Update on Agents for Type 2 Diabetes

Update on Agents for Type 2 Diabetes This presentation will: Outline the clinical considerations in the selection of pharmacotherapy for type 2 diabetes, including degree of A1C lowering achieved, patient-specific concerns, adverse drug reactions, and contraindications Discuss the role and timing of combination therapy in achieving A1C goals Explain the implications of recent, large randomized clinical trials on clinical decision-making

AACE Diabetes Algorithm Guide therapy based on A1C level Focus on lifestyle intensification at all levels Important tenets: Target A1C is <6.5% Based on associated lower risk of micro- and macrovascular complications Recommend monitoring A1C quarterly, along with fasting and postprandial blood glucose, with intensification of therapy until goal A1C is achieved Individualize A1C target based on comorbidities Patient should monitor fasting and postprandial blood glucose levels Use agents with maximal efficacy, associated with lowest risk of hypoglycemia Sulfonylureas are therefore much lower in algorithm Earlier use of incretin mimetics and DPP-4 inhibitors to stimulate insulin secretion without hypoglycemia A1C = glycated hemoglobin; DPP-4 = dipeptidyl-peptidase 4 AACE Comprehensive Diabetes Management Algorithm 2013. Endocr Pract. 2013;19(3):536-557.

Main Pathophysiological Defects in T2DM Islet b-cell The Ominous Octet Impaired insulin secretion Decreased incretin effect Increased lipolysis Islet a-cell Increased glucagon secretion Increased glucose reabsorption Increased hepatic glucose production Defronzo RA. Diabetes. 2009 Apr;58(4):773-95. Neurotransmitter dysfunction Decreased glucose uptake

Current Antihyperglycemic Medications Glinides Sulfonylureas TZDs Insulin replacement therapy Restore postprandial insulin patterns Generalized insulin secretagogue Reduce peripheral insulin resistance Biguanide Reduces hepatic insulin resistance GLP-1 analogs Stimulate beta-cells Suppress glucagon 12 groups with different mechanisms of action SGLT-2 inhibitors Block renal glucose reabsorption DPP-4 inhibitors Restore GLP-1 Levels Amylin analog Suppresses glucagon a-glucosidase inhibitors Delay CHO absorption Colesevelam Bile acid sequestrant Bromocriptine Hypothalamic pituitary reset CHO = carbohydrate; DPP-4 = dipeptidyl peptidase-4; GLP-1 = glucagon-like peptide-1; SGLT-2 = sodium-dependent glucose cotransporters-2; TZD = thiazolidinedione.

Clinical Considerations Combining therapeutic agents with different modes of action may be advantageous In many if not most patients (unless contraindicated or intolerance has been demonstrated), use metformin, which increases insulin sensitivity, and/or insulin sensitizers such as TZDs, as part of the therapeutic regimen Dosage of secretagogues or insulin should be adjusted as blood glucose levels decline when used in combination with metformin, TZD, DPP-4 inhibitors, and/or incretin mimetics (GLP-1 agonists) TZD = thiazolidinediones; DPP-4 = dipeptidyl peptidase-4; GLP-1 = glucagon-like peptide-1 AACE Comprehensive Diabetes Management Algorithm 2013. Endocr Pract. 2013;19(3):536-557. Sitagliptin [package insert]. Whitehouse Station, NJ; Merck Co. Inc.; 2010. Saxagliptin [package insert]. Princeton, NJ; Bristol Meyers Squibb; 2009; Linagliptin [package insert]. Ridgefield, CT: Boehringer Ingelheim Pharmaceuticals. 2011.

Risk of Hypoglycemia Plays a significant role in choice of agents in AACE algorithm For patients at highest risk of hypoglycemia, may consider close evaluation of agents chosen as well as therapeutic goal Patients with type 2 diabetes at highest risk of low blood glucose include those with: Diabetes duration >15 years Advanced macrovascular disease Hypoglycemia unawareness Limited life expectancy Severe comorbidities AACE Comprehensive Diabetes Management Algorithm 2013. Endocr Pract. 2013;19(3):536-557; AACE Algorithm for Glycemic Control, Endocr Pract. 2009;15(6):540-59.

