Cardiovascular Consequences of Diabetes Mellitus

Cardiovascular Consequences of Diabetes Mellitus William J. Elliott, M.D., Ph.D. 05 MAY 18 Disclosure Statement The speaker s research and educational activities have been supported in the past (but NOT in the last 12 months) by essentially every pharmaceutical company that makes, markets or distributes antihypertensive drugs in the USA. The information presented is therefore likely to be biased. Healthcare providers are therefore strongly cautioned NOT to use the information presented in their daily practices (see, for example, The People of the United States of America v Peter Gleason) until and unless the specific agent or therapy receives formal approval from the US FDA for exactly the indication under consideration by the healthcare professional. Affidavit of Originality The following material is based exclusively on the speaker s own opinion, knowledge and expertise. There is no organization, company, or entity that has exercised any control or influence over the content of this presentation, nor has any other person or organization had any part in drafting, scripting or designing its content. The information presented is based on the principles of Evidence-Based Medicine, and is intended to avoid promotion of any specific commercial interest, product, or company. 1

Disclaimers The speaker has participated (with known experts in the field) in writing a Scientific Statement from the American Heart Association on the topic of Treatment of Hypertension in Patients with Coronary Heart Disease. The speaker currently serves as the Chair of the Continuing Education Committee and on the Education Committee of the American Society of Hypertension, which was involved in producing the ACC/AHA 2017 US hypertension guideline. This presentation does not reflect opinion, consensus, or recommendations from the American Heart Association or The American Society of Hypertension.. Educational Objectives-1 At the end of this 50-minute presentation, the awake audience member should be able to: 1. Cite a summary odds ratio or hazard ratio, derived from epidemiological data, that reflects the relative risk of the following cardiovascular outcomes in diabetic persons, compared to those without diabetes mellitus, after adjusting for all other appropriate risk factors: a. Stroke. b. Myocardial infarction (or acute coronary syndrome). c. Heart failure. d. Cardiovascular death. e. First occurrence of nonfatal stroke, nonfatal myocardial infarction, or cardiovascular death (sometimes also including heart failure in the composite endpoint). Educational Objectives-2 2. Review recent clinical trials involving different approaches to controlling plasma glucose in diabetic subjects, with regard to impact on the risk of. a. Stroke. b. Myocardial infarction (or acute coronary syndrome). c. Heart failure. d. Cardiovascular death. e. First occurrence of nonfatal stroke, nonfatal myocardial infarction, or cardiovascular death (sometimes also including heart failure in the composite endpoint). 3. Explain the design and results of the STENO-2 randomized trial (performed in Denmark), and its implications for optimal management of Americans with diabetes mellitus. 2

Cardiovascular Consequences of Diabetes Mellitus Risk Factor Diabetes mellitus has long been recognized as a strong risk factor for major adverse cardiovascular events, but the proportion by which it increases these risks depends on many factors, including the population studied, the definition of diabetes mellitus, the type of cardiovascular event, and concomitant treatment (if any) for other risk factors (e.g., hypertension, dyslipidemia, etc.). In 1961, the Framingham Heart Study was the first to use the term, risk factor to connect age, cigarette smoking, weight, blood pressure and serum cholesterol with adverse heart-related outcomes. DM & CV Risk: Framingham It took >30 years to tease out glucose intolerance as a significant contributor to the risk of cardiovascular events. In Kannel and McGee s classic 1979 JAMA paper, after statistical adjustment for baseline differences in age, systolic blood pressure, cigarettes/day, serum cholesterol, and the presence of left ventricular hypertrophy on the electrocardiogram, diabetes increased the risk of cardiovascular events in each gender as follows: JAMA. 1979:241:2035-8 3

Diabetes Increases CV Risk JAMA. 1979:241:2035-8 DM & CV Risk: Framingham 10 Adjusted HR 2 2.11 2.03 1.82 3.75 4.99 4.16 2.18 2.17 2.06 1.66 2.06 1.66 1 CV Disease HF PVD Stroke CHD CV Death JAMA. 1979:241:2035-8 DM & CV Risk: Framingham The task of generating these relative risk estimates required >20 years of observation of the original cohort of 5209 individuals, development of statistical techniques for timedependent, multivariate analysis, and used classic (my students would say, outdated, or Fajan s ) criteria for the diagnosis of diabetes mellitus. Despite these challenges, these estimates are not far from those derived from many other sources (e.g., meta-analyses of large, prospective studies or outcome-based clinical trials). JAMA. 1979:241:2035-8 4

