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1 1: - 11:15 AM Decreasing Cardiovascular Risk with Antihyperglycemic Agents in Patients with T2DM SPEAKER Christopher P. Cannon, MD Bejamin M. Scirica, MD, MPH Disclosures This session is supported by an independent educational grant from Boehringer Ingelheim Pharmaceuticals, Inc. and Lilly USA, LLC The following relationships exist related to this presentation: Christopher P. Cannon, MD: Contracted Research for Amgen, Inc.; Arisaph Pharmaceuticals, Inc.; Boehringer Ingelheim Pharmaceuticals, Inc.; Bristol-Myers Squibb Company; Daiichi Sankyo; Janssen Pharmaceuticals, Inc.; Merck & Co., Inc.; and Takeda Pharmaceuticals U.S.A, Inc. Consulting Fees for Alnylam Pharmaceuticals Inc.; Amarin Pharma Inc.; Amgen, Inc.; Arisaph Pharmaceuticals, Inc.; AstraZeneca; Boehringer Ingelheim Pharmaceuticals, Inc.; Bristol-Myers Squibb Company; Eisai, Inc.; GlaxoSmithKline; Kowa Pharmaceuticals, Inc., Lipimetix Development Inc., Merck & Co., Inc., Pfizer Inc., Regeneron Pharmaceuticals, Inc., Sanofi US; and Takeda Pharmaceuticals U.S.A, Inc. Bejamin M. Scirica, MD, MPH: Contracted Research for AstraZeneca, Eisai Inc., Novartis Pharmaceuticals; and Merck & Co., Inc. Consultatn for AstraZeneca, Biogen Idec Inc., Boehringer Ingelheim, Covance, Dr. Reddy's Laboratory, Eisai Inc., Elsevier PracticeUpdate Cardiology, GlaxoSmithKline, Lexicon Pharmaceuticals, Merck, & Co., Inc., Novo Nordisk Inc., and Sanofi US. Off-Label/Investigational Discussion In accordance with pmicme policy, faculty have been asked to disclose discussion of unlabeled or unapproved use(s) of drugs or devices during the course of their presentations. Clinical Consequences of Insulin Resistance Factors contributing to insulin resistance Insulin resistance Obesity specifically Central obesity Genetic factors, Family History, Population Groups Sedentary lifestyle, Physical activity, Increasing age Metabolic and Vascular Abnormalities Hemostatic abnormalities, increased coagulation Vascular inflammation, Abnormal vascular SMC, media and endothelial dysfunction, oxidative stress Abnormal FAA, visceral and organs fat deposition; Hyperuricemia Dyslipidemia: High TGL, low HDL, small dense LDL Impaired glucose homeostasis Clinical consequences. Kendall DM and Harmel AP. Am J Manag Care 22; 8:S635 S653; Aroor AR et al. Heart Fail Clin. 212:8(4): Diabetes Hypertension ASCVD Heart Failure Sleep Apnea PVD Stroke PCOS NAFLD/NASH Case John, 48 HPI: Presents for follow-up to your office; had an NSTEMI 2 years ago Recently started seeing you, and you diagnosed him with type II diabetes (HbA1c at the time of diagnosis was 8.3%); He tried behavioral changes for 3 months. He reports exercising for 3 minutes per day 5X/week and has modified his diet, including cutting out red meats, reducing saturated fat, and eating more fresh vegetables and fewer carbohydrates. For further glucose control, you started metformin cases

2 Case John, 48 cases Case John, 48 cases Medical History: T2DM 6 months NSTEMI 2 years (s/p stent) HTN 1 years Hypercholesterolemia 5 years GERD 2 years Medications: Metformin 1 mg BID Metoprolol succinate 5 mg daily Lisinopril 4 mg daily Aspirin 81 mg daily Atorvastatin 8 mg daily Pantoprazole 4 mg daily Nitroglycerin PRN Family History: Father died of MI at age 52 Mother, living, HTN Social History: Lives at home with wife and 2 year old daughter Works as a Project Manager Denies smoking; occasional alcohol use Case John, 48 ROS: NAD, generally feeling well the past few weeks, but urinating more than normal. Otherwise, no complaints Physical Exam: Ht: 6 Wt: 245 lbs BMI: 33.2 kg/m 2 BP: 14/9 mmhg HR: 88 bpm General: Obese male in no acute distress Today s Labs A1c 7.6% Lipid Panel TC 194, TG 12, LDL 13, HDL 4 CBC wnl BMP wnl egfr 1 ml/min/ cases Growing Prevalence of T2DM The prevalence of diabetes is rapidly growing There are an estimated 3.3 million Americans living with diabetes By 23, the prevalence is estimated to rise to 54.9 million! 54.9 Million 23 CDC. National diabetes statistics report: estimates of diabetes and its burden in the United States, 217. Atlanta, GA