Biguanides Metformin Mechanism Insulin sensitivity Hepatic glucose production FPG more than PPG Efficacy A1C 1%-2% Advantages Disadvantages Contraindications No weight gain or hypoglycemia, potential weight loss GI side effects Lactic acidosis (rare) Renal disease; CHF Combinations available with SU, TZD, repaglinide, and DPP-4 inhibitors A1C = glycated hemoglobin; CHF = congestive heart failure; DPP-4 = dipeptidyl peptidase-4; FPG = fasting plasma glucose; GI = gastrointestinal; PPG = post-prandial glucose; SU = sulfonylurea; TZD = thiazolidinedione Metformin [package insert]. Princeton NJ; Bristol Myers Squibb; 2009.

Mechanism Sulfonylureas and Glinides Glipizide, Glimepiride, Glyburide Repaglinide, Nateglinide Insulin secretion FPG PPG Efficacy Advantages Moderate Strong short term efficacy Disadvantages Contraindications Weight gain, hypoglycemia, tend to lose efficacy after several years Avoid in severe hepatic and renal impairment Combinations available with metformin, TZD FPG = fasting plasma glucose; PPG = post-prandial glucose; TZD = thiazolidinedione Glyburide [package insert]. New York, NY; Pfizer; 2010. Glipizide [package insert]. New York, NY; Pfizer; 2010. Glimepiride [package insert]. Scoppito, Italy; Aventis Pharma S.p.A; 2001. Kahn SE, et al. NEJM. 2006;355:23.

Thiazolidinediones Pioglitazone, Rosiglitazone Mechanism Insulin sensitivity, especially at muscle, lowers both FPG and PPG, but effect may be delayed Efficacy Moderate ( A1C 1.0%-1.5%) Advantages No hypoglycemia, no reliance on renal excretion Disadvantages Contraindications Fluid retention, edema, heart failure, weight gain, slow onset of action, bone fractures, macular edema, osteoporosis, anemia, and bladder cancer Class III or IV CHF or hepatic impairment w/alt >2.5 times upper normal limits Combinations available with metformin and sulfonylurea A1C = glycated hemoglobin; ALT = alanine aminotransferase; CHF = congestive heart failure; FPG = fasting plasma glucose; PPG = postprandial plasma glucose. Pioglitazone [package insert]. Deerfield, IL: Takeda Pharmaceuticals America, 2011. Rosiglitazone Prescribing Information. Research Triangle Park, NC: GlaxoSmithKline, 2013.

Alpha-Glucosidase Inhibitors Acarbose, Miglitol Mechanism Efficacy Advantages Disadvantages Contraindications Rate of gut polysaccharide breakdown, thereby slowing absorption Modest ( A1C 0.5%-1.0%), PPG lowering Weight-neutral, non-systemic drug, targets postprandial glucose Bloating, flatulence, diarrhea w/slow titration, frequent dosing Severe renal impairment, diabetic ketoacidosis, malabsorption, obstruction, inflammatory bowel, or conditions aggravated by gas production Combinations available with sulfonylureas A1C = glycated hemoglobin; PPG = post-prandial glucose Acarbose [package insert]. Wayne, NJ; Bayer HealthCare Pharmaceuticals Inc.; 2009. Miglitol [package insert]. Wayne, NJ; Bayer HealthCare Pharmaceuticals Inc.; 2010.

Mechanism Dopamine Receptor Agonist Bromocriptine QR Exact mechanism of action unclear, believed to reduce sympathetic tone, inflammation, and insulin resistance Efficacy Modest ( A1C 0.5%) Advantages Disadvantages Contraindications May decrease cardiovascular risk Hypotension, syncope, hypoglycemia, nausea History of psychosis or during breastfeeding. Use caution with renal or hepatic impairment. A1C = glycated hemoglobin; QR = quick-release Cincotta et al. Taylor and Francis, Eds Hansen, B Shafrir, E London, 2002. 271-312. Defronzo RA et al. Diabetes Care. 2011 Apr;34(4):789-94.

