California Chapter of the American Association of Clinical Endocrinologists AACE Presents: Hot Topics in Diabetes and Endocrinology for Primary Care

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1 California Chapter of the American Association of Clinical Endocrinologists AACE Presents: Hot Topics in Diabetes and Endocrinology for Primary Care New Advances in Pharmacotherapy in Management of Patients with Type 2 Diabetes: Focus on: Incretin Therapy- DPP4i, GLP1-RA & SGLT2-i Herbert I. Rettinger, M.D., FACE Past President, CA-AACE Orange, CA.

2 Available Drugs for the Treatment of T2DM

3 Noninsulin Agents Available for Treatment of Type 2 Diabetes Class Primary Mechanism of Action Agent Available as a-glucosidase inhibitors Amylin analogue Biguanide Bile acid sequestrant DPP-4 inhibitors Delay carbohydrate absorption from intestine Decrease glucagon secretion Slow gastric emptying Increase satiety Decrease HGP Increase glucose uptake in muscle Decrease HGP? Increase incretin levels? Increase glucosedependent insulin secretion Decrease glucagon secretion Acarbose Miglitol Pramlintide Metformin Colesevelam Alogliptin Linagliptin Saxagliptin Sitagliptin Precose or generic Glyset Symlin Glucophage or generic WelChol Nesina Tradjenta Onglyza Januvia Dopamine-2 Activates dopaminergic Bromocriptine Cycloset agonist receptors HGP=hepatic glucose production. Garber AJ et al. Endocr Pract. 2013;19(suppl 2):1-48.

4 Noninsulin Agents Available for Treatment of Type 2 Diabetes Class Primary Mechanism of Action Agent Available as Glinides Increase insulin secretion GLP-1 receptor agonists SGLT2 inhibitor Increase glucose-dependent insulin secretion Decrease glucagon secretion Slow gastric emptying Increase satiety Increase urinary excretion of glucose Sulfonylureas Increase insulin secretion Thiazolidinediones Increase glucose uptake in muscle and fat Decrease HGP Nateglinide Repaglinide Exenatide Exenatide XR Liraglutide Albiglutide Starlix or generic Prandin Byetta Bydureon Victoza Tanzeum Dulaglutide Trulicity Lixisenatide Lyxumia * Dapagliflozin Farxiga/Forxiga Canagliflozin Invokana Empagliflozin Jardiance Iprafliflozin Suglat Glimepiride Amaryl or generic Glipizide Glucotrol or generic Glyburide Diabeta, Glynase, Micronase, or generic Pioglitazone Rosiglitazone Actos Avandia

5 Combination Agents Available for the Treatment of Type 2 Diabetes Class Added Agent Available as DPP4i + SGLT2i Saxagliptin/Empagliflozin Glyxambi Metformin + DPP-4 inhibitor Metformin + glinide Alogliptin Linagliptin Saxagliptin Sitagliptin Repaglinide Kazano Jentadueto Kombiglyze XR Janumet Prandimet Metformin + SGLT2 Canagliflozin Invokamet Dapagliflozin Xigduo Empaglifloin Synjardy Metformin + sulfonylurea Glipizide Metaglip and generic Glyburide Glucovance and generic Metformin + thiazolidinedione Pioglitazone Actoplus Met Thiazolidinedione + DPP-4 inhibitor Rosiglitazone Pioglitazone + alogliptin Avandamet Oseni Thiazolidinedione + sulfonylurea Pioglitazone + glimepiride Duetact Rosiglitazone + glimepiride Avandaryl

Treatment based on pathophysiology Decreased incretin effect and faster carb absorption β insulin 50-80% at diagnosis α Hyperglycemia Neurotransmitter dysfunction Hepatic glucose production

6 Treatment based on pathophysiology Decreased incretin effect and faster carb absorption β insulin 50-80% at diagnosis α Hyperglycemia Neurotransmitter dysfunction Hepatic glucose production INSULIN RESISTANCE glucose reabsorption Lipolysis increased Decreased glucose uptake glucagon secretion Islet- α cell DeFranzo R, et al. Diabetes Care, Volume 36, Supplement 2, August 2013 S

