ESC GUIDELINES ON DIABETES AND CARDIOVASCULAR DISEASES Pr. Michel KOMAJDA Institute of Cardiology - IHU ICAN Pitie Salpetriere Hospital - University Pierre and Marie Curie, Paris (France)
DEFINITION A metabolic disorder characterized by chronic hyper glycaemia resulting from defects in insulin secretion or action or both. Fasting plasma glucose 7 mmol/l. HbA1C 6.5%. On two consecutive measures. 2 hour post load plasma glucose 11.1 mmol/l.
Cardiovascular risk assessment DM = high cardiovascular risk. DM + one other risk factor / organ damage = very high risk. ESC Guidelines, CV Prevention, 2012
Risk Assessment Classical risk factors (smoking, BP, lipids, lifestyle, family history). Glycaemic status. Macro vascular disease (coronary / cerebrovascular / HF / PAD). Micro vascular disease (retinopathy / nephropathy / neuropathy). Arrhythmias.
Multifactorial management of CV risk Patient education and empowerment. Life style advice. Smoking cessation. Personalised treatment of blood pressure, lipids, glycemic control and thrombotic risk.
Steno-2 Gaede P et al., N Engl J Med, 2008;358:580-91
Cardiovascular safety of glucose lowering agents METFORMIN? + SULPHONYLUREA? INSULIN? + (ORIGIN) PIOGLITAZONE GLINIDES = GLP1 AGONISTS DPP4 Inhibitors Na Glucose Co Transporter 2 (SGLT-2) inhibitors + (PRO ACTIVE) - HF + (ELIXA) + (SAVOR EXAMINE-TECOS) HF - SAVOR HF +TECOS?( + EMPAREG)
Proportion with event Proportion with event UKPDS 80: The Legacy Effect of Intensive Glucose Control Myocardial Infarction Myocardial Infarction 1.0 0.8 0.6 0.4 0.2 0 Conventional (n = 1138) Sulfonylurea/Insulin (n = 2729) 15% reduction P = 0.01 0 5 10 15 20 25 Years since randomization Conventional Therapy 1138 1013 857 578 221 20 Sulfonylurea-Insulin 2729 2488 2097 1459 577 66 1.0 0.8 0.6 0.4 0.2 Conventional (n = 411) Metformin (n = 342) 33% reduction P = 0.005 0 0 5 10 15 20 25 Years since randomization Conventional Therapy 411 360 311 213 95 4 Metformin 342 317 274 214 106 16 In 10-yr post-trial follow-up, between-group A1c differences lost after 1 yr. Intensive treatment with sulfonylurea and/or insulin also resulted in a persistent 24% reduction in microvascular disease (P = 0.001) Holman, RR. et al. N Engl J Med. 2008;359:1577.
N Engl J Med, 2012 Jul 26;367(4):319-28 O R I G I N
CV Death, MI or Ischemic CVA (%) Primary Endpoint 14 12 10 8 6 4 2 HR 1.00 95% CI 0.89-1.12 p<0.001 (non-inferiority) p=0.99 (superiority) 2y KM Saxagliptin 7.3% Placebo 7.2% 0 0 6 12 18 24 Months Placebo 8212 7983 7761 7267 4855 Saxagliptin 8280 8071 7836 7313 4920
EXAMINE White WB, N Engl J Med, September 2, 2013 - DOI: 0.1056/NEJMOA1305889
Percent of patients with an event PRIMARY COMPOSITE CARDIOVASCULAR OUTCOME* PER PROTOCOL ANALYSIS FOR NONINFERIORITY Placebo Sitagliptin HR (95% CI): 0.98 (0.88, 1.09) Noninferiority P<0.001 0 4 8 12 18 24 30 36 42 48 0 4 8 12 18 24 30 36 42 48 Patients at risk: Months in the trial Sitaglipin 7,257 6,857 6,519 6,275 5,931 5,616 3,919 2,896 1,748 1,028 Placebo 7,266 6,846 6,449 6,165 5,803 5,421 3,780 2,743 1,690 1,005 Median FU 2 years F. Van de Werf (Leuven, BE), FP 4128 * CV death, nonfatal MI, nonfatal stroke, hospitalization for unstable angina
Meta-analysis of Intensive Control of Glucose (n=33 040 patients) -5 Trials UKPDS / PROactive / ADVANCE / VADT / ACCORD Non fatal MI HbA 1 C = 0.9% Death HbA 1 C = 0.9% Ray KK et al, Lancet 2009;373:1765-1772