Bays HE, et al. Arch Intern Med. 2008;168:1975-83. Fonseca VA, et al. Diabetes Care. 2008; 31:1479-1484. Fonseca V, et al. Diabetes Obes Metab. 2010;12(5);384-392. Goldberg RB, et al. Arch Intern Med. 2008;168:1531-1540; Colesevelam [package insert]. Parsippany, NJ; Daiichi Sankyo, 2011. Mechanism Bile Acid Sequestrants Colesevelam Efficacy Modest ( A1C 0.5%) Advantages Disadvantages Raises cholecystokinin, which slows gastric emptying and post-prandial glucose Exact mechanism unknown, may be mediated via TGR5, and/or farnesoid X receptor (FXR/bile acid receptor) effects on intestinal glucose LDL-C (also FDA approved for LDL-C reduction) weight neutral, no hypoglycemia, can complement statin treatment in lowering LDL and cardiac event risk Constipation, nausea, dyspepsia, myalgia, pharyngitis, triglycerides, drug interactions Contraindications History of bowel obstruction, TGs >500 mg/dl; history of hypertriglyceridemiainduced pancreatitis A1C = glycated hemoglobin; LDL-C = low-density lipoprotein cholesterol; TG = triglyceride

Strategies for Enhancing GLP-1 Action GLP-1 receptor agonists (injectable therapies) Short acting: exenatide BID, liraglutide, lixisenatide Long acting: exenatide QR, albiglutide, dulaglutide Under investigation: semaglutide and ITCA 650 DPP-4 inhibitors (oral therapies) Inhibit actions of DPP-4 Sitagliptin, saxagliptin, linagliptin, alogliptin

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;14:98-107. Nathan DM, et al. Diabetes Care. 2008;31:173-175.

A1C (%) Glucose Control With Sitagliptin: Selected Mono and Combination Therapy Studies Monotherapy vs Glipizide 52 Weeks 1 Initial Combo w/ Metformin 24 Weeks 2 Metformin 24 Weeks 3 Insulin 24 Weeks 4 Pioglitazone vs Met + Pio 12 Months 5 Rosiglitazone + Metformin 54 Weeks 6 N 1172 1091 701 641 151 278 Treatment Sit Glip Sit Met Sit+ Met Met Sit+ Met Ins Sit+ Ins Met + Pio Sit + Pio Rosi + Met Sit + Rosi + Met Baseline A1C (%) 0-0.5-1 -1.5 7.5 7.5 8.9 8.7 8.8 8.0 8.0 8.6 8.7 8.4 8.5 8.7 8.8-0.67-0.67-0.66-1.13-0.02-0.67 0-0.6 * * -1.4-1.4-0.3-1.1-2 *P<0.001 vs active comparator monotherapy. P<0.001 vs active comparator dual therapy. 1. Nauck MA, et al. Diabetes Obes Metab. 2007;9:194-205. 2. Goldstein BJ, et al. Diabetes Care. 2007;30:1979-1987. 3. Charbonnel B, et al. Diabetes Care. 2006;29:2638-2643. 4. Vilsbøll T, et al. Diabetes Obes Metab. 2010;12:167-177. 5. Derosa G, et al. Metab Clin Exp. 2010;59:887-895. 6. Dobs AS, et al. J Diabetes. 2013;5:68-79.. -1.9 *

