Update on CVD and Microvascular Complications in T2D

Update on CVD and Microvascular Complications in T2D Jay S. Skyler, MD, MACP Division of Endocrinology, Diabetes, and Metabolism and Diabetes Research Institute University of Miami Miller School of Medicine

Commercial Interests Board of Directors Member Dexcom, Moerae Matrix, Paean Therapeutics, VasoPrep Surgical Scientific Advisory Board Member Diavacs, Halozyme, Orgenesis, Sekris, Valeritas, Viacyte Advisor or Consultant Boheringer Ingelheim, Bristol-Myers Squibb/Astra-Zeneca, Elcelyx, Eli Lilly, Ideal Life, Intarcia, Julphar, Roche, Sanofi Stock or Option Holder Dexcom, Ideal Life, Moerae Matrix, Paean Therapeutics, Patton Medical Devices, Tandem Diabetes Care, VasoPrep Surgical Research Support (to University of Miami) Halozyme, Mesoblast

Adolescent Renal & Cardiovascular Disease Protection in Type 1 Diabetes AdDIT Study: David Dunger CVD Outcome Studies in Type 2 Diabetes: Angelyn Bethel Prevention of Cardio-Renal Complications: David Maahs

CVD in Diabetes

Glucose Paradox Glucose levels & hyperglycemic states are closely linked to increased CVD risk Definitive evidence that improving glucose control decreases major CVD events remains elusive

Effect of Intensive Glucose Lowering on Macrovascular Complications in T2DM ACCORD ADVANCE VADT Non-fatal MI Primary outcome Non-fatal stroke Non-fatal MI Non-fatal MI CVD death Non-fatal stroke Non-fatal stroke Hospitalization for CVD death CVD death CHF Revascularization HR for primary outcome (95% CI) 0.90 (0.78 1.04) 0.94 (0.84 1.06) 0.87 (0.73 1.04) HR for mortality (95% CI) 1.22 (1.01 1.46)* 1.46)* 0.93 (0.83 1.06) 1.065 (0.80 1.42) *p=0.04 VADT = Veterans Affairs Diabetes Trial VADT study ADVANCE Collaborative Group. N Engl J Med 2008;358:2560 72 ACCORD Study Group. N Engl J Med 2008;358:2545 59 59 VADT Study Group. N Engl J Med 2009;360:129 39 39

Comparison of ACCORD, ADVANCE, VADT Characteristic ACCORD ADVANCE VADT N 10,251 11,140 1,791 Mean Age 62 66 60.4 Duration of T2DM 10 yr 8 yr 11.5 yr History of CVD 35% 32% 40% BMI 32 28 31 Baseline A1C 8.3% 7.5% 9.4% Study Duration 3.4 5.0 6.0 ACCORD Study Group. N Engl J Med.. 2008;358:2545-59. 59. ADVANCE Collaborative Group. N Engl J Med 358:2560-72, 2008. Duckworth W for VADT. N Engl J Med 2009;360:129 :129-39

Cumulative Incidence of Any Predefined CV Outcome Cumulative Incidence of the First of Any of the Predefined CVD Outcomes 0.12 0.10 0.08 0.06 0.04 0.02 Risk reduction 42% 95% CI: 9 639 Log-rank p=0.016 Conventional treatment Intensive treatment 0.00 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 No. at Risk Years Since Entry Intensive 705 683 629 113 Conventional 714 688 618 92 Nathan DM, et al. N Engl J Med 2005;353;2643 53 53

Myocardial Infarction Hazard Ratio (fatal or non-fatal MI or sudden death) Intensive (SU/Ins) vs Conventional Glucose Control 1.4 1.2 MI HR=0.84 p=0.052 HR=0.85 p=0.014 1.0 HR (95%CI) HR 0.8 0.6 0.4 Number of Events Con: 168 212 239 271 296 319 Int: 387 450 513 573 636 678 1997 1999 2001 2003 2005 2007 UKPDS 80. N Eng J Me 2008;359:1577 89 89

