Cardiovascular Impact of Medications for Treating Type 2 Diabetes

Friday CME Breakfast Lecture Cardiovascular Impact of Medications for Treating Type 2 Diabetes Thomas Blevins, MD Endocrinologist, Private Practice Texas Diabetes and Endocrinology Austin, Texas Educational Objectives By the end of this activity, the participant will be better able to: 1. Review FDA requirements for new drugs for type 2 diabetes to establish CV safety. 2. Describe the results of cardiovascular outcomes trials with incretin modulators such as DPP4 inhibitors and GLP1 receptor agonists. 3. Describe the results and clinical implications of cardiovascular outcomes trials with SGLT2 inhibitors. 4. Discuss the FDA indication related to cardiovascular benefits of glucose lowering medications. 5. Review the updates to the American Diabetes Association treatment recommendations relating to the effect on CV outcomes of medications for treating type 2 diabetes. 6. Implement the clinical application of the results of cardiovascular outcomes trials in treating patients with type 2 diabetes. Speaker Disclosure Dr. Blevins has disclosed that he has received grant support and is on the speaker s bureau for AstraZeneca, Boehringer Ingelheim, Lilly and Sanofi, and he is on the advisory committee for Medtronic and Senseonics. 1

Management of Type 2 Diabetes Cardiovascular Outcomes Trials 2018 Speaker Disclosure Dr. Blevins has disclosed that he has received grant support and is on the speaker s bureau for AstraZeneca, Boehringer Ingelheim, Lilly and Sanofi, and he is on the advisory committee for Medtronic and Senseonics. Tom Blevins MD Texas Diabetes and Endocrinology Austin, Texas Learning Objectives By the end of this activity, the participant will be better able to: Review FDA requirements for new drugs for type 2 diabetes to establish CV safety. Describe the results of cardiovascular outcomes trials with incretin modulators such as DPP4 inhibitors and GLP1 receptor agonists. Describe the results and clinical implications of cardiovascular outcomes trials with SGLT2 inhibitors. Discuss the FDA indication related to cardiovascular benefits of glucose lowering medications. Review the updates to the American Diabetes Association treatment recommendations relating to the effect on CV outcomes of medications for treating type 2 diabetes. Implement the clinical application of the results of cardiovascular outcomes trials in treating patients with type 2 diabetes. Timeline of Major Diabetes Outcomes Trials Cardiovascular Outcomes Trials: A Brief History 1995 2000 2005 2010 2015 FDA CVOT Guidance 2008 Blue = Intensive vs standard control using same set of glucose-lowering agent(s) Purple = Intensive control with a specific agent vs standard care Red = Placebo- or active-controlled study * = FDA-mandated cardiovascular safety trial 2008 FDA guidance mandating assessment of CV safety of all antihyperglycemic agents in RCTs Designed as noninferiority studies to demonstrate study drug was not associated with more MACE than placebo Some study designs tested for superiority if noninferiority criteria were met Primary endpoint: Composite of cardiovascular death, nonfatal MI, and nonfatal stroke Some primary endpoints included additional components ACCORD, Action to Control Cardiovascular Risk in Diabetes; ADVANCE, Action in Diabetes and Vascular Disease: Preterax and Diamicron MR Controlled Evaluation; CANVAS, Canagliflozin Cardiovascular Assessment Study; DCCT, Diabetes Control and Complications Trial; DEVOTE, Trial Comparing Cardiovascular Safety of Insulin Degludec versus Insulin Glargine in Patients with Type 2 Diabetes at High Risk of Cardiovascular Events; EXAMINE, Examination of Cardiovascular Outcomes with Alogliptin versus Standard of Care; ELIXA, Evaluation of Lixisenatide in Acute Coronary Syndrome; EMPA-REG, EMPA-REG OUTCOME trial; Exenatide Study of Cardiovascular Event Lowering; LEADER, Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Outcome Results; ORIGIN, Outcome Reduction with an Initial Glargine Intervention; PROActive, Prospective Pioglitazone Clinical Trial in Macrovascular Events; RECORD, Rosiglitazone Evaluated for Cardiovascular Outcomes in Oral Agent Combination Therapy for Type 2 Diabetes; SAVOR-TIMI, Saxagliptin Assessment of Vascular Outcomes Recorded in Patients with Diabetes Mellitus Thrombolysis in Myocardial Infarction; STOP-NIDDM, Study to Prevent Non-Insulin-Dependent Diabetes Mellitus; SUSTAIN, Trial to Evaluate Cardiovascular and Other Long-Term Outcomes with Semaglutide in Subjects with Type 2 Diabetes; TECOS, Trial Evaluating Cardiovascular Outcomes with Sitagliptin; UKPDS, United Kingdom Prospective Diabetes Study; VADT, Veterans Affairs Diabetes Trial. 5 MACE = major adverse cardiovascular events; RCTs, randomized controlled trials. FDA. Guidance for industry: evaluating cardiovascular risk in new antidiabetic therapies to treat type 2 diabetes. http://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/ucm071627.pdf. 6 1

