How to manage Diabetes in the acute vascular accident ? Ines KHOCHTALI (Monastir, Tunisia) INTRODUCTION • Diabetes : Huge problem • Under diagnosed • Cardiovascular (CV) disease is the primary complication of diabetes; approximately 65% of deaths in people with diabetes are due to heart disease. • Three-quarters are attributable to coronary artery disease and the remainder to cerebrovascular or peripheral vascular events. • Hyperglycemia is an independant predictor of mortality • Each 1% increase in HbA1c poses 28% relative risk of cardiovascular event Lancet 2000: 355: 773-8 Cardiovascular mortality 100 80 60 Survey (%) 40 No diabetes, no MI (n=1,304) diabetes no MI (n=890) No diabetes with MI (n=69) Diabetes with MI (n=169) 20 0 0 1 2 3 4 YEARS Haffner SM et al. N Engl J Med. 1998;339:229-234. 5 6 7 8 Pathophysiology: Diabetic coronary heart disease • • • • • • Diffuse Woman Silent Ischemic myocardial Other cardiovascular risk factors High mortality Restenosis DIABETES AND STROKE – Independent risk factor for ischaemic stroke – Elevated blood glucose in the early phase of stroke is associated with death and poor recovery – BP in patients with diabetes should be <130/80mmHg Clinical Case • Mr M, 65 year-old-man Diabetes since 11 years : metformin : 2000 mg/day, glibenclamide: 10 mg/day Hypertension since 4 years : nifedipine : 40 mg/day Smoking : 10 cigarettes / day Chest pain ICU Diagnosis: acute MI : ST + Glycemia: 13 mmol/l, Hb A1c: 9%, TRP positive, creatinin: 1OO µmol/l, LDLc: 1.4 g/l, Tg: 1.1 g/l, HDL c: 0.5 g/l What do you recommend ? • Question n°1: glycemia goal? •Question n°2: which treatment ? Diabetes : prognosis factor of mortality STEMI, ST-segment elevation myocardial infarction UA/NSTEMI, unstable angina/ non-STEMI. JAMA, 2007—Vol 298, No. 7 Diabetes : prognosis factor of mortality Diabetes Metab Res Rev 2005; 21: 143–149. Glycemic Threshold in CABG Portland data suggest BG: < 150 mg/dl for mortality < 175 mg/dl for infection < 125 mg/dl for atrial fibrillation Furnary et al J Thorac Cardiovasc Surg 2003;123:1007-21 TREATMENT: insulin or oral anti diabetic?? Insulin > OAD ??? DIGAMI Study Diabetes, Insulin Glucose Infusion in Acute Myocardial Infarction(1997) • • • • • • 600 patients Acute MI With BG > 200 mg/dl Intensive Insulin Treatment IV Insulin For > 24 Hours Four Insulin Injections/Day For > 3 Months Reduced Risk of Mortality By: 28% Over 3.4 Years 51% in Those Not Previous Diagnosed JACC1997 Cardiovascular Risk Mortality After MI Reduced by Insulin Therapy in the DIGAMI Study Standard treatment IV Insulin 48 hours, then All Subjects .7 .5 .5 .4 .3 .3 .2 .2 .1 .1 0 0 1 2 3 4 Years of Follow-up (N = 272) Risk reduction (51%) P = .0004 .6 .4 0 Low-risk and Not Previously on Insulin .7 (N = 620) Risk reduction (28%) P = .011 .6 5 4 injections daily 0 1 2 3 4 Years of Follow-up 5 Malmberg, et al. BMJ. 1997;314:1512-1515. 