DIABETES UPDATE NON INSULIN THERAPY

Transcription

1 American College of Physicians (ACP) Northern California Chapter Scientific Meeting Walnut Creek (2017) DIABETES UPDATE NON INSULIN THERAPY FOCUS ON: INCRETIN THERAPY (DPP41, GLP1-RA) & SGLT2 INHIBITORS Jaiwant Rangi, MD, FACE

2 Disclosures Consultant and Speaker for Sanofi, Boehringer- Ingelheim, Astra Zeneca, Dexcom, AbbVie and Jannsen

3 Available Drugs for the Treatment of Type 2 Diabetes Mellitus- 2017

4 Non-Insulin Agents Available for Treatment of Type 2 Diabetes Class Primary Mechanism of Action Agent Available as ALPHA GLUCOSIDASE INHIBITORS Delay carbohydrate absorption from intestine Acarbose Miglitol Precose or generic Glyset AMYLIN ANALOGUES Decrease glucagon secretion Slow gastric emptying Increase satiety Pramlintide Symlin BIGUANIDES Decrease HGP Increase glucose uptake in muscle Metformin Glucophage or generic BILE ACID SEQUESTRANTS Decrease absorption / HGP? Increase incretin levels? Colesevelam WelChol DPP-4 INHIBITORS Increase glucose-dependent insulin secretion Decrease glucagon secretion Alogliptin Linagliptin Saxagliptin Sitagliptin Nesina Tradjenta Onglyza Januvia DOPAMINE AGONISTS Activates dopaminergic receptors Bromocriptine Cycloset

5 Non-Insulin Agents Available for Treatment of Type 2 Class Primary Mechanism Diabetes of Action Agent Available as Nateglinide Starlix or generic GLINIDES Increase insulin secretion Repaglinide Prandin GLP-1 RECEPTOR AGONISTS SGLT2 INHIBITORS Increase glucose-dependent insulin secretion Decrease glucagon secretion Slow gastric emptying Increase satiety Increase urinary excretion of glucose SULFONYLUREAS Increase insulin secretion THIAZOLIDINEDIONE S (TZD S) Increase glucose uptake in muscle and fat Decrease HGP Exenatide Exenatide XR Liraglutide Albiglutide Byetta Bydureon Victoza Tanzeum Dulaglutide Trulicity Lixisenatide Lyxumia * Dapagliflozin Farxiga Canagliflozin Invokana Empagliflozin Jardiance Iprafliflozin Suglat Glimepiride Amaryl or generic Glipizide Glucotrol or generic Glyburide Pioglitazone Rosiglitazone Diaeta, Glynase, Micronase, or generic Actos Avandia

6 Combination Agents Available for the Treatment of Type 2 Diabetes Class Added Agent Available as DPP4i + SGLT2i Saxagliptin/Empagliflozin Glyxambi METFORMIN + DPP-4 INHIBITOR Alogliptin Linagliptin Saxagliptin Sitagliptin Kazano Jentadueto Kombiglyze XR Janumet METFORMIN + GLINIDE Repaglinide Prandimet METFORMIN + SGLT2 INHIBITORS METFORMIN + SULFONYLUREA METFORMIN + THIAZOLIDINEDIONE Canagliflozin Dapagliflozin Empagliflozin Glipizide Glyburide Pioglitazone Rosiglitazone Invokamet Xigduo Synjardy TZD + DPP-4 INHIBITOR Pioglitazone + alogliptin Oseni Metaglip and generic Glucovance and generic Actoplus Met Avandamet TZD + SULFONYLUREA Pioglitazone + glimepiride Rosiglitazone + glimepiride Duetact Avandaryl

7 (accessed ) Updated Metformin CKD Prescribing Guidelines (April 2016) Obtain egfr before starting metformin and annually, more frequently in those at risk for renal impairment (e.g., elderly). Metformin contraindicated in patients with an egfr <30 Starting metformin in patients with an egfr between not recommended If egfr falls <45, assess the benefits and risks of continuing treatment. D/C if egfr falls <30 Hold metformin at the time of / before iodinated contrast procedure if egfr 30-60; if H/o Liver disease, Alcoholism, or Heart failure; or if Intra-arterial contrast. Recheck egfr 48 hrs after procedure and restart if renal function stable

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10 Treatment based on pathophysiology DPP IV inhibitors GLP-1 agonists Decreased incretin effect and faster carb absorption β Sulfonylureas Meglitinides Insulin α insulin 50-80% at diagnosis Hyperglycemia Neurotransmitter dysfunction GLP-1 agonists Hepatic glucose production Metformin INSULIN RESISTANCE glucose reabsorption SGLT-2 inhibitors GLP-agonists DPP IV inhibitors glucagon secretion Islet- α cell Lipolysis increased Insulin TZDs DeFranzo R, et al. Diabetes Care, Volume 36, Supplement 2, August 2013 S Decreased glucose uptake TZDs Insulin