Case #1 ARS Question 53 y/o female with Type 2 Diabetes x 6 years A1c is 7.2% on metformin and DPP4 On ACEi and statin BP is 118/72 LDL is 69 mg/dl Hx of MI 8 years ago What do you do? 1. Double statin to lower LDL further 2. Reduce the ACEi as her BP is too low to perfuse her coronary arteries 3. Discuss SGLT2 and GLP-1 CV risk reduction trials 4. No changes needed since the DPP-4 is cardioprotective 7 5,380 patients with ACS 16,492 patients with CVD or CVD Risk 14,671 patients with Type 2 diabetes and CVD 9 10 11 12 2

13 14 Case #2 ARS Question 66 y/o male with Type 2 Diabetes x 14 years A1c is 8.2% on basal and prandial insulin and metformin On BP meds and statin BP is 138/82 LDL is 55 mg/dl Hx of CAB 12 years ago What do you do? 1. Increase BP med 2. Make adjustments to the insulin and suggest another visit in 3-4 months 3. Discuss SGLT2 and GLP-1 CV risk reduction trials 15 7,020 with Type 2 Diabetes and CVD (2:1 empa:placebo 10,142 with Type 2 diabetes and high CV Risk Clinical Outcomes with Empagliflozin Study Design N=7020 patients with T2D and CV Coronary Artery Disease History of MI History of stroke EMPA-REG OUTCOME PAD Randomization Empagliflozin: n=4687 Placebo: n=2333 Noninferiority study: prespecified HR margin = 1.3 for primary endpoint Primary endpoint: composite of CV death, nonfatal MI (excluding silent MI), or nonfatal stroke Secondary endpoint: composite of CV death, nonfatal MI (excluding silent MI), nonfatal stroke, and hospitalization for unstable angina Median follow-up: 3.1 years Week 206 A1C, difference from placebo Empagliflozin 10 mg: -0.24% (95% CI, -0.40% to - 0.08%) Empagliflozin 25 mg: -0.36% (95% CI, -0.51% to - 0.20%) 17 CI, confidence interval; CV, cardiovascular; HF, heart failure; HR, hazard ratio; MI, myocardial infarction. Zinman B, et al. N Engl J Med. 2015;373:2117-2128. 18 3

19 20 21 23 Clinical Outcomes with Empagliflozin EMPA-REG OUTCOME Safety Results Pooled Empagliflozin (%) Placebo Event (%) Any adverse event 90.2 91.7 Serious adverse event 38.2 42.3 Death 3.8 5.1 Any hypoglycemia 27.8 27.9 Severe hypoglycemia 1.3 1.5 Urinary tract infection Male 10.5 9.4 Female 36.4 40.6 Genital infection Male 5.0 1.5 Female 10.0 2.6 Volume depletion 5.1 4.9 Diabetic ketoacidosis 0.1 <0.1 Bone fracture 3.8 3.9 Empaglifozin Indication Empaglifozin is a sodium-glucose co-transporter 2 (SGLT2) inhibitor indicated: As an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus To reduce the risk of cardiovascular death in adult patients with type 2 diabetes mellitus and established cardiovascular disease CI, confidence interval; CV, cardiovascular; HF, heart failure; HR, hazard ratio; MI, myocardial infarction. Zinman B, et al. N Engl J Med. 2015;373:2117-2128. 24 25 4