DM & Death: Meta-Analysis Data from 97 prospective studies, 123,205 deaths. 10 Adjusted HR 2 1.80 (1.71-1.90) 2.32 (2.11-2.56) 1.25 (1.19-1.31) 1.73 (1.62-1.85) 1 All-Cause Vascular Cancer Other N Engl J Med. 2011;364:829-41 Type of Death DM & MI Risk: INTERHEART The most recent attempt to study the relative impact of cardiovascular risk factors in a global population comes from the INTERHEART family of studies, which compiled data from 262 participating centers in 52 countries, comparing 15,152 people with incident myocardial infarction and 14,820 age-, gender-, and geographically-matched controls without heart disease. Lancet. 2004;364:937-52 INTERHEART: MI Risk Factors Risk Factor Odds Ratio Dyslipidemia 3.25 Smoking 2.87 Psychosocial Factors 2.67 Diabetes 2.37 Hypertension 1.91 Obesity 1.12 Regular Alcohol Intake 0.91 Regular Physical Activity 0.86 Dietary Fruits/Vegetables 0.70 Lancet. 2004;364:937-52 5

Population-Attributable Risk Diabetes Hypertension Alcohol Physical Activity Fruits/Veggies Obesity 10% Lancet. 2004;364:937-52 12% 7% 14% 18% 20% 33% Psychosocial RF 49% 36% Dyslipidemia Smoking DM & CVA Risk: INTERSTROKE More recently, the same strategy to identify the relative impact of cardiovascular risk factors in stroke in a global population was used in INTERSTROKE, which compiled data from 184 participating centers in 32 countries, comparing 26,919 acute stroke survivors and 13,472 age-, gender-, and geographicallymatched controls without cerebrovascular disease. Lancet. 2016;388:761-77 INTERSTROKE: CVA Risk Factors Risk Factor Odds Ratio Cardiac Conditions 3.17 Hypertension 2.98 Psychosocial Factors 2.20 Alcohol Intake 2.09 Dyslipidemia 1.84 Smoking 1.67 Obesity 1.44 Diabetes 1.16 Regular Physical Activity 0.70 Dietary Fruits/Vegetables 0.60 Lancet. 2016;388:761-77 6

Population-Attributable Risk Psychosocial RF Alcohol Diabetes Cardiac Conditions Smoking 9% 6%4% Obesity Unhealthy Diet 12% 17% 19% Lancet. 2016;388:761-77 48% 36% 23% 27% Dyslipidemia Hypertension Physical Inactivity A.H. Rubenstein, MD, 1978: In Type 2 diabetes, control the blood sugar within the normal range, and everything else will take care of itself. Important Trials of Glycemic Control in Type 2 Diabetes United Kingdom Prospective Diabetes Study (UKPDS), Avoiding Cardiovascular Complications of Diabetes (ACCORD), Action in Diabetes and Vascular disease: Preterax and Diamicron -MR Controlled Evaluation (ADVANCE), and Veterans Affairs Diabetes Trial (VADT). 7

UKPDS Simple Summary Designed in 1977, UKPDS randomized 5102 British subjects with newly-diagnosed type 2 diabetes to conventional therapy or intensive therapy for hyperglycemia, and followed them for ~10 years, using the primary endpoint of all diabetes-related endpoints (death, CV event, retinopathy, nephropathy, neuropathy). The median A1cs were 7.9% and 7.0%, respectively. The 1148 hypertensive diabetics were also randomized to a BP target of either < 150/85 (actual: 144/84) or < 180/105 mm Hg (154/89). UKPDS Initial Results After 9+ years of planned follow-up, a significant reduction in all diabetesrelated endpoints (the primary endpoint) was observed with more intensive glycemic control (compared to usual care, by 12%, P < 0.03); The effect of intensive BP control on this endpoint was even more impressive (reduction of 24%, P < 0.005). Lancet. 1998;352:837-53; Lancet. 1998;352:854-85. UKPDS Long-Term Results Ten years after the trial stopped, there was a significant 9% persistent benefit for the primary endpoint for individuals randomized to more intensive glucose-lowering therapy. However, the 7% benefit on this endpoint for individuals randomized to more intensive BP control was not significant, presumably because, after the trial stopped, the BPs were indistinguishable between randomized groups. N Engl J Med. 2008;359:1565-76; 1577-89 8