Patients Reporting Hypoglycemia (%) Hypoglycemia With Linagliptin: Mono and Combination Therapy Monotherapy Initial Combo w/ 24 Weeks 1 Metformin 24 Weeks 2 Initial Combo w/ Pioglitazone 24 Weeks 3 Metformin 24 Weeks 4 Metformin 2 Years 5 Metformin + SU 24 Weeks 6 N 503 791 389 700 1552 1055 Treatment PBO Lin Lin Met HD Lin + Met LD Lin + Met HD Pio Lin + Pio Met Lin + Met Glim + Met Lin + Met Met + SU Lin + Met + SU 40 35 36 30 25 22.7 20 15 14.8 10 5 0 0.6 0.3 0 3.4 3.5 0 0 2.8 1.2 0.6 7 HD, high-dose metformin (1000 mg twice daily); LD, low-dose metformin (500 mg twice daily). 1. Del Prato S, et al. Diabetes Obes Metab. 2011;13:258-267. 2. Haak T, et al. Diabetes Obes Metab. 2012;14:565-574. 3. Gomis R, et al. Diabetes Obes Metab. 2011;13:653-661. 4. Taskinen MR, et al. Diabetes Obes Metab. 2011;13:65-74. 5. Gallwitz B, et al. Lancet. 2012;380:475-483. 6. Owens DR, et al. Diabet Med. 2011;28:1352-61.

A1C (%) Glucose Control With Alogliptin: Mono and Combination Therapy Monotherapy Initial Combo w/ 26 Weeks 1 Pioglitazone 26 Weeks 2 Metformin 26 Weeks 3 Glyburide 26 Weeks 4 Met + Pio 52 Weeks 5 Insulin +/- Met 26 Weeks 6 N 329 655 527 500 803 390 Treatment PBO Alo Pio Alo Alo + Pio Baseline A1C (%) Met Alo + Met Gly Alo + Gly Met + Pio Alo + Met + Pio 7.9 7.9 8.8 8.8 8.8 8.0 7.9 8.1 8.1 8.1 8.3 9.3 9.3 Ins +/- Met Alo + Ins +/- Met * * * * * P<0.0001 vs comparator. * 1. DeFronzo RA, et al. Diabetes Care. 2008;31:2315 2317. 2. Rosenstock J, et al. Diabetes Care. 2010;33:2406 2408. 3. Nauck MA, et al. Int J Clin Pract. 2009;63:46-55.4. Pratley RE, et al. Diabetes Obes Metab. 2009;11:167-176. 5. Bosi E, et al. Diabetes Obes Metab. 2011;13:1088-1096. 6. Rosenstock J, et al. Diabetes Obes Metab. 2009;11:1145-1152.

Characteristics of GLP-1 Agonists Exenatide, Liraglutide, Albiglutide, Dulaglutide Mechanism Efficacy Mimic prolonged action of GLP-1 Decrease A1C levels 0.5% 2.0% (depends on entry of glucose into bloodstream from gut) Dosing Once- or twice-daily injection, weekly * Side effects Main risk Associated with Nausea, vomiting, weight loss C-cell thyroid tumors**, long-term safety unknown Pancreatitis possible *Dosing depends on GLP-1 agonist **With liraglutide, in rodents only A1C = glycated hemoglobin; GLP-1 = glucagon-like peptide-1. Nathan DM, et al. Diabetes Care. 2008;31:173-175; Drucker DJ, et al. Lancet. 2006;368:1696-1705. Exenatide [package insert]. San Diego, CA; Amylin Pharmaceuticals; 2010.; Tanzeum (albiglutide) [prescribing information].

