Lars Ryden, MD Stockholm, Sweden Cardio Diabetes Master Class - - PowerPoint PPT Presentation
Session: Diabetes & Cardiovascular Disease: How do they relate? Diabetes: The new challenge in cardiovascular risk management Lars Ryden, MD Stockholm, Sweden Cardio Diabetes Master Class February 22-23, 2019 - Barcelona, Spain Diabetes
Diabetes: The new challenge in cardiovascular risk management Lars Ryden, MD
Stockholm, Sweden
Session: Diabetes & Cardiovascular Disease: How do they relate?
Cardio Diabetes Master Class
February 22-23, 2019 - Barcelona, Spain
Lars Rydén
Department of Medicine, Solna Karolinska Institutet Stockholm, Sweden
Barcelona February 22, 2019
Advisory Board AstraZeneca, Bayer, Boehringer Ingelheim, Eli Lilly Speaker Lexington, MSD, Novo Nordisk, Sanofi Research Support Swedish Heart-Lung Foundation, Swedish Diabetes Foundation, Karolinska Institutet, Family E Persson´s Foundation, Private Foundations, Stockholm County Council, Swedish Medical Assembly, Amgen, Bayer, Boehringer Ingelheim, MSD, Novo Nordisk
Malmberg & Rydén Eur Heart J 9:256, 1988
10 20 30 40 50 60
%
At hospital After one year Mortality Reinfarction within one year
Died Died
Prevalence diabetes 21%
✓ On diabetes and cardiovascular risk ✓ The impact of target-driven management ✓ Residual risk ✓ How can we close the gap?
Cardiovascular risk management in type 2 diabetes A paradigm shift
✓ Future necessity – a preventive approach
1 2 3 CV death All-cause mortality Hazard ratio [95% CI] (diabetes vs no diabetes)
CI, confidence interval; CV, cardiovascular. Rao Kondapally Seshasai S et al. N Engl J Med 2011;364:829.
Mortality risk with vs. without diabetes (n=820,900) Estimated years of life lost due to diabetes
040 50 60 70 80 90 Age (years) Years of life lost
Men
40 50 60 70 80 90 Age (years)
Women
Vascular causes Other causes
7 6 5 4 3 2 1 7 6 5 4 3 2 1 Years of life lost
Number due to diabetes, HIV/AIDS, Tbc and malaria
International Diabetes Federation. IDF Diabetes Atlas – 7th Edition 2015. http://www.diabetesatlas.org. Accessed October 21, 2016.
Causes around the world
Cardiovascular deaths in type 2 diabetes = 52%
(Morrish et al Diabetologia 2001; 44:S14)
Morrish NJ et al. Diabetologia. 2001;44 suppl 2:S14
IHD
Cardiovascular deaths in type 2 diabetes = 52%
CVA Other
WHO Global Health Risks 2009. http:// http://www.who.int/healthinfo/global_burden_disease/global_health_risks/ IDF Diabetes Atlas – 7th Edition 2015. http://www.diabetesatlas.org. Accessed October 2017.
Mortality (no) attributed to 19 risk factors By country income levels
All related to and common in patients with Diabetes and/or Cardiovascular disease
WHO Global Health Risks 2009
DALYs lost (%) attributed to 19 risk factors By country and income level
WHO Global Health Risks 2009
All related to and common in patients with Diabetes and/or Cardiovascular disease
10-year CHD mortality/1,000 patient-years
Stamler J et al. Diabetes Care 1993;16:434.
Diabetes No diabetes
Serum cholesterol (mmol/L) 4 5 6 7 80 60 40 30 10 5 80 60 40 30 10 5 Systolic blood pressure (mmHg) 110 120 130 140 150 160
Libby P and Plutzky J. Circulation 2002;106:2760; Bays HE et al. Int J Clin Practice 2007;61:737 Jacobs MJ et al. Diabetes Res Clin Pract 2005;70:263.
