1. Screening and Prevention of Cardiovascular Disease in Diabetes Nathan D. Wong, PhD, FACC, FAHA Professor and Director Heart Disease Prevention Program Division of Cardiology University of California, Irvine Past President, American Society for Preventive Cardiology

2. Overview Is diabetes really a CHD risk equivalent? Why screen for subclinical cardiovascular disease (CVD) in diabetes? What is the evidence for atherosclerosis screening to improve CVD risk assessment? What is the evidence of benefit of individual and composite risk factor control in preventing CVD in diabetes?

4. Type 2 diabetes is increasingly prevalent Globally, 387 million people are living with diabetes 1 4 At least 68% of people >65 years with diabetes die of heart disease 2 This will rise to 592 million by 2035 1 1. IDF Diabetes Atlas 6th Edition 2014 http://www.idf.org/diabetesatlas; 2. Centers for Disease Control and Prevention 2011; 3. Seshasai et al. N Engl J Med 2011;364:829-41http://www.idf.org/diabetesatlas Mortality risk associated with diabetes (n=820,900) 3

5. Global Distribution of Diabetes, WHO 2011

6. Diabetes and CVD Atherosclerotic complications responsible for –80% of mortality among patients with diabetes –75% of cases due to coronary artery disease (CAD) –Results in >75% of all hospitalizations for diabetic complications 50% of patients with type 2 diabetes have preexisting CAD. (This number may be less now that more younger people are diagnosed with diabetes.) 1/3 of patients presenting with myocardial infarction have undiagnosed diabetes mellitus Lewis GF. Can J Cardiol. 1995;11(suppl C):24C-28C Norhammar A, et.al. Lancet 2002;359;2140-2144

7. Risk of Cardiovascular Events in Patients with Diabetes: Framingham Study Age-adjusted Biennial Rate Age-adjusted Per 1000 Risk Ratio Cardiovascular Event Men Women Men Women Coronary Disease 39 21 1.5** 2.2*** Stroke 15 62.9*** 2.6*** Peripheral Artery Dis. 8 183.4*** 6.4*** Cardiac Failure 23 214.4*** 7.8*** All CVD Events 76 65 2.2*** 3.7*** Subjects 35-64 36-year Follow-up **P<.001,***P<.0001 _________________________________________________________________

8. Haffner SM et al. NEJM 1998;339:229– 234. Patients with DM but no CHD experience a similar rate of MI as patients without DM but with CHD Events*/100 person-years Prior CHD 45 DM No DM No prior CHD 50 40 30 20 10 0 19 20 3.5 *Fatal or non-fatal MI CHD=Coronary heart disease, DM=Diabetes mellitus, MI=Myocardial infarction East-West Study Diabetes Mellitus and Risk of Myocardial Infarction: Is Diabetes a CHD Risk Equivalent in Finnish Men?

10. Is DM really a CHD Risk Equivalent? Meta-Analysis of 38,578 subjects (Bulugahapitiya et al. Diabetic Med 2008) DM without prior MI has a 43% lower risk of developing total CHD events compared to those without DM with prior MI, suggesting DM is not a coronary risk equivalent.

11. Global Risk Assessment in DM: US adults 2003-2006 10-year Total CVD Risk by Gender (Wong ND et al., Diab Vas Dis Res 2012) 32% of men and 48% of women are at calculated low to intermediate risk

12. 2013 Prevention Guidelines ASCVD Risk Estimator

13. ASCVD Risk Estimator For those 20-59 risk estimator provides lifetime risk estimate This is intended to drive discussions of greater adherence to heart-healthy lifestyle Part of risk discussion

14. UKPDS Risk Engine

15. The Detection Gap in CHD “Despite many available risk assessment approaches, a substantial gap remains in the detection of asymptomatic individuals who ultimately develop CHD” “The Framingham and European risk scores… emphasize the classic CHD risk factors…. is only moderately accurate for the prediction of short- and long-term risk of manifesting a major coronary artery event…” Pasternak and Abrams et al. 34 th Bethesda conf. JACC 2003; 41: 1855-1917

16. Criteria required for a good screening test Provides an accurate determination of the likelihood that an asymptomatic person has the condition (accuracy) Reproducible results (reliability) Detect individuals where early intervention is likely to have a beneficial impact Should provide incremental value to risk predicted by office-based risk assessment Redberg and Vogel et al., 34 th Bethesda Conf. JACC 2003; 41: 1855-1917

