Managing CV risk in T2DM beyond glucose Richard Hobbs, Professor - - PowerPoint PPT Presentation

Managing CV risk in T2DM beyond glucose

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

IDF diabetes atlas, 4th edition, 2009

2 0 1 0 2 0 3 0 Total number of people with diabetes (age 20-79) 285 million 438 million Prevalence of diabetes (age 20-79) 6.6 % 7.8 %

Prevalence of diabetes in 2 0 3 0

Coronary heart disease Coronary death Non-fatal myocardial infarction Cerebrovascular disease Ischaemic stroke Haemorrhagic stroke Unclassified stroke Other vascular deaths 2.00 (1.83 - 2.19) 2.31 (2.05 - 2.60) 1.82 (1.64 - 2.03) 1.82 (1.65 - 2.01) 2.27 (1.95 - 2.65) 1.56 (1.19 - 2.05) 1.84 (1.59 - 2.13) 1.73 (1.51 - 1.98) HR (95% CI) 26 505 11 556 14 741 11 176 3799 1183 4973 3826 Number

• f cases

64 (54-71) 41 (24-54) 37 (19-51) 42 (25-55) 1 (0-20) 0 (0-26) 33 (12-48) 0 (0-26) I2 (95% CI) 1 2 4 Hazard ratio (diabetes vs. no diabetes) Outcome

Emerging Risk Factors Collab. Lancet. 2010 Jun 26;375(9733):2215-22

Diabetes doubles the risk of vascular disease

Data from 102 prospective studies, 530,083 participants (adjusted for age sex, cohort, SBP, smoking, BMI)

Type 2 diabetes increases CHD/CVD risk

• ver time
• CVD/CHD risk at or prior to diagnosis is determined by conventional CHD risk

factors

• Hyperglycaemia in the diabetic range increases CHD risk over time
• After a diabetes duration of >10 years CHD risk equivalence is reached

Sattar N. Diabetologia 2013;56:686-695.

CHD risk Age Diagnosis ~10 years’ duration CHD equivalence threshold

Managing CV risk beyond glucose control

Jha N Engl J Med 2013; 368: 341-50

Smoking Hazards & Cessation Benefits

113,752 w and 88,496 m aged ≥25y in US NHIS

Lipid modification in diabetes

0.4 0.6 0.8 1 1.2 1.4 Nonfatal MI CHD death Any major coronary event CABG PTCA Unspecified Any coronary revascularisation Ischaemic stroke Haemorrhagic stroke Unknown stroke Any stroke Any major vascular event 2310 (0.9%) 1242 (0.5%) 3380 (1.3%) 816 (0.3%) 601 (0.2%) 1686 (0.6%) 3103 (1.2%) 987 (0.4%) 188 (0.1%) 555 (0.2%) 1730 (0.7%) 7136 (2.8%) 3213 (1.2%) 1587 (0.6%) 4539 (1.7%) 1126 (0.4%) 775 (0.3%) 2165 (0.8%) 4066 (1.6%) 1225 (0.5%) 163 (0.1%) 629 (0.2%) 2017 (0.8%) 8934 (3.6%) 0.74 (0.69 - 0.78) 0.80 (0.73 - 0.86) 0.76 (0.73 - 0.79) 0.76 (0.69 - 0.83) 0.78 (0.69 - 0.89) 0.76 (0.70 - 0.83) 0.76 (0.73 - 0.80) 0.80 (0.73 - 0.88) 1.10 (0.86 - 1.42) 0.88 (0.76 - 1.02) 0.85 (0.80 - 0.90) 0.79 (0.77 - 0.81)

Statin vs control: Proportional effects on major vascular events per mmol/L LDL-C reduction

(26 Trials, 170,000 Subjects)

• No. of events (% pa)

Statin Control Relative risk (CI) per mmol/L LDL-C reduction

Statin better Control better

99% or 95% CI

• CTT2. Lancet 2010;376:1670–81

Statin vs control: Proportional effects on vascular events per mmol/L LDL-C reduction, by baseline LDL