ACCORD Simple Summary The NIH-sponsored family of 3 clinical trials, Avoiding Cardiovascular Complications of Diabetes, randomized diabetics to: Glycemic control: Intensive (A1c < 6.0%) or Conventional (A1c < 7.0-7.9%); n = 10,251 Systolic BP control: Intensive (SBP < 120) or Conventional (SBP < 140 mm Hg); n = 4733 Simvastatin + HDL-cholesterol/triglyceride control: Intensive (fenofibrate) or Conventional (placebo); n = 5518 The primary outcome was CV death, MI or stroke. Planned follow-up was 5 years. ACCORD Initial Results The ACCORD-Glucose trial was terminated after only 3.5 of its planned 5 years, because of an unanticipated significant 22% increase in all-cause mortality in the 5128 intensively-treated subjects, compared to the 5123 conventionally-treated individuals; this was attributed to a significantly increased risk of sudden cardiac death and hypoglycemia in the intensively-treated group. The ACCORD-BP trial may have been underpowered (based on SPRINT), but it observed a non-significant (P = 0.20), 12% reduction in cardiovascular events in the 2362 diabetics randomized to systolic BP < 120 mm Hg over 4.7 years, compared to the 2371 diabetics randomized to systolic BP < 140 mm Hg. ACCORDION Results About 4 years after ACCORD was stopped, the only outcome that remained significantly elevated in those randomized to an A1c of < 6.0%, compared to those with a target A1c of 7.0-7.9% was cardiovascular death (which was originally 49% higher when ACCORD-Glucose was stopped, and was attenuated to only 20% higher when the follow-up period was included). About 4 years after ACCORD-BP was stopped, those initially treated to systolic BP < 120 mm Hg had a 9%, nonsignificant (P = 0.19) reduction in the primary endpoint, and the systolic BP difference between groups shrank from 14.5 to 4.2 mm Hg. 9

ADVANCE Simple Summary This industry-sponsored trial enrolled 11,140 diabetics at 215 ex-us sites in 20 countries, and randomized them twice (after a 6-week active runin period): Once to a modified-release formulation of glyclazide, a sulfonylurea, or usual care (and no glyclazide), Once to a low-dose combination of indapamide + perindopril, or placebo; the maximum dose of openlabel perindopril allowed in either group was 4 mg/day. The shared primary outcome was a composite of CV death, MI, stroke, worsening eye or kidney disease. Follow-up was planned for 4-5 years. ADVANCE Initial Results There was a small but significant (P = 0.01) 10% reduction in the primary composite endpoint (attributed mostly to prevention of microvascular endpoints) over 5 years of follow-up in the 5571 given glyclazide, compared to the 5569 given usual care (which excluded glyclazide). A small but significant (P = 0.04) 9% reduction in the shared primary composite endpoint (also seen with cardiovascular and all-cause mortality) in the 5569 diabetics given the combination BP pill over 4.3 years of follow-up, compared to the 5571 diabetics given placebo. N Engl J Med. 2008;358:2560-72; Lancet. 2008;370:829-40. 10