Meta-analysis: analysis: Major CVD Trials Number of Events (Annual Event Rate, %) More Intensive Less Intensive ΔA1c (%) Favours More Intensive Favours Less Intensive HR (95% CI) Major cardiovascular events ACCORD 352 (2.11) 371 (2.29) 1.01 0.90 (0.78 1.04) ADVANCE 557 (2.15) 590 (2.28) 0.72 0.94 (0.84 1.06) UKPDS 169 (1.30) 87 (1.60) 0.66 0.80 (0.62 1.04) VADT 116 (2.68) 128 (2.98) 1.16 0.90 (0.70 1.16) Overall 1,194 1,176 0.88 0.91 (0.84 0.99) (Q=1.32, p=0.72, I 2 =0.0%) 0.5 1.0 2.0 HR (95% CI) Turnbull FM, et al. Diabetologia 2009; 55:2288-2298 2298

Meta-analysis: analysis: All-cause Mortality Trials Number of Events (Annual Event Rate, %) More Intensive Less Intensive ΔA1c (%) Favours More Intensive Favours Less Intensive HR (95% CI) All-cause mortality ACCORD 257 (1.41) 203 (1.14) 1.01 1.22 (1.01 1.46) ADVANCE 498 (1.86) 533 (1.99) 0.72 0.93 (0.83 1.06) UKPDS 123 (0.13) 53 (0.25) 0.66 0.96 (0.70 1.33) VADT 102 (2.22) 95 (2.06) 1.16 1.07 (0.81 1.42) Overall 980 884 0.88 1.04 (0.90 1.20) (Q=5.71, p=0.13, I 2 =47.5%) 0.5 1.0 2.0 HR (95% CI) Turnbull FM, et al. Diabetologia 2009; 55:2288-2298 2298

Sub-group Analysis for Major CVD Events: History of Macrovascular Disease Pre-specified Subgroups Number of Patients/Events More Intensive Less Intensive Favours More Intensive Favours Less Intensive HR (95% CI) p value for Test of Difference History of macrovascular disease Present 3,974/555 3,947/544 1.00 (0.89 1.13) 0.04 Absent 10,346/639 8,782/632 0.84 (0.75 0.94) 0.5 1.0 2.0 HR (95% CI) p=0.04 Turnbull FM, et al. Diabetologia 2009; 55:2288-2298 2298

Comparison of ACCORD, ADVANCE, VADT Characteristic ACCORD ADVANCE VADT N 10,251 11,140 1,791 Mean Age 62 66 60.4 Duration of T2DM 10 yr 8 yr 11.5 yr History of CVD 35% 32% 40% BMI 32 28 31 Baseline A1C 8.3% 7.5% 9.4% Study Duration 3.4 5.0 6.0 Target A1c <6% vs 7 8% 7 <6.5% vs Usual <6% vs 8 9% 8 Achieved A1c 6.4% and 7.5% 6.4% and 7.0% 6.9% and 8.4% ACCORD Study Group. N Engl J Med.. 2008;358:2545-59. 59. ADVANCE Collaborative Group. N Engl J Med 358:2560-72, 2008. Duckworth W for VADT. N Engl J Med 2009;360:129 :129-39

Glucose Paradox Glucose levels & hyperglycemic states are closely linked to increased CVD risk Definitive evidence that improving glucose control decreases major CVD events remains elusive Possible reasons: Intervention too late Studies too short, too small A1c difference too small Post prandial hyperglycemia Adverse CV effects (e.g. from hypoglycemia) Adverse effects of T2D drugs?? Mechanism specific? Excellent control of other risk factors

Blood Pressure, Lipid and Aspirin Therapy Study SBP mmhg LDL-C mg/dl (mmol/l) On Statins, % On Aspirin, % ACCORD 127/67 91 (2.35) 88 76 ADVANCE 136/74 102 (2.63) 47 62 VADT 127/69 75 (1.94) 84 93 SBP = systolic blood pressure; LDL-C C = LDL-cholesterol ADVANCE Collaborative Group. N Engl J Med 2008;358:2560 72 ACCORD Study Group. N Engl J Med 2008;358:2545 59 59 VADT Study Group. N Engl J Med 2009;360:129 39 39