17. Evolution of CVD Screening Guidelines in DM ACCF/AHA 2010 Guideline: CAC Scoring for CV risk assessment in asymptomatic adults aged 40 and over with diabetes (Class IIa-B)ACCF/AHA 2010 Guideline: CAC Scoring for CV risk assessment in asymptomatic adults aged 40 and over with diabetes (Class IIa-B) ACCF/AHA 2010 Guideline: Stress MPI may be considered for advanced CV risk assessment in asymptomatic adults with diabetes or when previous risk assessment testing suggests a high risk of CHD, such as a CAC score of 400 or greater (Class IIb – Level of Evidence C)ACCF/AHA 2010 Guideline: Stress MPI may be considered for advanced CV risk assessment in asymptomatic adults with diabetes or when previous risk assessment testing suggests a high risk of CHD, such as a CAC score of 400 or greater (Class IIb – Level of Evidence C)

18. Prognostic Significance of CAC in DM Anand et al (Eur Heart J 2006) – 510 asymptomatic type 2 DM pts., mean follow-up 2.3 years, no events in those with CAC=0, CAC significantly improved c- statistic to 0.92 compared to 0.72 for UKPDS and 0.60 for FRS. Raggi et al (JACC 2004) – 10,377 asymptomatic pts (903 with DM), 5-year follow-up. CAC scores more strongly related to event risk in those with vs. without DM. Similar 99% survival rate in those with or without DM who had CAC=0.

19. Multiethnic Study of Atherosclerosis NIH multicenter prospective study of 6,814 subjects aged 45-84, Caucasian, Hispanic, African-American, and Chinese Follow-up now is approximately 10 years Standardized risk factor and follow-up for CVD events Coronary calcium done at baseline (2000- 2002) Exam 1 and repeated in subsets at Exams 2, 3, and 4. Measures of carotid IMT also performed.

20. CHD Risk in DM and MetS Depends on the Extent of Subclinical Disease Present (Malik and Wong et al., Diabetes Care 2011) Coronary Heart Disease Coronary Artery Calcium Score HR 6.2 (p =400 vs. 0 HR 1. 7 (n.s.) for CIMT 4 th quartile vs. 1 st quartile.

21. A Positive MPS in MetS and DM Infrequent Unless Moderate Subclinical Atherosclerosis is Present (Wong ND et al., Diabetes Care 2005; 28: 1445-50 )

22. DIAD Randomized Clinical Trial of Stress MPI Screening (Young, Inzucchi et al. JAMA 2009) Randomized NIH multicenter trial examining whether screening for myocardial ischemia using adenosine- stress MPI in 1123 persons with type 2 DM and no symptoms of CAD. Only 22% were positive for myocardial ischemia with only 6% have moderate or large defects 5-year 2.9% cumulative event rate (0.6% per year), much lower than expected Event rates similar in those screening (2.7%) vs. not screened (3.0%) (p=0.73) (authors note the study only had 20% power to detect a 20% difference between groups)

23. DIAD Study (continued) The authors conclude that screening for inducible ischemia in asymptomatic patients with T2DM cannot be advocated for 4 reasons: The yield of significant inducible ischemia is very low Overall cardiac event rates are low Routine screening does not appear to affect overall outcome Routine screening would be prohibitively expensive The much lower than expected event rates makes the study inconclusive in demonstrating the lack of efficacy of screening for subclinical CVD using MPI

24. Should we be using stress MPI to screen for CVD in all pts with DM? Stress MPI is meant to identify short-term risk due to functional deficit, rather than long-term prognosis such as that identified by a test to quantify atherosclerotic burden such as coronary calcium The radiation and costs are much higher for MPI as compared to coronary calcium, suggesting MPI might be best reserved for those DM at highest risk

26. Study Description The FACTOR-64 study was a randomized clinical trial of 900 patients with type 1 or type 2 diabetes. Patients were recruited from 45 clinics and practices of a single health system (Intermountain Healthcare, Utah) and enrolled at a single-site coordinating center. Patients were randomized 1:1 to CAD screening with CCTA-directed therapy or to Intermountain Healthcare’s systematized guidelines-directed optimal diabetes care.