ADVANCE-ON Results About 6 years after ADVANCE was stopped, no significant differences in any endpoint were seen across the two groups in the glucoselowering arm. However, significant differences were still evident in both all-cause (9%, P = 0.03) and cardiovascular mortality (12%, P = 0.04) favoring those who received the two BPlowering drugs (compared to placebo). N Engl J Med. 2014;371:1392-406 VADT Simple Summary The Department of Veterans Affairs Diabetes Trial randomized 1791 US veterans with poorlycontrolled diabetes to either an intensive glucose-lowering regimen (achieved A1c = 6.9%) over 5.6 years, or standard treatment (achieved A1c = 8.4%). All other cardiovascular risk factors were treated similarly in the VADT. The primary outcome was a composite of CV death, MI, stroke, CHF, vascular surgery, inoperable CHD, or amputation. VADT Results After 5.6 years, there was a nonsignificant (P = 0.14) 12% benefit on the primary endpoint. After a further ~5 years of follow-up, however, the primary endpoint was significantly (P = 0.04) reduced by 17% in the intensively-treated group; no significant differences were seen in all-cause (+5%, P = 0.54) or cardiovascular mortality (-12%, P = 0.42). N Engl J Med. 2009;360:129-39; N Engl J Med. 2016;372:2197-206 11

Does Glucose-Lowering Reduce CV Complications of Diabetes? Not if lowered too far: Hypoglycemia! (as in ACCORD-Glucose). With less-aggressive glycemic control, small benefits (e.g., 9-14%) exist, especially in the long-term. These benefits are more likely when other CV risk factors (e.g., BP) are also controlled. The benefits of BP control may be greater than glycemic control. What About CV Risk with Newer Antidiabetic Drugs? Especially in view of some older drugs being associated with MI (UGDP), heart failure (TZDs) FDA-Mandated CV Safety Trials As a condition for marketing approval in the US, since 2008 the FDA has required sponsors of newer hypoglycemic agents to perform a noninferiority trial in sufficient subjects to assure that the new drug, when added to standard care does not increase CV risk. The recommended primary outcome is a composite of CV death, MI or stroke. The recommended non-inferiority limit was an upper bound of the 95% confidence interval that must be < 1.30 (i.e., not > 30% worse than NOT using the new drug). 12

Why Are These Trials Important? If the noninferiority P value for the primary outcome is < 0.05, the drug can remain on the US market. If the noninferiority P value for the primary outcome is < 0.05, AND the primary outcome s superiority P value is < 0.05, the FDA will consider a Supplemental New Drug Application for a new claim of significant CV protection. The FDA may consider a claim for benefit regarding a pre-specified secondary endpoint, but there are no guarantees. Time Line: Diabetes Drugs CVOTs Diabetes Care. 2018;41:14-31. Some Diabetes Drugs CVOTs Acronym Drug Enrolled Diabetics SAVOR-TIMI 53 Saxagliptin > 40 y.o. and CVD, > 55 and 1 RF EXAMINE Alogliptin 15-90 days post ACS hospitalization TECOS Sitagliptin Established CVD ELIXA Lixisenatide < 180 days after coronary event LEADER Liraglutide > 50 y.o. and CVD, > 60 and 1 RF SUSTAIN-6 Semaglutide SC ditto EMPA REG Empagliflozin Established CVD CANVAS Canagliflozin > 30 y.o. and CVD, > 50 and 2 RF EXSCEL Exenatide-ER q week 18 y.o. And many others that are not yet completed, including: DEVOTE Degludec > 50 y.o. with CVD or CKD REWIND Delaglutide > 50 y.o. with CVD or 1 RF DECLARE Dapagliflozin > 40 y.o. with high CV risk 13