Achievement of Goals in US Diabetes Care 1999-2010 A1C Survey Participants, % p=0.009 N Engl J Med 2013;368:1613-24

Achievement of Goals in US Diabetes Care 1999-2010 Blood Pressure Survey Participants, % p=0.08 N Engl J Med 2013;368:1613-24

Achievement of Goals in US Diabetes Care 1999-2010 LDL-Cholesterol Survey Participants, % p<0.001 N Engl J Med 2013;368:1613-24

Achievement of Goals in US Diabetes Care 1999-2010 Smoking Status Survey Participants, % p=0.96 *self-report or cotinine >10 ng/ml N Engl J Med 2013;368:1613-24

Prevalence of Meeting A1C, BP, and LDL Goals Among People With Diabetes 1988 2010 Percent % Diabetes Care Publish Ahead of Print February 15, 2013

Age-adjusted Death Rates for CVD USA, 1958 2005

Deaths due to diseases of the heart (United States: 1900 2009) 1,000 800 Deaths in Thousands 600 400 200 0 1900 1910 1920 1930 1940 1950 1960 1970 1980 1990 2000 2009 Years Go et al. Circulation. 2013;127:e6-e245

1,200 1,000 800 Deaths in Thousands 600 400 200 0 1900 1910 1920 1930 1940 1950 1960 1970 1980 1990 2000 2005 2009 Go et al. Circulation. 2013;127:e6-e245

550 530 510 490 Deaths in Thousands 470 450 430 410 390 370 350 1979 1980 1985 1990 1995 2000 2005 2009 Males Females Go et al. Circulation. 2013;127:e6-e245

U.S. age standardized death rates* from cardiovascular diseases, 2000 2009 400 350 Deaths per 100,000 300 250 200 150 100 342.9 186.8 328.3 320.4 177.1 170.8 309.1 162.9 289.3 280.1 150.2 144.4 263.6 134.9 252.4 245.9 126.0 122.7 237.1 116.1 50 93.7 92.0 91.9 91.3 87.9 87.9 83.9 82.9 81.3 81.0 60.9 57.7 56.2 53.5 50.0 46.6 43.6 42.2 40.7 38.9 0 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 Total CVD Stroke CHD Other CVD** Go et al. Circulation. 2013;127:e6-e245

Decline in Age Standardized Mortality Rates from 1997 to 2006 Comparison of a Diabetic Cohort with the UK general population Men Women Diabetic Nondiabetic The study included a cohort of 48,556 subjects with type 2 diabetes first diagnosed between 1996 and 2006, drawn from 197 family practices in the United Kingdom General Practice Research Database (UKGPRD). There were 6,630 deaths observed Gulliford & Charlton. Am J Epidemiol 2009;169:455 461

Age-adjusted All-Cause Mortality Rates according to Diabetes Status, 1997 2004 Gregg et al. Diabetes Care 35:1252 1257, 2012

Age-adjusted CVD Mortality Rates according to Diabetes Status, 1997 2004 Gregg et al. Diabetes Care 35:1252 1257, 2012

Blood Pressure in Diabetes

ADA 2012

ADA 2013

..there is no clear evidence of benefits in general from initiating antihypertensive drug treatment at SBP levels 140 mmhg (high normal BP), nor there is evidence of benefits from aiming at targets 130 mmhg. This is due to the lack of suitable studies correctly investigating these issues. 2013 ESH/ESC Guidelines for the Management of Arterial Hypertension, European Heart Journal doi:10.1093/eurheartj/eht151

Ischemic CHD Mortality versus Usual BP Stratified by Age Prospective Studies Collaboration. Lancet. 2002;360:1903.