Treatment based on pathophysiology DPP IV inhibitors GLP-1 agonists Decreased incretin effect and faster carb absorption β Sulfonylureas Meglitinides GLP-1 ra insulin 50-80% at diagnosis α

9 Treatment based on pathophysiology DPP IV inhibitors GLP-1 agonists Decreased incretin effect and faster carb absorption β Sulfonylureas Meglitinides GLP-1 ra insulin 50-80% at diagnosis α 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 Decreased glucose uptake DeFranzo R, et al. Diabetes Care, Volume 36, Supplement 2, August 2013 S TZDs Insulin

10 Incretin Based Therapy GLP-1 receptor agonists (injectable therapies) Exenatide & QW Liraglutide Dulaglutide Abiglutide DPP-4 inhibitors (oral therapies) Inhibit actions of DPP-4 Sitagliptin, Saxagliptin, Linagliptin, Alogliptin

11 DPP-4 Inhibitors FDA-Approved Agents Alogliptin Linagliptin Saxagliptin Sitagliptin Key Features Oral administration Increase endogenous GLP-1 and GIP levels Increase glucosedependent insulin secretion Suppress glucagon production DPP-4, dipeptidyl peptidase 4; GIP, glucose-dependent insulinotropic polypeptide; GLP-1, glucagon-like peptide 1. Garber AJ, et al. Endocr Pract. 2013;19(suppl 2):

12 Characteristics of 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:

13 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 (%) Placebo-adjusted D 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:

14 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, D Weight (kg) 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:

15 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, Patients (%) 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:

16 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:

17 GLP-1 Receptor Agonists FDA-Approved Agents Albiglutide Dulaglutide Exenatide Exenatide ER Liraglutide Key Features Injectable administration Mimic action of native GLP-1(not DPP4 sensitive) Increase glucosedependent 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):

18 Glucose Control with GLP-1 Receptor Agonists Placebo-Adjusted 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 14 Baseline A1C (%) Placebo-adjusted D A1C (%) *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:

19 Weight Change with GLP-1 Receptor Agonists Absolute Change from Baseline (Not Head-to-Head Trials) D Weight (kg) 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:

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

Lir+ Met+ SU 1 0.4 0.5 0 D Systolic BP (mmhg) -1-2 -3-4 -5-6 *P<0.05 vs comparator. -0.7-3.6 * -1.8-2.3 * -0.9-0.7-0.9-1.1-2.3-2.8-5.6 * -4.0 * All liraglutide dosages shown are 1.8 mg QD. 1. Garber A, et al.

20 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 D Systolic BP (mmhg) *P<0.05 vs comparator * * * -4.0 * 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:

21 Hypoglycemia with GLP-1 Receptor Agonists Percentage of Patients Reporting Hypoglycemia (Not Head-to-Head Trials) Patients (%) 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:

22 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,

23 Antidiabetic Activities of GLP-1 Gastroenterology , DOI: ( /j.gastro

24 SGLT2 Inhibitors Sodium Glucose Transport Protein- subgroup 2

circulation SGLT2 inhibitors lower the threshold at which glucose is excreted, leading to Increased urinary glucose

25 SGLT2 Inhibitors Promote Urinary Glucose Excretion Glucose SGLT2 mediates most ( 90%) glucose reabsorption from the proximal renal tubular lumen back into the circulation Bowman s capsule SGLT2 Proximal renal tubule Urinary excretion 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 Chao E, Henry R. Nature Rev Drug Discov. 2010;9:

26 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 ( ê A1C %) Advantages Disadvantages Contraindications Insulin-independent glucose reduction, Low risk of hypoglycemia, Weight loss (to 4% BW), Blood pressure-lowering Osmotic diuresis causing Polyuria and lightheadedness, Bacterial urinary tract infections ( 5%), Fungal genital infections ( 10%), Increased LDL cholesterol, Hyperkalemia (canagliflozin), Bladder cancer concerns (dapagliflozin) 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.