3 CV Risk and T2DM Heart disease rates among adults with diabetes are 2 to 4 times higher than rates for adults without diabetes The rate of cardiovascular death is increased by 5% in those with diabetes Diabetes increases the risk of stroke, with RR ranging from fold increased risk The event rate for CHF is higher than any other complications after ACS in patients with diabetes Diabetic men and women 5 years of age live an average of 7.5 and 8.2 years less than their nondiabetic equivalents. The differences in life expectancy free of ASCVD are 7.8 and 8.4 years, respectively. Go AS, Mozaffarian D, Roger VL, et al.; on behalf of the American Heart Association Statistics Committee and Stroke Statistics Subcommittee. Circulation. 214;129:e28 e292; Franco OH, Steyerberg EW, Hu FB, Mackenbach J, Nusselder W. Arch Intern Med. 27;167: ; Malmberg K et al. Circulation. 2;12: Multimorbidity and T2DM By age 6, a history of any 2 of these conditions was associated with 12 years of reduced life expectancy; a history of all 3 conditions was associated with 15 years of reduced life expectancy. The Emerging Risk Factors Collaboration. Association of Cardiometabolic Multimorbodity with Mortality. JAMA. 215;314(1): Impact of Intensive Glycemic Control in Diabetes Study Microvascular ASCVD Mortality UKPDS DCCT/EDIC ACCORD ADVANCE VADT Bergenstal RM, Bailey C, Kendall DM. Am J Med. 21;123:374e9-e18.; UK Prospective Diabetes Study (UKPDS) Group. Lancet. 1998;352: ; Holman RR. N Engl J Med. 28;359(15): DCCT Research Group. N Engl J Med. 1993;329; ; Nathan DM, et al. N Engl J Med. 25;353: ; Gerstein HC, et al. N Engl J Med. 28;358: ; Patel A, et al. N Engl J Med. 28;358: Duckworth W, et al. N Engl J Med. 29;36: ; Hayward RA, et al. N Engl J Med. 215;372: Initial Trial Long term Follow up CV Risk is Not Well-Managed Despite Improvements NHANES Study Percentage % meeting ABC goals among adults aged 2 years with diagnosed diabetes, Percentage (%) A1C <7.% A1C <8.% BP <13/8 mmhg Casagrande SS et al. Diabetes Care. 213;36; BP <14/9 mmhg LDL <1 mg/dl On Statin A1C <7.%, BP <13/8 mmhg, and LDL <1 mg/dl

4 John, 48 cases? A New Era of Diabetes Management: Safety, Efficacy & CV Impact Beyond Lowering HbA1c Now, back to John... He has not been able to further bring down his HbA1c despite making changes to his diet and exercise regimen and being on maximal dose of metformin. Traditional Antihyperglycemic Therapies and CV Risk Metformin SUs TZDs AGIs Insulin resistance BP or or Dyslipidemia TG HDL LDL or or NA or or or or NA C-reactive protein NA Body weight or Hypoglycemia risk Low risk Moderate risk Low risk Low risk AGI = alpha-glucosidase inhibitor; HDL = high-density lipoprotein; NA = data not available; SU = sulfonylurea; TG = triglyceride; TZD = thiazolidinedione. Granberry MC et al. Am J Cardiovasc Drugs. 25;5: Time to Reassess the Role of Metformin? Meta-analysis of CV Death Metformin Control RR Study/Group Events Total Events Total M-H, fixed (95% CI) Chiasson 21a Chiasson 21b DeFronzo 1995a DeFronzo 1995b Hermann Holman Horton 2a Horton 2b Hällsten Kooy Rachimani UKPDS Total Total events Griffin SJ et al. Diabetologia 217;6:162 Favors metformin Favors control

5 IRIS TRIAL: Pioglitazone after Ischemic Stroke or TIA Cumulative Probability of Event free Survival (MI or Stroke) Primary end point HR=.76 (95% CI ) P = Years Since Randomization Kernan WN, et al. Pioglitazone after Ischemic Stroke or Transient Attack. NEJM 216; 374: Pioglitazone Exponential Growth of Cardiovascular Outcomes Trials (CVOTs) for T2DM Cumulative Number of Cardiovascular Trial Participants, thousands Holman RR et al. Lancet. 214; 383: FDA Guidance Year Over 2, planned participants in CVOTs for T2DM by 22 With So Many Classes of Medications, Which to choose? ADA/EASD T2DM Hyperglycemia Management If ASCVD or HF/CKD Predominates ASCVD Metformin + Lifestyle GLP-1 RA w/ proven ASCVD benefit EITHER/OR SGLT2i w/ proven ASCVD benefit if egfr adequate ADA/EASD GUIDELINES If further intensification is required/ patient is now unable to tolerate GLP-1 RA and/or SGLT2i, choose agents demonstrating CV safety Consider adding the other class (GLP-1 RA and/or SGLT2i) w/ proven ASCVD benefit DPP-4i if not GLP-1 RA Basal insulin TZD SU HF or CKD Preferred: SGLT2i w/ evidence of reducing HF and/or CKD progression in CVOTs if EGFR adequate OR If SGLT2i not tolerated/ contraindicated/if egfr less than adequate add GLP-1 RA w/ proven ASCVD benefit Davies MJ, et al. Consensus ADA and EASD Report. Diabetes Care 218, on-line Avoid TZD in the setting of HF Choose agents demonstrating CV safety Consider adding the other class w/ proven ASCVD benefit DPP-4i (not saxagliptin) in the setting of HF (if not on GLP-1 RA) Basal insulin SU