Different Enrolled Populations DPP-4 Inhibitors (-gliptins) Saxa- Alo- Sita- Empa - SGLT2s (-gliflozins) Cana- Lixisen a- GLP1 Agonists (-tides) Liraglu - Semag lu- Exenan 16492 5380 14671 7034 10142 6068 9340 3297 10782 Age 65 61 66 63 63 60 64 64.6 62 T2DM 10.3 7.2 9.4 >10? 13.5 9.3 12.8 13.9 12 BMI 31 29 29 30.6 32 30.1 32.5 32.8 31.7 A1c 8.0 8.0 7.3 8.1 8.2 7.7 9.7 8.7 8.0 CVD 78% 100% 100% 99% 65.6% 100% ~81% ~83% 73% HTN 81% 83% 86% 94% 90% 76% 92% 93% 90% Insulin 41% 30% 23% 48% 50% 38% 44% 58% 46% HRs, P-values: DPP-4 Trials Outcome Saxagliptin Alogliptin Sitagliptin Primary P noninferiority CV death Nonfatal MI Nonfatal stroke UA Hosp HF Hosp 1.00 (0.89-1.12) P = 0.99 P < 0.001 1.00 (0.87-1.22) P = 0.72 0.95 (0.80-1.12) P = 0.52 1.11 (0.88-1.39) P = 0.38 1.19 (0.89-1.60) P = 0.24 1.27 (1.07-1.51) P = 0.007 0.96 (?-1.16) P = 0.32 P < 0.001 0.79 (0.60-1.04) P = 0.10 1.08 (0.88-1.33) P = 0.47 0.91 (0.55-1.50) P = 0.71 0.90 (0.60-1.37) P = 0.63 1.07 (0.79-1.46) P = 0.66 0.98 (0.89-1.08) P = 0.65 1.03 (0.89-1.19) P = 0.71 0.95 (0.81-1.11) P = 0.49 0.97 (0.79-1.19) P = 0.76 0.90 (0.70-1.16) P = 0.42 1.00 (0.83-1.20) P = 0.98 HRs, P-values: SGLT-2 Trials Outcome Empagliflozin Canagliflozin Primary P noninferiority CV death Nonfatal MI Nonfatal stroke UA Hosp HF Hosp 0.86 (0.74-0.99) P = 0.04 P < 0.001 0.62 (0.49-0.77) P < 0.001 0.87 (0.70-1.09) P = 0.23 1.24 (0.92-1.67) P = 0.16 0.99 (0.74-1.34) P = 0.97 0.65 (0.50-0.85) P = 0.002 0.86 (0.75-0.97) P = 0.02 P < 0.001 0.87 (0.72-1.06) Not reported 0.85 (0.69-1.05) Not reported 0.90 (0.71-1.15) Not reported Not reported 0.67 (0.52-0.87) Not reported 14

HRs, P-values: GLP-1 Trials Outcome Lixisena- Liraglu- Semaglu- Primary P noninferiority CV death Nonfatal MI Nonfatal stroke UA Hosp HF Hosp 1.02 (0.89-1.17) P = 0.81 Not reported 0.62 (0.49-0.77) P < 0.001 0.87 (0.70-1.09) P = 0.23 1.24 (0.92-1.67) P = 0.16 0.99 (0.74-1.34) P = 0.97 0.65 (0.50-0.85) P = 0.002 0.87 (0.78-0.97) P = 0.01 P < 0.001 0.78 (0.66-0.93) P = 0.007 0.86 (0.73-0.99) P = 0.046 0.86 (0.71-1.06) P = 0.16 0.98 (0.76-1.26) P = 0.87 0.87 (0.73-1.05) P = 0.14 0.74 (0.58-0.95) P = 0.02 P < 0.001 0.98 (0.65-1.48) P = 0.92 0.74 (0.51-1.09) P = 0.12 0.61 (0.38-0.99) P = 0.04 0.82 (0.47-1.44) P = 0.49 1.11 (0.77-1.61) P = 0.57 HRs, P-values: Another GLP-1 Outcome Primary P noninferiority CV death Fatal/nonfatal MI Fatal/nonfatal stroke ACS Hosp HF Hosp Exenatide-ER weekly 0.91 (0.83-1.00) P = 0.06 P < 0.001 0.88 (0.76-1.02) Not reported 0.97 (0.85-1.10) Not reported 0.85 (0.70-1.03) Not reported 1.05 (0.94-1.18) Not reported 0.94 (0.78-1.13) Not reported N Engl J Med. 2017;377:1228-39. Product Information Changes On 02 DEC 16, empagliflozin was the first agent to receive a new indication to reduce the risk of cardiovascular death in adult patients with type 2 diabetes mellitus and cardiovascular disease; this was extended to all of its marketed combinations on 07 JAN 17. On 25 AUG 17, the indication, 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 was added to the label for liraglutide. 15