Sodium-glucose co-transporter 2 inhibitors (SGLT2)

Weight loss Improved systolic BP A1c reduction Other

27 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

28 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 (%) Placebo-adjusted D A1C (%) * * -1.2 *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:

29 Weight Change with SGLT2 Inhibitors Absolute Change from Baseline (Not Head-to-Head Trials) Monotherapy Add-on to Metformin Add-on to Insulin +/- OAs D Weight (kg) 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:

30 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) Change (kg) Placebo + MET (n=86) (24 Weeks) Farxiga 10 mg + MET (n=83) Total lean tissue mass Total fat mass Placebo + MET (n=71) (102 Weeks) Farxiga 10 mg + MET (n=66) Adjusted mean change (95% CI) FAS (including data after hyperglycemia rescue therapy) MET: Metformin 30 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 ³ 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

31 Blood Pressure Changes with SGLT2 Inhibitors Absolute Change from Baseline (Not Head-to-Head Trials) D Systolic BP (mmhg) 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:

32 Hypoglycemia with SGLT2 Inhibitors Percentage of Patients Reporting Hypoglycemia (Not Head-to-Head Trials) Monotherapy Add-on to Metformin Add-on to Insulin +/- OAs Patients (%) 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:

33 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 Increased incidence of bladder cancers in patients receiving dapagliflozin Bladder cancer 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

34 Time course of egfr (meta-analysis) (ml/min/1.73 m 2 ) 15 Change from baseline in egfr 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 < endocrinologicandmetabolicdrugsadvisorycommittee/ucm pdf>

35 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 Do not initiate if egfr <45 ml/min/1.73m 2 Severe renal impairment, ESRD, dialysis Do not initiate if egfr <60 ml/min/1.73m 2 Severe renal impairment, ESRD, dialysis Do not initiate if egfr <45 ml/min/1.73m 2 Warnings and Precautions Hypotension Impaired renal function Hyperkalemia Hypoglycemia: concomitant insulin or secretagogues Hypotension Impaired renal function Hypoglycemia: concomitant insulin or secretagogues Genital mycotic infections Hypotension Impaired renal function Hypoglycemia: concomitant insulin or secretagogues Genital mycotic infections Genital mycotic infections Hypersensitivity reactions LDL-C increases Bladder cancer imbalance LDL-C increases Urinary tract infections 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

36 SOLIQUA: single-injection fixed-ratio combination of GLP1-RA & Analog Basal Insulin- lixisenatide (Adlyxin/ Lyxumia) & Glargine (Lantus) "Improved Glucose Control without Increased Hypoglycemia Risk at Any Level of HbA1c Reduction with Insulin Glargine/Lixisenatide Fixed-Ratio Combination (LixiLan) vs. Insulin Glargine Alone Both Added On to Metformin in Type 2 Diabetes (T2DM)" Xultophy: combination therapy for the treatment of type 2 diabetes KEY POINTS Xultophy is an injection combining insulin degludec with liraglutide for T2D 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

Large Non-Insulin CVOTs in T2DM Study SAVOR EXAMINE TECOS CAROLINA CARMELINA DPP4-i saxagliptin alogliptin sitagliptin linagliptin linagliptin Comparator placebo placebo placebo sulfonylurea placebo

37 Large Non-Insulin CVOTs in T2DM Study SAVOR EXAMINE TECOS CAROLINA CARMELINA DPP4-i saxagliptin alogliptin sitagliptin linagliptin linagliptin Comparator placebo placebo placebo sulfonylurea placebo N 16,500 5,400 14,000 6,000 8,300 Results June Study LEADER ELIXA SUSTAIN 6 EXSCEL REWIND FREEDOM GLP1-RA liraglutide lixisenatide semaglutide exenatide LR Dulaglutide ITCA-650 Comparator placebo placebo placebo placebo Placebo Placebo N 16,500 14,000 6,000 5,400 8, Results Study EMPA-REG CANVAS DECLARE NCT SGLT-2-i empaglifozin canagliflozin dapagliflozin ertugliflozin Comparator POSITIVE placebo placebo placebo placebo N , Results Sept

38 PROactive Study EASD Athens 2005 >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) CV = cardiovascular; T2DM = type 2 diabetes mellitus Major leg amputation (above the ankle) Acute coronary syndrome Cardiac intervention PROspective Actos Clinical Trial In macrovascular Events (PROactive) results. Accessed February 2011.

