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)

File reference

World Health Organisation 1999

20 40 60 80 100 120 140

20-44 45-64 65+ Population (millions)

1995 2025

Asian countries

Age group (years)

5 10 15 20 25 30 35 40 45 50

20-44 45-64 65+ Population (millions)

1995 2025

US and Europe

Diabetes and obesity trends in the USA from 1990−1998

77 70 90 98 7 6.5 6 5.5 5 4.5 4 97 96 95 94 93 92 91 71 72 73 74 75 76

Year Weight (kg) DM (%)

Weight DM(%)

Mokdad AH et al. Diab Care 2000;23:1278-1283.

Prevalence of overweight and obesity in UK children and adolescents

5 10 15 20 25 30 35 6 7 8 9 10 11 12 13 14 15

Overweight (BMI>85th centile) Obese (BMI>95th centile)

Adapted from Reilly & Dorosty . Lancet 1999; 354: 1874-1875

Prevalence (%) Age (years)

1 2 3 CV death All-cause mortality Hazard ratio (95% CI) (diabetes vs no diabetes)

Type 2 diabetes is increasingly prevalent

• Globally, 387 million people

are living with diabetes1

• 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

• At least 68% of people >65 years

with diabetes die of heart disease2

This will rise to 592 million by 20351 Mortality risk associated with diabetes (n=820,900)3

Diabetes is associated with significant loss of life years

Seshasai et al. N Engl J Med 2011;364:829-41

.

7 6 5 4 3 2 1 40 50 60 70 80 90 Age (years) Years of life lost

Men

7 6 5 4 3 2 1 40 50 60 70 80 90 Age (years)

Women

Non-vascular deaths Vascular deaths

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

Is diabetes a CVD risk equivalent?

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

Haffner et al. NEJM 1998;339:229-34.

Fatal & nonfatal MI in subjects with and without Type 2 DM

5 10 15 20 25 30 35 40 45 50

No prior MI Prior MI

Non-DM Type 2 DM 7-year incidence of fatal and nonfatal MI in 1373 nondiabetic and 1059 diabetic subjects (p<0.001)

Incidence (%)

Finnish East West Study

Diabetes and long-term survival following acute MI: Comparability of risk with prior MI

Mukamal KJ et al. Diabetes Care 2001 Proportion alive Following Acute MI

Non-diabetics = 1525 Diabetics = 396

No diabetes No diabetes with prior MI Diabetes Diabetes with prior MI

6 5 4 3 2 1 0.0 0.2 0.4 0.6 0.8 1.0

NIH-ONSET STUDY

Diabetics at High Risk of Cardiovascular Mortality in ACS: OASIS Registry

0,00 0,05 0,10 0,15 0,20

Event Rate

3 6 9 12 15 18 21 24

Diabetes + CVD No diabetes/CVD(+) RR=1.71 (1.41, 2.06) No diabetes/CVD(-) RR=1.00 Diabetes/CVD(+) RR=2.85 (2.30, 3.53) Diabetes/CVD(-) RR=1.71 (1.25, 2.33)

Months

No diabetes + CVD Diabetes + no CVD No diabetes + no CVD

Adapted from Malmberg K et al. Circulation. 2000;102:1014

n=8013

OASIS = Organization to Assess Strategies for Ischemic Syndromes

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/ Patients Follow-up RR CHD death* Diabetes CHD Both Nurses’ Health Study 20 yrs 8.7 10.6 25.8 US male physicians 5 yrs 3.3 5.6 12.0

*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

* CHD, Stroke, revascularization

10 20 30 40 DM Alone CHD Alone CHD + DM

PRIOR DISEASE Percent developing 1st major vascular event

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

• f CHD (Baseline Epidemiologic Data)

Variable P-value

• 1. LDL-C

<0.0001

• 2. HDL-C

0.0001

• 3. HbA1c

0.0022

• 4. Systolic BP

0.0065

• 5. Smoking

0.056 Variable P-value

• 1. LDL-C

<0.0001

• 2. HDL-C

0.0001

• 3. HbA1c

0.0022

• 4. Systolic BP

0.0065

• 5. Smoking

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

DM, diabetes; ND, no diabetes; Prev, previous

10-year cumulative incidence of CHD (%)