Hematocrit over time in patients treated with empagliflozin 10 mg, empagliflozin 25 mg, and placebo. Silvio E. Inzucchi et al. Dia Care 2018;41:356-363 2018 by American Diabetes Association Clinical Outcomes with Canagliflozin CANVAS Program Study Design N=10,142 patients with T2D and high CV risk CANVAS: n=4330 CANVAS-R: n=5812 Randomization (across both studies) Canagliflozin: n=5795 Placebo: n=4347 Endpoints Primary endpoint: composite of CV death, nonfatal MI, or nonfatal stroke Secondary endpoints: All-cause death CV death Albuminuria progression Composite of CV death and HF hospitalization CANVAS, Canaglflozin Cardiovascular Assessment Study; CI, confidence interval; CV, cardiovascular; HF, heart failure; HR, hazard ratio; MI, myocardial infarction. Neal B, et al. N Engl J Med. 2017;377:644-657. 28 29 Adverse Events with Canagliflozin CANVAS Program* Safety Results Canagliflozin Placebo Event P value Events per 1000-patient years 104.3 120.0 All serious adverse events 0.04 Adverse events leading to discontinuation 35.5 32.8 0.07 Diabetic ketoacidosis (adjudicated) 0.6 0.3 0.14 Events of interest occurring in significantly more canagliflozin-treated patients Amputation 6.3 3.4 <0.001 Bone fracture (adjudicated) All 15.4 11.9 0.02 Low trauma 11.6 9.2 0.06 Infection of male genitalia 34.9 10.8 <0.001 Osmotic diuresis 34.5 13.3 <0.001 Volume depletion 26.0 18.5 0.009 Mycotic genital infection in women 68.8 17.5 <0.001 30 *Includes patients from CANVAS and CANVAS-R (N=10,142). CANVAS-only population (n=4330). Neal B, et al. N Engl J Med. 2017 Jun 12 [epub ahead of print]. 31 5

CVD-REAL Study Study Objectives Primary Compare risk of HHF (Hospitalization for heart failure) in patients with Type 2 diabetes newly initiated on SGLT-2 inhibitors versus other glucose-lowering drugs (GLDs) Secondary Compare risk of all-cause death between the two treatment groups Compare risk of HHF or all-cause death between the two treatment groups Kosiborod M, et al. Lower risk of heart failure and death in patients initiated on SGLT-2 inhibitors versus other glucoselowering drugs: The CVD-REAL Study. Circulation. 2017 May 18. Case #4 ARS Question 46 y/o male with Type 2 Diabetes x 4 years A1c is 6.2% on basal insulin and metformin On BP meds and statin BP is 128/82 LDL is 65 mg/dl Hx of PAD and femoral artery stent 1 year ago What do you do? 1. Increase BP med 2. No more to do. His A1c, BP, and LDL are at goal 3. Discuss SGLT2 and GLP-1 CV risk reduction trials 37 6