90% Are overweight or obese 70% Have dyslipidaemia 66% Have arterial hypertension
100%
Have dysglycaemia
✓ On diabetes and cardiovascular risk ✓ The impact of target-driven management ✓ Residual risk ✓ How can we close the gap? ✓ Future necessity – a preventive approach
Cardiovascular risk management in type 2 diabetes A paradigm shift
Best practice
ASA, acetylsalicylic acid; CVD, cardiovascular disease; LDL-C, low-density lipoprotein cholesterol; SBP, systolic blood pressure. Rydén L et al. Eur Heart J 2013;34:3035.
Glycaemic control (HbA1c)
In general <7.0% Individual basis <6.5%–6.9%
Antiplatelet therapy
Patients with CVD ASA 75–160 mg/day
Blood pressure control
<140/85 mmHg Nephropathy: SBP <130 mmHg
Lipid control (LDL-C)
Very high risk <1.8 mmol/L High risk <2.5 mmol/L or –50%
Lifestyle modification
. Oellgaard et al. Diabetologia 2018; 61:1724
Patients Diabetes + microalbuminuria Treatment Intensive n=80 Conventional n=80 Trial design PROBE 7.8 years Observational +13.4 years
Survival free from heart failure or myocardial infarction
Intensive therapy Conventional therapy
From Swedish National Diabetes Register (no = 271,174)
Matched for age, sex and county (no = 1,355,870)
According to age and risk-factor control HbA1c, blood pressure,, albuminuria, smoking & LDL-cholesterol
Median 5.7 years
Death, AMI, stroke and heart failure hospitalisation
AMI, acute myocardial infarction; LDL, low-density lipoprotein. Rawshani A et al. N Engl J Med 2018;379:633.
Excess mortality in relation to range of risk factor control
Adj Hazard Ratio 1 2 3 4 6 8 Adj Hazard Ratio 1 2 3 4 6 8
AMI, acute myocardial infarction; LDL, low-density lipoprotein. Rawshani A et al. N Engl J Med 2018;379:633.
Control ≥80 yr Reference Reference Reference Reference ≥65 to <80 yr Reference Reference Reference Reference ≥55 to <65 yr Reference Reference Reference Reference <55 yr Reference Reference Reference Reference No risk factors ≥80 yr 0.99 [0.84; 1.17] 0.72 [0.49; 1.07] 0.95 [0.74; 1.22] 1.12 [0.89; 1.41] ≥65 to <80 yr 1.01 [0.92; 1.12] 0.80 [0.69; 0.93] 0.90 [0.76; 1.06] 1.42 [1.28; 1.58] ≥55 to <65 yr 1.15 [1.00; 1.34] 0.93 [0.73; 1.18] 0.94 [0.72; 1.23] 1.61 [1.31; 1.97] <55 yr 1.29 [0.94; 1.77] 0.91 [0.62; 1.35] 1.22 [0.70; 2.13] 2.40 [1.63; 3.54] 1 risk factor ≥80 yr 0.94 [0.88; 