GLP-1 Modulates Numerous Functions in Humans GLP-1: Secreted upon the ingestion of food Promotes satiety and reduces appetite 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 Alpha cells:  Postprandial glucagon secretion What Happens to the Incretin Effect in Diabetes? Liver:  Glucagon reduces hepatic glucose output Beta cells: Enhances glucose-dependent insulin secretion Stomach: Helps regulate gastric emptying Data from Flint A, et al. J Clin Invest. 1998;101:515-520; Data from Larsson H, et al. Acta Physiol Scand. 1997;160:413-422 Data from Nauck MA, et al. Diabetologia. 1996;39:1546-1553; Data from Drucker DJ. Diabetes. 1998;47:159-169

Leveraging the Therapeutic Potential of GLP-1 5/18/2018 11:28 PM Leveraging the Therapeutic Potential of GLP-1 GLP-1 Short half-life (2 minutes) Rapidly degraded by dipeptidyl peptidase-IV (DPP-IV) DPP-IV inhibition Could extend endogenous GLP-1 half-life Incretin mimetics Mimic many of the glucoregulatory effects of GLP-1 Resistant to DPP-IV 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. The active ingredient is exenatide. Adapted from Drucker DJ. Diabetes Care. 2003;26:2929-2940

Exenatide, DPP-4 Inhibitors and Long-Acting GLP-1 Agonists: Similarities and Differences Properties/Effect Exenatide1 DPP-4 Inhibitor1 Liraglutide, Exenatide-OW2,3 Glucose-dependent insulin secretion Yes Glucose-dependent glucagon Slows gastric emptying No Little or no Effect on body weight Weight loss Weight neutral Effect on A1c ~1% <1% >1% Effect on fasting glucose Modest Good Effect on postprandial glucose Effect on CVD risk factors Improve (with weight loss) No consistent change Side effects Nausea (pancre-atitis, CRF) ~ None observed (pancreatitis) Less nausea, skin, (?pancreatitis, CRF, MTC) Administration Subcutaneous Twice daily Oral Once daily Daily or weekly 1. Amori RE, et al. JAMA. 2007;298:194-206. 2. Exenatide LAR (once weekly): Drucker DJ, et al. Lancet. 2008;372:1240-1250. 3. Liraglutide: Buse JB, et al. Lancet. 2009;374:39-47.

If absorptive capacity exceeded = glucosuria “Sodium Glucose Co-transporter 2” Mediates Glucose Reabsorption in S1/S2 Segments of Renal Proximal Tubule; SGLT1 in S3 Segment SGLT1 also in GI SGLT2 is “heavy lifter” Normal GFR, reabsorption capacity ~300g/day, typical load average 180g/day If absorptive capacity exceeded = glucosuria Ferrannini, E. & Solini, A. Nat. Rev. Endocrinol .2010; EM Wright et al, Physiol Rev, 2010.

SGLT2 Inhibition Lowers Renal Threshold for Glucose Excretion (RTG) Below RTG Minimal Glucosuria Occurs 150 125 Above RTG Glucosuria Occurs Urinary Glucose Excretion (g/d) RTG SGLT2i- Treated Healthy SGLT2i- Treated T2DM 100 Untreated T2DM Untreated Healthy 75 RTG 50 25 2 4 6 8 10 12 14 Plasma Glucose (mmol/l) Increased UGE occurs only when Plasma Glucose Exceeds RTG SGLT2 Inhibition Lowers RTG UGE: Urinary Glucose Excretion. Adapted from Sha S, et al. Diabetes Obes Metab 2011;13:669–672

Comparison of Selectivity of SGLT2 Inhibitors Compound Selectivity SGLT2/1 Method used (EC50s or IC50s) Empagliflozin ~2500 IC50 Dapagliflozin ~1200 EC50 Canagliflozin ~160 Sotagliflozin* ~20 EC50, half maximal effective concentration; IC50, half maximal inhibitory concentration; SGLT, sodium–glucose co-transporter; Dual SGLT1 and SGLT2 inhibitor 1. Han S, et al. Diabetes 2008;57:1723–9; 2. Liang Y, et al. Poster presentation at ADA 2009, NewOrleans, LA: 534-p; 3. Grempler R, et al. Poster presentation at ADA 2009, New Orleans, LA: 521-p; 4. Zambrowicz B, et al. Clin Pharmacol Ther 2012;92:158–69

1. Liakos A et al. Diabetes Obes Metab 2014;16:984-93 Empagliflozin Empagliflozin is a highly selective inhibitor of the sodium glucose cotransporter 2 (SGLT2) in the kidney Glucose reduction occurs by reducing renal glucose reabsorption and thus increasing urinary glucose excretion In patients with type 2 diabetes, empagliflozin leads to1: Significant reductions in HbA1c Weight loss Reductions in blood pressure without increases in heart rate Does it have an Impact on MACE and if so how??? 1. Liakos A et al. Diabetes Obes Metab 2014;16:984-93

Patients with event/analysed CV death, MI and stroke Patients with event/analysed Empagliflozin Placebo HR (95% CI) p-value 3-point MACE 490/4687 282/2333 0.86 (0.74, 0.99)* 0.0382 CV death 172/4687 137/2333 0.62 (0.49, 0.77) <0.0001 Non-fatal MI 213/4687 121/2333 0.87 (0.70, 1.09) 0.2189 Non-fatal stroke 150/4687 60/2333 1.24 (0.92, 1.67) 0.1638 Table 15.2.4.1.1: 1 Table 15.2.4.1.2: 1 Table 15.2.4.1.3: 1 Table 15.2.4.1.5: 1 Table 15.2.4.1.8: 1 Table 15.2.4.1.9: 1 Cox regression analysis. MACE, Major Adverse Cardiovascular Event; HR, hazard ratio; CV, cardiovascular; MI, myocardial infarction *95.02% CI Favours empagliflozin Favours placebo

EMPA-REG OUTCOME®: Therapeutic considerations Empagliflozin, as used in this trial, for 3 years in 1,000 patients with type 2 diabetes at high CV risk: 25 lives saved (82 vs 57 deaths) 22 fewer CV deaths (59 vs 37) 14 fewer hospitalizations for heart failure (42 vs 28) 53 additional genital infections (22 vs 75)

Humalog/Novolog/Apidra 5/18/2018 11:28 PM Humalog/Novolog/Apidra Regular NPH / Lente Another way to look at it, or to think about it, is that Humalog is very rapid acting, like a rocket. It gets into the bloodstream quickly , then it is gone. Regular, although, quick-acting, is not as fast as Humalog. It takes a little longer to peak, and to get into the blood stream. NPH and Lente take even longer. They last for many hours into the day. Ultralente is the slowest acting insulin and lasts for a very long time. Lantus /Ultralente/Detimir