EMPA REG Simple Summary Investigators from 590 sites in 42 countries enrolled 7020 diabetics, and randomized them (after a 2-week open-label placebo run-in) to: 10 mg of empagliflozin or placebo 25 mg of empagliflozin or placebo And followed them for 3.1 years, during which time 25.4% discontinued study medication. Efforts were made to treat all appropriate CV risk factors in a similar fashion across groups. The primary analysis was noninferiority for the composite endpoint, pooling all subjects who received empagliflozin or placebo. N Engl J Med. 2015;373:2117-28 EMPA REG Results Not only did the primary analysis show significant (P < 0.001) noninferiority (HR = 0.86, 95% CI: 0.74-0.99), but also the superiority P- value was 0.04, indicating that empagliflozin was associated with significantly reduced CV risk. Those randomized to empagliflozin also had a 32% reduction in death, and 38% reduction in CV death (both P < 0.001 for noninferiority). These endpoints were not evaluated statistically because they were not prespecified, and did not meet established criteria for the four-step hierarchical testing procedure. N Engl J Med. 2015;373:2117-28 N Engl J Med. 2015;373:2117-28 16

N Engl J Med. 2015;373:2117-28 Silvio Inzucchi, M.D. This is the first time in my lifetime that a diabetes drug has shown improved outcomes in high-risk cardiovascular patients. More EMPA REG Outcomes A subsequent analysis of renal outcomes in EMPA REG showed a significantly reduced risk of nephropathy (by 41%), doubling of serum creatinine (by 44%), and renal replacement therapy (by 55%) in the group given empagliflozin. On 02 DEC 16, the FDA approved empagliflozin to reduce CV death in diabetics with established CV disease (validating the Advisory Committee s 12-11 vote). N Engl J Med. 2016;375:323-34 17

N Engl J Med. 2016;375:323-34 Doubling Scr, ESRD, death from renal causes N Engl J Med. 2016;375:323-34 LEADER Simple Summary Investigators from 410 sites in 32 countries enrolled 9340 diabetics, and randomized them (after a 2-week open-label placebo run-in) to: 1.8 mg of SC liraglutide or placebo daily. GLP-1 receptor agonists, DPP-4 inhibitors and pramlintide were prohibited after randomization. And followed them for 3.5 years, during which time 16% discontinued study medication. Efforts were made to treat all appropriate CV risk factors in a similar fashion across groups. The primary analysis was noninferiority for the composite endpoint. N Engl J Med. 2016;375:311-23. 18

LEADER Results Not only did the primary analysis show significant (P < 0.001) noninferiority (HR = 0.87, 95% CI: 0.78-0.97), but also the superiority P- value was 0.01, indicating that liraglutide was associated with significantly reduced CV risk. Those randomized to liraglutide also had a 15% reduction in death, and 22% reduction in CV death (both P < 0.001 for noninferiority). These endpoints were reported to be statistically significant in superiority analyses (with P = 0.02, and 0.007, respectively) but were not subjected to correction for multiple (19!) comparisons. N Engl J Med. 2016;375:311-23. N Engl J Med. 2016;375:311-23. N Engl J Med. 2016;375:311-23. 19

N Engl J Med. 2016;375:311-23. SUSTAIN-6 Simple Summary Investigators from 230 sites in 20 countries enrolled 4346 diabetics, and randomized them (after a 2-week open-label placebo run-in) to: 0.5 mg of SC semaglutide or placebo weekly. 1.0 mg of SC semaglutide or placebo weekly. GLP-1 receptor agonists, DPP-4 inhibitors were prohibited after randomization. And followed them for 2.0 years, during which time 20% discontinued study medication. Efforts were made to treat all appropriate CV risk factors in a similar fashion across groups. The primary analysis was noninferiority for the composite endpoint, pooling all subjects who received semaglutide or placebo. N Engl J Med. 2016;375:311-23. SUSTAIN-6 Results Not only did the primary analysis show significant (P < 0.001) noninferiority (HR = 0.74, 95% CI: 0.58-0.95), but also the superiority P- value was 0.02, indicating that semaglutide was associated with significantly reduced CV risk. Those randomized to semaglutide also had a 5% increase in death, and a 2% reduction in CV death (both were said to be nonsignificant). Supplemental analyses showed benefit on stroke, revascularization, retinopathy, and nephropathy. N Engl J Med. 2016;375:311-23. 20