27. Medical Management Standard optimal diabetes care –Recommended for all controls and CCTA patients with normal coronary artery scans –Targets: HgA1C<7.0%, LDL<100 mg/dL, systolic BP<130 mm Hg Aggressive risk factor reduction care –Recommended for all CCTA patients with at least some documented CAD –Emphasize diet and exercise –Targets: LDL 50 mg/dL, TG<150 mg/dL, HgA1C<6%, systolic BP<120 mm Hg

28. Changes in Critical Quality Indicators for Diabetes Medical Management From Baseline to One Year Scanned Patients Assigned to Standard Versus Aggressive Medical Management

29. Primary Endpoint (Death/MI/Unstable Angina) HR = 0.80 (0.49, 1.32)

30. StrategyComplication Reduction of Complication Blood glucose control▪Heart attack  37% 1 Blood pressure control ▪Cardiovascular disease ▪Heart failure ▪Stroke ▪Diabetes-related deaths  51% 2  56% 3  44% 3  32% 3 Lipid control ▪Coronary heart disease mortality ▪Major coronary heart disease event ▪Any atherosclerotic event ▪Cerebrovascular disease event  35% 4  55% 5  37% 5  53% 4 Treating the ABCs Reduces Diabetic Complications 1 UKPDS Study Group (UKPDS 33). Lancet. 1998;352:837-853. 2 Hansson L, et al. Lancet. 1998;351:1755-1762. 3 UKPDS Study Group (UKPDS 38). BMJ. 1998;317:703-713. 4 Grover SA, et al. Circulation. 2000;102:722-727. 5 Pyŏrälä K, et al. Diabetes Care. 1997;20:614-620.

31. JNC-8 Recommendation for BP Control in Diabetes In patients aged ≥18 years with diabetes, initiate pharmacologic treatment at systolic BP ≥140mmHg or diastolic BP ≥90mmHg and treat to a goal systolic BP <140mmHg and goal diastolic BP <90mmHg. (Expert Opinion–Grade E) For Adults with diabetes aim for the same BP goals as in the general population Treat if BP >140/90; Aim for <140/90

32. Diabetes Mellitus: Effect of an HMG-CoA Reductase Inhibitor Cholesterol Treatment Trialists’ (CTT) Collaborators. Lancet 2008;37:117- 25 Meta-analysis of 18,686 patients with DM randomized to treatment with a HMG-CoA Reductase Inhibitor Statins reduce CV events 21% in diabetics (similar to non-diabetics)

34. D iabetes P revention P rogram: Reduction in Diabetes Incidence

35. Look AHEAD (Action for Health in Diabetes): Trial Halted Early 1, 2. Look AHEAD Research Group. Diabetes Care. 2007;30:1374-1383 and Arch Intern Med. 2010;170:1566–1575; http://www.nih.gov/news/health/oct2012/niddk-19.htm. Intensive lifestyle intervention resulted in 1 –Average 8.6% weight loss –Significant reduction of A1C –Reduction in several CVD risk factors However, trial halted after 11 years of follow-up because there was no significant difference in primary cardiovascular outcome between weight loss, standard care group HR=0.95 (0.80-1.05), p=0.51 NEJM June 24, 2013

36. Look Ahead Trial Risk Factor Differences Diminished differences between groups over time: 1) weight 2) physical fitness, 3) waist circumference 4) HbA1c.

37. PREDIMED STUDY (n=7447): Primary Prevention of High Risk Pts with DM or 3+ Risk Factors Randomized to Mediterranean Diet with Extra Virgin Olive Oil or Nuts vs. AHA Diet

38. Number of events More intensive Less intensive Difference in HbA1c (%) HR (95% CI) Stroke378370-0.880.96 (0.83, 1.10) Myocardial infarction730745-0.880.85 (0.76, 0.94) Hospitalisation for or death from heart failure 459446-0.881.00 (0.86, 1.16) Meta-analysis of intensive glucose control in T2DM: major CV events including heart failure 38 Favours more intensiveFavours less intensive Meta-analysis of 27,049 participants and 2370 major vascular events from: – ADVANCE – UKPDS – ACCORD – VADT HR, hazard ratio; CV, cardiovascular Turnbull FM et al. Diabetologia 2009;52:2288–2298

39. Recent trials of newer glucose-lowering agents have been neutral on the primary CV outcome 39 SAVOR-TIMI 53 EXAMINE HR: 1.0 (95% CI: 0.89, 1.12) HR: 0.96 (95% CI: UL ≤1.16) TECOS HR: 0.98 (95% CI: 0.88, 1.09) EMPA-REG OUTCOME ® ELIXA HR: 1.02 (95% CI: 0.89, 1.17) Empagliflozin DPP-4 inhibitors* Lixisenatide CV, cardiovascular; HR, hazard ratio; DPP-4, dipeptidyl peptidase-4 *Saxagliptin, alogliptin, sitagliptin Adapted from Johansen OE. World J Diabetes 2015;6:1092-96 201320142015

