Diabetes: The new challenge in cardiovascular risk management Lars - - 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 November 16 - 17, 2018 - Dubai, UAE Diabetes - The
Stockholm, Sweden
November 16 - 17, 2018 - Dubai, UAE
Session: Diabetes & Cardiovascular Disease: How do they relate?
Lars Rydén
Department of Medicine, Solna Karolinska Institutet Stockholm, Sweden
Dubai November 16-17, 2018
WHO Global Health Risks 2009
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%
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
Walker et al. Diabetes Care 2018;61:108
From Scottish Care Info – Diabetes database no = 272,597
Stratified for socioeconomic status no = 2,750 000
Age specific life expectancy In people 40 – 89 years
2012-2014
Men 2 4 6 2 4 6 Difference in life expectancy Years (95% CI) Women Most deprived ------------- Least deprived Midpoint of age
Estimated years of life lost due to diabetes
10-year CHD mortality/1,000 patient-years
CHD, coronary heart disease. 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.
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%
Di Loreto C et al. Diabetes Care 2005;28:1295.
+ 0.8 + 1.0 + 0.03
+ 0.1 + 3.4 + 0.1 + 0.6 + 1.0
+ 1.1 + 2.1
+ 0.1
+ 2.9
+ 5.6
+ 10.4
+ 6.3
Body weight, kg HbA1c, % RRsys, mmHg RRdia, mmHg Chol, mg/dl LDL-Chol, mg/dl HDL-Chol, mg/dl TG, mg/dl CHD risk % Waist circ., cm Walking hours/week + 0.8 + 1.0 + 0.03
+ 0.1 + 3.4 + 0.1 + 0.6 + 1.0
+ 1.1 + 2.1
+ 0.1
+ 2.9
+ 5.6
+ 10.4
+ 6.3
1,5 4 5,5 7,5 12
p<0.05
p value refers to change vs basal. CHD, coronary heart disease; Chol, cholesterol; circ, circumference; HDL-Chol, high-density lipoprotein cholesterol; LDL-Chol, low-density lipoprotein cholesterol; RRdia, diastolic blood pressure; RRsys, systolic blood pressure; TG, triglyceride. Di Loreto C et al. Diabetes Care 2005;28:1295.
Gyberg et al Cardiovasc Diabetology 2015; 14:133
Low activity (62%) Moderate activity (14%) High activity (25%) Overall activity level (mean proportion of patients)
96% 81% 79% 75% 62% 69% 65% 71% 68% 65% 68% 74% 72% 71% 64% 68% 61% 58% 56% 62% 54% 44% 20% 38% 9% 11% 8% 12% 24% 16% 19% 12% 14% 17% 14% 6% 7% 7% 12% 7% 14% 15% 15% 9% 13% 14% 31% 12% 5% 9% 13% 13% 14% 15% 16% 18% 19% 19% 19% 21% 22% 22% 24% 25% 26% 27% 29% 29% 33% 42% 49% 50%
0% 10% 20% 30% 40% 50% 60% 70% 80% 90% 100% Turkey Lithuania Ireland Slovenia Russian Fed. Spain Romania UK Sweden Greece Serbia Bulgaria Czech Rep. Latvia Ukraine Cyprus Belgium Croatia France Poland Finland Netherlands Bosnia Herzegovina Germany
Proportion of coronary patients reporting low, moderate and high physical activity
. 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
HDL, high-density lipoprotein; SBP, systolic blood pressure; UKPDS, United Kingdom Prospective Diabetes Study. Gaede P and Pedersen O. Diabetes. 2004;53 (Suppl 1):S39.
UKPDS score in the intensive arm of STENO 2 Smoking 3% SBP 11% HbA1c 13%
Total cholesterol 48%
Lipids 73%
HDL cholesterol 25%
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.
AMI, acute myocardial infarction; CI, confidence interval; yr, year. 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
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
AMI, acute myocardial infarction; CI, confidence interval; yr, year. Rawshani A et al. N Engl J Med 2018;379:633.
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
1-year mortality (%)
No diabetes Diabetes
1995 1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013 2014 2015 2016 5 10 15 20 25 30 35
Swedeheart annual report 2017
x x
Data are mean ± 95% CI. HR [95% CI] are patients with T2D vs matched controls. CI, confidence interval; CV, cardiovascular; HR, hazard ratio; yr, years. 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
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
Rydén L and the EUROASPIRE Investigators Data on file
Completion Q1 2019
By courtesy F F M Baeres Presented June -19 Presented 10/11 -19
2.1 1.5 3.0 2.1 3.2
Saxagliptin Sitagliptin Alogliptin Lixisenatide Exenatide
Rydén et al Clin Ther 2016;38:1279; ClinicalTrials.gov.
DPP 4 inhib GLP-1 RA
Type 2 diabetes high CV risk CV death MI Stroke
Trial Drug Patients FU (years) Prim endpoint Result
SGLT-2 inhibition
Empagliflozin
Zinman B et al. N Engl J Med 2015;373:2117
GLP-1RA
Liraglutide
Marso SP et al. N Engl J Med 2015;375:311
GLP-1RA
Semaglutide
Marso SP et al. N Engl J Med 2016;375:1834
SGLT-2 inhibition
Canagliflozin
Neal B et al. N Engl J Med 2017;377:644
GLP-1RA, glucagon-like peptide 1 receptor agonist; SGLT-2, sodium–glucose co-transporter-2.
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 (%)
SGLT-2 inhibition September 2015
GLP-1RA June 2016 Reduction 14% Rapid onset Heart failure-driven Reduction 13% Slow onset Mortality-driven
CI, confidence interval, CV, cardiovascular; GLP-1RA, glucagon-like peptide-1 receptor agonist; HR, hazard ratio: MI, myocardial infarction; SGLT-2, sodium–glucose co-transporter-2.
