GLP-1. GLP-1 is produced by the L-cells of the gut after food intake in two biologically active forms It is rapidly degraded by DPP-4.

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1 GLP-1 GLP-1 is produced by the L-cells of the gut after food intake in two biologically active forms It is rapidly degraded by DPP-4 Food intake éinsulin Gut églucose uptake Pancreas Beta cells Alpha cells Glucose homeostasis GLP-1 & GIP DPP-4 inhibitors X DPP-4 äglucagon ä Glucose release

2 Physiological effects of incretin hormones Brain Bone formation Memory Bone Memory Food intake Insulin Pancreas Beta-cell mass GIP Fat accumulation GLP-1 Beta-cell mass Glucagon Glucagon Fat Insulin GI tract Gastric acid secretion Yabe D, Seino Y. Progress in Biophysics and Molecular Biology 2011;107: Heart Gastric emptying Cardioprotection Cardiac output

3 Impaired incretin response in type 2 diabetes may be due to decreased levels of GLP-1 following meals 20 GLP-1 (pmol/l) 15 Plasma GLP-1 concentrations in type 2 diabetes patients ( ) were significantly (P<0.05) decreased compared with normal glucose tolerant ( ) and impaired glucose tolerant ( ) subjects. Meal was started 10 at time 0 and finished in the minute period. 5 P<0.05 between Type 2 diabetes and normal groups min 180 Adapted from Toft-Nielsen MB, et al. J Clin Endocrinol Metabl 2001;86:

4 GLP-1 reduces liver glucose production and increases peripheral glucose uptake Muscle glucose uptake Insulin secretion -cell -cell Glucagon secretion Liver glucose production Nauck MA. Am J Med 2009;122:S3-S10

5 The incretin system as a target for T2D therapy The impairment of the incretin system in T2D affects insulin secretion and enhances glucagon secretion. Native GLP-1 in vivo is rapidly metabolized by the serine protease dipeptidyl-peptidaseiv (DPP-IV). Two strategies to increase GLP-1 Inhibition of DPP-IV GLP-1 Receptor Agonists Sitagliptin Saxagliptin Vildagliptin Linagliptin Alogliptin DPP-IV INHIBITORS Exenatide Exenatide LAR Liraglutide Lixisenatide Albiglutide INCRETINS Dicembrini I et al. E. Ex Diab Res 2011.

6 DPP-4 inhibitors: mechanism of action Food intake DPP-4 inhibitor β-cells Stomach Increases and prolongs GLP-1 and GIP effect on β-cells: Insulin release Pancreas DPP-4 GI tract Net effect: Blood glucose Incretins α-cells Increases and prolongs GLP-1 effect on α-cells: Glucagon secretion Intestine Kulasa K, Edelman S, et al. Core Evidence 2010;5:23 37

7 Increasing plasma GLP-1 concentrations Vomiting Diarrhoea Nausea Abdominal pain GLP-1 level during treatment with incretin mimetics Appetite Food intake Weight loss Gastric emptying Insulin secretion Glucagon secretion GLP-1 effects Madsbad S. Lancet 2009;373: Plasma glucose GLP-1 level during treatment with incretin enhancers

8 alogliptin significantly increases active GLP-1 and decreases glucagon levels in Type 2 diabetes patients Glucagon levels GLP-1 levels alogliptin 25mg Time (h) Mean (+ SE) glucagon at Week 16 (ng/)l Mean (+ SE) GLP-1 at Week 16 (pmol/l) 14 Placebo Time (h) P<0.05; P<0.01; P<0.001 compared to placebo Statistically significant differences in postprandial active GLP-1 (increased) and glucagon (decreased) vs placebo after 16 weeks of treatment in type 2 diabetes patients. 1. Adapted from Eliasson B, et al. Diabetalogia. 2012;55:

9 DPP-4 inhibitors address multiple pathologies of Type 2 diabetes Insulin secretion Glucose production Glucose uptake Glucagon secretion DPP-4 inhibitors Neurotransmitter dysfunction Incretin effect Lipolysis Glucose reabsorption 1. Vipidia (alogliptin) SPC. Available at: [Accessed January 2014]; 2. Figure adapted from DeFronzo RA. Am J Med. 2010; 123(3 suppl):s38 s48