Marketed GLP-1 RAs Exenatide BID Liraglutide Exenatide ER Albiglutide Dulaglutide Lixisenatide Initial U.S. approval Trade name Description 2005 2010 2012 2014 2014 2014 Byetta Victoza Bydureon Tanzeum (US) Eperzan (EU) Synthetic exendin-4, a peptide identified in H. suspectum that activates GLP-1 and is resistant to DPP-4 degradation GLP-1 modified a to be resistant to DPP-4 degradation Exenatide contained in a hydrolyzable polymer microspheres for extended release An albumin fusion protein made of 2 copies of modified human GLP-1 Trulicity A fusion protein with 2 disulfidelinked human GLP-1 analog sequence chains, connected by a small peptide linker to human immunoglobulin G4 (IGG4) Adlyxin (US) Lyxumia (EU) A peptide containing 44 amino acids, amidated at the C-terminal amino acid (position 44) Half-life 2.4 hours 13 hours > 1 week 5 days 5 days 3 hours Dosing 2X daily, before meals 1X daily, any time 1X weekly 1X weekly 1X weekly a Amino acid substitution and addition of acyl chain. BID = twice daily; DPP-4 = dipeptidyl peptidase-4; ER = extended release; E.U. = European Union; GLP-1 = glucagon-like peptide-1; IGG4 = human immunoglobulin; U.S. = United States. Byetta (exenatide) [Prescribing Information (PI)]; Victoza (liraglutide) [PI]; Bydureon (exenatide extended-release for injectable suspension) [PI].; Neumiller JJ. J Am Pharm Assoc. 2009;49(S1):S16-S29.; DeYoung M, et al. Diabetes Technol Ther. 2011;13:1145-54.; Tanzeum (albiglutide) [PI]; Lyxumia (lixisenatide) [PI]; Trulicity (dulaglutide) [PI]; Kuritzky L, et al. PostGrad Med. 2014;126(6):60-72. 1X daily, before 1st meal

A1C (%) 1. Garber A, et al. Lancet. 2009;373:473-481. 2. Nauck M, et al. Diabetes Care. 2009;32:84-90. 3. Pratley RE, et al. Lancet. 2010;375:1447-1456. 4. Marre M, et al. Diabet Med. 2009;26:268-278. 5. Zinman B, et al. Diabetes Care. 2009;32:1224-1230. 6. Russell-Jones D, et al. Diabetologia. 2009;52:2046-2055. Glucose Control with Liraglutide with/without Oral Agents Monotherapy vs Glimepiride 52 Weeks 1 Metformin 26 Weeks 2 Metformin 26 Weeks 3 Sulfonylurea 26 Weeks 4 MET + TZD 26 Weeks 5 MET + SU 26 Weeks 6 N 746 1091 665 1041 821 581 Treatment GLIM LIRA MET GLIM + MET Baseline A1C (%) 0.5 0 0.09 LIRA + MET SIT + MET LIRA + MET SU ROSI + SU 0.23 LIRA + SU ROSI + MET LIRA + MET + ROSI + SU MET GLAR + MET + SU 8.4 8.3 8.4 8.4 8.4 8.5 8.4 8.4 8.4 8.5 8.4 8.6 8.3 8.2 8.3 LIRA + MET + SU -0.5-0.51-0.44-0.5-0.24-1 -1.5-2 -1.14 * -0.98-1.00 * -0.9-1.50 ** -1.13 ** * ** -1.50-1.09-1.33 ** *** *P<0.0001 vs monotherapy. **P<0.0001 vs dual therapy. ***P=0.0015 vs glargine. All liraglutide dosages shown are 1.8 mg QD. A1C = glycated hemoglobin; GLAR = glargine; GLIM = glimepiride; LIRA = liraglutide; MET = metformin; QD = once daily; ROSI = rosiglitazone; SIT = sitagliptin; SU = sulfonylurea; TZD = thiazolidinedione.