11 Incretin Based Therapy GLP-1 receptor agonists (injectable therapies) Exenatide Liraglutide Dulaglitide Abiglutide DPP-4 inhibitors (oral therapies) Sitagliptin Saxagliptin Linagliptin, Alogliptin

12 DPP 4 Inhibitor's DIPEPTIDYL PEPTIDASE 4 INHIBITORS (GLIPTINS)

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14 DPP-4 Inhibitors Alogliptin, Linagliptin, Saxagliptin, Sitagliptin Mechanism Inhibit enzymatic degradation of GLP-1 and GIP; glucose-dependent Efficacy Decrease A1C levels 0.6% 0.9% Dosing Side effects Main risk Once daily Headaches, nasopharyngitis Viral infection; long-term safety unknown A1C = glycated hemoglobin; GIP = gastric inhibitory polypeptide; GLP-1 = glucagon-like peptide-1 Rosenstock J, et al. Curr Opin Endocrinol Diabetes Obes. 2007;14: Nathan DM, et al. Diabetes Care. 2008;31:

15 FDA-Approved Agents DPP-4 Inhibitors Key Features Alogliptin Linagliptin Saxagliptin Sitagliptin Oral administration Increase endogenous GLP-1 and GIP levels Increase glucose-dependent insulin secretion Suppress glucagon production

16 Placebo-adjuste d A1C (%) Glucose Control with DPP-4 Inhibitors Placebo-Adjusted Change from Baseline (Not Head-to-Head Trials) Monotherapy Add-on to Metformin Add-on to SU Alo 1 Lin 2 Sax 3 Sit 4 Alo 5 Lin 6 Sax 7 Sit 8 Alo 9 Lin 10, * Sax 11 Sit 12, Baseline A1C (%) *SU + metformin. With or without metformin. Absolute change from baseline (active-controlled trial). 1. DeFronzo RA, et al. Diabetes Care. 2008;31: Del Prato S, et al. Diabetes Obes Metab. 2011;13: Rosenstock J, et al. Curr Med Res Opin. 2009;25: Nauck MA, et al. Diabetes Obes Metab. 2007;9: Nauck MA, et al. Int J Clin Pract. 2009;63: Taskinen MR, et al. Diabetes Obes Metab. 2011;13: DeFronzo RA, et al. Diabetes Care. 2009;32: Charbonnel B, et al. Diabetes Care. 2006;29: Pratley RE, et al. Diabetes Obes Metab. 2009;11: Owens DR, et al. Diabet Med. 2011;28: Chacra AR, et al. Int J Clin Pract. 2009;63: Hermansen K, et al. Diabetes Obes Metab. 2007;9:

17 Weight (kg) Weight Change with DPP-4 Inhibitors Absolute Change from Baseline (Not Head-to-Head Trials) Monotherapy Add-on to Metformin Add-on to SU Alo 1 Lin 2 Sax 3 Sit 4 Alo 5 Lin 6 Sax 7 Sit 8 Alo 9 Lin 10, * Sax 11 Sit 12, NR NR 0.27 NR, value not reported. *SU + metformin. With or without metformin. 1. DeFronzo RA, et al. Diabetes Care. 2008;31: Del Prato S, et al. Diabetes Obes Metab. 2011;13: Rosenstock J, et al. Curr Med Res Opin. 2009;25: Nauck MA, et al. Diabetes Obes Metab. 2007;9: Nauck MA, et al. Int J Clin Pract. 2009;63: Taskinen MR, et al. Diabetes Obes Metab. 2011;13: DeFronzo RA, et al. Diabetes Care. 2009;32: Charbonnel B, et al. Diabetes Care. 2006;29: Pratley RE, et al. Diabetes Obes Metab. 2009;11: Owens DR, et al. Diabet Med. 2011;28: Chacra AR, et al. Int J Clin Pract. 2009;63: Hermansen K, et al. Diabetes Obes Metab. 2007;9:

18 Patients (%) Hypoglycemia with DPP-4 Inhibitors Percentage of Patients Reporting Hypoglycemia (Not Head-to-Head Trials) Monotherapy Add-on to Metformin Add-on to SU Alo 1 Lin 2 Sax 3 Sit 4 Alo 5 Lin 6 Sax 7 Sit 8 Alo 9 Lin 10, * Sax 11 Sit 12, NR, value not reported. *SU + metformin. With or without metformin. 1. DeFronzo RA, et al. Diabetes Care. 2008;31: Del Prato S, et al. Diabetes Obes Metab. 2011;13: Rosenstock J, et al. Curr Med Res Opin. 2009;25: Nauck MA, et al. Diabetes Obes Metab. 2007;9: Nauck MA, et al. Int J Clin Pract. 2009;63: Taskinen MR, et al. Diabetes Obes Metab. 2011;13: DeFronzo RA, et al. Diabetes Care. 2009;32: Charbonnel B, et al. Diabetes Care. 2006;29: Pratley RE, et al. Diabetes Obes Metab. 2009;11: Owens DR, et al. Diabet Med. 2011;28: Chacra AR, et al. Int J Clin Pract. 2009;63: Hermansen K, et al. Diabetes Obes Metab. 2007;9:

19 Incidence of Selected Adverse Events with Sitagliptin: Pooled Data Adverse Event Incidence per 100 patient-years Difference (95% CI) Sitagliptin 100 mg Nonexposed Constipation (0.1, 1.4) Diarrhea (-3.6, -1.0) Headache (-0.7, 1.4) Nasopharyngitis (-0.3, 2.1) Pancreatitis (-0.20, 0.14) Rash (-0.1, 0.8) Upper respiratory tract infection (-1.6, 1.0) Williams-Herman D, et al. BMC Endocr Disord. 2010;10(7). Engel SS, et al. Int J Clin Pract. 2010;64:

20 GLP-1's GLUCAGON LIKE PEPTIDE 1 INHIBITOR'S

21 GLP-1 Receptor Agonists FDA-Approved Agents Key Features Albiglutide Dulaglutide Exenatide Exenatide ER Liraglutide Injectable administration Mimic action of native GLP-1 Increase glucose-dependent insulin secretion Suppress glucagon production Slow gastric emptying ER, extended release; GLP-1, glucagon-like peptide 1. Garber AJ, et al. Endocr Pract. 2013;19(suppl 2):1-48.

22 Anti-diabetic Activities of GLP-1 Gastroenterology , DOI: ( /j.gastro

23 Placebo-adjuste d A1C (%) Glucose Control with GLP-1 Receptor Agonists Placebo-Adjusted Change from Baseline (Not Head-to-Head Trials) Baseline A1C (%) 0 Monotherapy Add-on to Metformin Add-on to SU Alb 1 Dul 2 Exe 3 Exe ER 4 Lir 5 Alb 6 Dul 7 Exe 8 Exe ER 9 Lir 10 Alb 11, * Exe 12 Exe ER 13, Lir *Metformin with or without SU or TZD. Metformin with or without SU. Absolute change from baseline (active-controlled trial). 1. Tanzeum (albiglutide) injection prescribing information. Research Triangle Park, NC: GlaxoSmithKline; Umpierrez G, et al. Diabetes Care. 2014;37: Moretto TJ, et al. Clin Ther. 2008;30: Russell-Jones D, et al. Diabetes Care. 2012;35: Garber A, et al. Lancet. 2009;373: Ahrén B, et al. Diabetes Care. 2014;37: Dungan KM, et al. Lancet. 2014;384: DeFronzo RA et al. Diabetes Care. 2005;28: Bergenstal RM, et al. Lancet. 2010;376: Pratley RE, et al. Lancet. 2010;375: Pratley RE, et al. Lancet Diabetes Endocrinol. 2014;2: Buse JB, et al. Diabetes Care. 2004;27: Diamant M, et al. Lancet. 2010;375: Marre M, et al. Diabet Med. 2009;26:

24 Weight (kg) Weight Change with GLP-1 Receptor Agonists Absolute Change from Baseline (Not Head-to-Head Trials) Monotherapy Add-on to Metformin Add-on to SU Alb 1 Dul 2 Exe 3 Exe ER 4 Lir 5 Alb 6 Dul 7 Exe 8 Exe ER 9 Lir 10 Alb 11, * Exe 12 Exe ER 13, Lir *Metformin with or without SU or TZD. Metformin with or without SU. 1. Tanzeum (albiglutide) injection prescribing information. Research Triangle Park, NC: GlaxoSmithKline; Umpierrez G, et al. Diabetes Care. 2014;37: Moretto TJ, et al. Clin Ther. 2008;30: Russell-Jones D, et al. Diabetes Care. 2012;35: Garber A, et al. Lancet. 2009;373: Ahrén B, et al. Diabetes Care. 2014;37: Dungan KM, et al. Lancet. 2014;384: DeFronzo RA et al. Diabetes Care. 2005;28: Bergenstal RM, et al. Lancet. 2010;376: Pratley RE, et al. Lancet. 2010;375: Pratley RE, et al. Lancet Diabetes Endocrinol. 2014;2: Buse JB, et al. Diabetes Care. 2004;27: Diamant M, et al. Lancet. 2010;375: Marre M, et al. Diabet Med. 2009;26:

25 Systolic BP (mmhg) Blood Pressure Changes with Liraglutide Monotherapy vs Glimepiride 52 Weeks 1 Add-on to Metformin 26 Weeks 2 Add-on to Metformin 26 Weeks 3 Add-on to Sulfonylurea 26 Weeks 4,5 Add-on to Met + TZD 26 Weeks 6 Add-on to Met + SU 26 Weeks 7 N Treatment Glim Lir Met Glim + Met Lir+ Met Sit+ Met Lir+ Met SU Rosi + SU Lir+ SU Rosi + Met Lir+ Rosi+ Met Met+ SU Glar+ Met+ SU Lir+ Met+ SU * * * -4.0 * *P<0.05 vs comparator. All liraglutide dosages shown are 1.8 mg QD. 1. Garber A, et al. Lancet. 2009;373: Nauck M, et al. Diabetes Care. 2009;32: Pratley RE, et al. Lancet. 2010;375: Marre M, et al. Diabet Med. 2009;26: Colagiuri S, et al. Diabetes. 2008;57(suppl 2): Abstr. 554-P. 6. Zinman B, et al. Diabetes Care. 2009;32: Russell-Jones D, et al. Diabetologia. 2009;52:

26 Patients (%) Hypoglycemia with GLP-1 Receptor Agonists Percentage of Patients Reporting Hypoglycemia (Not Head-to-Head Trials) 40 Monotherapy Add-on to Metformin Add-on to SU Alb 1 Dul 2 Exe 3 Exe ER 4 Lir 5 Alb 6 Dul 7 Exe 8 Exe ER 9 Lir 10 Alb 11, * Exe 12 Exe ER 13, Lir *Metformin with or without SU or TZD. Metformin with or without SU. 1. Nauck M, et al. Diabetes. 2013;62(suppl 2): Abstr. 55-LB. 2. Umpierrez G, et al. Diabetes Care. 2014;37: Moretto TJ, et al. Clin Ther. 2008;30: Russell-Jones D, et al. Diabetes Care. 2012;35: Garber A, et al. Lancet. 2009;373: Ahrén B, et al. Diabetes Care. 2014;37: Dungan KM, et al. Lancet. 2014;384: DeFronzo RA et al. Diabetes Care. 2005;28: Bergenstal RM, et al. Lancet. 2010;376: Pratley RE, et al. Lancet. 2010;375: Pratley RE, et al. Lancet Diabetes Endocrinol. 2014;2: Buse JB, et al. Diabetes Care. 2004;27: Diamant M, et al. Lancet. 2010;375: Marre M, et al. Diabet Med. 2009;26:

27 Safety Considerations with GLP1 Receptor Agonists GI adverse events Pancreatitis Pancreatic cancer Medullary thyroid cancer Renal impairment Common Usually dose dependent and transient Usually reduced with dose titration Pancreatitis has been reported with postmarketing use of some of incretin agents, although no causal relationship has been established Extensive review by FDA of studies involving >80,000 patients has not uncovered reliable evidence of increased pancreatic risk with incretins vs other agents Labeling for all incretins states these agents should be immediately discontinued if pancreatitis is suspected Labeling for GLP-1 receptor agonists suggests consideration of other therapies for patients with a history of pancreatitis Extensive review by FDA of studies involving >80,000 patients has not uncovered reliable evidence of increased pancreatic risk with incretins vs other agents Further assessments required from long duration-controlled studies or epidemiological databases Animal data showed an increased incidence of C-cell tumors with liraglutide and exenatide ER treatment, but confirmatory population studies are lacking Labeling for liraglutide and exenatide ER: Patients should be counseled regarding medullary thyroid carcinoma and the signs/symptoms of thyroid tumors Contraindicated in patients with personal/family history of MTC or multiple endocrine neoplasia syndrome type 2 Renal Impairment has been reported postmarketing, usually in association with nausea, vomiting, diarrhea, or dehydration. Use caution when initiating or escalating doses in patients with renal impairment. Exenatide is contraindicated in patients with severe renal insufficiency or ESRD ER, extended release. Garber AJ, et al. Endocr Pract. 2013;19(suppl 2):1-48. ADA/EASD/IDF statement concerning the use of incretin therapy and pancreatic disease [news release]. Alexandria, VA: American Diabetes Association, European Association for the Study of Diabetes, International Diabetes Federation; June 28,

28 SGLT-2 Inhibitors SODIUM GLUCOSE CO-TRANSPORTER 2 INHIBITOR'S

29 SGLT2 Inhibitors Canagliflozin, Dapagliflozin, Empagliflozin Mechanism Inhibits sodium-glucose transport protein subtype 2 (SGLT2) which is responsible for at least 90% of glucose reabsorption in the kidney causing blood glucose is eliminated in the urine Efficacy Modest (HbA1C %) Advantages Insulin-independent glucose reduction, Low risk of hypoglycemia, Weight loss (to 4% BW), Blood pressure-lowering Disadvantages Osmotic diuresis causing Polyuria and lightheadedness, Bacterial urinary tract infections ( 5%), Fungal genital infections ( 10%), Increased LDL cholesterol, Hyperkalemia (canagliflozin), Bladder cancer concerns (dapagliflozin) Contraindications History of genital fungal infections, caution in chronic kidney disease Invokana [Package Insert] Janssen Pharmaceuticals, Inc. Titusville, NJ.; Lavalle-gonzález FJ, Januszewicz A, Davidson J, et al. Diabetologia. 2013; Stenlöf K, Cefalu WT, Kim KA, et al. Diabetes Obes Metab. 2013;15(4):372-82; Burki TK. Lancet. 2012;379(9815):507.