Effects of more VS less intensive glycaemic control Number of events Trials All-cause mortality ACCORD ADVANCE UKPDS VADT Overall Cardiovascular death ACCORD ADVANCE UKPDS VADT Overall (annual event rate, %) more less intensive 257 (1.41 ) 203 ( 1.14 ) 498 ( 1.86 ) 533 ( 1.99 ) 123 ( 0.13 ) 53 ( 0.25 ) 102 ( 2.22 ) 95 ( 2.06 ) 980 884 135 (0.79 ) 94 ( 0.56 ) 253 ( 0.95 ) 289 ( 1.08 ) 71 ( 0.53 ) 29 ( 0.52 ) 38 ( 0.83 ) 29 ( 0.63 ) 497 441 intensive HbA1c -1.01-0.72-0.66-1.16-0.88-1.01-0.72-0.66-1.16-0.88 (%) Favors more intensive Favors less intensive Hazard ratio (95% CI) 1.22 (1.01 1.46) 0.93 (0.83-1.06) 0.96 (0.70-1.33) 1.07 (0.81-1.42) 1.04 (0.90 1.20) (Q=5.71, p =0.13, I 2 =47.5%) 1.35 (1.04-1.76) 0.88 (0.74-1.04) 1.02 (0.66-1.57) 1.32 (0.81 2.14) 1.10 (0.84 1.42) (Q=8.61, p =0.04, I 2 =65.1%) Non-cardiovascular death ACCORD ADVANCE UKPDS VADT Overall 115 (0.63 ) 98 ( 0.55 ) 245 ( 0.92 ) 244 ( 0.91 ) 52 ( 0.39 ) 24 ( 0.43 ) 64 (1.40 ) 66 ( 1.43 ) 476 432-1.01-0.72-0.66-1.16-0.88 1.14 (0.87-1.49) 1.00 (0.84-1.20) 0.90 (0.55-1.46) 0.97 (0.69-1.36) 1.02 (0.89 1.18) (Q=0.99, p =0.80, I 2 =0.0%) 0.5 1.0 2.0 Hazard ratio (95% CI) Turnbull et al Diabetologia August 09 (CONTROL collaboration)
Intensive Glucose Control Microvascular disease Macrovascular Medium Term Macrovascular Long Term (DCCT UKPDS) (ACCORD, ADVANCE, VADT, ORIGIN) except recent DM w/o CVD (DCCT UKPDS) Individualized Care
Glycaemic control individualised care HbA1c <53 mmol/mol (7.0%) HbA1c 42 48 mmol/mol (6.0 6.5%) in selected patients with short disease duration long life expectancy no significant cardiovascular disease HbA1c <58 64 mmol/mol (7.5-8.0%) in elderly patients with long-standing and/or complicated disease All targets to be achieved without hypoglycaemia or other adverse effects
Heart Failure T2 DM is a major risk factor for HF. Combination of T2 DM and HF increases substantially the risk of mortality. Pharmacological management similar to non DM. Some antidiabetic drugs contra indicated (glitazones).
Individual Endpoints ITT Population 2-year KM rate (%) Placebo (N=8,212) Saxagliptin (N=8,280) HR p value for superiority CV Death 2.9 3.2 1.03 (0.87-1.22) 0.72 MI 3.4 3.2 0.95 (0.80-1.12) 0.52 Ischemic Stroke 1.7 1.9 1.11 (0.88-1.39) 0.38 Hosp for Cor. Revasc 5.6 5.2 0.91 (0.80-1.04) 0.18 Hosp for UA 1.0 1.2 1.19 (0.89-1.60) 0.24 Hosp for Heart Failure 2.8 3.5 1.27 (1.07-1.51) 0.007 All-Cause Mortality 4.2 4.9 1.11 (0.96-1.27) 0.15
Percent of patients with an event TIME TO FIRST HOSPITALIZATION FOR HEART FAILURE* Placebo Sitagliptin HR (95% CI): 1.00 (0.84 1.20) P = 0.95 Patients at risk: 0 4 8 12 18 24 30 36 42 48 Months in the trial Sitaglipin 7,332 7,189 7,036 6,917 6,780 6,619 4,728 3,515 2,175 1,324 Placebo 7,339 7,204 7,025 6,903 6,712 6,549 4,599 3,443 2,131 1,315 F. Van de Werf (Leuven, BE), FP 4128 * ITT population
Blood pressure control in diabetes Recommendations Class a Level b Blood pressure control is recommended in patients with DM and hypertension to lower the risk of cardiovascular events. It is recommended that a patient with hypertension and DM is treated in an individualized manner, targeting a blood pressure of < 140/85 mmhg. It is recommended that a combination of blood pressure lowering agents is used to archiveve blood pressure control. A RAAS blocker (ACE-I or ARB) is recommended in the treatment of hypertension in DM, particularly in the presence of proteinuria or microalbuminuria. Simultaneous administration of two RAAS blockers should be avoided in patients with DM. I I I I III A A A A B
Blood Pressure Meta-analysis 13 RCTs Intensive BP 135 Standard BP 140 All cause mortality HR = 0.90 Stroke HR = 0.83 Serious adverse events HR = 1.40 Bangalore, Circulation, 2011;123, 2795
Blood pressure control treatment targets - individualised care Lowering systolic blood pressure 140/ 85 mm Hg has favourable cardiovascular effects. A systolic blood pressure target <130 mm Hg may be considered in the presence of nephropathy with overt proteinuria. A blood pressure <130/80 mm Hg may increase the risk for adverse events in elderly patients and those with a long diabetes duration. The risk/benefit balance of intensive blood pressure management needs to be carefully considered and individualised.