0.5 0.75 1 1.25 1.5

Statin/more better Control/less better <2.0 ³2,<2.5 ³2.5,<3.0 ³3,<3.5 ³3.5 Total 910 (14.7%) 1528 (14.0%) 1866 (12.4%) 2007 (12.3%) 4508 (13.0%) 10973 (13.0%) 1012 (16.4%) 1729 (15.9%) 2225 (14.7%) 2454 (15.2%) 5736 (16.5%) 13350 (15.8%) 0.78 (0.61 - 0.99) 0.77 (0.67 - 0.89) 0.77 (0.70 - 0.85) 0.76 (0.70 - 0.82) 0.80 (0.76 - 0.83) 0.78 (0.76 - 0.80)

• No. of events (% pa)

Statin/more Control/less

<2.0 ³2,<2.5 ³2.5,<3.0 ³3,<3.5 ³3.5 Total 704 (17.9%) 1189 (18.4%) 1065 (20.1%) 517 (20.4%) 303 (23.9%) 3837 (19.4%) 795 (20.2%) 1317 (20.8%) 1203 (22.2%) 633 (25.8%) 398 (31.2%) 4416 (22.3%) 0.71 (0.52 - 0.98) 0.77 (0.64 - 0.94) 0.81 (0.67 - 0.97) 0.61 (0.46 - 0.81) 0.64 (0.47 - 0.86) 0.72 (0.66 - 0.78) <2.0 ³2,<2.5 ³2.5,<3.0 ³3,<3.5 ³3.5 Total 206 (9.0%) 339 (7.7%) 801 (8.2%) 1490 (10.8%) 4205 (12.6%) 7136 (11.0%) 217 (9.7%) 412 (9.1%) 1022 (10.5%) 1821 (13.3%) 5338 (15.9%) 8934 (13.8%) 0.87 (0.60 - 1.28) 0.77 (0.62 - 0.97) 0.76 (0.67 - 0.86) 0.77 (0.71 - 0.84) 0.80 (0.77 - 0.84) 0.79 (0.77 - 0.81)

More vs less statin Statin vs control All trials Relative risk (CI) per mmol/L LDL-C reduction

99% or 95% CI

• CTT2. Lancet 2010;376:1670–81

Statin vs control: Proportional effects on cause- specific mortality per mmol/L LDL-C reduction

0.4 0.6 0.8 1 1.2 1.4 Statin/more better Control/less better Vascular causes Non-vascular CHD Other cardiac All cardiac Ischaemic stroke Haemorrhagic stroke Unknown stroke Stroke Other vascular Any vascular Cancer Respiratory Trauma Other non-vascular Any non-vascular Unknown death Any death 1887 (0.5%) 1446 (0.4%) 3333 (0.9%) 153 (0.0%) 102 (0.0%) 228 (0.1%) 483 (0.1%) 404 (0.1%) 4220 (1.2%) 1781 (0.5%) 224 (0.1%) 127 (0.0%) 811 (0.2%) 2943 (0.8%) 479 (0.1%) 7642 (2.1%) 2281 (0.6%) 1603 (0.4%) 3884 (1.1%) 139 (0.0%) 89 (0.0%) 273 (0.1%) 501 (0.1%) 409 (0.1%) 4794 (1.3%) 1798 (0.5%) 237 (0.1%) 127 (0.0%) 832 (0.2%) 2994 (0.8%) 539 (0.1%) 8327 (2.3%) 0.80 (0.74 - 0.87) 0.89 (0.81 - 0.98) 0.84 (0.80 - 0.88) 1.04 (0.77 - 1.41) 1.12 (0.77 - 1.62) 0.85 (0.66 - 1.08) 0.96 (0.84 - 1.09) 0.98 (0.81 - 1.18) 0.86 (0.82 - 0.90) 0.99 (0.91 - 1.09) 0.88 (0.70 - 1.11) 0.98 (0.70 - 1.38) 0.96 (0.83 - 1.10) 0.97 (0.92 - 1.03) 0.87 (0.76 - 0.99) 0.90 (0.87 - 0.93)

• No. of deaths(% pa)