30 SGLT2 Inhibitors Promote Urinary Glucose Glucose Excretion SGLT2 mediates most ( 90%) glucose reabsorption from the proximal renal tubular lumen back into the circulation Bowman s capsule Proximal renal tubule SGLT2 Return to circulation SGLT2 inhibitors lower the threshold at which glucose is excreted, leading to Increased urinary glucose excretion Decreased return of glucose to circulation Decreased blood glucose levels Urinary excretion

31 Sodium-glucose co-transporter 2 inhibitors (SGLT2) Canagliflozin (Invokana 100 & 300 mg) GFR>45 ml/min/1.73m² Dapaglifozin (Farxiga 5 & 10 mg QD) GFR>60 Empagliflozin (Jardiance 10 & 25 mg) GFR>45 Benefits: Weight loss Improved systolic BP A1c reduction Other effects Increase LDL Increase risk of yeast infections Not recommended in over 75 y/o

32 Placebo-adjusted A1C (%) Glucose Control with SGLT2 Inhibitors Placebo-Adjusted Change from Baseline (Not Head-to-Head Trials) Monotherapy Add-on to Metformin Add-on to Insulin +/- OAs Can 1 Dap 2 Emp 3 Can 4 Dap 5 Emp 6 Can 7 Dap 8 Emp 9 Baseline A1C (%) * * *Absolute change from baseline (active-controlled trial). 1. Stenlof K, et al. Diabetes Obes Metab. 2013;15: Ferrannini E, et al. Diabetes Care. 2010;33: Roden M, et al. Lancet Diabetes Endocrinol. 2013;1: Cefalu WT, et al. Lancet. 2013;382: Nauck MA, et al. Diabetes Care. 2011;34: Haring HU, et al. Diabetes Care. 2014;37: Yale J-F, et al. Diabetes Obes Metab. 2013;15: Wilding JPH, et al. Ann Intern Med. 2012;156: Rosenstock J, et al. Diabetes Care. 2014;37:

33 Weight (kg) Weight Change with SGLT2 Inhibitors Absolute Change from Baseline (Not Head-to-Head Trials) Monotherapy Add-on to Metformin Add-on to Insulin +/- OAs Can 1 Dap 2 Emp 3 Can 4 Dap 5 Emp 6 Can 7 Dap 8 Emp Stenlof K, et al. Diabetes Obes Metab. 2013;15: Ferrannini E, et al. Diabetes Care. 2010;33: Roden M, et al. Lancet Diabetes Endocrinol. 2013;1: Cefalu WT, et al. Lancet. 2013;382: Nauck MA, et al. Diabetes Care. 2011;34: Haring HU, et al. Diabetes Care. 2014;37: Yale J-F, et al. Diabetes Obes Metab. 2013;15: Wilding JPH, et al. Ann Intern Med. 2012;156: Rosenstock J, et al. Diabetes Care. 2014;37:

34 Change Overseas phase III clinical study - A metformin combination study (D1690C00012) Changes in body composition from the baseline (24 and 102 weeks after start of treatment) (kg) Placebo + MET (n=86) (24 Weeks) Farxiga 10 mg + MET (n=83) Placebo + MET (n=71) (102 Weeks) Farxiga 10 mg + MET (n=66) Total lean tissue mass Total fat mass Adjusted mean change (95% CI) FAS (including data after hyperglycemia rescue therapy) MET: Metformin Subjects: Patients with type 2 diabetes mellitus poorly controlled as to blood glucose by uncombined metformin (MET) therapy [182 patients included in safety analysis; 180 patients included in efficacy analysis (FAS)] Methods: A randomized, double-blind, placebo-controlled, multicenter, parallel-group comparative study. Subjects were allocated at random to the Forxiga 10 mg + MET group and the placebo + MET group. Once daily treatment (combined with MET 1,500 mg/day) in the morning was continued for 102 weeks, and mean adjusted change in body composition at 24 and 102 weeks after the start of treatment was analyzed. Safety: The incidence of adverse reactions was 19.8% (18/91) in the Forxiga 10 mg + MET group and 14.3% (13/91) in the placebo + MET group. Note) The starting dose level of Forxiga Tablet in Japan is 5 mg/day. Before use, reference to the latest package insert is needed. Bolinder J. et al.: Diabetes Obes Metab. 16(2): , 2014

35 Systolic BP (mmhg) Blood Pressure Changes with SGLT2 Inhibitors Absolute Change from Baseline (Not Head-to-Head Trials) Monotherapy Add-on to Metformin Add-on to Insulin +/- OAs Can 1 Dap 2 Emp 3 Can 4 Dap 5 Emp 6 Can 7 Dap 8 Emp Stenlof K, et al. Diabetes Obes Metab. 2013;15: Ferrannini E, et al. Diabetes Care. 2010;33: Roden M, et al. Lancet Diabetes Endocrinol. 2013;1: Cefalu WT, et al. Lancet. 2013;382: Nauck MA, et al. Diabetes Care. 2011;34: Haring HU, et al. Diabetes Care. 2014;37: Yale J-F, et al. Diabetes Obes Metab. 2013;15: Wilding JPH, et al. Ann Intern Med. 2012;156: Rosenstock J, et al. Diabetes Care. 2014;37:

36 Patients (%) Hypoglycemia with SGLT2 Inhibitors Percentage of Patients Reporting Hypoglycemia (Not Head-to-Head Trials) Monotherapy Add-on to Metformin Add-on to Insulin +/- OAs Can 1 Dap 2 Emp 3 Can 4 Dap 5 Emp 6 Can 7 Dap 8 Emp < Stenlof K, et al. Diabetes Obes Metab. 2013;15: Ferrannini E, et al. Diabetes Care. 2010;33: Roden M, et al. Lancet Diabetes Endocrinol. 2013;1: Cefalu WT, et al. Lancet. 2013;382: Nauck MA, et al. Diabetes Care. 2011;34: Haring HU, et al. Diabetes Care. 2014;37: Yale J-F, et al. Diabetes Obes Metab. 2013;15: Wilding JPH, et al. Ann Intern Med. 2012;156: Rosenstock J, et al. Diabetes Care. 2014;37:

37 Safety Considerations with SGLT2 Inhibitors Genitourinary infection Increased incidence; patients should be monitored and treated if necessary Increased LDL-C Small increases in LDL-C have been observed in clinical trials Bladder cancer Increased incidence of bladder cancers in patients receiving dapagliflozin Dapagliflozin labeling recommends not using in patients with active bladder cancer and should be used with caution in patients with a history of bladder cancer Renal impairment Monitor kidney function during therapy, especially in patients with GFR <60 ml/min/1.73 m 2 Garber AJ, et al. Endocr Pract. 2013;19(suppl 2):1-48. Farxiga (dapagliflozin) prescribing information. Princeton, NJ: Bristol-Meyers Squibb Company Invokana (canagliflozin) prescribing information. Titusville, NJ: Janssen Pharmaceuticals, Inc

38 Change from baseline in egfr Time course of egfr (meta-analysis) (ml/min/1.73 m 2 ) Changes in egfr Placebo (n=1,955) Farxiga 10 mg (n=2,026) Baseline Mean (ml/min/1.73 m 2 ) Placebo Forxiga 10 mg Number of patients Forxiga 10 mg 2,026 Placebo 1,955 BL (Week) 1,697 1,629 1,655 1,570 1,777 1,671 1,600 1,513 1,663 1, Subjects/Methods: Meta-analysis of the combined subjects of Phase IIb/III studies conducted across the world (including Japan and Asia) (30-MU: data cut off on November 15, 2012) Note) The starting dose level of Forxiga Tablet in Japan is 5 mg/day. Before use, reference to the latest package insert is needed. EMDAC data < pdf>

39 Prescribing Information Comparison* CANAGLIFLOZIN DAPAGLIFLOZIN EMPAGLIFLOZIN Dosing 100 mg once daily before first meal 300 mg if egfr 60 ml/min/1.73m 2 5 or 10 mg once daily in morning, with or without food 10 or 25 mg once daily in morning, with or without food Contraindications Severe renal impairment, ESRD, dialysis Severe renal impairment, ESRD, dialysis Severe renal impairment, ESRD, dialysis Do not initiate if egfr <45 ml/min/1.73m 2 Do not initiate if egfr <60 ml/min/1.73m 2 Do not initiate if egfr <45 ml/min/1.73m 2 Warnings and Precautions Hypotension Impaired renal function Hypotension Impaired renal function Hypotension Impaired renal function Hyperkalemia Hypoglycemia: concomitant insulin or secretagogues Hypoglycemia: concomitant insulin or secretagogues Genital mycotic infections Hypoglycemia: concomitant insulin or secretagogues Genital mycotic infections Genital mycotic infections Bladder cancer imbalance Urinary tract infections Hypersensitivity reactions LDL-C increases LDL-C increases LDL-C increases Key Adverse Events (>5% incidence) Female genital mycotic infections Urinary tract infections Female genital mycotic infections Nasopharyngitis Female genital mycotic infections Urinary tract infections Increased urination Urinary tract infections Differences are bold and in red. *Accurate comparison of SGLT2 inhibitors requires head-to-head studies, which have not yet been conducted. Farxiga (dapagliflozin) prescribing information. Princeton, NJ: Bristol-Meyers Squibb Company Invokana (canagliflozin) prescribing information. Titusville, NJ: Janssen Pharmaceuticals, Inc

40 Combination options (Basal Insulin and GLP-1 Agonists) for the treatment of Type 2 diabetes Xultophy (Degludec / Liraglutide) Administered once daily by sc injection, It is supplied as a 3ml prefilled pen containing 100 units/3.6mg insulin Degludec/liraglutide per ml; The proportion of patients reaching target HbA1c was higher with Xultophy than with insulin degludec or liraglutide Adverse effects are typical of the component drugs, with a lower incidence of gastrointestinal effects but less weight loss than Liraglutide Soliqua (Glargine U-100 and Lixisenetide) LixiLan, single-injection fixed-ratio combination of GLP1-RA & Analog Basal Insulin- Lixisenatide (Lyxumia) & Glargine (Lantus) 24-week, double-blind trial, 495 patients with type 2 diabetes inadequately controlled with Insulin Glargine and Metformin (mean HbA1C 8.4 percent) were randomly assigned to the addition of Lixisenatide or placebo The reduction in A1C was significantly greater in the Lixisenatide group (-0.6 versus -0.3 percent)