Clinical Trials of BP Lowering in Diabetic Patients: Mean Achieved Systolic (SBP) Trial N Mean SBP less intense Mean SBP more intense CVD Risk Reduction SHEP 583 155 146 22-56% Syst-EUR 492 162 153 62-69% HOT 1,501 148 144 30-67% UKPDS 1,148 154 144 32-44% ABCD 470 138 132 No CVD ADVANCE 11,140 140 135 14% mortality ACCORD 4,733 133 119 No CVD

ACCORD Blood Pressure Study Systolic Pressures (Mean + 95% CI) Mean # Meds Intensive: 3.2 3.4 3.5 3.4 Standard: 1.9 2.1 2.2 2.3 140 SBP (mm Hg) 130 120 Average : 133.5 Standard vs. 119.3 Intensive, Delta = 14.2 110 N = 4382 4050 2391 359 0 1 2 3 4 5 6 7 8 Years Post-Randomization Intensive Standard ACCORD Study Group. N Engl J Med 2010; 362:1575-1585 1585

ACCORD Blood Primary Outcome Pressure Study Primary Outcome Nonfatal MI, (Nonfatal Stroke MI, or CVD Nonfatal Death Stroke, or CVD Death) 20 Patients with Events (%) 15 10 5 Primary Outcome Nonfatal MI, Nonfatal Stroke or CVD Death HR = 0.88 95% CI (0.73-1.06) HR = 0.88 95% CI (0.73-1.06) 0 0 1 2 3 4 5 6 7 8 Years Post-Randomization ACCORD Study Group. N Engl J Med 2010; 362:1575-1585 1585

ACCORD Study Group. N Engl J Med 2010; 362:1575-1585 1585 ACCORD Blood Pressure Study Stroke Outcomes 20 Nonfatal Stroke 20 Total Stroke Patients with Events (%) 15 10 5 HR = 0.63 95% CI (0.41-0.96) Patients with Events (%) 15 10 5 HR = 0.59 95% CI (0.39-0.89) 0 0 0 1 2 3 4 5 6 7 8 Years Post-Randomization 0 1 2 3 4 5 6 7 8 Years Post-Randomization

Effects of intensive blood pressure reduction on myocardial infarction and stroke in diabetes. Myocardial Infarction Journal of Hypertension.2011; 29:1253 1269. 7

Effects of intensive blood pressure reduction on myocardial infarction and stroke in diabetes. Stroke Journal of Hypertension.2011; 29:1253 1269. 7

Intensive versus standard blood pressure control and all-cause mortality Bangalore, S. et al. Circulation 2011;123:2799-2810

Intensive versus standard blood pressure control and stroke Bangalore, S. et al. Circulation 2011;123:2799-2810

2013 ESH/ESC Guidelines for the Management of Arterial Hypertension European Heart Journal doi:10.1093/eurheartj/eht151

Lipids in Diabetes

ADA/ACC Consensus Statement Treatment Goals in Patients With Cardiometabolic Risk and Lipoprotein Abnormalities Highest-risk patient Known CVD Diabetes plus 1 additional major CVD risk factor* High-risk patients No diabetes or known CVD but 2 major CVD risk factors* Diabetes but no other major CVD risk factors* LDL-C (mg/dl) Non HDL-C (mg/dl) Apo B (mg/dl) <70 <100 <80 <100 <130 <90 *Major risk factors beyond dyslipidemia include smoking, hypertension, and family history or premature CHD. ACC=American College of Cardiology; ADA=American Diabetes Association; Apo B=apolipoprotein B; CHD=coronary heart disease; CVD=cardiovascular disease; HDL-C=high-density lipoprotein cholesterol; LDL-C=low-density lipoprotein cholesterol. Brunzell JD et al. Diabetes Care. 2008;31:811-822.