N Engl J Med. 2016;375:311-23. CANVAS: Simple Summary Combined data from 2 trials with different dosing schemes: 1:1:1 randomization to placebo, 100 or 300 mg/d of canagliflozin 1:1 randomization to placebo or 100 mg/d of canagliflozin, with optional titration to 300 mg/d after 13 weeks. Enrolled 10,142 participants (63.3 years of age, 36% women, 13.5 years of diabetes, 66% with preexisting cardiovascular disease), followed for 3.62 years for CV death, MI, stroke. N Engl J Med. 2017;377:644-57. CANVAS: Primary Outcome N Engl J Med. 2017;377:644-57. 21

CANVAS: Other Outcomes? Although not prespecified, canagliflozin showed improved renal outcomes: Slowed progression of albuminuria (HR = 0.73, 95% CI: 0.67-0.79) Fewer hard renal events (sustained 40% drop in egfr, ESRD, or death) HR = 0.60, 95% CI: 0.47-0.77. Adverse experiences were all as expected, except canagliflozin was associated with an increased risk of amputations (HR = 1.97, 95% CI: 1.41-2.75), mostly toes/metatarsals. N Engl J Med. 2017;377:644-57. Conclusion from 4 Trials Taken together, these data suggest that several modern hypoglycemic agents can, when used as part of standard care, not only NOT increase, but also significantly decrease cardiovascular risk. But they were all funded by the pharmaceutical industry. What Is the Evidence (Independent of Big Pharma) that Multifaceted Treatment of Diabetics Improves CV Outcomes? 22

STENO-2 Investigators at the Steno Diabetes Center in Copenhagen gathered data on whether such a complex, multifactorial intervention was beneficial by performing a clinical trial. They randomized 160 diabetics to 1 of 2 treatment regimens. The primary endpoint was a composite of cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, revascularization procedure, or amputation. The study stopped as planned after a mean follow-up of 7.8 years. Treatment Arms The Intensive Regimen involved a stepwise implementation, using a "team approach" (physician, nurse, nutritionist) of behavior modification and pharmacological therapy that targeted hyperglycemia, hypertension, dyslipidemia, and microalbuminuria, along with aspirin for prevention of cardiovascular disease. The Conventional Therapy group received treatment in accordance with Danish national treatment guidelines. N Engl J Med. 2003;348:383-393 Changing Guidelines Variable Conventional Intensive Therapy Therapy 1993-99 2000-01 1993-99 2000-01 Blood pressure (BP, mm Hg) < 160/95 < 135/85 < 140/85 < 130/80 Glycosylated hemoglobin (%) < 7.5 < 6.5 < 6.5 < 6.5 Fasting serum cholesterol (mg/dl) < 250 < 190 < 190 < 175 Fasting serum triglycerides (mg/dl) < 195 < 180 < 150 < 150 Treatment with ACE inhibitor, No Yes Yes Yes irrespective of BP Aspirin therapy For patients with known ischemia Yes Yes Yes Yes For patients with PVD No No Yes Yes For patients without CHD or PVD No No No Yes ACE = angiotensin converting enzyme; BP = blood pressure; PVD = peripheral vascular disea CHD = coronary heart disease N Engl J Med. 2003;348:383-393 23

STENO-2 The treatment groups were very similar at randomization (including 80 in each group). Major significant differences were seen during follow-up for: - glycosylated hemoglobin (A1c in the USA), - total and LDL-cholesterol and triglycerides, - systolic and diastolic blood pressure. More diabetics in the Intensive-Therapy Group achieved the specified goals. N Engl J Med. 2003;348:383-393 STENO-2: "Surrogate Endpoints" % of Subjects Reaching 2001 Goal 80 70 60 50 40 30 20 10 0 P = 0.001 SBP < 130 mm Hg P = 0.21 P = 0.001 DBP < 80 mm Hg [Chol] < 175 mg/dl Intensive Therapy Conventional Therapy P = 0.19 TG < 150 mg/dl P = 0.06 A1c < 6.5% Other Outcomes in STENO-2 Despite a great deal of counseling and nutritional advice, the only significant dietary differences between groups at the end of the study were the relative intakes of carbohydrate and fat. Although the total number of primary events was 85 in the Conventional-Therapy group and 33 in the Intensive-Therapy group, the numbers of subjects with first events were: N Engl J Med. 2003;348:383-393 24