6 If No Established ASCVD or HF/CKD: Need to Minimize Hypoglycemia Metformin + Lifestyle DPP-4i GLP-1 RA SGLT2i TZD SGLT2i SGLT2i GLP-1 RA SGLT2i Davies MJ, et al. Consensus ADA and EASD Report. Diabetes Care 218, on-line OR OR OR OR DPP- 4i GLP- 1 RA DPP- 4i TZD OR OR TZD TZD still. Continue with addition of other agents ADA/EASD GUIDELINES Consider the addition of SU or basal insulin Choose later generation of SU with lower risk of hypoglycemia Consider basal insulin with lower risk of hypoglycemia If No Established ASCVD or HF/CKD: Need to Minimize Wt Gain or Promote Wt Loss Metformin + Lifestyle GLP-1 RA* GLP-1 RA* SGLT2i *With good weight loss efficacy Davies MJ, et al. Consensus ADA and EASD Report. Diabetes Care 218, on-line EITHER/OR SGLT2i If triple therapy required or SGLT2i and/or GLP-1 RA not tolerated or contraindicated use regimen with lowest risk of wt gain PREFERABLY DPP-4i (if not on GLP-1 RA) based on weight neutrality ADA/EASD GUIDELINES If DPP-4i not tolerated or contraindicated or patient already on GLP-1 RA, cautiously add SU TZD Basal insulin If No Established ASASCVD or HF/CKD: Cost Effective Metformin + Lifestyle SU TZD TZD Davies MJ, et al. Consensus ADA and EASD Report. Diabetes Care 218, on-line SU Insulin therapy basal insulin with lowest acquisition cost OR ADA/EASD GUIDELINES Consider DPP-4i OR SGLT2i with lowest acquisition cost Entry A1C < 7.5% Hierarchy of usage Lifestyle AACE/ACE Comprehensive Type 2 Diabetes Management Algorithm 218 Monotherapy Metformin GLP-1 RA SGLT2i DPP-4i TZD AGI SU/GLN If not at goal in 3 mo Entry A1C 7.5% Hierarchy of usage Metformin + Dual Therapy GLP-1 RA SGLT2i DPP-4i TZD Basal Insulin Colesevelam Bromocriptine QR AGI SU/GLN If not at goal in 3 mo Hierarchy of usage Metformin + + Triple Therapy GLP-1 RA SGLT2i TZD Basal Insulin DPP-4i Colesevelam Bromocriptine QR AGI SU/GLN If not at goal in 3 mo, use or intensify insulin therapy (refer to Insulin Algorithm) AACE/ACE GUIDELINES Entry A1C > 9.% Symptoms NO Dual OR Triple therapy YES Insulin ± other agents If not at goal in 3 mo, use or intensify insulin therapy (refer to Insulin Algorithm)

7 DPP- 4 Inhibitors FDA-Approved DPP-4 Inhibitors Medication Dosage forms Adverse Events* Dosing Linagliptin 1 Tablets: 5 mg Nasopharyngitis 5 mg once daily Sitagliptin 2 Tablets: 1 mg, 5 mg, 25 mg Upper respiratory tract infection, nasopharyngitis, headache 1 mg once daily *dose adjustment with moderate and severe renal impairment Saxagliptin 3 Tablets: 5 mg, 2.5 mg Alogliptin 4 Tablets: 25 mg, 12.5 mg, 6.25 mg Upper respiratory tract infection, urinary tract infection, headache, hypersensitivity events (e.g., urticaria, facial edema) Nasopharyngitis, headache, upper respiratory tract infection** 2.5 mg or 5 mg once daily *dose adjustment with moderate and severe renal impairment 25 mg once daily *dose adjustment with moderate and severe renal impairment *Treatment-emergent AE with 5% incidence in clinical trials; ** Common AE reported in 4% in patients treated with 25 mg References: 1. Linagliptin full prescribing information Sitagliptin full prescribing information Saxagliptin full prescribing information Alogliptin full prescribing information. Completed CVOTs of DPP- 4 Inhibitors Primary CV outcome SAVOR-TIMI 53 (saxagliptin) DPP-4 inhibitor Patients with event (%) HR (95% CI) HR (95% CI) p-value 1. (.89, 1.12).99 SAVOR-TIMI 53, EXAMINE, TECOS and CARMELINA: Hospitalization for Heart Failure Hospitalization for HF SAVOR-TIMI 53 (saxagliptin) DPP-4 inhibitor Patients with event (%) HR (95% CI) HR (95% CI) p-value 1.27 (1.7, 1.51).7 EXAMINE (alogliptin) (n/a, 1.16).32 EXAMINE (alogliptin) (.89, 1.59).24 TECOS (sitagliptin) (.89, 1.8).65 TECOS (sitagliptin) (.83, 1.2).98 CARMELINA (linagliptin) (.89, 1.17).74 CARMELINA (linagliptin) (.74, 1.8) Favors DPP-4 inhibitor Favors placebo Favors DPP-4 inhibitor Favors placebo 1. Scirica BM et al. N Engl J Med 213;369:1317; 2. White WB et al. N Engl J Med 213;369:1327; 3. Green JB et al. N Engl J Med 215;373:232; Adapted from McGuire D et al, JAMA Cardiol 216;1:126