41 CVOT's CARDIOVASCULAR OUTCOME TRIALS

42 Large Non-Insulin CVOTs in T2DM Study SAVOR EXAMINE TECOS CAROLINA CARMELIN A DPP4-i Comparat or saxaglip tin alogliptin sitaglipti n linagliptin linagliptin placebo placebo placebo sulfonylurea placebo N 16,500 5,400 14,000 6,000 8,300 Study LEADER ELIXA SUSTAIN 6 EXSCEL REWIN D GLP1- RA Comparat or Results June liraglutide lixisenatid 2015 semaglutide e exenatide LR Dulaglutide 650 placebo placebo placebo placebo Placebo FREEDOM Study EMPA-REG CANVAS DECLARE Placebo NCT N 16,500 14,000 6,000 5,400 8, ITCA- Results SGLT-2-i empaglifozin POSITIVE canagliflozin dapagliflozin ertugliflozin Comparat or placebo placebo placebo placebo N , Results Sept

43 PROactive Study >5,000 patients in 19 European countries involving over 320 investigators Investigated effect of insulin resistance on CV morbidity and mortality in patients with T2DM Investigated Pioglitazone s ability to prevent the progression of macrovascular disease The primary endpoint was time to first occurrence of any of the following events from time of randomization: All-cause mortality Stroke Leg revascularization Non-fatal MI (including silent) Major leg amputation (above the ankle) Acute coronary syndrome Cardiac intervention CV = cardiovascular; T2DM = type 2 diabetes mellitus PROspective Actos Clinical Trial In macrovascular Events (PROactive) results. Accessed February 2011.

44 Kaplan-Meier Event Rate Kaplan-Meier Event Rate PROactive Study, Secondary Endpoints Pioglitazone Had No Significant Effect on Primary Composite CV Endpoints Benefit Seen in Select Secondary Endpoints Time to ACS PIO.06 Placebo.05 (35/1230) (54/1215) Time to Fatal/Nonfatal MI (excluding silent MI) PIO (65/1230) (88/1215) Placebo N at Risk: HR 95% CI.0 HR 95% CI P value P value PIO vs placebo , PIO vs placebo , (139) N at (139) Risk: l l l l l l l l l l l l l l l l Time From Randomization (mo) Time From Randomization (mo) CV=cardiovascular; ACS=acute coronary syndromes; MI=myocardial infarction The official PROspective Actos Clinical Trial In macrovascular Events (PROactive) results website. Available at Dormandy JA, et al. Lancet. 2005;366: PROactive results Web site. Available at results.com /html/analysis.htm. October 10, 2006.

45 Pioglitazone after Ischemic Stroke or Transient Ischemic Attack Primary Outcome Kernan WN et al. N Engl J Med 2016;374:

46 Pioglitazone after Ischemic Stroke or TIA Primary and Secondary Outcomes Kernan WN et al. N Engl J Med 2016;374:

47 EMPA-REG Clinical Outcomes with Empagliflozin EMPA-REG OUTCOME Pooled Analysis (N=7020) Hazard ratio (95% CI) 14% P value Primary composite endpoint* 0.86 ( ) 0.04 Secondary composite endpoint 0.89 ( ) % Death from any cause 0.68 ( ) < % CV death 0.62 ( ) <0.001 Fatal or nonfatal MI 35% 0.87 ( ) 0.23 Hospitalization for HF 34% 0.65 ( ) Hospitalization for HF or CV death 0.66 ( ) <0.001 *CV death, nonfatal MI (excluding silent MI), or nonfatal stroke; CV death, nonfatal MI (excluding silent MI), nonfatal stroke, and hospitalization for unstable angina. CI, confidence interval; CV, cardiovascular; HF, heart failure; HR, hazard ratio; MI, myocardial infarction. Zinman B, et al. N Engl J Med. 2015;373: Favors empagliflozin

48 CVOT- Empa-Reg Trial HR 0.62 (95% CI 0.49, 0.77) p< Cumulative incidence function. HR, hazard ratio

49 Number needed to treat (NNT) to prevent one death across landmark trials in patients with high CV risk Simvastatin 1 for 5.4 years High CV risk 5% diabetes, 26% hypertension Ramipril 2 for 5 years High CV risk 38% diabetes, 46% hypertension Empagliflozin for 3 years T2DM with high CV risk 92% hypertension 1. 4S investigator. Lancet 1994; 344: , 2. HOPE investigator N Engl J Med 2000;342:145-53, Pre-ACEi/ARB era >80% ACEi/ARB Pre-statin era <29% statin >75% statin

50 LEADER (Liraglutide)- Primary outcome CV death, non-fatal myocardial infarction, or non-fatal stroke The primary composite outcome in the time-to-event analysis was the first occurrence of death from cardiovascular causes, non-fatal myocardial infarction, or non-fatal stroke. The cumulative incidences were estimated with the use of the Kaplan Meier method, and the hazard ratios with the use of the Cox proportional-hazard regression model. The data analyses are truncated at 54 months, because less than 10% of the patients had an observation time beyond 54 months. CI: confidence interval; CV: cardiovascular; HR: hazard ratio. Presented at the American Diabetes Association 76 th Scientific Sessions, Session 3-CT-SY24. June , New Orleans, LA, USA.