10 Clinical benefits of DPP-4 inhibitors Glycaemic control: As a class, DPP-4 inhibitors have extensive evidence for efficacy in reducing HbA1c in patients with Type 2 diabetes Reductions in HbA1c -0.5 to 0.8%1 Reductions are additive when DPP-4 inhibitors are used together with insulin, thiazolidinediones, metformin and sulphonylureas1 Tolerability: DPP-4 inhibitors are generally well tolerated as monotherapy and in combination with other agents Low risk of hypoglycaemia1 t associated with gastrointestinal side effects1 Generally suitable for patients with renal insufficiency (with appropriate dose reductions) 1 Weight-neutral effects: Could increase patient adherence to therapy1 D Alessio D. Peak Issues Available at:

11 Differentiating factors of available DPP-4 inhibitors DPP-4 Chemistry Metabolism & Excretion Safety & tolerability Deacon CF. Diabetes, Obesity and Metabolism 2011;13:7 18 DPP-4 inhibition Selectivity Use in special populations Distribution Potential for drug-to-drug interactions Glycaemic efficacy

12 Pharmacokinetic differences of available DPP-4 inhibitors Alogliptin1-4 Linagliptin1-3,5 Saxagliptin1-3 Sitagliptin1-3 Vildagliptin1-3 β-amino acidbased Cyanopyrrolidine Molecular Structure Chemistry Therapeutic dose (mg/day) Oral Bioavailability Protein Binding Metabolism Elimination Half life, hours Drug-to-drug interactions Modified Xanthine-based Cyanopyrrolidine pyrimidinedione x 50 ~100% ~30% ~67% ~87% 85% 20% Extensive Negligible 38% 10% Renal Biliary Renal Hydrolysis Renal CYP450 3A4/5 Renal 2 4 (parent) (active metabolite) 1. Deacon CF. Diabetes Obes Metab. 2011;13: Scheen AJ. Diabetes Obes Metab 2010;12: Golighty LK, et al. Clin Pharmacokinet 2012;51: Ndefo UA, et al. Am J Health Syst Pharm 2014;71: Trajenta (linagliptin) SPC Available at: Product_Information/human/002110/WC pdf [Accessed July 2014]

13 Use of DPP-4 inhibitors in special populations Elderly1-5 Alogliptin Linagliptin Saxagliptin Sitagliptin Vildagliptin restriction <80 years restriction Caution in patients 75 years restriction Hepatic Insufficiency6,7 Mild 7 Moderate 7 Severe 7 Moderate Reduced dose Reduced dose Reduced dose Reduced dose Severe/ESRD Reduced dose Reduced dose Reduced dose Reduced dose Hepatic Function Monitoring Renal Insufficiency6,7 Mild Renal Function Monitoring Renal insufficiency: Mild: CrCl 50 ml/min, Moderate: CrCl 30 <50 ml/min, Severe/ESRD: CrCl <30 ml/min CrCl=creatinine clearance; ESRD=end-stage renal disease; EU=Europe; min=minute; NR=not recommended 1. Vipidia (alogliptin) Summary of Product Characteristics (SmPC) Trajenta (linagliptin) SmPC Onglyza (saxagliptin) SmPC Januvia (sitagliptin) SmPC Galvus (vildagliptin) SmPC Deacon CF. Diabetes Obes Metab. 2011;13: Deacon CF, et al. Expert Opin Pharmacother. 2013;14:

14 Comparative Efficacies of DPP-4s Placebo-corrected change from baseline in HbA1c - Monotherapy Alogliptin mg 25 mg 7.9% 7.9% Linagliptin2 5 mg 5 mg 8.1% 8.0% Saxagliptin3 5 mg 7%-10% 5 mg 8.0% Sitagliptin4 100 mg 100 mg 8.0% 8.0% Vildagliptin5 50 mg BID 50 mg 8.6% 8.4% ΔHbA1c (%) The current DPP-4s have comparative efficacy DeFronzo R, et al. Diabetes Care 2008;31: Linagliptin Prescribing Information. 3. Saxagliptin Prescribing Information. 4. Sitagliptin Prescribing Information. 5. Vildagliptin Summary of Product Characteristics.

15 Targeting the kidney to treat type 2 diabetes rmal renal glucose handling The kidney filters approximately 180 L of plasma each day, which contains about 162 g of glucose. SGLT2 mediates glucose transport in the S1 segment and absorbs about 80% to 90% of filtered glucose. SGLT1 has high affinity but low capacity for glucose transport and mediates glucose transport in the S3 segment and reabsorbs the remaining 10% to 20% of filtered glucose. Majority of glucose is reabsorbed by SGLT2 (90%) Proximal tubule SGLT2 Remaining glucose is reabsorbed by SGLT1 (10%) Glucose Glucose filtration Minimal to no glucose excretion Wright EM. Am J Physiol Renal Physiol 2001;280:F10 18; 2. Lee YJ, et al. Kidney Int Suppl 2007;106:S27 35; Hummel CS, et al. Am J Physiol Cell Physiol 2011;300:C14 21.

