management of patients with T2DM & CVD Richard Hobbs, MD - - PowerPoint PPT Presentation

Targeting CV risk: Implications for clinical management of patients with T2DM & CVD Richard Hobbs, MD

Oxford, United Kingdom

Session: Game changing clinical trials in T2DM & CVD: Novel insights & implications

Cardio Diabetes Master Class

February 22-23, 2019 - Barcelona, Spain

Targeting CV risk: implications for clinical management of patients with T2DM

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, Novartis, Novo Nordisk, Pfizer

Is targeting cardiovascular disease prevention important?

GBD 2010, Lancet 2013

Comparison of 10 leading diseases/injuries & leading risk factors on % deaths/DALYsk

Global Distribution of Mortality Attributed to 10 Leading CV Risk Factors

Attributable mortality in millions (total 55.9 million)

Blood pressure Tobacco Lipids Underweight Unsafe sex Low fruit and vegetable intake High body mass index (BMI) Physical inactivity Alcohol Unsafe water, S&H*

1 2 3 4 5 6 7 8

Higher-mortality developing regions Lower-mortality developing regions Developed regions

The World Health Report 2002: reducing risks, promoting healthy life. Geneva, Switzerland: World Health Organization; 2002 * Sanitation and hygiene

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)

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 2030

Diabetes risk is not fully explained by conventional risk factors

Ischaemic stroke

Age and sex Plus smoking status Plus BMI Plus SBP Plus non-HDL-C Plus HDL cholesterol Plus log-triglycerides 2.06 (1.82-2.34) 2.10 (1.85-2.39) 2.00 (1.78-2.25) 1.91 (1.70-2.14) 1.93 (1.71-2.16) 1.87 (1.67-2.09) 1.87 (1.67-2.09) HR (95% CI) 1 2 4 2.56 (2.15-3.05) 2.59 (2.16-3.09) 2.45 (2.08-2.88) 2.27 (1.94-2.65) 2.26 (1.94-2.64) 2.24 (1.94-2.60) 2.24 (1.94-2.59) 1 2 4 HR (95% CI) Adjusted for

Coronary heart disease

1 2 4 1 2 4 Hazard ratio (diabetes vs. no diabetes)

• Lancet. 2010 Jun 26;375(9733):2215-22

DM duration matters to CVD

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, Shaper, Whincup, Lennon, Sattar. Br Reg Heart Survey.Arch Intern Med. 2011,14;171(5):404-10

Type 2 diabetes increases 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

Diabetes associated with significant loss of life years

11

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 (year) Years of life lost

Men

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

Women

Non-vascular deaths Vascular deaths

On average, a 50-year old with diabetes but no history of vascular disease is ~6 years younger at time of death than a counterpart without diabetes

Managing CV risk beyond glucose control

Summary evidence

• n smoking, blood pressure,

and lipid 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

Effectiveness of pharmacological aids to stopping smoking

5 10 15 20 25 Varenicline Single form NRT Dual form NRT* NRT for 'reduce to quit' Varenicline for 'reduce to quit' ↑ % abstinent >6m

Data from RCTs; Cochrane reviews (NRT 2013; Varenicline 2016); Wu 2015 doi:10.3390/ijerph120910235; *Estimated by combining effect sizes; All comparisons are active medication versus placebo in context of behavioural support

Effectiveness of psychological support for stopping smoking

2 4 6 8 10 12 14 16 Individual face-to-face Group face- to-face Telephone SMS text messaging Printed materials ↑ % abstinent >6m

Data from RCTs; Cochrane reviews (2008, 2009, 2013, 2016); Indirect estimates compared with nothing; Insufficient data on smartphone apps; Mixed data on websites

Stop-Smoking+

5 10 15 20 25 30 35 40 45 Specialist support Brief support Self support ↑ % abstinent >6m

Data based on varenicline; assumes psychological support and medication rate ratios combine multiplicatively

The most effective and costly Less effective but more popular Small effect but can be very popular

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%

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

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

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

10 mmHg SBP reduction reduces all-cause mortality, macro- & micro-vascular T2DM outcomes

22

Meta-analysis of 40 large scale, randomised, controlled trials of BP-lowering treatment including patients with diabetes (n=100,354 participants). Emdin et al. JAMA 2015;313:603–15.

Stroke

Outcome All-cause mortality Macrovascular disease CV disease CHD Stroke Heart failure Microvascular disease Renal failure Retinopathy Albuminuria 0.5 1.0 2.0 Favours BP lowering Favours control

Relative risk (95% CI)

Effect of 10 mmHg reduction in SBP on CV

• utcomes by baseline ≥ 140 or < 140 mmHg

23

Meta-analysis of 40 trials of BP-lowering treatment including patients with diabetes (n=100,354 participants). Emdin et al. JAMA 2015;313:603–15.