8 GLP 1 Receptor Agonists FDA Approved GLP-1 RAs Medication Dosage forms Adverse Events * Dosing Exenatide BID -5 μg/dose in 1.2-mL prefilled pen -1 μg/dose in 2.4-mL prefilled pen Nausea, vomiting, dyspepsia 1. Start at 5 μg twice daily (1 hour before morning and evening meals) 2. Increase to 1 μg twice daily after 1 mo Nausea, vomiting, N=14, Initiate at 1 mcg once daily for 14 days. On Injection: headache, diarrhea, day 15, increase dosage to 2 mcg once daily Lixisenatide -5 mcg/ml solution dizziness, and Administer once daily within one hour before -1 mcg/ml solution hypoglycemia the first meal of the day -Prefilled, multidose pen that 1 Nausea, diarrhea, 1. Initiate at.6 mg once daily, regardless of meals Liraglutide delivers doses of.6 mg, 1.2 mg, or 1.8 mg vomiting, constipation, 5 headache 2. AfterHazard 1 week, ratio: increase.98 dose to 1.2 mg 3. If glycemic (95% CI: control.89, 1.8) is not acceptable, dose can P=.65 be increased to 1.8 mg Nausea, diarrhea, Exenatide QW -Single-dose tray with 2 mg vial injection-site nodule, 1. Administer at 2. mg once every -Single-dose 2 mg prefilled pen constipation, headache, 7 days (weekly), independent of meals Composite of CV death, MI, or Composite of CV death, dyspepsia nonfatal MI, Composite of CV death, nonfatal or nonfatal stroke. *Treatment-emergent adverse reactions with 5% incidence in clinical trials with drug as monotherapy MI, nonfatal (excluding stroke, hypoglycemia). or hospitalization for unstable angina Drugs@FDA ( Drugs@FDA ( Drugs@FDA Drugs@FDA FDA Approved GLP-1 RAs (cont.) Medication Dosage forms Adverse Events * Dosing Dulaglutide Semaglutide Single-dose pen: -.75 mg/.5 ml solution -1.5 mg/.5 ml solution Single-dose prefilled syringe: -.75 mg/.5 ml solution -1.5 mg/.5 ml solution Nausea, diarrhea, vomiting, abdominal pain, and decreased appetite N=14, Initiate at.75 mg subcutaneously once weekly. 2. Dose can be increased to 1.5 mg once weekly for additional glycemic control Initiate at.25 mg once weekly Single-patient-use pen that delivers 2. After 4 weeks increase dose to.5.25 mg or.5 mg per injection Nausea, vomiting, 1 diarrhea, mg once weekly. If after at least 4 Single-patient-use pen that delivers 1 constipation, abdominal pain weeks add l glycemic control mg per injection 5 Hazard ratio:.98 (95% CI: increase.89, 1.8) to 1 mg once weekly P= Composite of CV death, MI, or Composite of CV death, nonfatal MI, Composite of CV death, nonfatal or nonfatal stroke. MI, nonfatal stroke, or URTI, upper respiratory tract infection. hospitalization for unstable angina *Treatment-emergent adverse reactions with 5% incidence in clinical trials with drug as monotherapy (excluding hypoglycemia). Traynor K. Am J Health Syst Pharm. 214;71(11):888; Dulaglutide prescribing information. Lixisenatide prescribing information. GLP-1 RA: Renal Considerations Increasing half-life GLP-1 RA Renal Considerations Exenatide BID Should not be used in patients with severe renal impairment or ESRD Lixisenatide OD Not recommended in patients with N=14,671 ESRD Liraglutide OD None 1 Dulaglutide OW Monitor renal function in patients with renal impairment reporting severe GI AEs 5 Hazard ratio:.98 Semaglutide OW Monitor renal function in patients with renal impairment (95% CI:.89, reporting 1.8) severe GI AEs P=.65 Exenatide OW Not recommended in patients with 4severe renal 24 3 impairment or ESRD hhttps:// ttps://