1.00] 1.05 [0.93; 1.19] 1.06 [0.95; 1.18] 1.17 [1.08; 1.27] ≥65 to <80 yr 1.05 [1.02; 1.09] 1.05 [0.97; 1.14] 1.11 [1.04; 1.18] 1.46 [1.39; 1.53] ≥55 to <65 yr 1.23 [1.16; 1.31] 1.14 [1.04; 1.25] 1.27 [1.14; 1.41] 1.80 [1.63; 1.98] <55 yr 1.56 [1.34; 1.81] 1.46 [1.26; 1.69] 1.55 [1.23; 1.95] 2.37 [1.99; 2.82] 2 risk factors ≥80 yr 0.99 [0.94; 1.04] 1.38 [1.27; 1.49] 1.13 [1.04; 1.24] 1.23 [1.15; 1.32] ≥65 to <80 yr 1.17 [1.13; 1.20] 1.44 [1.39; 1.50] 1.32 [1.26; 1.38] 1.62 [1.56; 1.68] ≥55 to <65 yr 1.32 [1.27; 1.38] 1.54 [1.44; 1.65] 1.59 [1.50; 1.69] 2.11 [1.98; 2.26] <55 yr 1.68 [1.56; 1.80] 2.08 [1.90; 2.27] 2.04 [1.76; 2.36] 2.71 [2.40; 3.05] 3 risk factors ≥80 yr 1.13 [1.06; 1.21] 1.78 [1.60; 1.98] 1.35 [1.21; 1.51] 1.42 [1.31; 1.54] ≥65 to <80 yr 1.46 [1.42; 1.50] 2.11 [2.02; 2.20] 1.73 [1.65; 1.82] 2.01 [1.92; 2.10] ≥55 to <65 yr 1.63 [1.55; 1.71] 2.16 [2.02; 2.31] 2.13 [2.01; 2.27] 2.82 [2.63; 3.02] <55 yr 2.21 [2.05; 2.37] 3.02 [2.80; 3.27] 2.78 [2.46; 3.16] 3.93 [3.50; 4.42] 4 risk factors ≥80 yr 1.47 [1.28; 1.70] 2.32 [1.78; 3.01] 1.54 [1.12; 2.11] 1.81 [1.42; 2.30] ≥65 to <80 yr 2.10 [1.96; 2.26] 2.87 [2.62; 3.14] 2.31 [2.09; 2.55] 2.88 [2.64; 3.14] ≥55 to <65 yr 2.53 [2.37; 2.70] 3.32 [3.02; 3.66] 2.66 [2.30; 3.08] 3.85 [3.47; 4.26] <55 yr 2.80 [2.51; 3.13] 4.56 [4.01; 5.18] 3.34 [2.72; 4.10] 5.70 [4.84; 6.71] 5 risk factors ≥80 yr 1.39 [0.51; 3.80] 3.19 [1.23; 8.28] 2.65 [0.96; 7.30] 2.76 [0.82; 9.25] ≥65 to <80 yr 3.10 [2.53; 3.80] 4.60 [3.37; 6.29] 3.54 [2.36; 5.31] 3.93 [2.75; 5.60] ≥55 to <65 yr 3.88 [3.07; 4.92] 4.84 [3.78; 6.21] 2.79 [1.88; 4.14] 6.54 [4.85; 8.81] <55 yr 4.99 [3.43; 7.27] 7.69 [5.02; 11.77] 6.23 [3.22; 12.05] 11.35 [7.16; 18.01] 2 4 6 8 5 10 5 10 15 5 10 15 20
Excess AMI in relation to range
Excess stroke in relation to range of risk factor control
Hazard ratio [95% CI]
Mortality MI Stroke Heart failure
Rawshani A et al. N Engl J Med 2018;379:633.
✓ On diabetes and cardiovascular risk ✓ The impact of target-driven management ✓ Residual risk ✓ How can we close the gap? ✓ Future necessity – a preventive approach
Cardiovascular risk management in type 2 diabetes A paradigm shift
Swedeheart annual report 2017
1988
x x
1-year mortality (%)
No diabetes Diabetes
5 10 15 20 25 30 35
Rawshani A et al. N Engl J Med 2017;376:1407.
