T2DM and cardiovascular risk Richard Hobbs, Professor and Head - PowerPoint PPT Presentation

T2DM and cardiovascular risk Richard Hobbs, Professor and Head Nuffield Department of Primary Care Health Sciences University of Oxford, United Kingdom

Competing interests Speaker or congress sponsorship disclosures in past 5 years: Amgen, Bayer, Boehringer Ingelheim, Daichi Sankyo, Merck, Novartis, Pfizer, Roche, Takeda

Projected increases in Diabetes Mellitus in Asia, US and Europe (1995-2025) Asian countries US and Europe 140 50 1995 1995 45 120 Population (millions) 2025 40 2025 Population (millions) 100 35 30 80 25 60 20 15 40 10 20 5 0 0 20-44 45-64 65+ 20-44 45-64 65+ Age group (years) World Health Organisation File reference 1999

Diabetes and obesity trends in the USA from 1990 − 1998 7 77 Weight DM(%) 76 6.5 75 6 Weight (kg) DM (%) 74 5.5 73 5 72 4.5 71 70 4 90 91 92 93 94 95 96 97 98 Year Mokdad AH et al. Diab Care 2000;23:1278-1283.

Prevalence of overweight and obesity in UK children and adolescents Prevalence (%) Overweight (BMI>85th centile) 35 Obese (BMI>95th centile) 30 25 20 15 10 5 0 6 7 8 9 10 11 12 13 14 15 Age (years) Adapted from Reilly & Dorosty . Lancet 1999; 354: 1874-1875

Type 2 diabetes is increasingly prevalent • Globally, 387 million people • At least 68% of people >65 years are living with diabetes 1 with diabetes die of heart disease 2 Mortality risk associated with diabetes (n=820,900) 3 3 Hazard ratio (95% CI) (diabetes vs no diabetes) 2 1 This will rise to 592 0 million by 2035 1 CV death All-cause mortality 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;364:829-41

Diabetes is associated with significant loss of life years Men Women 7 7 Non-vascular deaths 6 6 Vascular deaths 5 5 Years of life lost 4 4 3 3 2 2 1 1 0 0 0 40 50 60 70 80 90 0 40 50 60 70 80 90 Age (years) Age (years) On average, a 50-year-old individual with diabetes and no history of vascular . disease will die 6 years earlier compared to someone without diabetes Seshasai et al. N Engl J Med 2011;364:829-41

Is diabetes a CVD risk equivalent?

Evidence that diabetes confers a SIMILAR risk of CV events to prior CHD

Finnish East West Study Fatal & nonfatal MI in subjects with and without Type 2 DM 50 Incidence (%) 45 40 35 30 Non-DM 25 20 Type 2 DM 15 10 5 0 No prior MI Prior MI 7-year incidence of fatal and nonfatal MI in 1373 nondiabetic and 1059 diabetic subjects ( p <0.001) Haffner et al. NEJM 1998;339:229-34.

Diabetes and long-term survival following acute MI: Comparability of risk with prior MI NIH-ONSET STUDY 1.0 0.8 Proportion alive 0.6 Following Acute MI 0.4 No diabetes No diabetes with prior MI Non-diabetics = 1525 Diabetes 0.2 Diabetics = 396 Diabetes with prior MI 0.0 0 1 2 3 4 5 6 Mukamal KJ et al. Diabetes Care 2001

Diabetics at High Risk of Cardiovascular Mortality in ACS: OASIS Registry OASIS = Organization to Assess Strategies for Ischemic Syndromes Diabetes + CVD n=8013 0,20 0,15 No diabetes + CVD Event Rate Diabetes + no CVD 0,10 No diabetes + no CVD 0,05 0,00 3 6 9 12 15 18 21 24 Months No diabetes/CVD(+) RR=1.71 (1.41, 2.06) Diabetes/CVD(+) RR=2.85 (2.30, 3.53) Diabetes/CVD(-) RR=1.71 (1.25, 2.33) No diabetes/CVD(-) RR=1.00 Adapted from Malmberg K et al. Circulation. 2000;102:1014

HOPE: CHD risk is similar in people with diabetes and prior CHD No. patients Incidence of composite outcome in placebo group (%) Overall 9297 17.8 CVD 8162 18.7 No CVD 1135 10.2 Diabetes 3577 19.8 No diabetes 5720 16.5 Composite outcome: MI, stroke, or death from cardiovascular causes Yusuf et al. N Engl J Med 2000;342:145

Evidence that diabetes confers a LOWER risk of CV events than prior CHD

Lower risk of CV events with diabetes vs prior CHD Kaplan-Meier survival curve: time to hospital admission for MI Evans et al. BMJ 2002;324:1357

MRFIT: Lower risk of CHD death with diabetes vs prior CHD Kaplan-Meier curves for post-trial total mortality Eberly et al. Diabetes Care 2003;26:848

Lower risk of CHD death with diabetes versus prior CHD Study/ Follow-up RR CHD death* Patients Diabetes CHD Both Nurses’ Health 20 yrs 8.7 10.6 25.8 Study US male 5 yrs 3.3 5.6 12.0 physicians *vs patients without diabetes or CHD Hu et al. Arch Intern Med 2001;161:1717 Lotufo et al. Arch Intern Med 2001;161:242

HPS: % of Patients in HPS Placebo Group with Major Vascular Events* by Prior Disease 40 Percent developing 1 st major vascular event 30 20 10 0 DM Alone CHD Alone CHD + DM PRIOR DISEASE * CHD, Stroke, revascularization Adapted from Collins et al. Lancet. 2003 Jun 14;361(9374):2005

Why the discrepancies in reported risk?