Weight (kg) Weight Reduction with Liraglutide: Mono and Dual Combination Therapy Monotherapy vs Glimepiride 52 Weeks 1 Metformin 26 Weeks 2 Metformin 26 Weeks 3 Sulfonylurea 26 Weeks 4 MET + TZD 26 Weeks 5 MET + SU 26 Weeks 6 N 746 1091 665 1041 821 581 Treatment GLIM LIRA MET GLIM + MET 3 2 1 0-1 -2-3 -4 1.10 1.00-2.50 * -1.50 LIRA + MET -2.80 * ** 1. Garber A, et al. Lancet. 2009;373:473-481. 2. Nauck M, et al. Diabetes Care. 2009;32:84-90. 3. Pratley RE, et al. Lancet. 2010;375:1447-1456. 4. Marre M, et al. Diabet Med. 2009;26:268-278. 5. Zinman B, et al. Diabetes Care. 2009;32:1224-1230. 6. Russell-Jones D, et al. Diabetologia. 2009;52:2046-2055. SIT + MET -0.96 LIRA + MET -3.38 SU ROSI + SU -0.10 *** 2.10 LIRA + SU -0.20 * ROSI + MET 0.60 LIRA + MET + ROSI + SU MET -0.42 GLAR + MET + SU 1.60-2.00-1.80 * * *P<0.0001 vs glargine, rosiglitazone, sitagliptin, or SU. **P<0.01 vs metformin. ***P<0.05 vs SU. All liraglutide dosages shown are 1.8 mg QD. GLAR = glargine; GLIM = glimepiride; LIRA = liraglutide; MET = metformin; QD = once daily; ROSI = rosiglitazone; SIT = sitagliptin; SU = sulfonylurea; TZD = thiazolidinedione. * LIRA + MET + SU

Safety: Renal Impairment Renal impairment affects the clearance of exenatide BID & ER, but not that of liraglutide, albiglutide or dulaglutide. Hypovolemia due to nausea and vomiting may worsen renal function. Renal impairment with GLP-1 RAs has been reported postmarketing, usually in association with nausea, vomiting, diarrhea, or dehydration. BID = twice daily; ER = extended release; GLP-1 RA = glucagon-like peptide-1 receptor agonist. Linnebjerg H, et al. Br J Clin Pharmacol. 2007;64:317-327. Jacobsen L, et al. Br J Clin Parmacol. 2009;68:898-905.; Byetta PI 2013.

Safety: Pancreatitis Pancreatitis has been reported with all incretinbased therapies, although no causal relationship has been established. Patients should know signs and symptoms of pancreatitis and stop taking incretin-based therapies if signs and symptoms occur. If pancreatitis is confirmed, therapy should not be restarted. Ahmad SR, et al. N Engl J Med. 2008;358:1970-1971.; Garg R, et al. Diabetes Care. 2010;33:2349-2354.; Byetta PI 2013.; Victoza PI 2013.; Bydureon PI 2013.; Januvia PI 2013.; Onglyza PI 2013.; Tradjenta PI 2013.; Nesina PI 2013.

Patients with an event (%) LEADER Trial: Primary Outcome First occurrence of CV death, nonfatal myocardial infarction, or nonfatal stroke in the time-toevent analysis in patients with type 2 diabetes and high CV risk. 20 15 Hazard ratio, 0.87 (95% CI, 0.78 0.97) P<0.001 for noninferiority P=0.01 for superiority 10 5 Placebo Liraglutide 0 Marso SP et al., NEJM 2016 0 6 12 18 24 30 36 42 48 54 Months since randomization CI = confidence interval; CV = cardiovascular; LEADER = Liraglutide Effect and Action in Diabetes: Evaluation of cardiovascular outcome Results.

Summary: GLP-1 Receptor Agonists Good glycemic efficacy, glucose-dependent action Complement the actions of oral antihyperglycemic agents Can be used as monotherapy if MET is contraindicated and in combination with other oral agents and/or insulin Favorable weight effects and low hypoglycemic risk Consider patient risk factors and educate patients about potential risks and/or adverse effects (eg, nausea, history of thyroid tumors, pancreatitis) No increased risk of pancreatitis relative to other antihyperglycemic agents Potential for gastrointestinal side effects Cardioprotective (LEADER trial) GLP-1 = glucagon-like peptide-1; LEADER = Liraglutide Effect and Action in Diabetes: Evaluation of cardiovascular outcome Results; MET = metformin.