0.5 1.0 2.0 Favours BP lowering Favours control Overall Baseline SBP <140 mmHg Baseline SBP 140 mmHg Outcome Mortality CVD CHD Stroke Relative risk (95% CI)

CV outcomes based on mean SBP achieved (≥ 130

• r < 130 mmHg

24

Meta-analysis of 40 trials of BP-lowering treatment including patients with diabetes (n=100,354 participants). Emdin et al. JAMA 2015;313:603–15.

0.5 1.0 2.0 Favours BP lowering Favours control Overall Achieved SBP <130 mmHg Achieved SBP 130 mmHg Outcome Mortality CVD CHD Stroke Relative risk (95% CI)

Recent updates to blood pressure goals reflect limited evidence of benefit <140/90 mmHg

25

*<130/80 mmHg in chronic kidney disease and albuminuria; †SBP < 130 mmHg in nephropathy.

• 1. Rydén et al. Eur Heart J 2013;34:3035–87. 2. Mancia et al. J Hypertens 2013;31:1281–357.. 3. http://guidance.nice.org.uk/CG127;
• 4. http://www.nice.org.uk/guidance/cg87; 5. Weber. J Hypertens 2014;32:3–15; 6. James. JAMA 2014;5;311:507–20.
• 7. American Diabetes Association. Diabetes Care 2015;38(suppl. 1):S1–S94. 8. Daskalopoulou et al. Can J Cardiol 2015;31:549–68.

Guidelines Goal BP (mmHg) General Diabetes Elderly (≥80 years) ESC/EASD 20131 <140/85† ESH/ESC 20132 <140/90 <140/85 <150/90 NICE 20113,4 <140/90 <140/80* <150/90 ASH/ISH 20135 <140/90 <140/90* <150/90 JNC 8 20146 <140/90 <140/90* <150/90 (Aged ≥60 years) ADA 20157 <140/90 CHEP8 <140/90 <130/80 <150/90

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 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 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 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

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

• 32
• 24
• 23
• 22
• 24
• 31
• 25
• 44
• 37
• 8
• 42
• 19
• 25
• 18
• 11
• 60
• 50
• 40
• 30
• 20
• 10

RR reduction or hazard ratio (%) Combined

Statin therapy similar reductions in CV risk in DM

31

• 1. Ryden et al. Eur Heart J 2007;28:88–136. 2. Libby. J Am Coll Cardiol 2005;46:1225–8. 3. LaRosa et al. N Engl J Med 2005;352:1425–35.
• 4. Shepherd et al. N Engl J Med 1995;333:1301–8. 5. Downs et al. JAMA 1998;279:1615–22. 6. Ridker et al. N Engl J Med 2008;359:2195.
• 7. Colhoun et al. Lancet 2004;364:685–96. 8. ALLHAT-LLT. JAMA 2002;288:2998–3007.

6605 6595 20,536 4159 9014 4444 N 10,001 17,802

Non-diabetes Diabetes

AFCAPS/ TexCAPS5 4S1,2 LIPID1,2 CARE1,2 WOSCOPS4 Trial HPS1,2 TNT3 JUPITER6 Secondary prevention Primary prevention High risk CARDS7 ALLHAT-LLT8 2838 10,355

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

Alternatives to statins in modifying lipid CV risks?

Fibrates and CVD risk reduction among those with atherogenic dyslipidemia: TG>200mg/dl and HDL <39mg/dl

Sacks et al NEJM 2 0 1 0

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

– LDL-C reduction of 44% – RR of 6.4% (non fatal MI & Stroke)

– Hs CRP levels remained high (>3 mg/L) in both arms

• Primary event rates:

– 32.7% Ezetemibe 34.7% placebo arm

• NNT to prevent 1 non-fatal event

– 50 for 7 years – 350 for 1 year

HDL intervention; failures

Torcetrapib, Dalcetrapib, Niacin

CETP inhibition: HPS-REVEAL Anacetrapib trial

Anacetrapib CETPi 100mg od in 30499 ASVD patients with baseline LDL of 1.6 mmol/l (61 mg/dl) and max statin – 40% LDL reduction 100% HDL raising

HPS-REVEAL Trial: Anacetrapib

The HPS3/TIMI55-REVEAL Collaborative Group* August 29, 2017 DOI: 10.1056/ NEJM oa1706444

10 20 30 40 50 60 70 80 90 100 12 24 36 48 60 72 84 96 108 120 132 144 156 168 LDL Cholesterol (mg/dl) Weeks

Novel LDL modification via PCSK9 inhibition

Evolocumab (median 30 mg/dl, IQR 19-46 mg/dl) Placebo 59% mean reduction (95%CI 58-60), P<0.00001 Absolute reduction: 56 mg/dl (95%CI 55-57) Fourier Trial, NEJM Evolocumab sc 2 weekly in FOURIER Trial 27564 stable CVD (MI, Stroke, PAD)