Statin/more Control/less Relative risk (CI) per mmol/L LDL-C reduction

99% or 95% CI

• CTT2. Lancet 2010;376:1670–81

Statin vs control: Proportional effects on site specific cancer per mmol/L LDL-C reduction

0.4 0.6 0.8 1 1.2 1.4

Relative risk (CI) per mmol/L LDL-C reduction Statin/more better Control/less better

Gastrointestinal Genitourinary Respiratory Female breast Haematological Melanoma Other/unknown Any 1166 (0.3%) 1596 (0.5%) 813 (0.2%) 267 (0.3%) 305 (0.1%) 159 (0.0%) 754 (0.2%) 5060 (1.4%) 1194 (0.3%) 1645 (0.5%) 814 (0.2%) 241 (0.3%) 291 (0.1%) 142 (0.0%) 737 (0.2%) 5064 (1.4%) 0.97 (0.87 – 1.09) 0.97 (0.88 – 1.06) 1.00 (0.88 – 1.15) 1.07 (0.84 – 1.38) 1.04 (0.84 – 1.30) 1.14 (0.83 – 1.56) 1.04 (0.89 – 1.21) 1.00 (0.96 – 1.04)

99% or 95% CI

• No. of first cancers (% pa)

Statin/more Control/less

• CTT2. Lancet 2010;376:1670–81

0.4 0.6 0.8 1 1.2 1.4

More statin better Less statin better

Nonfatal MI CHD death Any major coronary event CABG PTCA Unspecified Any coronary revascularisation Ischaemic stroke Haemorrhagic stroke Unknown stroke Any stroke Any major vascular event 1175 (1.3%) 645 (0.7%) 1725 (1.9%) 637 (0.7%) 1166 (1.3%) 447 (0.5%) 2250 (2.6%) 440 (0.5%) 69 (0.1%) 63 (0.1%) 572 (0.6%) 3837 (4.5%) 1380 (1.5%) 694 (0.7%) 1973 (2.2%) 731 (0.9%) 1508 (1.8%) 502 (0.6%) 2741 (3.2%) 526 (0.6%) 57 (0.1%) 80 (0.1%) 663 (0.7%) 4416 (5.3%) 0.85 (0.76 - 0.94) 0.93 (0.81 - 1.07) 0.87 (0.81 - 0.93) 0.86 (0.75 - 0.99) 0.76 (0.69 - 0.84) 0.87 (0.74 - 1.03) 0.81 (0.76 - 0.85) 0.84 (0.71 - 0.99) 1.21 (0.76 - 1.91) 0.79 (0.51 - 1.21) 0.86 (0.77 - 0.96) 0.85 (0.82 - 0.89)

• No. of events (% pa)

More statin Less statin Relative risk (CI)

Statin vs more statin: Proportional effects on major vascular events per extra 1 mmol/L LDL reduction

(5 more vs. less statin trials, 39,612 subjects)

• CTT2. Lancet 2010;376:1670–81

99% or 95% CI

Cholesterol Trialists Collaboration, Lancet 2005

Year Events (%) Treatment Control RR & CI (Treatment : Control) Rate Ratio (CI) 0-1 year 1747 (3·9) 1951 (4·3)

0·90 (0.85 – 0·96)

1-2 years 1231 (2·9) 1603 (3·8)

0·78 (0·73 – 0·83)

2-3 years 1151 (2·8) 1543 (3·9)

0·74 (0·69 – 0·79)

3-4 years 946 (2·6) 1306 (3·8)

0·72 (0·67 – 0·78)

4-5 years 811 (2·9) 993 (3·7)

0·79 (0·74 – 0·86)

5+ years 468 (2·8) 598 (3·8)

0·74 (0·67 – 0·82)

Overall 6354 (14·1) 7994 (17·8) 0·79 (0·77 – 0·81) p < 0·00001 0·5 1·0 1·5 Treatment Control better better Test for trend: c 2 = 13·9; p = 0·0002

Effects on major vascular events per mmol/L LDL-C reduction by years of treatment

Statins – similar reductions in CV events in diabetes versus non diabetes

(per 1 mmol/L or 39mg/dl lower LDL-C)