Lancet 2008; 371: 117 125

Lancet 2008;371:117 25

Lancet 2012; 380: 581 590

Lancet 2012; 380: 581 90

Vascular deaths avoided (per 1000) by 5-year risk & LDL cholesterol reduction Lancet 2012; 380: 581 90

Major vascular events avoided (per 1000) by 5-year risk & LDL cholesterol reduction Lancet 2012; 380: 581 90

Plasma Lipid Levels During Trial Total Cholesterol Placebo Fenofibrate LDL Cholesterol HDL Cholesterol Triglycerides ACCORD Study Group. N Engl J Med 2010; 362:1563-1574 1574

Aspirin Therapy in Diabetes

Anti-Platelet Therapy Consider aspirin therapy (75-162 mg/day) as a primary prevention strategy in T1D or T2D at increased CVD risk (>10% over 10 yrs), including most men >50 years old and women >60 years old, with additional risk factors (family history of CVD, hypertension, smoking, dyslipidemia, or albuminuria) Use aspirin therapy (75 162 mg/day) as a secondary prevention strategy in those with diabetes with a history of CVD. For patients with CVD and aspirin allergy, clopidogrel (75 mg/day) should be used Combination therapy with aspirin (75 162 mg/day) and clopidogrel (75 mg/day) is reasonable for up to 1 year after an acute coronary episode American Diabetes Association. Diabetes Care. 2013; 36 (suppl 1):S11 :S11-S66S66

Aspirin for Primary Prevention serious vascular events dropped from 0 57% to 0 51% 0 per year by the use of aspirin risk of major bleeds increased from 0 07% 0 07% to 0 10% 0 per year by the use of aspirin. Antithrombotic Trialists (ATT) Collaboration; Lancet 2009; 373: 1849 1860 1860

Serious Vascular Events Antithrombotic Trialists (ATT) Collaboration; Lancet 2009; 373: 1849 1860 1860

Microvascular Outcomes in T2D

Microvascular Outcomes in T2D Trials Nephropathy Retinopathy Neuropathy VADT ACCORD ADVANCE (albuminuria) (albuminuria) (albuminuria) +/-

Effects of Intensive vs Standard Therapy for Glycemia on Microvascular End Points in ACCORD, Pretransition and Over 5 years (selected outcomes) End point Pretransition, HR (95% CI) Total follow-up, HR (95% CI) Microalbuminuria 0.79 (0.69 0.90) 0.90) p=0.0005 0.85 (0.77 0.94) 0.94) p=0.0012 Cataract surgery 0.90 (0.79 1.02) p=0.105 0.89 (0.80 0.99) 0.99) p=0.0265 3-line change in visual acuity 0.84 (0.73 0.97) 0.97) p=0.0163 0.94 (0.89 1.00) p=0.0467 Loss of ankle jerk during Jendrassik maneuver 0.94 (0.87 1.01) p=0.10 0.90 (0.84 0.97) 0.97) p=0.005 Loss of pressure sensation 0.88 (0.77 1.00) p=0.0451 0.85 (0.75 0.95) 0.95) p=0.0043 Lancet 2010; 376:419-430 430

ACCORD Eye Study N Engl J Med 2010;363:233-44

Intensive Glucose Control and Renal End Points in T2D Meta-analysis analysis Coca et al. Arch Intern Med 2012; 172:761-769

Intensive Glucose Control and Renal End Points in T2D Meta-analysis 7 RCTs of intensive vs. conventional glucose control (ACCORD, ADVANCE, Kumamoto, UKPDS 33, UKPDS 34, VADT, VA-Feasibility) Median follow-up 2 to 11 years Mean duration of DM 6.5 to 12 yrs (except UKPDS) Outcomes Microalbuminuria, Macroalbuminuria Doubling of Serum Creatinine, ESRD, Renal Death Coca et al. Arch Intern Med 2012; 172:761-769

Pooled risk ratios for renal endpoints Event Risk Ratio (95% CI) Microalbuminuria 0.86 (0.76 0.96) Macroalbuminuria 0.74 (0.65 0.85) Cr doubling 1.06 (0.92 1.22) ESRD 0.69 (0.46 1.05) Renal death 0.99 (0.55 1.79) Coca et al. Arch Intern Med (2012); 172: 761-769

American Journal of Kidney Diseases 2012; 60:747-769

New onset microalbuminuria New onset macroalbuminuria Doubling of serum creatinine

All cause mortality Cardio vascular mortality End stage renal disease

Conclusions Reducing the complications of type 2 diabetes requires attention to multiple risk factors glycemia, blood pressure, lipids, smoking cessation.