STENO-2: Kaplan-Meier Plot 35 Events 19 Events N Engl J Med. 2003;348:383-393 STENO-2: Kaplan-Meier Plot Primary Composite Endpoint (%) 60 50 40 30 20 10 P=.007* Conventional therapy Adjusted hazard ratio=0.47 (95% CI, 0.22-0.74) 53% Intensive Therapy 0 0 12 24 36 48 60 72 84 96 No. at Risk Months of Follow-up Conventional 80 72 70 63 59 50 44 41 13 Intensive 80 78 74 71 66 63 61 59 19 N Engl J Med. 2003;348:383-393 STENO-2: Outcomes Intensive Conventional Hazard Ratio Therapy Therapy (95% CI), P-value Composite 1 Endpoint 19 35 0.45 (0.23-0.91), P = 0.02 Cardiovascular death 3 1 Nonfatal MI 4 8 Nonfatal stroke 3 11 Revascularizations 7 12 Amputations 2 3 Renal Endpoints Proteinuria > 300 mg/d 16 31 0.39 (0.17-0.87), P = 0.003 Dialysis 0 3 Diabetic Eye Disease Progressive retinopathy 27 38 0.42 (0.21-0.86), P = 0.02 Blindness 1 7 Diabetic Nerve Disease Autonomic neuropathy 24 43 0.37 (0.18-0.79), P = 0.002 Peripheral neuropathy 40 37 1.09 (0.54-2.22), P = 0.66 Minor hypoglycemic episodes 42 39 Major hypoglycemic episodes 12 5 P = 0.12 (impaired consciousness or required medical assistance) 25

Concerns about STENO-2? No blinding, thus potential bias of surgeon/ physician performing a revascularization? - Supplemental analysis: HR = 0.45 (0.23-0.91). Expert care (i.e., nurses, dieticians) for one group; "routine" care for the other. Baseline differences in duration of diabetes, age, gender, smoking, existing CVD? - Supplemental analysis: HR = 0.47 (0.22-0.74). Withdrawals: 2 (conventional), 1 (intensive) - Supplemental analysis with hypotheticalevent at time of withdrawal: HR = 0.50 (0.29-0.86). Any Long-Term Benefits? "OK, But I Asked You About Death!" When STENO-2 was completed, all Danish physicians and diabetics received information about the regimen that was so successful. The Danish national treatment guidelines were changed to agree with STENO-2. The STENO-2 investigators followed-up their subjects 5.5 years later regarding mortality. Death occurred in 24 of the Intensive Therapy group, vs. 40 in the Conventional Therapy group (HR = 0.54, 95% CI: 0.32-0.80, P = 0.02). N Engl J Med. 2008;358:589-591 STENO-2 Follow-Up: Mortality N Engl J Med. 2008;358:589-591 26

STENO-2 Follow-Up: Morbidity N Engl J Med. 2008;358:589-591 # of Subjects with Event STENO-2 Follow-Up: 2 Endpoint 25 20 15 10 5 First Events-Intensive Group Subsequent Events-Intensive First Events-Conventional Group Subsequent Events-Conventional 0 CV Death MI Stroke CABG/PCI Limb Revasc Amputation Conclusions Diabetes mellitus increases the risk of cardiovascular events or death by ~2-fold. Controlling dysglycemia alone impacts cardiovascular risk in both directions (hypoglycemia increases sudden death), with mild CV benefits if less aggressive. Reduction in CV risk in diabetics is greater if glycemic control is but one part of a multifaceted treatment, which includes BP, dyslipidemia, aspirin, and smoking cessation. 27