CTT Lancet 2 0 0 8 , 3 7 1 , 1 1 7 -2 5

Efficacy of fibrates in CV risk reduction

Lee M, Efficacy of fibrates for CV risk reduction: a meta-analysis. Atherosclerosis, 2011 a

Fibrates and CVD risk reduction in those with atherogenic dyslipidemia TG>1.7mmol/L & HDL <1mmol/L

Sacks et al NEJM 2010

IMPROVE-IT: Reduction in endpoints driven by reductions in MI and ischemic stroke

15,4 6,9 5,7 13,1 4,2 3,4 15,3 6,8 5,8 14,8 4,8 4,2

5 10 15 20

All-cause death CV death CHD death MI Stroke Ischemic stroke Ezetimibe Placebo HR 0.99 RRR 1% p=0.782 HR 1.00 RRR 0% p=0.997 HR 0.96 RRR 4% p=0.499 HR 0.87 RRR 13% p=0.002

Patients (%)

Cannon C. AHA, Chicago, IL, November 17 2014; LBCT.02

Ezetimibe did not significantly reduce all-cause death, CV death, or CHD death

HR 0.79 RRR 21% p=0.008 HR 0.86 RRR 14% p=0.052

*CV death, MI, hospital admission for UA, revascularization, or stroke;

†Death due to any cause, major coronary event, or nonfatal stroke; ‡CHD death, nonfatal MI, or urgent coronary revascularization; §CV death, nonfatal MI, hospital admission for UA, revascularization, and nonfatal stroke

IMPROVE-IT: Results in context

• 7 years Trial; patients 10 000  18 0000
• RR of 6.4% (non fatal MI & Stroke)
• Primary event rates:

– 32.7% Ezetemibe 34.7% placebo arm

• NNT to prevent 1 non-fatal event: 50 for 7 years and 350 for 1 year
• Simvastatin+ Ezetimibe: LDL-C reduction of 44%
• Hs CRP levels remained high (>3 mg/L) in both arms

Statins and diabetes incidence

Statins increase risk of dysglycaemia

Sattar N et al. Lancet. 2010;375:735-42.

Incidence of new diabetes greater with increasing age

Sattar N et al. Lancet. 2010;375:735-42.

Risk of T2DM with Atorvastatin is Strongly Correlated to the Presence of Risk Factors (TNT)

Waters et al. J Am CWoll Cardiol 2011;57:1535-1545．

Prognosis of Patients with New-Onset T2DM

TNT, IDEAL and SPARCL TNT, IDEAL and SPARCL Atorvastatin 80 mg groups With new-onset T2DM Without new-

• nset T2DM

Diabetes at baseline* With new-onset T2DM Without new-

• nset T2DM

Diabetes at baseline* Incidence of MCVE n / N (%) 157 / 1,387 (11.3%) 1,884/ 17,472 (10.8%) 832 / 4,761 (17.5%) 76 / 756 (10.1%) 867 / 8,684 (10.0%) 358 / 2,359 (15.2%) Univariate analysis** (HR=1.03, 95% CI 0.78-1.35, p=0.83) – – (HR=0.90, 95% CI 0.60-1.34, p=0.59) – – Multivariate analysis** (HR=1.02, 95% CI 0.77-1.35, p=0.69) – – (HR=0.87, 95% CI 0.58-1.30, p=0.49) – – *Patients were excluded from the new-onset T2DM study **MCVEs in patients with and without new-onset T2DM were assessed with an extensive time-dependent Cox proportional hazard analysis Waters DD et al. JACC. 2011;

Summary on lipids in T2DM

• Statin therapy remains best lipid modifying agent
• Lower cholesterol targets (intensive statins) based on

absolute risk. 50% LDL-C reduction or LDL-C <70mg/dl or 30%/ 100mg/dl in lower risk

• Fibrates, used as monotherapy or in combination

therapy may have CVD benefit among those with atherogenic dyslipidemia and DM

Blood pressure modification in diabetes

Results of randomised trials of antihypertensive drug therapy

• 50
• 40
• 30
• 20
• 10

Heart failure Fatal/Nonfatal stroke Fatal/Nonfatal CHD Risk reduction (%)