Howard et al. Diabetes Care 2006; 29:391-397

Age-adjusted CHD prevalence & NCEP metabolic syndrome (MS) status

NHANES population aged 50+

8,7% 13,9% 17,5% 0% 5% 10% 15% 20% No MS MS Diabetes

Overall CHD Prevalence 11.7%

% of pop = 54.2% 28.7% 17.1%

11.7%

Alexander C, et al. Diabetes 52: 1210-1214, 2003

Age-adjusted CHD prevalence & NCEP metabolic syndrome status in diabetes

NHANES population aged 50+

Overall CHD Prevalence 11.7%

Alexander C, et al. Diabetes 52: 1210-1214, 2003

7,5% 19,2%

0% 5% 10% 15% 20% 25% DM/no MS DM plus MS

% of pop = 2.3% 14.8%

Effect of length of time with diabetes and CVD risk

Duration of diabetes increases risk of CHD events

Outcome Crude Age and sex adjusted Multivariable adjusted HR 95% CI HR 95% CI HR 95% CI CVD death

1.50† 1.02- 2.21 1.30 0.89- 1.90 1.44 0.97- 2.15

CHD death

1.83‡ 1.18- 2.83 1.59 † 1.04- 2.42 1.86 ‡ 1.17- 2.93 †P < 0.05; ‡ P < 0.01

Risk of events for each 10-yr increase in diabetes duration

Fox et al. Diabetes Care 2004;27:704

ICES: Absolute Risk of AMI by Gender and Diabetes Status

Diabetes: Men Women No diabetes: Men Women All lines fitted according to a polynomial equation; R2= 0.99–1.00 for each Booth GL, et al. Lancet. 2006;367:29–36

Age group

0.0 0.5 1.0 1.5 2.0 2.5 3.0

20-30 31-40 41-45 46-50 51-55 56-60 61-65 66-70 71-75 76-80 81-85

• No. events per 100

person- years

ICES: Age and Risk of CVD Events by DM and MI Status

All lines fitted according to a polynomial equation; R2= 0.99–1.00 for each Booth GL, et al. Lancet. 2006;367:29–36 Diabetes: MI No MI No diabetes: MI No MI

• No. events per 100 person-

years Age group

4 8 12 16 20 24

31-40 41-45 46-50 51-55 56-60 61-65 66-70 71-75 76-80

DM duration and CVD events

Men with diabetes without MI Men with MI None N=3197 Late onset N=307 Mean duration 1.7 years Early onset N=107 Mean duration 16 years Without diabetes N=368 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 (Sweden) 25 10 P<0.001 FINMONICA Men Women 44.2 36.9 32.6 20.2 OR 1.36 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*

Thourani et al. Ann Thorac Surg 1999;67:1045

*With diabetes vs without diabetes

10 20 30 40 50 60

Early Mortality from Acute MI Pre-CCU Era (pre-1962) CCU Era (1962-1984) Lytic Era (1984-2000) Diabetes Total Group Defibrillation Hemodynamic Monitoring Thrombolysis Beta-blockade Aspirin PCI Era (2000-- ) PCI IIbIIIa Inhibitors Clopidrogel Statins Digoxin Diuretics

Modified by Richard Nesto from NEJM 1997; 337: 1361

Diabetes Confers a Doubling of Risk for Early MI Mortality Despite Advances in Cardiac Care

Diabetes and Lifetime Risk for CHD

Lloyd Jones et al Circ 2006;113:791 Diabetic Non Diabetic

67% 30% 57% 16% Attained Age

0.1 0.2 0.3 0.4 0.5 0.6 0.7 50 60 70 80 90

Adjusted cummulative incidence Men Women

0.1 0.2 0.3 0.4 0.5 0.6 0.7 50 60 70 80 90

Diabetes confers the highest lifetime risk for CHD

• f any single risk factor

How is diabetes considered in CVD guideline updates?