6,068 patients with recent ACS Clinical Outcomes with Lixisenatide ELIXA (Patients with T2D and CVD; N=6068) 9340 patients with T2D and high CV risk Hazard ratio (95% CI) P value Primary composite endpoint* 1.02 (0.89-1.17) 0.81 Secondary composite endpoint 0.97 (0.85-1.10) 0.63 CV death 0.98 (0.78-1.22) 0.85 3297 patients with T2D with CVD, CHF, CKD, or age 60 with 1 CV risk factor Fatal or nonfatal MI 1.03 (0.87-1.22) 0.71 Stroke 1.12 (0.79-1.58) 0.54 Unstable angina 1.11 (0.47-2.62) 0.81 Hospitalization for heart failure 0.96 (0.75-1.23) 0.75 Death from any cause 0.94 (0.78-1.13) 0.50 0.00 1.00 2.00 3.00 Favors lixisenatide 14,752 patients with T2D with or without CVD EXSCEL *CV death, nonfatal MI, or nonfatal stroke, and hospitalization for unstable angina; CV death, nonfatal MI, nonfatal stroke, hospitalization for unstable angina, hospitalization for HF, and coronary revascularization. CI, confidence interval; CV, cardiovascular; HF, heart failure; HR, hazard ratio; MI, myocardial infarction. Pfeffer MA, et al. N Engl J Med. 2015;373:2247-2257. 40 Study Design Clinical Outcomes with Liraglutide LEADER N=9340 patients with T2D and high CV risk Liraglutide Age of >50 History of MI Prior MI or TIA Prior revascularization >50% stenosis of coronary, carotid or lower extremity arteries Symptomatic CHD Heart failure CKD CVD risk factors (age> 60) Microalbuminuria or proteinuria Htn and LVH Ankle brachial index <0.9 Randomization Liraglutide: n=4672 Placebo: n=4668 Key Results Noninferiority study: Primary endpoint: composite of CV death, nonfatal MI (including silent MI), or nonfatal stroke Secondary endpoint: composite of CV death, nonfatal MI (including silent MI), nonfatal stroke, coronary revascularization, and hospitalization for unstable angina or HF Median follow-up: 3.5 years Difference from placebo at 36 months A1C: 0.40% (95% CI, 0.45% to 0.34%) Weight: 2.3 kg (95% CI, 2.0 to 2.5 kg) SBP: 1.2 mm Hg (95% CI, 0.5 to 1.9 mm Hg) Lower numerical incidence of pancreatitis in liraglutide group (not statistically significant) CI, confidence interval; CV, cardiovascular; HF, heart failure; HR, hazard ratio; MI, myocardial infarction. Marso SP, et al. N Engl J Med. 2016:375:311-322. 41 42 Clinical Outcomes with Liraglutide LEADER Adverse Events Leading to Discontinuation Event Liraglutide (%) Placebo (%) P value (n=4668) (n=4672) Any adverse event 9.5 7.3 <0.001 Serious adverse event 4.1 5.2 0.01 Nausea 1.6 0.4 <0.001 Vomiting 0.7 <0.1 <0.001 Diarrhea 0.6 0.1 <0.001 Increased lipase level 0.3 0.2 0.43 Decreased appetite 0.2 <0.1 0.01 Abdominal discomfort 0.2 0 0.002 Liraglutide Indication Liraglutide is a glucagon like peptide 1 (GLP 1) receptor agonist indicated: As an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus To reduce the risk of major adverse cardiovascular events (cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke) in adults with type 2 diabetes mellitus and established cardiovascular disease Marso SP, et al. N Engl J Med. 2016:375:311-322. 43 44 7