From Swedish National Diabetes Register
Matched for age, sex and county
10,000 person-years
200 250 300 350 400 50 100 150 200 250
All-cause death CV death CV hospitalisation Coronary death
Standardised incidence rate (per 10,000 person-yr) Standardised incidence rate (per 10,000 person-yr) 100 400 200 300 Standardied incidence rate (per 10,000 person-yr) 100 200 150 50 Standardised incidence rate (per 10,000 person-yr)
HR=0.87 95% CI [0.85; 0.89] p<0.001 HR=0.94 95% CI [0.90; 0.98] p=0.004 HR=0.94 95% CI [0.89; 0.98] p=0.009 HR=1.27 95% CI [1.22; 1.32] p<0.001
✓ On diabetes and cardiovascular risk ✓ The impact of target-driven management ✓ Residual risk ✓ How can we close the gap? ✓ Future necessity – a preventive approach
Cardiovascular risk management in type 2 diabetes A paradigm shift
Finland France Germany Netherlands Slovenia Spain Belgium Ireland UK Greece Poland Latvia Lithuania Romania Russia Croatia Bulgaria Kyrgyzstan Turkey Serbia Bosnia & Herzegovina Ukraine Sweden Portugal Kazakhstan Czech Republic Egypt
Kotseva K et al for the EUROASPIRE Investigators Eur J Prevent Card 2019; In press
27 countries (131 centers) Interviewed patients 8 261 Female 26% Mean age 64 years Period 2016-17
ASA, acetylsalicylic acid; CVD, cardiovascular disease; LDL-C, low-density lipoprotein cholesterol; SBP, systolic blood pressure. Rydén L et al. Eur Heart J 2013;34:3035.
Lipid control (LDL-C)
Very high risk <1.8 mmol/L High risk <2.5 mmol/L or –50%
Adjusted for age and gender
EAV: Prevalence of selfreported dysglycaemia
Diabetes, IFG/IGT or using any glucose lowering drug
19% 21% 23% 24% 25% 26% 26% 26% 26% 29% 30% 30% 30% 31% 32% 33% 34% 34% 34% 37% 39% 41% 41% 42% 44% 53% 59%
IRE LAT KAZ KYR RUS NED BEL UK LIT UKR CRO GER FIN BH POR SWE SLO CZE BUL TUR ROM POL SPA ITA EGY SER GRE
Rydén et al for the EAV investigators. Data on file
Kotseva K et al for the EUROASPIRE Investigators Eur J Prevent Card 2019; In press
Glucose control in patients with diabetes and coronary artery disease
Recommended HbA1c <7.0%
0% 10% 20% 30% 40% 50% 60% 70% 80% 90% 100% New diabetes Known diabetes < 8% < 7% < 6.5% < 6% >
HbA1c
Treatment %
Diet/Lifestyle 57 Oral drugs 74 Insulin 32
>7% 54%
(64 mmol/mol) (53 mmol/mol) (48 mmol/mol) (42 mmol/mol)
>8 !!!
Rydén et al for the EAV investigators. Data on file
Rydén et al for the EAV investigators. Data on file
LDL-cholesterol and BP in patients with diabetes and coronary artery disease
Recommended BP <140/90 and LDL-chol <1.8 mmol/l (116 mg/dl)
Rydén et al for the EAV investigators. Data on file
0% 10% 20% 30% 40% 50% 60% 70% 80% 90% 100% >3 !!! Proportion reaching different LDL- cholesterol targets
é
<2.5 <1.8 <3.0 >3.0
116 mg/dl 97 mg/dl 70 mg/dl
> 0% 10% 20% 30% 40% 50% 60% 70% 80% 90% 100% >150/100 !!! Proportion reaching different blood pressure targets
é
<150/100 <140/90 <130/80
LDL-cholesterol and BP in patients with diabetes and coronary artery disease
Recommended BP <140/90 and LDL-chol <1.8 mmol/l (116 mg/dl)
Rydén et al for the EAV investigators. Data on file
0% 10% 20% 30% 40% 50% 60% 70% 80% 90% 100% >3 !!! Proportion reaching different LDL- cholesterol targets
é
<2.5 <1.8 <3.0 >3.0
116 mg/dl 97 mg/dl 70 mg/dl
> 0% 10% 20% 30% 40% 50% 60% 70% 80% 90% 100% >150/100 !!! Proportion reaching different blood pressure targets
é
<150/100 <140/90 <130/80
Inadequate in many patients
Disappointing
Completion Q1 2019