40. Empagliflozin Empagliflozin is a highly selective inhibitor of the sodium glucose cotransporter 2 (SGLT2) in the kidney Glucose reduction occurs by reducing renal glucose reabsorption and thus increasing urinary glucose excretion In patients with type 2 diabetes, empagliflozin leads to 1 : –Significant reductions in HbA1c –Weight loss –Reductions in blood pressure without increases in heart rate 40 1. Liakos A et al. Diabetes Obes Metab 2014;16:984-93

41. EMPA-REG OUTCOME ® Randomised, double-blind, placebo-controlled CV outcomes trial Objective To examine the long-term effects of empagliflozin versus placebo, in addition to standard of care, on CV morbidity and mortality in patients with type 2 diabetes and high risk of CV events 41 CV, cardiovascular

42. EMPA-REG Primary outcome: 3-point MACE 42 HR 0.86 (95.02% CI 0.74, 0.99) p=0.0382* Cumulative incidence function. MACE, Major Adverse Cardiovascular Event; HR, hazard ratio. * Two-sided tests for superiority were conducted (statistical significance was indicated if p≤0.0498)

43. CVD Risk Factor Control in DM Remains Poor and We Can do Better! 2009-2010 US adults with Type 2 DM from NHANES 56% HbA1c <7% 53% BP <130/80 mmHg 54% LDL-C <100 mg/dl 10% with BMI <25 kg/m 2 25% at goal for HbA1c, BP, and LDL-C 4% at goal for all four measures Wong ND et al. Diab Vas Dis Res 2013

44. Benefit of Comprehensive, Intensive Management: STENO 2 Study Treatment Goals: –Intensive TLC –HgbA1c <6.5% –Cholesterol <175 –Triglycerides <150 –BP <130/80 0 0 10 20 40 50 60 Conventional Therapy Intensive Therapy 30 Months of Follow Up Primary End Point=CV events (%) 1224364860728496 n =80 Gaede, P. et al, NEJM 2003;348:390-393

45. Projected Percent of CHD Events Over 10 Years Prevented in US Adults with T2DM, from Statistical Projections of Individual and Composite Risk Factor Control (Wong ND, et al., Am J Cardiol 2014) Goal(ADA Guidelines)NominalAggressive HbA1C*7%7%1% AR2% AR Systolic Blood Pressure130mmHg10% RR20% RR Total Cholesterol170mg/dl (4.4mmol/L)25% RR50% RR HDL-Cholesterol40mg/dl(M), 50 mg/dl(F)10% relative increase 20% relative increase RR-Relative Reduction; AR- Absolute Reduction; HbA1C levels were not allowed to be reduced further than 6.5%

46. Cardiovascular Risk Factor Targets and Cardiovascular Disease Event Risk in Diabetes Mellitus, a Pooling Project of Atherosclerosis Risk in Communities Study, Multiethnic Study of Atherosclerosis, and Jackson Heart Study Wong ND, Zhao Y, Patel R, Patao C, Malik S, Bertoni AG, Correa A, Folsom AR, Kachroo S, Mukherjee J, Taylor H, Selvin E. Diabetes Care 2016 (in press) Examined composite goal attainment for blood pressure (BP), low density lipoprotein-cholesterol (LDL-C) and glycated hemoglobin (HbA1c) with CHD and CVD events in US adults with DM. 2,018 adults aged 28-86 years (43% male, 55% African-American) with DM but without known CVD from the Atherosclerosis Risk in Communities, Multiethnic Study of Atherosclerosis and Jackson Heart Studies. Cox regression examined coronary heart disease (CHD) and CVD events over a mean 11-year follow-up in those at BP, LDL-C and HbA1c targets and by number of controlled risk factors. 41.8%, 32.1% and 41.9% were at target for BP, LDL-C and HbA1c, respectively 41.1%, 26.5% and 7.2% were at target for any 1, 2, or 3 factors, respectively Being at BP, LDL-C or HbA1c targets related to 17%, 33% and 37% lower CVD risks and 17%, 41% and 36% lower CHD risks, respectively. Those at 1, 2, or 3 risk factors at target (vs. none) had incrementally lower adjusted risks of CVD events of 36%, 52%, and 62%, respectively, and CHD events of 41%, 56%, and 60%, respectively