9 Completed CVOTs with GLP-1 RAs Trial, Drug ELIXA, lixisenatide Study Population Patients with T2DM and prior MI or hospitalization for UA Composite Outcome CV death, nonfatal MI, nonfatal stroke, hospitalization for UA Trial Length Key Findings EXSCEL, Patients with T2DM and Exenatide QW was noninferior to placebo with CV death, nonfatal exenatide various CV risks; 3% of 5.5 N=14,671 y respect to cardiovascular safety but was not MI, nonfatal stroke QW patients had no prior CV event superior to placebo with respect to efficacy 15 Primary outcome occurred in significantly fewer CV death causes, Median LEADER, Patients with T2DM and high patients with liraglutide (P=.1 for superiority). nonfatal MI, nonfatal follow-up: liraglutide CV risk 1 Significant reductions also observed for stroke 3.8 y CV-related death and death from any cause 5 Hazard ratio:.98 Patients 5 years old with Primary (95% outcome CI:.89, 1.8) occurred in significantly fewer SUSTAIN-6, T2DM and established CV CV death, nonfatal patients P=.65 with semaglutide (P=.2 for 14 wk semaglutide disease or CKD OR 6 years MI, nonfatal stroke superiority). Significant reductions also old with 1 CV risk factor observed for nonfatal stroke FREEDOM- Patients with T2DM and CV death causes, coronary, cerebrovascular, or CVO, * Composite of CV death, MI, or Composite nonfatal of CV MI, death, nonfatal nonfatal MI, 3 y Met primary and secondary endpoints. PAD or multiple CV risk or nonfatal strokestroke. ITCA 65 factors 25 mo Lixisenatide did not significantly increase the rate of major CV events *ITCA 65 awaiting FDA approval References: Pfeffer MA, et al. N Engl J Med. 215;373(23): Mentz RJ, et al. Am Heart J. 217;187:1-9. AstraZeneca. Bydureon EXSCEL trial meets primary safety objective in type-2 diabetes patients at wide range of cardiovascular risk. May 1, 217. Marso SP, et al. N Engl J Med. 216;375(4): Recent Developments* Trial, Drug Study Population Composite Outcome HARMONY OUTCOMES, Albiglutide* REWIND, Dulaglutide PIONEER 6, Oral Semaglutide Patients with T2DM and ASCVD Patients with T2DM, 5 yrs, A1C 9.5%, and CV event/cvd/ 2 risk factors; majority of patients did not have established CVD Patients with T2DM 5 yrs and CVD or CKD (stage 3) or 6 yrs with 1 other CV risk factor) CV death, MI, or stroke CV death, MI, or nonfatal stroke CV death, non-fatal MI, or non-fatal stroke Trial Length 1.6 y 8 y 2.1 y * Albiglu de is no longer on the market in the US. Oral semaglu de is not yet FDA approved Hernandez et al. The Lancet. Published online Oct 2, 218. Key Findings Primary outcome occurred in significantly fewer patients with albiglutide (p<.1 for noninferiority; p=.6 for superiority) than placebo **Top-line results only** Met primary endpoint. Significantly reduced major adverse events. **Top-line results only** Noninferiority for MACE. Significant reduction in CV death and all-cause mortality. ELIXA Study: Lixisenatide vs Time to first occurrence of the primary CV event: CV death, non fatal MI, non fatal stroke or hospitalization for unstable angina Patients with Event (%) HR=1.2 (95% CI ) LEADER Study: Liraglutide vs Patients With Event (%) Primary Outcome (death from CV causes, nonfatal myocardial infarction, or nonfatal stroke) HR:.87 (95% CI:.78,.97) P<.1 for noninferiority P=.1 for superiority Liraglutide 13% N = 6,68 Pfeffer MA, et al. N Engl J Med. 215 Dec 3;373(23): Marso SP. N Engl J Med. 216 Sep 16; 375: Since Randomization N = 9,34

10 LEADER Study: Liraglutide vs CV Related Death Liraglutide LEADER Study: Liraglutide vs Death From Any Cause Liraglutide Patients With Event (%) HR:.78 (95% CI:.66,.93) P=.7 22% Patients With Event (%) HR:.85 (95% CI:.74,.97) P=.2 15% Marso SP. N Engl J Med. 216 Sep 16; 375: Since Randomization N = 9,34 Marso SP. N Engl J Med. 216 Sep 16; 375: Since Randomization N = 9,34 LEADER Study: Liraglutide vs Liraglutide: New FDA Indication Patients With Event (%) HR:.87 (95% CI:.73, 1.5) P=.14 HF Hospitalization Liraglutide August 217: FDA approved a new indication for liraglutide for reducing the risk of myocardial N=14,671 infarction, stroke, and cardiovascular 15 death in adults with T2DM who have 1established cardiovascular disease. 5 Hazard ratio:.98 (95% CI:.89, 1.8) P= Time From Randomization (months) Composite of CV death, MI, or Composite of CV death, nonfatal MI, or nonfatal stroke. Marso SP et al. N Engl J Med. 216;375:

11 SUSTAIN-6 Study: Semaglutide vs Patients With Event, % HR:.74 (95% CI,.58.95) P<.1 for noninferiority P=.2 for superiority Primary Outcome* 26% SUSTAIN-6 Study: Semaglutide vs Patients With Event, % Death From CV Causes HR:.98 (95% CI, ) P=.92 N.S. change *Death from CV causes, nonfatal MI, or nonfatal stroke Marso SP et al. N Engl J Med. 216;375: Weeks Since Randomization *Death from CV causes, nonfatal MI, or nonfatal stroke Marso SP et al. N Engl J Med. 216;375: Weeks Since Randomization SUSTAIN-6 Study: Semaglutide vs EXSCEL Study: Exenatide QW vs Nonfatal Stroke Primary Outcome (3 point MACE) Death From Any Cause Patients With Event, % HR:.61 (95% CI,.38.99) P=.4 39% Patients With Event (%) HR =.91 (95% CI,.83 1.) P<.1 for noninferiority P=.6 for superiority HR =.86 (95% CI,.77.97) *Death from CV causes, nonfatal MI, or nonfatal stroke Marso SP et al. N Engl J Med. 216;375: Weeks Since Randomization Time Since Randomization, yr Holman RR et al. N Engl J Med. 217; 377: Time Since Randomization, yr Exenatide QW

12 EXSCEL Study: Exenatide QW vs HARMONY Outcomes: Albiglutide vs. Death From CV Causes Hospitalization for HF Primary Outcome (3 point MACE) CV Death Patients With Event (%) HR =.88 (95% CI, ) Time Since Randomization, yr Holman RR et al. N Engl J Med. 217; 377: HR =.94 (95% CI, ) Time Since Randomization, yr Exenatide QW Cumulative % With Event 22% Time from Randomization, mo * Albiglutide, a long acting OW GLP 1 RA, is no longer on the market in the US. Hernandez A, et al. Lancet. Available online 2 October 218 [In Press] 4 2 HARMONY Outcomes: Albiglutide vs. Summary of CV Outcomes for GLP-1 RAs MI Stroke So far, all trials have met their primary goals showing that there is no increased risk of ASCVD Cumulative % With Event 25% Time from Randomization, mo LEADER (liraglutide) and SUSTAIN-6 (semaglutide) demonstrated a benefit on MACE and mortality (liraglutide) 15 Liraglutide has additional FDA indication for T2DM and ASCVD 5 Hazard ratio:.98 (95% CI:.89, 1.8) P=.65 placebo group - supporting potential CV effect HARMONY OUTCOMES (albiglutide) showed significant superiority in MACE 1 N=14,671 EXSCEL (exenatide QW) demonstrated nonsignificant benefit (p =.6) regarding MACE and study design favoring drop in SGLT2i & GLP1-RA in the over Composite placebo; of CV death, Top-line MI, or results Composite from of CV death, REWIND nonfatal MI, (dulaglutide) also showed or nonfatal stroke. significant superiority in MACE over placebo Hernandez A, et al. Lancet. Available online 2 October 218 [In Press].

13 SGLT 2 Inhibitors FDA- Approved SGLT-2 Inhibitors Medication Dosage Adverse Events * Dosing Canagliflozin 1 Dapagliflozin 2 Tablets: 1 mg 3 mg Tablets: 5 mg 1 mg Female genital mycotic infections, urinary tract infection, and increased urination 1 mg/3 mg prior to first meal of day N=14,671 5 mg/1 mg in the morning Female genital mycotic infections, 15 independent of meals nasopharyngitis, and urinary tract infections. 1 Tablets: 1 mg/25 mg in the morning Empagliflozin 3 Urinary tract infections and 1 mg 5 Hazard ratio: independent.98 of meals female genital mycotic infections (95% CI:.89, 1.8) 25 mg P=.65 Tablets: Ertugliflozin 4 55 mg/15 mg once daily in 5 mg Female genital mycotic infections morning independent of meals 15 mg Composite of CV death, MI, or Composite of CV death, nonfatal MI, or nonfatal stroke. *Treatment emergent adverse reactions with 5% incidence References: 1. Invokana (canagliflozin) full prescribing information Farxiga (dapagliflozin) full prescribing information. 3.Rosenwasser RF, et al. Diabetes Metab Syndr Obes. 213;6: Steglatro (ertugliflozin) full prescribing information: SGLT-2 Inhibitors: Renal Adjustments Medication egfr (ml/min/1.73m 2 ) Dapagliflozin Canagliflozin Empagliflozin Ertugliflozin < >6 Do not start drug Do not start drug D/C if D/C if on drug N=14,671 on drug and egfr <6 persistently Do not start drug D/C if on drug Do not start drug D/C if on drug Do not start drug D/C if on drug Do not start drug D/C if on drug Do not start drug D/C if on drug and egfr <45 Do not start drug D/C if on drug and egfr <45 Do not start drug D/C if on drug Start at 1 mg QD Start at 1 mg QD Increase to Do not 1 increase dose 3 mg QD If on 3 mg, decrease dose as needed to decrease to 1 5 mg Hazard ratio:.98glucose (95% CI:.89, 1.8) Start at 1 mg and increase P=.65 to Start at 1 mg and increase 25 mg QD as needed to to 25 mg QD as needed to decrease glucose decrease glucose Do not start drug D/C if on drug and egfr <6 persistently References: Mudaliar S et al. Diabetes Care. 215;38: ; Steglatra (ertugliflozin) prescribing information Start at 5 mg QD Increase to 1 mg QD as needed to decrease glucose Start at 5 mg QD Increase dose to 15 mg QD as needed to decrease glucose CVOTs with SGLT-2 Inhibitors Trial, Agent EMPA REG, Empagliflozin CANVAS, Canagliflozin DECLARE TIMI 58, Dapagliflozin Study Population Patients with T2DM and established ASCVD Patients with T2DM and high CV risk T2DM and CV risk or ASCVD Composite of CV death, MI, or Composite Outcome Empagliflozin showed reduction in CV CV death, nonfatal MI, nonfatal stroke 3.1 years mortality, nonfatal MI, nonfatal stoke and allcause N=14,671 mortality CV death, nonfatal MI, nonfatal stroke CV death, MI, Trial Length 15 Key Findings 1 Canagliflozin showed reduction in CV Mean mortality, nonfatal myocardial infarction, and 3.6 years 5 Hazard ratio:.98 (95% CI: nonfatal.89, 1.8) stroke P= ** Top line results released only ** Up to 6 Non inferiority in MACE, significant reduction years in hospitalization for HF or CV death References: Zinman B et al. N Engl J Med. 215;373: ; Neal B, et al. NEJM. 217 ; AZ Press Release, Sept 24, 218: centre/press releases/218/farxiga achieved a positive result in the phase iii declare timi 58 trial alarge cardiovascular outcomes trial in 17 patients with type 2 diabetes html

