3 intensive insulin therapy (Build 3) REFERENCE: 1. Nathan DM, Buse JB, Davidson MB, et al. Management of hyperglycemia in type 2 diabetes: a consensus algorithm for the initiation and adjustment of therapy: update regarding thiazolidinediones: a consensus statement from the American Diabetes Association and the European Association for the Study of Diabetes. Diabetes Care. 2009;32(1):193-203. Lifestyle + MET + basal insulin MET, metformin PIO, pioglitazone SFU, sulfonylurea Lifestyle + MET + PIO + SFU STEP 3 Lifestyle + MET + intensive insulin *Validation based on clinical trials and clinical judgment. †Insufficient clinical use to be confident regarding safety. Adapted from Nathan DM, et al. Diabetes Care. 2009. 7 7 7

Liraglutide (Victoza) and Exenatide (Byetta) Newer GLP 1 analogue. Indicated in monotherapy or in combination with metformin, SU, TZD, or combination therapy. Dosed once or twice daily Uses the convenient pen. Maintains weight loss and glycemic control.

Why Insulin in Type 2 Diabetes?

Beta-Cell Function Declines as Diabetes Progresses DISCUSSION: Beta-Cell Function Declines as Diabetes Progresses The reason that diabetes develops and progresses is because there is a loss of beta-cell function. The data points for the time of diagnosis (0) and the subsequent 6 years were taken from a subset of the UKPDS population and were determined by the homeostatic assessment model (HOMA). The beginning of beta-cell loss was estimated by extrapolation back to 100% function and the lack of significant insulin secretion by extrapolation forward. In the earliest phase, when beta-cell function is not impaired, the ability of the beta cells to hypersecrete insulin masks the impaired glucose tolerance, often for years. As beta cell function declines further, mild postprandial hyperglycemia develops, reflecting the inability of the beta cell to hypersecrete enough insulin to overcome insulin resistance. Based on this hypothetical model, at the time of diagnosis, beta-cell function has typically declined by 50%. Reference Lebovitz HE. Insulin secretagogues: old and new. Diabetes Reviews. 1999;7:139-153. 10

Possible Barriers to the Initiation of Insulin DISCUSSION: Possible Barriers to the Initiation of Insulin There are patient-related and health care professional–related barriers to initiating insulin, some of which overlap. Patient-related barriers include: Fear of needles Negative misconceptions about insulin Inconvenience Patient perception as personal failure Health care professional–related barriers include: Lack of available educational tools/resources Lack of familiarity/comfort with insulin Time constraints Overlapping barriers include: Fear of hypoglycemia Weight gain Complexity of dosing regimen Cost References Korytkowski M. When oral agents fail: practical barriers to starting insulin. Int J Obes. 2002;26(suppl 3):S18-S24. Larme AC, Pugh JA. Evidence-based guidelines meet the real world: the case of diabetes care. Diabetes Care. 2001;24:1728-1733. Snoek FJ. Breaking the barriers to optimal glycaemic control-what physicians need to know from patients’ perspectives. Int J Clin Pract Suppl. 2002;129:80-84. 11

Mimicking Physiology: Basal and Prandial Insulin Breakfast Lunch Dinner Prandial Insulin 3/day Plasma Insulin Plus DISCUSSION: Good glycemic control requires a combination of long-acting (basal) and rapid-acting (prandial) insulin1 Once an individual is given an appropriate basal insulin dose, the fine-tuning required to achieve tight glycemic control usually involves adjustments in the timing and dosage of rapid-acting prandial insulin1 These prandial doses make it possible to compensate for postprandial elevations in blood glucose, ideally without exceeding healthy insulin levels in the blood between meals and at night1 Reference White JR Jr, Campbell RK, Hirsch IB. Novel insulins and strict glycemic control: analogues approximate normal insulin secretory response. Postgrad Med. 2003;113:30-36. Basal 1/day 4:00 8:00 12:00 16:00 20:00 24:00 4:00 8:00 Time