Mechanism SGLT2 Inhibitors Canagliflozin, Dapagliflozin, Empagliflozin 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 ( A1C 0.8-1.2%) 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 Reabsorption of glucose is mediated by SGLTs in proximal convoluted tubule Independent of insulin SGLT2 and SGLT1 located on luminal surface of epithelial cells lining proximal convoluted tubule SGLTs in other organs 2: liver 1: small intestine S1 segment of proximal tubule: SGLT2 S3 segment of proximal tubule: SGLT1 90% reabsorption 10% reabsorption 90% glucose is reabsorbed in S1 by SGLT2 Low affinity, high capacity transporter 10% reabsorbed in S3 by SGLT1 High affinity, low capacity transporter Bays, H. Diabetes Therapy, 2013 Chao EC, et al. Nat Rev Drug Discovery. 2010;9:551-559

Weight Effects with SGLT2 Inhibitors a as Monotherapy Roden M et al. Lancet Diabetes Endocrinol. 2013;1:208-219. Stenlöf K et al. Diabetes Obes Metab. 2013;15:372-382. Ferrannini E et al. Diabetes Care. 2010;33:2217-2224. US FDA. Drugs@FDA. http://www.accessdata.fda.gov/scripts/cder/drugsatfda/.

SGLT2 Inhibitors Safety: Adverse Reactions The most frequent adverse effects of SGLT2 inhibitors (occurring in 5% patients) are female genital mycotic and urinary tract infections Patients may also experience increased urination, dehydration, or nasopharyngitis SGLT2 = sodium-glucose cotransporter-2 Empagliflozin/Jardiance PI 2016.; Dapagliflozin/Farxiga PI 2016.; Canagliflozin/Invokana PI 2016.

SGLT2 Inhibitors Safety: Warnings and Precautions SGLT2 inhibitor use may be associated with hypotension, ketoacidosis, impaired renal function, hypoglycemia, and increased LDL-C Patients should be closely monitored, particularly those with a history of, or at risk for, these conditions Dapagliflozin should not be used in patients with a history of bladder cancer Canagliflozin may be associated with hyperkalemia and bone fracture Bone fracture risk should be considered before use, and potassium levels should be monitored during use LDL-C = low-density lipoprotein cholesterol; SGLT2 = sodium-glucose cotransporter-2 Empagliflozin/Jardiance PI 2016.; Dapagliflozin/Farxiga PI 2016.; Canagliflozin/Invokana PI 2016.

Empagliflozin Effects on A1C Change in A1C % 0.2 0.1 Monotherapy 0.1 Initial comb with metformin Combo with metformin + sulfonylurea Add on to met vs. glipizide + met Comb with pioglitazone Comb with insulin 0.1 0-0.1-0.2-0.3-0.1-0.2-0.1-0.4-0.5-0.4-0.6-0.7-0.8-0.9-0.7-0.7-0.8-0.8-0.8-0.8-0.6-0.7-0.7-0.7-0.6 10 mg 25 mg Placebo/comparator Jardiance Package Insert, 2014

Empagliflozin Effects on Weight % Weight Change 3 Monotherapy Initial comb with metformin Combo with metformin + sulfonylurea Add on to met vs. glipizide + met Comb with pioglitazone Comb with insulin 2 2 2 1 0.7 0-1 -0.4-0.5-0.5-0.6-2 -1.8-3 -4-2.8-3.2-2.5-2.9-2.9-3.2-3.9-2.4-2.4-5 10 mg 25 mg Placebo/comparator Jardiance Package Insert, 2014

EMPA-REG: Cardiovascular Death HR 0.62 (95% CI 0.49, 0.77) p<0.001 HR = hazard ratio. Zinman B et al. N Engl J Med 2015;373:2117-28. Supplement to: Zinman B et al. N Engl J Med 2015;373:2117-28.

EMPA-REG: Renal Function Over Time Wanner C et al. N Engl J Med 2016. DOI: 10.1056/NEJMoa1515920

Treatment of Type 2 Diabetes What Have We Learned? Outlined the clinical considerations in the selection of pharmacotherapy for type 2 diabetes Discussed the role of combination therapy and when it should be initiated based on A1C goals Discussed modes of action and clinical potential of recently introduced agents in the management of patients with type 2 diabetes Explained the implications of recent clinical trials and metaanalyses on clinical practice decisions