49. Adjusted Hazard Ratios (95% Confidence Interval) for CVD and CHD Events Among Subjects with DM by Status of Individual and Composite Risk Factor Targets (Wong ND et al. Diabetes Care 2016, in press) Risk factor comparison Incident CVD EventsIncident CHD Events HR (95%CI), Unadjusted HR (95%CI), Adjusted for Covariates HR (95%CI), Adjusted for Propensity Score HR (95%CI), Unadjusted HR (95%CI), Adjusted for Covariates HR (95%CI), Adjusted for Propensity Score Individual risk factor controlled BP < 130/80 mmHg vs. BP ≥ 130/80 mmHg 0.81 (0.69-0.95) *0.83 (0.70-0.98)*0.81 (0.68-0.96)*0.86 (0.70-1.05)0.83 (0.67-1.02) 0.78 (0.63- 0.97)* LDL-C < 2.6 mmol/l [100 mg/dl] vs. LDL-C ≥ 2.6 mmol/l [100 mg/dl] 0.71 (0.58-0.86) ‡ 0.67 (0.54-0.82) § 0.71 (0.58-0.87) ‡ 0.64 (0.49-0.83) ‡ 0.59 (0.45-0.77) ‡ 0.62 (0.48-0.81) ‡ HbA1c < 53.0 mmol/mol [7%] vs. HbA1c ≥ 53.0 mmol/mol [7%] 0.64 (0.54-0.76) § 0.63 (0.53-0.76) § 0.70 (0.58-0.84) § 0.68 (0.54-0.84) ‡ 0.64 (0.51-0.81) ‡ 0.74 (0.59-0.93) * Number of risk factors at target Any one (BP, LDL-C, HbA1c) at Target vs. none at Target 0.67 (0.56-0.80) § 0.64 (0.53-0.77) § 0.65 (0.54-0.78) § 0.65 (0.52-0.82) ‡ 0.59 (0.47-0.75) § 0.60 (0.47-0.76) § Any two (BP, LDL-C, HbA1c) at Target vs. none at Target 0.52 (0.41-0.64) § 0.48 (0.38-0.61) § 0.47 (0.38-0.60) § 0.51 (0.38-0.68) § 0.44 (0.33-0.59) § 0.42 (0.32-0.57) § All three (BP, LDL-C, HbA1c) at Target vs. none at Target 0.46 (0.30-0.69) ‡ 0.38 (0.25-0.58) § 0.41 (0.27-0.62) § 0.53 (0.32-0.88) * 0.40 (0.24-0.67) ‡ 0.41 (0.25-0.70) ‡ Covariates include: age, gender, ethnicity, smoking status, HDL-C, BMI, family history of pre-mature CVD, hypertension medication, anti-diabetic medication and lipid-lowering medication (also include LDL-C and HbA1c for BP analysis; systolic/diastolic BP and HbA1c for LDL-C analysis; LDL-C and systolic/diastolic BP for HbA1c analysis). *p <.05, † p <.01, ‡ p <.001, § p <.0001. Those at targets for HbA1c, BP, and LDL-C had 62% lower CVD events and 60% lower CHD events compared to those at none of these targets

50. Up to 80% of heart disease, stroke and type 2 diabetes and over a third of the most common cancers could be prevented by eliminating obesity, unhealthy diets and physical inactivity Call for commitments at the global and national level to address these risk factors including: –Control food supply, food information and marketing and promotion of energy-dense, nutrient-poor foods that are high in saturated, trans-fat, salt or refined sugars Nutrition, physical activity and NCD prevention

51. Conclusions (1) 1)Most persons with DM are still suboptimally treated for CVD risk factors and will die of CVD- related consequences. 2)But there is great heterogeneity in risk for CVD events in those with DM warranting the need for better efforts at CVD risk assessment. 3)Global risk assessment (e.g., ACC/AHA Pooled Cohort, Framingham, UKPDS risk engine or similar) could be used to identify those most likely to benefit from therapy or screen out those at low risk unlikely to benefit from further screening

52. Conclusions (2) 4) Screening for subclinical atherosclerosis may result in improved risk factors and motivate improvements in lifestyle modification and adherence to preventive therapies, although definitive data on hard outcomes are limited. 5) Evidence exists for a benefit from BP, lipid, and glycemic control, in particular when in combination, to significantly reduce CVD events in persons with diabetes

53. American Society for Preventive Cardiology www.aspconline.org Thank you for your attention www.heart.uci.edu