Group 1 Clinical ASCVD

CHD, stroke, and peripheral arterial disease, all of presumed atherosclerotic origin

Group 3 Diabetes mellitus

+ age 40–75 years + LDL-C 70–189 mg/dL (~1.8–5 mmol/L)

Group 4 ASCVD risk ≥7.5%

No diabetes + age 40–75 years + LDL-C 70–189 mg/dL (~1.8–5 mmol/L)

Group 2 LDL-C ≥190 mg/dL (~5 mmol/L)

CHD, coronary heart disease

US Guidelines identify four statin benefit groups

Stone NJ, et al. J Am Coll Cardiol 2014;63:2889–2934

Treatment decision flow for four statin benefit groups

Estimate 10-year ASCVD risk with Pooled Cohort Equations ASCVD-prevention benefit of statin therapy may be less clear in other groups Consider additional factors influencing ASCVD risk and potential ASCVD risk benefits and adverse effects, drug–drug interactions, and patient preferences for statin treatment

Clinical ASCVD

High-intensity statin Age ≤75 years (moderate-intensity statin if not candidate for high-intensity statin) Moderate-intensity statin Age >75 years or if not candidate for high-intensity statin Adults aged >21 years and a candidate for statin therapy Moderate-to-high intensity statin

Yes No

High-intensity statin (Moderate-intensity statin if not candidate for high-intensity statin)

Yes

Moderate-intensity statin High-intensity statin Estimated 10-year ASCVD risk ≥7.5%

No No Yes No

High-intensity statin Expected to reduce LDL-C by ≥50% Moderate-intensity statin Expected to reduce LDL-C by 30–<50%

LDL-C ≥190 mg/dL Diabetes* ≥7.5% 10-year ASCVD risk* Yes *Aged 40–75 years

ASCVD statin benefit groups In individuals not receiving cholesterol-lowering drug therapy, recalculate estimated 10-year ASCVD risk every 4–6 years in individuals aged 40–75 years without clinical ASCVD or diabetes and with LDL-C 70–189 mg/dL (~1.8–5 mmol/L)

Stone NJ, et al. J Am Coll Cardiol 2014;63:2889–2934

Guidelines specify statin doses

High-intensity therapy* Moderate-intensity therapy† Low-intensity therapy‡ Atorvastatin 40–80 mg Atorvastatin 10–20 mg Simvastatin 10 mg Rosuvastatin 20–40 mg Rosuvastatin 5–10 mg Pravastatin 10–20 mg Simvastatin 20–40 mg Lovastatin 20 mg Pravastatin 40–80 mg Fluvastatin 20–40 mg Lovastatin 40 mg Pitavastatin 1 mg Fluvastatin XL 80 mg Fluvastatin 40 mg BID Pitavastatin 2–4 mg

*LDL-C reduced by ~≥50%;

†LDL-C reduced ~30–50%; ‡ LDL-C reduced ~<30%

BID, twice-daily dosing Stone NJ, et al. J Am Coll Cardiol 2014;63:2889–2934

ESC: Other very high risk groups

10-year SCORE risk ≥10% Type 1 or 2 diabetes + ≥1 CV risk factor and/or target organ damage Grade 4–5 CKD (GFR <30 mL/min/1.73m2) Statin Target: LDL-C <70 mg/dL (<~1.8 mmol/L) (≥50% ↓ if target not met)

CKD, chronic kidney disease; CV, cardiovascular; GFR, glomerular filtration rate

Sixth Joint Task Force on CVD Prevention. 2016 EHJ doi/10.1093/eurheartj/ehw106

NICE lipid guidelines: Type 1 diabetes

Type 1 diabetes (no CVD)

Age >40 years Diabetes for >10 years Established nephropathy Other CVD risk factors

Offer statin Start with atorvastatin 20 mg Do not use a risk assessment tool

NICE Lipid modification July 2014 http://www.nice.org.uk/Guidance/CG181

NICE lipid guidelines: Type 2 diabetes

QRISK2 assessment

Type 2 diabetes (no established CVD)

10-year CVD risk ≥10% Offer atorvastatin 20 mg

NICE Lipid modification July 2014 http://www.nice.org.uk/Guidance/CG181

45 year old male

Should we use lifetime CVD risk estimation?

Diabetes is a major risk factor for CVD

• Most diabetes patients are at high risk for

atherosclerotic CVD

• If diabetes patients suffer CVD it is more

severe

• CV risk factor modification (cholesterol and bp-

lowering) are important components of CV risk reduction in diabetes

• Badging diabetes as a CHD risk equivalent is

pragmatic and may increase the likelihood of appropriate CVD primary and secondary prevention