Recommendations for lipid control in patients with diabetes Recommendations Class Level Statin therapy is recommended in patients with T1DM and T2DM at very high risk (i.e. if combined with documented CVD, severe CKD or with one or more CV risk factors and/or target organ damage) with an LDL-C target of <1.8 mmol/l (<70 mg/dl) or at least a 50% LDL-C reduction if this target goal cannot be reached. Statin therapy is recommended in patients with T2DM at high risk (without any other CV risk factor and free of target organ damage) with an LDL-C target of <2.5 mmol/l (<100 mg/dl). Statins may be considered in T1DM patients at high risk for cardiovascular events irrespective of the basal LDL-C concentration. It may be considered to have a secondary goal of non HDL-C <2.6 mmol/l (<100 mg/dl) in patients with DM at very high risk and of <3.3 mmol/l (<130 mg/dl) in patients at high risk. Intensification of statin therapy should be considered before the introduction of combination therapy with the addition of ezetimibe. The use of drugs that increase HDL-C to prevent CVD in T2DM is not recommended. I I IIb IIb IIa III A A C C C A
Options for Revascularisation 1. Acute coronary syndromes: Early revascularization (as in non DM). 2. Stable coronary artery disease : CABG preferred option if myocardial area at risk is large. PCI with DES may be performed for symptom control in single and two-vessel disease.
Event free survival (%) Myocardial revascularisation vs. medical therapy in people with diabetes 100 80 Event free survival in the BARI 2 D study Revascularisation 77% 60 Medical therapy 76% 40 58% of medical patients did not need revascularisation during follow-up 20 0 0 1 2 3 4 5 Follow-up (years) BARI 2D Study group New Engl J Med 2009; 360: 2503
Event free survival (%) Myocardial revascularisation vs. medical therapy in people with diabetes 100 Event free survival in the BARI 2 D study CABG stratum 80 Revascularisation 78% Medical therapy 70% 60 p = 0.01 40 20 Compared to medical treatment alone prompt revascularisation decreased major CV events in the CABG stratum 0 0 1 2 3 4 5 Follow up (years) BARI 2D Study group New Engl J Med 2009; 360: 2503
CABG vs PCI Clinical Evidence Meta-analysis PCI diabetes (bare metal stents) CABG diabetes CABG no diabetes PCI no diabetes (BMS) 1.233 patients with Diabetes Hlatky et al Lancet 2009: 1190
Death, myocardial infarction, or stroke (%) Death from any cause (%) CABG vs. PCI in people with diabetes The FREEDOM trial Primary Outcome Death 60 50 p=0.005 by log rank test 5-year event rate 26.6 vs.18.7% 60 50 p=0.049 by log rank test 5-year event rate 16.3 vs.10.9% 40 40 30 PCI 30 20 10 0 CABG 0 1 2 3 4 5 Years since randomization 7.9% 20 10 0 PCI CABG 0 1 2 3 4 5 Years since randomization 5.4% Farkouh et al New Engl J Med 2012; 367: 2375
Revascularisation in people with diabetes Recommendations Class Level Optimal medical treatment should be considered as preferred treatment in patients with stable CAD and DM unless there are large areas of ischaemia or significant left main or proximal LAD lesion. CABG is recommended in patients with DM and multivessel or complex (SYNTAX Score >22) CAD to improve survival free from major cardiovascular events. PCI for symptom control may be considered as an alternative to CABG in patients with DM and less complex multivessel CAD (SYNTAX score 22) in need of revascularization. Primary PCI is recommended over fibrinolysis in DM patients presenting with STEMI if performed within recommended time limits. In DM patients subjected to PCI, DES rather than BMS are recommended to reduce risk of target vessel revascularization. Renal function should be carefully monitored after coronary angiography/pci in all patients on metformin. If renal function deteriorates in patients on metformin undergoing coronary angiography/pci it is recommended to withhold treatment for 48 h or until renal function has returned to its initial level. IIa I IIb I I I I B A B B A C C
Recommendation for antiplatelet therapy in people with diabetes Recommendations Class Level Antiplatelet therapy with aspirin in DM-patients at low CVD risk is not recommended. Antiplatelet therapy for primary prevention may be considered in high risk patients with DM on an individual basis. Aspirin at a dose of 75-160 mg/day is recommended as secondary prevention in DM. III IIb I A C A A P2Y 12 receptor blocker is recommended in patients with DM and ACS for 1 year and in those subjected to PCI (duration depending on stent type). In patients with PCI for ACS preferably prasugrel or ticagrelor should be given. I A Clopidogrel is recommended as an alternative antiplatelet therapy in case of aspirin intolerance. I B
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