By courtesy F F M Baeres Presented June -19 Presented 10/11 -19
6 12 18 30 24 42 36 48 20 10 5 15 Patients with an event (%) Empagliflozin (n=4,687) Placebo (n=2,333)
HR=0.86 95% CI [0.74; 0.99] p=0.0382
CV death, MI, or stroke
Time from randomisation (months)
HR=0.87 95% CI [0.78; 0.97] p=0.01
6 12 18 24 30 36 42 48 54 Placebo (n=4,672) Liraglutide (4,668) 5 10 15 20 Patients with an event (%)
EMPA-REG1
SGLT-2 inhibition September 2015
LEADER2
GLP-1RA June 2016 Reduction 14% Rapid onset Heart failure-driven Reduction 13% Slow onset Mortality-driven
Type 2 diabetes high CV risk
Drug class Patients HbA1c Endpoint Risk reduction Trial Compound % (MACE) Absolute Relative
CV death MI Stroke Empagliflozin Canagliflozin GLP-1 RA Semaglutide Albiglutide Liraglutide 13 26 22 1.6 14
1.9 2.3 2.0 8.0
8.1
7.7
7.3
7.7
SGLT-2 inhib
Add agent reducing MACE ± CV mortality Add agent considering drug + patient specific factors ASCVD? YES No
GLP1-RA SGLT-2 inh
60 30 20 12 4 2 1 1 10 20 30 40 50 60 70
Metformin Insulin SUs Incretins* SGLT-2 inhibitors Glitazones Glinides α-glucosidase inhibitors
Patients with coronary artery disease and diabetes (%)
Treatment %
Diet / lifestyle 57 Oral drugs 74 Insulin 32
*Gliptins and/or glucagon-like peptide-1 receptor agonists. SGLT-2, sodium–glucose co-transporter-2; SU, sulphonylurea. EUROASPIRE V Investigators; data on file.
Use of glucose lowering drugs in EUROASPIRE V
<2008
HbA1c – the lower the better HbA1c – the lower the better but…without weight gain, hypoglycaemia and side effects Cardiovascular risk including: blood pressure, LDL-cholesterol, glucose lowering with agents of proven safety and efficacy
2008 2018
Future perspective But…
✓ On diabetes and cardiovascular risk ✓ The impact of target-driven management ✓ Residual risk ✓ How can we close the gap? ✓ Future necessity – a preventive approach
Cardiovascular risk management in type 2 diabetes A paradigm shift
Strategies for disease prevention Rose´s paradox – high risk strategy
Procentuell risk årsrisken att utveckla hjärt-kärlsjukdom inom 10 år Procentuell andel av befolkningen Populations- strategi Högrisk- strategi Optimal fördelning Nuvarande fördelning Högrisk
Optimal distribution
Proportionate risk to for cardiovascular disease in 10 years
Population strategy High risk strategy
Proportion of the population Relatively few but at high risk
Strategies for disease prevention Rose´s paradox – low risk strategy
Procentuell risk årsrisken att utveckla hjärt-kärlsjukdom inom 10 år Procentuell andel av befolkningen Populations- strategi Högrisk- strategi Optimal fördelning Nuvarande fördelning Högrisk
Present distribution Optimal distribution
Proportionate risk to for cardiovascular disease in 10 years
Population strategy High risk strategy
Proportion of the population Relatively few but at high risk
Optimal distribution
Strategies for disease prevention Rose´s paradox – population based strategy
Emerging Risk Factor Collaboration Lancet 2010;375:2215
¨
Coronary heart disease No history of diabetes at baseline Known history of diabetes at baseline Mean fasting blood glucose (mmol/l) Hazard Ratio (95% CI)
Lancet 2010; 375:2215
Meta-analysis Studies 102 People 698 782 Median time to first outcome 10.8 years Person-years at risk 8.49 million Outcomes (nonfatal or fatal) 52 765
Emerging Risk Factors Collaboration et al. Lancet. 2010;375::2215.