Clinical Outcomes with Exenatide EXSCEL Clinical Outcomes with Exenatide EXSCE(N=14,752) Study Design N=14,752 patients with T2D with or without CVD By design, 70% had CVD (n=10,782; 73.1%) Randomization Exenatide: n=7356 Placebo: n=7396 Primary endpoint: composite of CV death, nonfatal MI, or nonfatal stroke Secondary endpoints: all-cause death, CV death, nonfatal or fatal MI, nonfatal or fatal stroke, and hospitalization for acute coronary syndrome or HF Key Results Median follow-up: 3.2 years Difference from placebo at trial end A1C: 0.53% (95% CI, 0.57% to 0.50%; P<0.001) Weight: 1.3 kg (95% CI, 1.4 to 1.1 kg; P<0.001) SBP: 1.6 mm Hg (95% CI, 1.9 to 1.2 mm Hg; P<0.001) No difference between treatment groups in confirmed cases of pancreatitis, pancreatic cancer, or medullary thyroid carcinoma CI, confidence interval; CV, cardiovascular; EXSCEL, Exenatide Study of Cardiovascular Event Lowering; HF, heart failure; HR, hazard ratio; MI, myocardial infarction. Holman RR, et al. N Engl J Med. 2017 Sept 14 [Epub before print]. 45 Holman RR, et al. N Engl J Med. 2017 Sept 14 [Epub before print]. 46 New Antihyperglycaemic Medication Usage 16 1021 14 Clinical Outcomes with Exenatide EXSCEL Serious Adverse Events and Events of Special Interest 12 782 10 692 652 549 8 508 450 401 6 35 6 274 265 4 146 173 182 2 0 Metformin Sulfonylureas Thiazolidinediones DPP-4i SGLT-2i* GLP-1 Receptor Insulin Agonists** Exenatide Placebo Subjects are considered to have taken a new medication if there is no indication of usage at baseline visit as well as indication of usage during at least one postrandomisation visit. Percentages presented are for available data. * Information regarding SGLT-2 inhibitor usage was added to the ecrf on 9th May, 2013. Percentages presented are for ITT population. ** Includes GLP-1 receptor agonist usage other than study medication Proportion (%) Event Exenatide (%) Placebo (%) (n=7344) (n=7372) Any serious AE 16.8 16.6 Serious adverse treatment-related event 0.8 0.5 Serious AE leading to study withdrawal 1.5 1.4 Events of Clinical Interest Adjudicated pancreatitis 0.4 0.3 Severe pancreatitis <0.1 <0.1 Adjudicated cancer (any) 4.8 4.9 Adjudicated medullary thyroid carcinoma <0.1 <0.1 Adjudicated pancreatic cancer 0.2 0.2 Severe hypoglycemia 3.4 3.0 Event rate 1.6 per 100 pt-years 1.8 per 100 pt-years AE, adverse event. Holman RR, et al. N Engl J Med. 2017 Sept 14 [Epub before print]. 48 Clinical Outcomes with Semaglutide SUSTAIN 6 Study Design N=3297 patients with T2D with CVD, CHF, CKD, or age 60 with 1 CV risk factor Randomization Semaglutide: n=1648 Placebo: n=1649 Noninferiority study: Primary endpoint: composite of CV death, nonfatal MI (including silent MI), or nonfatal stroke Key secondary endpoints Composite of CV death, nonfatal MI, nonfatal stroke, coronary or peripheral revascularization, and hospitalization for unstable angina or HF Composite of all-cause death, nonfatal MI, nonfatal stroke Retinopathy complications New or worsening nephropathy Composite of CV death, nonfatal MI (including silent MI), or nonfatal stroke CI, confidence interval; CHF, congestive heart failure; CKD, chronic kidney disease; CV, cardiovascular; CVD, cardiovascular disease; HF, heart failure; HR, hazard ratio; MI, myocardial infarction; SUSTAIN, Trial to Evaluate Cardiovascular and Other Long-term Outcomes with Semaglutide in Subjects with Type 2 Diabetes. Marso SP, et al. N Engl J Med. 2016:375:1834-1844. 49 50 8

