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

Session: Game changing clinical trials in T2DM & CVD: Novel insights & implications Targeting CV risk: Implications for clinical management of patients with T2DM & CVD Richard Hobbs, MD Oxford, United Kingdom 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?

Comparison of 10 leading diseases/injuries & leading risk factors on % deaths/DALYs k GBD 2010, Lancet 2013

Global Distribution of Mortality Attributed to 10 Leading CV Risk Factors Blood pressure Tobacco Lipids Underweight Unsafe sex Low fruit and vegetable intake High body mass index (BMI) Higher-mortality developing regions Physical inactivity Lower-mortality developing regions Alcohol Developed regions Unsafe water, S&H* 0 1 2 3 4 5 6 7 8 Attributable mortality in millions (total 55.9 million) * Sanitation and hygiene The World Health Report 2002: reducing risks, promoting healthy life. Geneva, Switzerland: World Health Organization; 2002

Diabetes doubles the risk of vascular disease Data from 102 prospective studies, 530,083 participants (adjusted for age sex, cohort, SBP, smoking, BMI) Outcome I 2 (95% CI) Number HR (95% CI) of cases Coronary heart disease 26 505 2.00 (1.83 - 2.19) 64 (54-71) Coronary death 11 556 2.31 (2.05 - 2.60) 41 (24-54) Non-fatal myocardial 14 741 1.82 (1.64 - 2.03) 37 (19-51) infarction Cerebrovascular disease 11 176 1.82 (1.65 - 2.01) 42 (25-55) Ischaemic stroke 3799 1 (0-20) 2.27 (1.95 - 2.65) Haemorrhagic stroke 1183 1.56 (1.19 - 2.05) 0 (0-26) Unclassified stroke 4973 1.84 (1.59 - 2.13) 33 (12-48) Other vascular deaths 3826 1.73 (1.51 - 1.98) 0 (0-26) 1 2 4 Hazard ratio (diabetes vs. no diabetes) Emerging Risk Factors Collab. Lancet. 2010 Jun 26;375(9733):2215-22

Prevalence of diabetes in 2030 2 0 1 0 2 0 3 0 Total number of people 285 million 438 million with diabetes (age 20-79) Prevalence of diabetes 6.6 % 7.8 % (age 20-79) IDF diabetes atlas, 4th edition, 2009

Diabetes risk is not fully explained by conventional risk factors Ischaemic stroke Coronary heart disease HR (95% CI) Adjusted for HR (95% CI) Age and sex 2.06 (1.82-2.34) 2.56 (2.15-3.05) Plus smoking status 2.10 (1.85-2.39) 2.59 (2.16-3.09) Plus BMI 2.00 (1.78-2.25) 2.45 (2.08-2.88) Plus SBP 1.91 (1.70-2.14) 2.27 (1.94-2.65) Plus non-HDL-C 1.93 (1.71-2.16) 2.26 (1.94-2.64) Plus HDL cholesterol 1.87 (1.67-2.09) 2.24 (1.94-2.60) Plus log-triglycerides 1.87 (1.67-2.09) 2.24 (1.94-2.59) 1 1 2 2 4 4 1 1 2 2 4 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 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, Shaper, Whincup, Lennon, Sattar. Br Reg Heart Survey.Arch Intern Med. 2011,14;171(5):404-10

Type 2 diabetes increases CVD risk over time CHD equivalence threshold CHD risk ~10 years’ Diagnosis duration Age • 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 .

Diabetes 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 (year) Age (year) 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 11 Seshasai et al. N Engl J Med 2011;364:829-41.

Managing CV risk beyond glucose control

Summary evidence on smoking, blood pressure, and lipid control

Smoking Hazards & Cessation Benefits 113,752 w and 88,496 m aged ≥ 25y in US NHIS Jha N Engl J Med 2013; 368: 341-50

Effectiveness of pharmacological aids to stopping smoking 25 20 ↑ % abstinent >6m 15 10 5 0 Varenicline Single form Dual form NRT for Varenicline NRT NRT* 'reduce to for 'reduce quit' to quit' 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 16 14 ↑ % abstinent >6m 12 10 8 6 4 2 0 Individual Group face- Telephone SMS text Printed face-to-face to-face messaging materials 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+ The most effective and 45 costly 40 ↑ % abstinent >6m 35 30 Less effective but 25 more popular 20 Small effect but can be 15 very popular 10 5 0 Specialist support Brief support Self support Data based on varenicline; assumes psychological support and medication rate ratios combine multiplicatively

Blood pressure modification in diabetes

Results of randomised trials of antihypertensive drug therapy Heart Fatal/Nonfatal Fatal/Nonfatal Vascular failure stroke CHD deaths 0 -16% -10 -21% -20 -30 -38% -40 -52% -50 BP CTC, Collins R et al Lancet 1990 Risk reduction (%) 17 trials, 47 653 patients, SBP diff 10-12 mm Hg, DBP diff 5-6 mm Hg Moser & Herbert J Am Coll Cardiol 1996

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 CV mortality Actively-controlled trials 1.50 MIDAS/ NICS/ VHAS Placebo-controlled studies UKPDS C vs A p = 0.002 or trials with an untreated (experimental/ reference) 1.25 control group NORDIL INSIGHT HOT L vs H STOP2/ ACEIs HOT M vs H Odds ratio MRC1 1.00 MRC2 STOP2/ CCBs SHEP HEP 0.75 STONE Syst-Eur CAPPP EWPHE HOPE UKPDS L vs H RCT70-80 Syst-China 0.50 PART2/ SCAT STOP1 ATMH 0.25 –5 0 5 10 15 20 25 Difference* in SBP (mmHg) * 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 Favours BP lowering Outcome Favours control All-cause mortality Macrovascular disease CV disease Stroke CHD Stroke Heart failure Microvascular disease Renal failure Retinopathy Albuminuria 0.5 1.0 2.0 Relative risk (95% CI) 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. 22

Effect of 10 mmHg reduction in SBP on CV outcomes by baseline ≥ 140 or < 140 mmHg Favours BP Outcome lowering Favours control Mortality Baseline SBP  140 mmHg Baseline SBP <140 mmHg CVD Overall CHD Stroke 0.5 1.0 2.0 Relative risk (95% CI) 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. 23

CV outcomes based on mean SBP achieved (≥ 130 or < 130 mmHg Favours BP Outcome lowering Favours control Mortality Achieved SBP  130 mmHg Achieved SBP <130 mmHg CVD Overall CHD Stroke 0.5 1.0 2.0 Relative risk (95% CI) 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. 24

Recent updates to blood pressure goals reflect limited evidence of benefit <140/90 mmHg Guidelines Goal BP (mmHg) General Diabetes Elderly (≥80 years) ESC/EASD 2013 1 <140/85 † ESH/ESC 2013 2 <140/90 <140/85 <150/90 NICE 2011 3,4 <140/90 <140/80* <150/90 ASH/ISH 2013 5 <140/90 <140/90* <150/90 <150/90 JNC 8 2014 6 <140/90 <140/90* (Aged ≥60 years) ADA 2015 7 <140/90 CHEP 8 <140/90 <130/80 <150/90 *<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. 25

Lipid modification in diabetes