51 LEADER Trial Primary and secondary CV Outcomes *Hazard ratios and p-values were estimated with the use of a Cox proportional-hazards model with treatment as a covariate. The primary composite outcome in the time-to-event analysis consisted of the first occurrence of death from cardiovascular causes (181 patients in the liraglutide group vs. 227 in the placebo group), non-fatal (including silent) myocardial infarction (275 vs. 304), or non-fatal stroke (152 vs. 163). The p-value is for superiority. The expanded composite outcome included death from cardiovascular causes, non-fatal myocardial infarction, non-fatal stroke, coronary revascularization, or hospitalization for unstable angina pectoris or heart failure. This analysis was not prespecified. CI: confidence interval; CV: cardiovascular; UAP: unstable angina pectoris. Presented at the American Diabetes Association 76 th Scientific Sessions, Session 3-CT-SY24. June , New Orleans, LA, USA.

52 LEADER Trial: Time to first renal event Macroalbuminuria, doubling of serum creatinine, ESRD, renal death The cumulative incidences were estimated with the use of the Kaplan Meier method, and the hazard ratios with the use of the Cox proportional-hazard regression model. The data analyses are truncated at 54 months, because less than 10% of the patients had an observation time beyond 54 months. CI: confidence interval; ESRD: end-stage renal disease; HR: hazard ratio. Presented at the American Diabetes Association 76 th Scientific Sessions, Session 3-CT-SY24. June , New Orleans, LA, USA.

53 LEADER TRIAL: NNT to treat to prevent one CV: cardiovascular; MACE: major adverse cardiovascular event. Presented at the American Diabetes Association 76 th Scientific Sessions, Session 3-CT-SY24. June , New Orleans, LA, USA.

54 CANVAS: Canagliflozin and Cardiovascular and Renal Events in Type 2 Diabetes Compared with patients taking placebo, patients taking Canagliflozin had lower A1C levels (mean difference percent) and reductions in weight and systolic and diastolic blood pressure After a mean follow-up of 3.6 years, the primary outcome, a composite of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke, occurred in fewer patients in the Canagliflozin group (26.9 vs patients per 1000 patient-years, The rate of hospitalization for heart failure was lower in the canagliflozin group (5.5 versus 8.7 patients per 1000 patient-years in the placebo group, HR 0.67, 95% CI ) Progression of albuminuria (a secondary endpoint) occurred less frequently in the Canagliflozin group (89.4 versus participants per 1000 patient-years in the placebo group, HR 0.73, 95% CI )

55 CANVAS and CANVAS -R Adverse reactions were consistent with the previously reported risks associated with canagliflozin except for an increased risk of amputation Amputation incidence 5.9 and 2.8 per 1000 patient-years for patients taking canagliflozin and placebo, respectively, in the first trial, and 7.5 and 4.2 per 1000 patient-years, respectively, in the second trial Patients were followed for a mean 5.7 and 2.1 years, respectively Amputations were primarily at the level of the toe or metatarsal Patients with a history of prior amputation, peripheral vascular disease, and neuropathy were at highest risk for amputation

56 Summary: CVOT's of SGLT-2 Inhibitors The large cardiovascular benefit of Empagliflozin and Canagliflozin while impressive, was in a very high-risk population with established CVD at baseline Benefit in patients taking Canagliflozin must be balanced with the increased risk of amputations The difference in glycemia between the treatment groups was minimal, suggesting that extra-glycemic effects of the drugs were responsible for the CVD outcome It is unknown whether Empagliflozin, Canagliflozin, or other SGLT2 inhibitors, will have similar CVD effects in the majority of persons with type 2 diabetes who do not have overt CVD Wait for DECLARE (with Dapagliflozin)

57 Look beyond your patient's HbA1c DIABETES TECHNOLOGY: CGMS, INSULIN PUMPS AND OTHER OPTIONS

58 Look Beyond Your Patient's HbA1c

59 Summary: DM Contemporary Care Identify individual treatment goals Institute personalized comprehensive care for people with diabetes Start intensive lifestyle modification for glycemic control while concomitantly starting medications Choose medications based on safety, efficacy and characteristics Monitor every three months intensify/advance treatment as needed Per the AACE Algorithm Consider GLP1 RA and SGLT- 2 Inhibitors as first options with metformin based on safety efficacy in reducing glucose and positive effect on CV risk parameters especially weight and blood pressure

60 THANK YOU