Influence of additional CVD risk factors with diabetes

UKPDS: Order of Importance for Prediction of CHD (Baseline Epidemiologic Data) Variable Variable P-value P-value 1. LDL-C 1. LDL-C <0.0001 <0.0001 2. HDL-C 2. HDL-C 0.0001 0.0001 3. HbA1c 3. HbA1c 0.0022 0.0022 4. Systolic BP 4. Systolic BP 0.0065 0.0065 5. Smoking 5. Smoking 0.056 0.056 N=2693 type 2 diabetes patients UKPDS: United Kingdom Prospective Diabetes Study Modified from Turner RC, et al. BMJ. 1998;316:823-28

CHD rates vary in people with diabetes with risk factors 10-year cumulative incidence of CHD (%) DM, diabetes; ND, no diabetes; Prev, previous Howard et al. Diabetes Care 2006; 29:391-397

Age-adjusted CHD prevalence & NCEP metabolic syndrome (MS) status NHANES population aged 50+ 20% 17,5% Overall CHD 15% 13,9% Prevalence 11.7% 11.7% 10% 8,7% 5% 0% No MS MS Diabetes % of pop = 54.2% 28.7% 17.1% Alexander C, et al. Diabetes 52: 1210-1214, 2003

Age-adjusted CHD prevalence & NCEP metabolic syndrome status in diabetes NHANES population aged 50+ 25% Overall CHD 19,2% Prevalence 11.7% 20% 15% 10% 7,5% 5% 0% DM/no MS DM plus MS % of pop = 2.3% 14.8% Alexander C, et al. Diabetes 52: 1210-1214, 2003

Effect of length of time with diabetes and CVD risk

Duration of diabetes increases risk of CHD events Risk of events for each 10-yr increase in diabetes duration Outcome Crude Age and sex Multivariable adjusted adjusted HR 95% HR 95% HR 95% CI CI CI CVD death 1.50† 1.02- 1.30 0.89- 1.44 0.97- 2.21 1.90 2.15 CHD death 1.83‡ 1.18- 1.59 † 1.04- 1.86 ‡ 1.17- 2.83 2.42 2.93 †P < 0.05; ‡ P < 0.01 Fox et al. Diabetes Care 2004;27:704

ICES: Absolute Risk of AMI by Gender and Diabetes Status 3.0 No. events per 100 2.5 person- years 2.0 1.5 1.0 0.5 0.0 20-30 31-40 41-45 46-50 51-55 56-60 61-65 66-70 71-75 76-80 81-85 Age group Diabetes: Men Women No diabetes: Men Women All lines fitted according to a polynomial equation; R 2 = 0.99–1.00 for each Booth GL, et al. Lancet. 2006;367:29–36

ICES: Age and Risk of CVD Events by DM and MI Status 24 No. events per 100 person- 20 16 years 12 8 4 0 31-40 41-45 46-50 51-55 56-60 61-65 66-70 71-75 76-80 Age group Diabetes: MI No MI No diabetes: MI No MI All lines fitted according to a polynomial equation; R 2 = 0.99–1.00 for each Booth GL, et al. Lancet. 2006;367:29 – 36

DM duration and CVD events Men with diabetes without MI Men with MI None Late onset Early onset Without N=3197 N=307 N=107 diabetes Mean duration Mean duration N=368 1.7 years 16 years CVD events (n=534) Age 1.00 1.59 (1.19,2.12) 2.61 (1.73,3.96) 2.35 (1.88,2.95) Adj 1.00 1.53 (1.15,2.06) 2.52 (1.65,3.84) 2.23 (1.76,2.83) Wannamethee SG, Shaper AG, Whincup PH, Lennon L, Sattar N. Arch Intern Med. 2011 Mar 14;171(5):404-10. doi: 10.1001/archinternmed.2011.2

Effect of diabetes on severity of cardiovascular events

High mortality rate in diabetic patients after first MI Study 1-yr mortality rate (%) Diabetes No diabetes Herlitz et al 25 10 P<0.001 (Sweden) FINMONICA Men 44.2 32.6 OR 1.36 Women 36.9 20.2 OR 1.83 Herlitz et al. Cardiology 1992;80:237 Miettinen et al. Diabetes Care 1998;21:69

High mortality rate in diabetic patients after CABG Patients Survival rate (%) 5-yr 10-yr With diabetes 78 50 Without diabetes 88 71 P≤0.05* P ≤0.05* *With diabetes vs without diabetes Thourani et al. Ann Thorac Surg 1999;67:1045

Diabetes Confers a Doubling of Risk for Early MI Mortality Despite Advances in Cardiac Care Early Mortality from Acute MI Diabetes Digoxin 60 Diuretics Total Group 50 Defibrillation 40 Hemodynamic Monitoring 30 Thrombolysis PCI Beta-blockade IIbIIIa Inhibitors 20 Aspirin Clopidrogel Statins 10 0 Pre-CCU Era CCU Era Lytic Era PCI Era (pre-1962) (1962-1984) (1984-2000) (2000-- ) Modified by Richard Nesto from NEJM 1997; 337: 1361

Diabetes and Lifetime Risk for CHD Diabetic Non Diabetic Men Women 67% 0.7 0.7 Adjusted cummulative 0.6 0.6 57% 0.5 0.5 incidence Diabetes confers the highest lifetime risk for CHD 0.4 0.4 of any single risk factor 30% 0.3 0.3 0.2 0.2 16% 0.1 0.1 0 0 50 60 70 80 90 50 60 70 80 90 Attained Age Lloyd Jones et al Circ 2006;113:791

How is diabetes considered in CVD guideline updates?