14 EMPA-REG: Empagliflozin vs Primary Outcome* EMPA-REG: Empagliflozin vs Death From CV Causes Patients With Event, % HR.86 95% Cl (.74,.99) P <.1 for noninferiority P=.4 for superiority,492 14% Patients With Event, % HR.62 95% Cl (.49,.77) P<.1 38% *Death from CV causes, nonfatal myocardial infarction, or nonfatal stroke Zinman B et al. N Engl J Med. 215;373: *Death from CV causes, nonfatal myocardial infarction, or nonfatal stroke Zinman B et al. N Engl J Med. 215;373: EMPA-REG: Empagliflozin vs Empagliflozin: New FDA Indication Patients With Event, % Hospitalization for HF HR.65 95% Cl (.5,.85) P=.2 35% December 216: FDA Approved a new indication for empagliflozin for reducing N=14, the risk of cardiovascular death in adults 1 with T2DM and cardiovascular disease. 5 Hazard ratio:.98 (95% CI:.89, 1.8) P= Composite of CV death, MI, or Composite of CV death, nonfatal MI, or nonfatal stroke. *Death from CV causes, nonfatal myocardial infarction, or nonfatal stroke Zinman B et al. N Engl J Med. 215;373:

15 CANVAS: Canagliflozin vs Primary Outcome CANVAS: Canagliflozin vs Death From CV Causes Patients with Event (%) HR.86 95% Cl ( ) P <.1 for noninferiority P=.2 for superiority,492 14% Patients with Event (%) HR.87 95% Cl ( ) 13% Weeks Since Randomization Weeks Since Randomization *death from CV causes, nonfatal myocardial infarction, or nonfatal stroke Neal B, et al. N Engl J Med. 217 *death from CV causes, nonfatal myocardial infarction, or nonfatal stroke Neal B, et al. N Engl J Med. 217 CANVAS: Canagliflozin vs Patients with Event (%) *death from CV causes, nonfatal myocardial infarction, or nonfatal stroke Neal B, et al. N Engl J Med. 217 Hospitalization for HF HR.67 95% Cl ( ) Weeks Since Randomization 33% CANVAS: Canagliflozin vs Outcome Primary outcome (CV death, nonfatal MI, nonfatal stroke) Canagliflozin n = 5795 n = % 3.1%.86 (.75,.97) N=14,671 CV death 1.2% 1.3% (.72, 1.6) HR (95% CI) P Value <.1 for noninferiority P=.2 for superiority 1 MI (nonfatal or fatal) 1.1% 1.3%.89 (.73, 1.9) Stroke (nonfatal or fatal).8% 5 Hazard ratio:.98 1%.87 (95%(.69, CI:.89, 1.9) 1.8) P=.65 Hospitalization for HF.5%.8%.67 (.52,.87) Death from CV causes or hospitalization 1.7% 2.1%.78 (.67,.91) for HF Composite of CV death, MI, or Composite of CV death, nonfatal MI, or nonfatal stroke. Amputation.6%.3% <.1 References: Neal B, et al. N Engl J Med. 217