Clinical Outcomes with Semaglutide SUSTAIN 6 Results (N=3297) Median follow-up: 2.1 years Hazard ratio (95% CI) P value Primary composite endpoint* 0.74 (0.58-0.95) 0.02 Clinical Outcomes with Semaglutide SUSTAIN 6 Selected Adverse Events Semaglutide 1 mg (%) Placebo Event 1 mg (%) (n=822) (n=825) Any adverse event 89.1 89.2 Serious adverse event 33.6 36.1 Expanded composite endpoint 0.88 (0.81-0.96) 0.002 Gastrointestinal disorder 52.3 35.2 All-cause death, nonfatal MI, nonfatal stroke 0.77 (0.61-0.97) 0.03 Death from any cause 1.05 (0.74-1.50) 0.79 CV death 0.98 (0.65-1.48) 0.92 Diarrhea 18.4 10.5 Nausea 21.9 8.1 Vomiting 14.8 4.1 Acute pancreatitis 0.4 1.1 Nonfatal MI 0.74 (0.51-1.08) 0.12 Gallbladder disorder 3.2 2.8 Nonfatal stroke 0.61 (0.38-0.99) 0.04 Cholelithiasis 2.1 1.5 Revascularization 0.65 (0.50-0.86) 0.003 Acute cholecystitis 0 0.2 Retinopathy complications 1.76 (1.11-2.78) 0.02 Severe or symptomatic hypoglycemia 21.7 21.0 New or worsening nephropathy 0.64 (0.46-0.88) 0.005 Injection site reaction 0.7 0.3 0.00 1.00 2.00 3.00 Neoplasm (any) 10.8 8.4 Favors semaglutide Any malignant 4.9 4.2 *CV death, nonfatal MI (including silent MI), or nonfatal stroke; CV death, nonfatal MI, nonfatal stroke, coronary or peripheral revascularization, and hospitalization for unstable angina or HF. Malignant pancreatic 0.1 0.2 CI, confidence interval; CV, cardiovascular; HF, heart failure; MI, myocardial infarction. Marso SP, et al. N Engl J Med. 2016:375:1834-1844. 51 Marso SP, et al. N Engl J Med. 2016:375:1834-1844.. 52 Baseline Patient Characteristics for CV Risk Reduction Empaglifozin Coronary Artery Disease History of MI History of stroke PAD Liraglutide Age of >50 History of MI Prior MI or TIA Prior revascularization >50% stenosis of coronary, carotid or lower extremity arteries Symptomatic CHD Heart failure CKD CVD risk factors (age> 60) Microalbuminuria or proteinuria Htn and LVH Ankle brachial index <0.9 9

Clinical Guidelines and CVOT AACE ADA Cardiovascular Risk Reduction in Diabetes 2018 10

Case #3 ARS Question 47 y/o female with Type 2 Diabetes x 15 years A1c is 7.8% on metformin + GLP-1 med On ACEi and statin BP is controlled LDL is 60 mg/dl BMI is 32 Hx of coronary stent placed last year What do you do? 1. Add basal insulin 2. Discussed exercise and weight loss 3. Discuss SGLT2 CV risk reduction trials 11

Q and A ARS #1. True/False Before 2O15, there was limited data that showed that glucose lowering medications reduce cardiovascular disease 1. True 2. False ARS #2 The following meds have been shown to reduce cardiovascular events in outcomes trials 1. Sitagliptin 2. Empaglifozin 3. Exenatide 4. Liraglutide 5. 2 and 4 ARS #3 Baseline characteristics in the Empaglifozin trial which showed reduction in CV death included the following: 1. Smoking 2. Heart calcium (Agatson) score of >450 3. Prior MI 4. Prior stroke 5. 3 and 4 6. 2 and 3 12

Medication Index Cardiovascular Impact of Medications for Treating Type 2 Diabetes The following medications were discussed in this presentation. The table below lists the generic and trade name(s) of these medications. Generic Name Albiglutide Alogliptin Alogliptin/Metformin Bromocriptin Canagliflozin Canagliflozin/Metformin Clopidogrel Colesevelam Dapagliflozin Dapagliflozin/Metformin Dapagliflozin/Saxagliptin Dulaglutide Empaglifilozin Empagliflozin/Metformin Ertugliflozin Ertugliflozin/Linagliptin Ertugliflozin/Metformin Ertugliflozin/Sitagliptin Exenatide Glimepiride Insulin Degludac Linagliptin Linagliptin/Metformin Liraglutide Liraglutide/Insulin Degludec Lixisenatide Metformin Saxagliptin Saxagliptin/Metforum Semaglutide Sitagliptin Sitagliptin/Metforum Trade Name Tanzeum Nesina Kazano Cycloset, Parlodel Invokana Invokamet Plavix Welchol Farxiga Xigduo XR Qtern Trulicity Jardiance Synjardy Steglatro Glyxambi Segluromet Streglujan Bydureon, Byetta Amaryl Tresiba Trajenta Jentdueto Saxenda, Victoza Xultrophy Adlyxin Fortamet, Glucophage, Glumetza, Riomet Onglyza Kombiglyze XR Ozempic Januvia Janumet

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