16 SGLT2 INHIBITORS Gliflozin offers an insulin-independent mechanism to lower blood glucose levels by inhibiting SGLT2. Pro: The inhibition of SGLT2 results in daily urinary glucose excretion of approximately 70g providing: Significant and sustained HbA1c reductions versus placebo when added to metformin Secondary benefits: 1) weight loss (due to the loss of calories into the urine) 2) lowering blood pressure (due to fluid and sodium depletion) SGLT2 Gliflozins Con: Increased risk of urinary tract infections. Increased risk of bladder cancer (?) Proximal tubule Gliflozin SGLT2 Glucose Abdul-Ghani MA. Curr Diab Rep : Parkinson C. New treatment options. Downloaded on v 2014 Glucose filtration Increased urinary glucose excretion

17 The Kidneys Play an Important Role in Glucose Control rmal Renal Glucose Physiology 180 g of glucose is filtered each day Virtually all glucose reabsorbed in the proximal tubules & reenters the circulation SGLT2 reabsorbs about 90% of the glucose SGLT1 reabsorbs about 10% of the glucose Virtually no glucose excreted in urine Mather, A & Pollock, C. Kidney International. 2011;79:S1-S6.

18 Rationale for SGLT2 Inhibitors SGLT2 is a low-affinity, high capacity glucose transporter located in the proximal tubule and is responsible for 90% of glucose reabsorption Selective SGLT2 inhibitors have a novel & unique mechanism of action reducing blood glucose levels by increasing renal excretion of glucose Decreased glycemia will decrease glucose toxicity leading to further improvements in glucose control Selective SGLT2 inhibition, would also cause urine loss of the calories from glucose, potentially leading to weight loss Brooks AM, Thacker SM. Ann Pharmacother. 2009;42(7):

19 SGLT2 Inhibitors in Phase 3 Development Empagliflozin Canagliflozin Dapagliflozin Ipragliflozin

20 Empagliflozin: Change in A1C Randomized, double-blind, 12 week trial comparing empagliflozin and open-label metformin P.001 vs. placebo 500 mg BID for four weeks, then 1000 mg BID or the maximum tolerate dose Ferrannini E, et al. Abstract 877. EASD 2010.

21 Empagliflozin: Change in Plasma Glucose in the Fasting State Randomized, double-blind, 12 week trial comparing empagliflozin and open-label metformin P.001 vs. placebo 500 mg BID for four weeks, then 1000 mg BID or the maximum tolerate dose Ferrannini E, et al. Abstract 877. EASD 2010.

22 Canagliflozin Metformin + Canagliflozin Dose-Ranging Study Mean Baseline A1C (%) Rosenstock J, et al. Abstract 77-OR. ADA P.001 vs. placebo calculated using LS means

23 Canagliflozin Mean Baseline Weight (kg) SGLT2 Inhibition for Type 2 Diabetes: Metformin + Canagliflozin Dose-Ranging Study Rosenstock J, et al. Abstract 77-OR. ADA P.001 vs. placebo calculated using LS means

24 Canagliflozin Trials Symptomatic genital infections in 3-8% canagliflozin arms 2% placebo 2% SITA Urinary tract infections in 3-9% canagliflozin arms 6% placebo 2% SITA Hypoglycemia in 0-6% canagliflozin arms 2% placebo 5% SITA Rosenstock J, et al. Abstract 77-OR. ADA 2010.

25 Changes from Baseline in A1C in Phase 3 Dapagliflozin Studies Placebo Dapa 2.5mg Dapa 5mg Dapa 10mg Wilding JPH, et al. Abstract 78-OR. ADA 2010; Strojek K, et al. Abstract 870. EASD 2010; Ferrannini E, et al. Diabetes Care. 2010;33(10): ; Bailey CJ, et al. Lancet. 2010;375(9733):

26 Changes from Baseline in Body Weight in Phase 3 Dapagliflozin Studies Placebo Dapa 2.5mg Dapa 5mg Dapa 10mg Wilding JPH, et al. Abstract 78-OR. ADA 2010; Strojek K, et al. Abstract 870. EASD 2010; Ferrannini E, et al. Diabetes Care. 2010;33(10): ; Bailey CJ, et al. Lancet. 2010;375(9733):

27 Perspectives on SGLT2 Inhibition Potential advantages Insulin Independence Weight loss (75g urine glucose = 300kcal/day) Low risk of hypoglycemia Blood pressure lowering? Concerns Polyuria Electrolyte disturbances Bacterial urinary tract infections Fungal genital infections Malignancies

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