Characteristic Number of participants Number of cases HR (95% CI) Interaction p-value
Sex
Male
306533 20218 <0.0001
Female
223550 6287
Age
40–59 years
410833 17686 <0.0001
60–69 years
75785 5045
≥70 years
43465 3774
Smoking status
Other
343864 13702 <0.0001
Current
186219 12803
BMI
Bottom third
176274 6701 0.0143
Middle third
176332 9103
Top third
177477 10701
Systolic BP
Bottom third
183314 4915 <0.0001
Middle third
192622 9079
Top third
154147 12511
1,0 2,0 3,0 4,0
All patients suffer but in particular those at lowest risk
Prediabetes Frank diabetes Insulin resistance Endogenous Insulin Fasting blood glucose Macrovascular complications Microvascular complications Time Years to decades Time for typical diagnosis of diabetes Postprandial blood glucose
Adapted after Laakso et al. Eur Heart J. 2003; 5:B5
IDF Diabetes Atlas – 8th Edition 2017. http://www.diabetesatlas.org
One in two adults with diabetes are undiagnosed (>212 million)
Millions Age (years) Prevalence (%) Year % Millions 2013 6.9 316 2035 8.0 471
IDF Diabetes Atlas. Sixth edition. http://www.diabetesatlas.org. 2013. Accessed October 21, 2016.
Type 2 diabetes & CVD
Inflammation
hsCRP IL-1 IL-6 TNF-alfa MMPs CD40-lig PAI-1 Adipokines
Dyslipidemia
small dense LDL HDL FFAs Triglycerides ApoB, ApoA-1
Hypercoagulability
PAI-1 Fibrinogen Antitrombin activity
GH system
IGF-I IGFBP-1 IBFBP-3
Dysglycaemia
Beta-cell dysfunction Insulin-resistance
Oxidative stress
AGEs
PAF-acetylhydrolas
Endothelial dysfunction
vWF tPA-antigen adhesion mol. ET-1, NO
Insulin resistance
Insulin resistance
Dysglycaemia Hypertension Dyslipidaemia Endothelial dysfunction Inflammatory activation Thrombogenicity
Enhanced production Decreased lysis
Causes Is counteracted by Physical activity Insulin sensitizing drugs
Pioglitazone
The concept tested Da Qing PROACTIVE IRIS
Reaven GM Diabetes 1988;37:1595
Li et al Lancet Diab & Endocrin 2014; 2: 474
Control Intervention Control Interventio n HR 0.71 (95% CI 0.51-0.99)
All cause mortality
Cardiovascular mortality
HR 0.59 (95% CI 0.36-0.96)
Dormandy et al Lancet 2015; 366:1279
Primary endpoint
Death, MI/ACS, stroke, leg amputation, coronary or leg revascularization
Secondary endpoint
Death, MI or stroke
Time of follow up (months) Proportion of events Pioglitazone Placebo
HR 0.90 (CI 0.80-1.02) P=0.095
Time of follow up (months) Proportion of events
HR 0.84 (CI 0.72-0.98) P=0.027
Patients (n=5238) with type 2 diabetes with macrovascular disease Pioglitazone vs. Placebo as add on therapy
Kernan et al New Engl J Med 2016; 374:1371
Patient characteristics No 3 876 Age (mean; years) 63 Males (%) 65 History Ischemic stroke or TIA Type 2 diabetes No HOMA-index Insulin resistant Primary endpoint
Fatal or nonfatal stroke or nonfatal MI
Diabetes Pioglitazone 3.8% Placebo 7.7% HR 0.48 95%CI 0.33-0.69 p<0.001
Young et al Circulation 2017; 135:1882
Patient characteristics No 3 876 Age (mean; years) 63 Males (%) 65 History Ischemic stroke or TIA Cor artery disease (%) 12 Type 2 diabetes No HOMA-index Insulin resistant
Time to an acute coronary syndrome HR 0.71; 95%CI 0.54-94 p=0.02
Impact on MI type 1 Not on MI type 2
IGT 20% DM 19%
Screening
R
Lifestyle - reinforced Lifestyle – reinforced + SGLT-2 inh / GLP-1 RA / Pioglitazone
Glycaemic development annually Cardiovascular events finally CV-death, MI, PAD, HF…
Cardiology Diabetology Primary care …