↓14% p=0.04 ↓38% p<0.0001 ↓32% p<0.0001 ↓35% p=0.0017 ↓39% p<0.001
3P-MACE1 CV death1 All-cause mortality1 HHF1 Composite renal
3P-MACE RRR 14% ARR 1.6%
p=0.04
*Incidence or worsening nephropathy, defined as progression to macroalbuminuira (urinary albumin-to-creatinine ratio >300 mg/g), a doubling of serum creatinine accompanied by an eGFR
cardiovascular; eGFR, estimated glomerular filtration rate; HHF, hospitalisation for heart failure; MACE, major adverse cardiovascular event; MDRD, Modification of Diet in Renal Disease; 3P, three-point; RRR, relative risk reduction; SGLT-2, sodium–glucose co-transporter-2. 1. Zinman B et al. N Engl J Med 2015;373:2117; 2. Wanner C et al. N Engl J Med 2016;375:323.
↓13% p=0.01 ↓22% p=0.007 ↓15% p=0.02 n.s. ↓22% p=0.003
3P-MACE RRR 13% ARR 1.9%
p=0.01
*Defined as new-onset persistent macroalbuminuria, persistent doubling of serum creatinine level, end-stage renal disease or death due to renal disease. p values refer to liraglutide vs placebo. ARR, absolute risk reduction; CV, cardiovascular; GLP-1, glucagon-like peptide-1; HHF, hospitalisation for heart failure; MACE, major adverse cardiovascular event; n.s., not significant; 3P, three-point; RRR, relative risk reduction.
3P-MACE1 CV death1 All-cause mortality1 HHF1 Composite renal
Type 2 diabetes high CV risk
Drug class Patients HbA1c Endpoint Risk reduc (%) 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
✮ Glucose lowering ✮ Weight loss ✮ Blood pressure reduction ✮ Renal protection Shared Separate
GLP-1 Receptor Agonism Slowing atherosclerosis Plaque stabilisation SGLT-2 inhibition Heart failure reduction
❖ EMPA-REG and LEADER – a paradigm shift in the treatment of type 2 diabetes ❖ SGLT-2 inhib and GLP-1 RA* – second-line drugs in patients at high risk ❖ A reasonable HbA1c target – ≤7.0–8.0% (≤53–62 mmol/mol) ❖ DPP-4 inhibitors – safe but some to be avoided in heart failure-sensitive patients ❖ An immediate possibility to treat a sizeable and vulnerable patient population
*Included following label updates for cardiovacular benefits in patients with type 2 diabetes. DPP-4, dipeptidyl peptidase-4. American Diabetes Association. Diabetes Care. 2018;41 (Suppl 1):S1; Draft ADA/EASD Consensus Report 2018. Presented at the American Diabetes Association 78th Scientific Sessions, June 22–26, 2018, Orlando, Florida, USA.
In patients with type 2 diabetes and established atherosclerotic cardiovascular disease begin with lifestyle management and metformin then choose an agent proven to reduce major adverse cardiovascular events and cardiovascular mortality (currently empagliflozin and liraglutide) after considering drug-specific and patient factors
Evidence level A: Supportive evidence from well conducted trials
ADA, American Diabetes Association; CVOT, cardiovascular outcomes trial American Diabetes Association. Diabetes Care 2018;41(Suppl 1):S73–S85
Lifestyle management
Combination injectable therapy Monotherapy
Metformin Not at target HbA1c after ~3 months
Basal insulin¶, GLP-1RA§, mealtime insulin**
Dual therapy*† Triple therapy*‡
SU TZD SGLT-2i Insulin SU TZD DPP-4i GLP-1RA Insulin SU TZD SGLT-2i Insulin SU DPP-4i SGLT-2i GLP-1RA Insulin TZD DPP-4i SGLT-2i GLP-1RA Insulin TZD DPP-4i SGLT-2i GLP-1RA Not at target HbA1c after ~3 months Not at target HbA1c after ~3 months SGLT-2i DPP-4i TZD SU Insulin (basal) GLP-1RA
Disease progression
*Order is not meant to denote any specific preference. Choice dependent on variety of patient- and disease-specific factors; †Consider starting at this stage when HbA1c is ≥9.0% (75 mmol/mol); ‡Consider starting at this stage when HbA1c is ≥10.0% (86 mmol/mol), blood glucose is ≥300 mg/dL (16.7 mmol/L), or subject is markedly symptomatic, in which case combination injectable therapy is the preferred initial regimen. ¶Switch to basal insulin if subject on oral combination, or add basal insulin if on GLP-1RA; §Switch to GLP-1RA as alternative to basal insulin if subject on oral combination, or add GLP-1RA if on optimally titrated basal insulin; **Add mealtime insulin as alternative to GLP-1RA if subject on optimally titrated basal insulin. ADA, American Diabetes Association; ASCVD, atherosclerotic cardiovascular disease; CV, cardiovascular; DPP-4i, dipeptidyl peptidase-4 inhibitor; GLP-1RA, glucagon-like peptide-1 receptor agonist; MACE, major adverse cardiovascular event; SGLT-2i, sodium-glucose co-transporter-2 inhibitor; SU, sulphonylurea; TZD, thiazolidinedione. Adapted from: Inzucchi SE et al. Diabetes Care 2015;38:140–9; American Diabetes Association (ADA). Diabetes Care 2018;401(Suppl. 1):S73–85.
If ASCVD present, add agent proven to reduce MACE and/or CV mortality
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
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
➤ Patient-centred professional collaboration ➤ Target-driven and comprehensive management ➤ Adequate use of novel pharmacological modalities ➤ Improved understanding of true mechanisms of action ➤ Better designed CVOTs with extended periods of follow-up