16 Canagliflozin: New FDA Indication October 218: FDA Approved a new indication for canagliflozin for reducing N=14, the risk of major adverse cardiovascular 1 events in adults with T2DM and 5 Hazard ratio:.98 (95% CI:.89, 1.8) cardiovascular disease. P= Composite of CV death, MI, or Composite of CV death, nonfatal MI, or nonfatal stroke. 71 Key Outcomes in the CANVAS Program and EMPA-REG OUTCOME CV death, nonfatal myocardial infarction, or nonfatal stroke CV death Non-fatal myocardial infarction Non-fatal stroke Hospitalization for heart failure CV death or hospitalization for heart failure All-cause mortality Progression to macroalbuminuria* Renal composite* Hazard ratio (95% CI) Favors SGLT2i Favors *CANVAS Program endpoints comparable with EMPA-REG OUTCOME. Zinman Bet al. N Engl J Med. 215 ;373(22): ; Wanner K et al. N Engl J Med. 216;375(4): CANVAS Program EMPA-REG OUTCOME DECLARE-TIMI 58: Dapagliflozin vs Cardiovascular Death or Hospitalization for Heart Failure DECLARE-TIMI 58: Dapagliflozin vs MACE Cumulative Incidence (%) HR.83 (95% CI ) P=.5 superiority 16% Cumulative Incidence (%) HR.93 (95% CI ) P=.17 superiority Days *MACE defined as CV death, MI, or Days

17 DECLARE-TIMI 58: Dapagliflozin vs Summary of CV Outcomes for SGLT-2 Inhibitors Cumulative Incidence (%) Death from Any Cause HR.93 (95% CI ) So far, all trials have met their primary goals showing that there is no increased risk of ASCVD EMPA-REG (empagliflozin) and CANVAS (canagliflozin) demonstrated a benefit in MACE and mortality (empagliflozin) and N=14,671 hospitalization for heart failure; but canagliflozin also increased incidence of amputation. 15 Empagliflozin has an additional FDA indication for T2DM and ASCVD Canagliflozin has an additional FDA indication for T2DM 5 and ASCVD Hazard ratio:.98 (95% CI:.89, 1.8) P= reduction in hospitalization for HF or CV death Top-line data from DECLARE-TIMI 58 (dapagliflozin) also showed a significant Further CVOTs are ongoing Composite of CV death, MI, or 1 Composite of CV death, nonfatal MI, or nonfatal stroke. Days SGLT-2 Inhibitors: Future HF Trials John, 48 cases Trial Treatment Arm Sample Size Outcome Including Pts without DM John returns 3 months later Dapa HF Dapagliflozin 45 (HFrEF) ASCVD/HF Hosp. Yes At the last visit you had decided to start him on the GLP- 1 RA liraglutide based on his cardiac risk. EMPEROR Preserved EMPEROR Reduced SOLOIST WHF Trial Empagliflozin Empagliflozin Sotagliflozin 4126 (HFpEF) 285 (HFrEF) Recruiting ASCVD/HF Hosp. ASCVD/HF Hosp. ASCVD/HF Hosp. Yes Yes No He reports doing well. He is continuing his new diet and exercise regimen and is taking medications as prescribed. At this visit his A1c is 6.8%. He has lost 15 lbs. Although he does report some occasional nausea, this has reduced over time and he prefers to stay on liraglutide. Source: Clinicaltrials.gov

18 Case 2 / Cynthia, 58 cases Cynthia, 58 cases HPI: Has been a patient of yours for the past 5 years. Recently diagnosed with Heart Failure with Reduced Ejection Fraction (EF: 4%) and has a strong family history of heart disease. She also has a 1 year history of T2DM and you recently started her on the DPP-4 inhibitor saxagliptin Medications: Lisinopril 4 mg QD Carvedilol 12.5 mg BID Metformin 1 mg BID Saxagliptin 2.5 mg daily Venlafaxine ER 75 mg BID Atorvastatin 4 mg daily Family History: Father died of MI at age 58 Mother, living, CHD, PVD, T2DM Sister, living, CHD, T2DM Social History: Lives at home with husband Works as a Bank Teller for 28 years Smokes ½ pack day for 15 years; no alcohol use Moderate exercise on weekends Medical History: HFrEF x 1 year T2DM x 1 years Hypercholesterolemia x 1 year HTN x 5 years Surgical History: Angiogram with no obstructive vascular disease. Cynthia, 58 ROS: Occasional dyspnea on exertion and pedal edema Physical Exam: Ht: 5 6 Wt: 185 lbs BMI: 29.9 kg/m 2 BP: 142/85 mmhg HR: 62 bpm General: Overweight female in no acute distress Labs A1c 8.1% Lipid Panel TC 15, LDL 55, HDL 5 CBC wnl BMP wnl egfr 52 ml/min/ cases Conclusion: Take Home Points Patients with T2DM are at HIGH risk of CV events Liraglutide, empagliflozin, and canagliflozin are now FDA indicated for the reduction of adverse cardiovascular events in patients with T2DM with ASCVD Semaglutide also showed improved reduction in MACE Albiglutide showed improved reduction in MACE but is not available in the US Dulaglutide also showed improved reduction in MACE (top-line results only) Both empagliflozin and canagliflozin showed significant reduction in hospitalizations for heart failure in addition to reduction in MACE; top-line results of dapagliflozin showed noninferiority in MACE and significant reduction in hospitalization for HF or CV death Renal dosing must be considered when using SGLT2 inhibitors, as well as other antihyperglycemic therapies Additional cardiovascular outcomes trials are underway!