Kaplan-Meier Event Rate.06.05.04.03.02.01.

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

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

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

42 PROactive Professor Dormandy- lead author, St George s Hospital, London concluded that.. The results are probably generalizable to the population of persons with diabetes (including) those persons who have not yet suffered a macrovascular event. (Pio- increases insulin sensitivity, improves dyslipidemia) NNT of 48 to prevent 1 event over 3 years. 42

EMPA-REG Clinical Outcomes with Empagliflozin EMPA-REG OUTCOME Pooled Analysis (N=7020) EASD 2015 Stockholm Hazard ratio (95% CI) P value Primary composite endpoint* 14% 0.86 (0.74-0.99) 0.

23 Hospitalization for HF 35% 0.65 (0.50-0.85) 0.002 Hospitalization for HF or CV death 34% 0.66 (0.55-0.79) <0.

43 EMPA-REG Clinical Outcomes with Empagliflozin EMPA-REG OUTCOME Pooled Analysis (N=7020) EASD 2015 Stockholm Hazard ratio (95% CI) P value Primary composite endpoint* 14% 0.86 ( ) 0.04 Secondary composite endpoint 0.89 ( ) 0.08 Death from any cause 32% 0.68 ( ) <0.001 CV death 36% 0.62 ( ) <0.001 Fatal or nonfatal MI 0.87 ( ) 0.23 Hospitalization for HF 35% 0.65 ( ) Hospitalization for HF or CV death 34% 0.66 ( ) <0.001 Favors empagliflozin *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:

44 CV death HR 0.62 (95% CI 0.49, 0.77) p< % decrease Cumulative incidence function. HR, hazard ratio 44

45 Number needed to treat (NNT) to prevent one death across landmark trials in patients with high CV risk Simvastatin 1 for 5.4 years Ramipril 2 for 5 years Empagliflozin for 3 years High CV risk 5% diabetes, 26% hypertension Pre-statin era High CV risk 38% diabetes, 46% hypertension Pre-ACEi/ARB era <29% statin T2DM with high CV risk 92% hypertension >80% ACEi/ARB >75% statin S investigator. Lancet 1994; 344: , 2. HOPE investigator N Engl J Med 2000;342:145-53, 45

46 EMPA-REG: Renal Function over Time. Wanner C et al. N Engl J Med DOI: /NEJMoa

47 EMPA-REG: Risk Comparison for Seven Renal Outcomes. Wanner C et al. N Engl J Med DOI: /NEJMoa

LEADER- 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

48 LEADER- 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.

Primary and secondary cardiovascular outcomes* *Hazard ratios and p-values were estimated with the use of a Cox proportional-hazards model with treatment as a covariate.

49 Primary and secondary cardiovascular 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.

Time to first renal event Macroalbuminuria, doubling of serum creatinine, ESRD, renal death The cumulative incidences were estimated with the use

The data analyses are truncated at 54 months, because less than 10% of the patients had an observation time beyond 54 months.

50 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 proportionalhazard 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.

51 Number needed 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.

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).

52 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. (accessed )

53 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 GLP1ra and SGLT2i as first options with metformin based on safety efficacy in reducing glucose and positive effect on CV risk parameters especially weight and blood pressure 53

54 THANK YOU FOR YOUR KIND ATTENTION

California Chapter of the American Association of Clinical Endocrinologists AACE Presents: Hot Topics in Diabetes and Endocrinology for Primary Care

California Chapter of the American Association of Clinical Endocrinologists AACE Presents: Hot Topics in Diabetes and Endocrinology for Primary Care New Advances in Pharmacotherapy in Management of Patients