0% 2% 4% 6% 8% 10% 12% 14% 16%

PCSK9 Fourier: Primary Endpoint

Evolocumab Placebo

Months from Randomization

CV Death, MI, Stroke, Hosp for UA, or Cor Revasc

6 12 18 24 30 36

Hazard ratio 0.85 (95% CI, 0.79-0.92) P<0.0001 12.6% 14.6%

FOURIER - Comparison to CTT meta-analysis

Major Coronary Events Stroke Coronary revascularization Urgent Elective Major Vascular Events 0.78 (0.70-0.86) 0.80 (0.71-0.90) 0.77 (0.66-0.91) 0.77 (0.63-0.94) 0.75 (0.67-0.84) 0.73 (0.62-0.86) 0.84 (0.73-0.98) 0.77 (0.73-0.82) 0.83 (0.76-0.90)

Lipid-lowering therapy better Lipid-lowering therapy worse

Hazard Ratio (95% CI) per 1 mmol/L reduction in LDL-C

2.0 1.0

CTTC Meta-analysis Year 2 FOURIER Year 2

CTTC data from Lancet 2010;376:1670-81

0.5

Patients with event/analysed

Empa Plac HR (95% CI)

p-value 3-point MACE

490/4,687 282/2,333 0.86 (0.740.99)* 0.0382

CV death

172/4,687 137/2333 0.62 (0.490.77) <0.0001

Non-fatal MI

213/4,687 121/2,333 0.87 (0.701.09) 0.2189

Non-fatal stroke

150/4,687 60/2,333 1.24 (0.921.67) 0.1638

4-point MACE

599/4,687 333/2,333 0.89 (0.781.01)* 0.0795 4-point MACE = CV death, non-fatal MI, non-fatal stroke or hospitalization for UA Cox regression analysis *95.02% CI Favors empagliflozin Favors placebo

EMPA-REG OUTCOME: Empagliflozin reduced CVD without

reduction in non-fatal MI or stroke

Zinman B, et al. N Engl J Med 2015;373:2117-28

Glycaemia control

Trials Number of events (annual event rate, %) ΔHbA1c (%) Favours more intensive Favours less intensive More intensive Less intensive Major cardiovascular events*

ACCORD 352 (2.11) 371 (2.29)

• 1.01

ADVANCE 557 (2.15) 590 (2.28)

• 0.72

UKPDS 169 (1.30) 87 (1.60)

• 0.66

VADT 116 (2.68) 128 (2.98)

• 1.16

Overall 1194 1176

• 0.88

Stroke Overall 378 370

• 0.88

Myocardial infarction Overall 730 745

• 0.88

Hospitalised/fatal heart failure Overall 459 446

• 0.88

Meta-analysis including 27,049 participants and 2370 major vascular events

Modest benefit of intensive glycaemic control

• n macrovascular risk with traditional Rx

45

*Major CV events = CV death or non-fatal stroke or non-fatal MI. †Diamonds incorporate point estimate (vertical dashed line) and encompass 95% CI of overall effect for each

• utcome.

Turnbull et al. Diabetologia 2009;52:2288–98.

1.0 0.5 2.0 Hazard ratio (95% CI)

†

Overall HR (95% CI) 0.91 (0.84–0.99) 0.96 (0.83–1.10) 0.85 (0.76–0.94) 1.00 (0.86–1.16)

No evidence from trials of older Rx that more intensive glycaemic control reduces mortality

46

Turnbull et al. Diabetologia 2009;52:2288–98.

Meta-analysis including 27,049 participants and 2370 major vascular events

0.5 1.0 2.0 Hazard ratio (95% CI) ACCORD 257 (1.41) 203 (1.14)

• 1.01

ADVANCE 498 (1.86) 533 (1.99)

• 0.72

UKPDS 123 (0.13) 53 (0.25)

• 0.66

VADT 102 (2.22) 95 (2.06)

• 1.16

Overall 980 884

• 0.88

ACCORD 137 (0.79) 94 (0.56)

• 1.01

ADVANCE 253 (0.95) 289 (1.08)

• 0.72

UKPDS 71 (0.53) 29 (0.52)

• 0.66

VADT 38 (0.83) 29 (0.63)

• 1.16

Overall 497 441

• 0.88

All-cause mortality Cardiovascular death Trials Number of events (annual event rate, %) More intensive Less intensive ∆HbA1c (%) Favours more intensive Favours less intensive Overall HR (95% CI) 1.04 (0.90–1.20) 1.10 (0.84–1.42)

Multi-factorial treatments

CV risk reduction in T2D may require multiple interventions including BP and lipid management

*Non-fatal MI, CHD, stroke and all-cause mortality.