BP CTC, Collins R et al Lancet 1990 17 trials, 47 653 patients, SBP diff 10-12 mm Hg, DBP diff 5-6 mm Hg Moser & Herbert J Am Coll Cardiol 1996

Vascular deaths

• 52%
• 38%
• 16%
• 21%

Greater differences in BP reduction show greater reduction in CV-related mortality

MRC2 MIDAS/ NICS/ VHAS UKPDS C vs A NORDIL INSIGHT HOT L vs H HOT M vs H MRC1 HEP EWPHE

STOP1 ATMH

PART2/ SCAT CAPPP Syst-China

0.25 0.50 0.75 1.00 1.25 1.50

Syst-Eur STONE UKPDS L vs H RCT70-80

Odds ratio (experimental/ reference)

p= 0.002

CV mortality

–5 5 10 15 20 25 Difference* in SBP (mmHg) Actively-controlled trials Placebo-controlled studies

• r trials with an untreated

control group

HOPE SHEP STOP2/ ACEIs STOP2/ CCBs * Reference treatment minus experimental treatment Negative values indicate tighter BP control on reference treatment Staessen JA, et al. Hypertens Res 2005; 28: 385–407

Similar proportional reductions in risk with BP lowering in diabetes as non-diabetes

BP treatment Trialists. Arch Int Med 2005, 165, 1410-1419

ACCORD trial – blood pressure changes

110 120 130 140 1 2 3 4 5 6 7 8

SBP (mm Hg)

Years Post-Randomization

Intensive Standard

• Int. N = 2174 1973 1150 156
• Std. N = 2208 2077 1241 201

Average after 1 st year: 1 3 3 .5 Standard 1 1 9 .3 I ntensive, Delta = 1 4 .2

NEJM 2010, 362, 1575-1585

ACCORD Trial - Primary & Secondary Outcomes

Intensive Events (%/yr) Standard Events (%/yr) HR (95% CI) P Primary

208 (1.87) 237 (2.09) 0.88 (0.73-1.06) 0.20

Total Mortality

150 (1.28) 144 (1.19) 1.07 (0.85-1.35) 0.55

Cardiovascular Deaths

60 (0.52) 58 (0.49) 1.06 (0.74-1.52) 0.74

Nonfatal MI

126 (1.13) 146 (1.28) 0.87 (0.68-1.10) 0.25

Nonfatal Stroke

34 (0.30) 55 (0.47) 0.63 (0.41-0.96) 0.03

Total Stroke

36 (0.32) 62 (0.53) 0.59 (0.39-0.89) 0.01

NEJM 2010, 362, 1575-1585

BP summary

• Actual BP achieved more important than agent used

(BPTT meta-analysis

• Target BP <140/90 SBP for all
• More intensive target < 120 SBP results in stroke

benefits

Anti-platelets in diabetes

Effect of aspirin primary prevention of major CVD events in diabetes

De Berardis G et al. BMJ 2009;339:bmj.b4531

Significant increase in risk of bleeding with aspirin

Aspirin: summary for DM patients

• Men- benefit on NFMI
• Women none overall for any endpoint
• Absolute benefits are modest and approximately

equal to the risk of bleeding

• For every 10, 000 people Tx in PP about 5 fewer

NFMI, but 1 extra haemorrhagic stroke and 3 major bleeds

Lifestyle modification and CVD in diabetes

• 27%

Lifestyle interventions over 6 years can prevent or delay diabetes for up to 14 years after the active intervention, and also leads to reduced CVD mortality

Lifestyle vs Metformin vs placebo

DPP : N Engl J Med 2002; 346: 393-403.

Diabetes Prevention Program

• 58%
• 31%

Parallel

Lifestyle intervention

• 50%

BMJ 2007

Summary

• CVD Risk in diabetes is accelerated

– Traditional risk factors are more important in diabetes – Very large evidence base on risk interventions

• CV Risk Management
• CV Risk scores to decide on Rx vary by region
• Lifestyle, BP and smoking guidance
• Lipid management changes

– Dominance of statin therapy

• Many barriers to CVD Guideline implementation