• 1. Sattar. Diabetologia 2013;56:686–95.
• 2. Ray et al. Lancet 2009;373:1765–72.
• 12,5
• 8,2
• 2,9
• 14
• 12
• 10
• 8
• 6
• 4
• 2

No of CV events* prevented per 200 patients for 5 years Per 4 mmHg lower SBP1 Per 1 mmol/L lower LDL-C1 Per 0.9% lower HbA1c

1,2

48

A multifactorial approach is recommended for control of CV risk in patients with T2D

*Lower targets (e.g., <130/80 mmHg) may be appropriate for certain individuals, such as younger patients, if they can be achieved without undue treatment burden. †More or less stringent goals may be appropriate for individuals. ‡Not recommended for those at low CV risk.

• 1. American Diabetes Association. Diabetes Care 2015;38(suppl. 1):S1–S94. 2. Rydén et al. Eur Heart J 2013;34:3035–87.

Risk factor Goal1 Recommendation1 Raised blood pressure < 140/90 mmHg* ACE inhibitor or ARB Abnormal blood lipids LDL cholesterol < 100 mg/dL (< 2.6 mmol/L) Lifestyle modification and statin therapy Tobacco use Smoking cessation Counselling and pharmacological therapy Hyperglycaemia HbA1c < 7%† (< 53 mmol/mol) Lifestyle modification and then metformin as initial monotherapy Raised CV risk: 10-year risk > 10% Antiplatelet use ASA (75–162 mg/day)‡

• American1 and European2 recommendations on CV risk factor management are similar

49

Steno-2: Intensive multifactorial control of CV risk factors reduces CV risk in patients with T2D and microalbuminuria

50

Composite endpoint: CV death, non-fatal MI, non-fatal stroke revascularisation and amputation. Gaede et al. N Engl J Med 2003;348:383–93.

Unadjusted HR 0.47 (95% CI: 0.24‒0.73); p = 0.008 12 24 36 48 60 72 84 96 Months of follow-up Primary composite endpoint (%) 60 10 20 40 50 30 Conventional (85 events) Intensive (33 events)

Lifestyle modification for diabetes prevention

Lifestyle vs Metformin vs placebo

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

Diabetes Prevention Program

• 58%
• 31%

Parallel

Pooled estimates of effects of lifestyle intervention

• 50%

BMJ 2007

But current care?

Despite improvement over 20 years, many patients with diabetes not reaching CV goals

55

*p < 0.01, †p < 0.05, each vs 2007–2010. NHANES 1988–2010. Casagrande et al. Diabetes Care 2013;36:2271–9.

1988–1994 1999–2002 2003–2006 2007–2010 Patients reaching goal (%) 90 70 40 20 30 50 60 80 10

HbA1c < 7.0% (< 53 mmol/mol)

* †

BP < 130/80 mmHg

* * †

BP < 140/90 mmHg

* *

LDL < 100 mg/dL (2.6 mmol/L)

† * *

On statin

* * *

From 2007–2010, 81.2% of patients did not achieve the composite ABC goal1

HbA1c < 7.0%, BP < 130/80 mmHg and LDL < 100 mg/dL (2.6 mmol/L)

* *

Is impact of diabetes likely to change? Predicted trends in diabetes

Prevalence)of)obe sity 30% Women Men 25% 20% 15% 10% 5% 0% Adult (aged 16+) obesity: BMI ≥ 30kg/m2 Patterns and trends in adult obesity

Trendin obesityprevalenceamongadults

Health Survey for England 1993 to 2014 (three-year average)

Age-Adjusted Prevalence of Obesity and Diagnosed Diabetes Among U.S. Adults Aged 18 Years or older

Diabetes Obesity (BMI ≥30 kg/m2) 1994 1994 2000 2000

No Data <14.0% 14.0-17.9% 18.0-21.9% 22.0-25.9% >26.0%

2010 2010

No Data <4.5% 4.5-5.9% 6.0-7.4% 7.5-8.9% >9.0%

CDC’s Division of Diabetes Translation. National Diabetes Surveillance System available at http:// www.cdc.gov/diabetes/statistics

Relative risk of type 2 diabetes

Relative Risk for type 2 diabetes 84,941 nurses: 16 years follow-up

10 20 30 40

15

38.8 20.1 7.6 1.0

20 25 30 35 40

Body mass index

Hu FB. N Engl J Med. 2001; 345:790-7.

Conclusions

• CVD is the world’s most important cause of

– Premature and total mortality – Rates of disability and healthcare spend

• CVD risk is accelerated in diabetes

– Traditional risk factors remain important in diabetes – Very large evidence base on interventions to reduce these risks

• CV risk management in diabetes

⎼ Limited evidence for glucose reduction & reduced CVD until recent novel agent trials ⎼ Despite evidence for main CV risk factors

⎼ High residual risk ⎼ Major gaps in routine care provision