6-11 DIGAMI 2 • DESIGN: DIGAMI 2 : multicentre, prospective randomized, open trial with blinded evaluation comparing three different management strategies in patients with type 2 diabetes and acute myocardial infarction. • 1253 patients , 48 centers , 2 years • Group 1: 24 h insulin– glucose infusion followed by a subcutaneous insulin-based longterm glucose control (n=474) • Group 2: insulin – glucose fellowed by standard therapy (n=473) • Group 3: routine therapy (n= 306) HbA1C : 7,2% in 3 groups JACC 2002 Malmberg K, Eur Heart Journ 2005 , 26, 650 DIGAMI 2 P > .05 Effect of glucose insulin- potassium infusion : GIK The CREATE-ECLA Randomized Controlled Trial Purpose: To determine the effect of high-dose GIK infusion on mortality in patients with STEMI. Methods : Randomized controlled trial conducted in 470 centers worldwide among 20 201 patients with STEMI who presented within 12 hours of symptom onset. The mean age of patients was 58.6 years, and evidence-based therapies were commonly used. Main Outcome Measures Mortality, cardiac arrest, cardiogenic shock, and reinfarction at 30 days after randomization Conclusion: In this large, international randomized trial, high-dose GIK infusion had a neutral effect on mortality, cardiac arrest, and cardiogenic shock in patients with acute STEMI. JAMA 2005: 293(4):437-446 Intensive Insulin Therapy in Critically Ill Patients—Morbidity and Mortality Benefits Insulin therapy: post cardiac surgery Percent Reduction Mortality Sepsis Dialysis Blood Transfusion Polyneuropathy 0 -10 -20 -30 -40 -50 34% 46% 41% 44% 50% -60 van den Berghe G, et al. N Engl J Med. 2001;345:1359–1367. QUEL ANTIDIABETIQUE ORAL ? Sulfonylureas and ischemic events Sulfonylureas and ischemic events Stimulus physiologique Pharmacologic Action Therapeutic Response Pancreatic -cell glucose Close channels Insulin secretion Open channels Ischemic preconditioning Tissu SUR 1 myocardium O2 SUR 2A Ii t Sulfonylureas and ischemic events Pharmacological agents that open K-ATP channels have a protective effect similar to that of prior ischemia, and agents closing the channels oppose preconditioning by ischemia. -Glimepiride, gliclazide, glibenclamide ( glyburide) METFORMIN 1. Reduction of excessive Hepatic Glucose Output 2. Stimulation of insulin-mediated muscle glucose uptake -glycogen synthesis is increased 3. Weight loss 4. Increased fibrinolytic activity 5. Decreased platelet aggregability • Contraindications: Patients with hepatic or renal impairment, cardiac failure, patients > 75 yrs of age. Stable period ? • Question n°1: glycemia goal? •Question n°2: which treatment ? Any Diabetes Related Endpoint ( UKPDS) 1401 of 3867 patients (36%) % of patients with an event 60% Conventional (1138) Intensive (2729) p=0.029 40% 20% Risk reduction 12% (95% CI: 1% to 21%) 0% 0 3 6 9 12 Years from randomisation 15 N Engl J Med 2008;359:1577-89. METAANALYSE Differences between the ACCORD and ADVANCE studies Characteristic ACCORD ADVANCE Outcome (intensive vs standard) •Median HbA1C at study end (%) •Death from any cause (%) •Death from cardiovascular cause (%) •Nonfatal MI (%) •Nonfatal stroke (%) •Major/severe hypoglycemia (%/y) •Weight gain (kg) •Current smoking (%) 6.4 vs 7.5* 6.4 vs 7.0* 5.0 vs 4.0* 8.9 vs 9.6 2.6 vs 1.8* 4.5 vs 5.2 3.6 vs 4.6* 2.7 vs 2.8 1.3 vs 1.2 3.8 vs 3.8 3.1 vs 1.0* 0.7 vs 0.4 3.5 vs 0.4 0.0 vs -1.0* 10 vs 10 8 vs 8 N Engl J Med 2008; 358:2630-2633. Glycemic Recommendations for Non-Pregnant Adults with Diabetes (1) A1C <7.0%* Preprandial capillary plasma glucose 70–130 mg/dl* (3.9–7.2 mol/l) Peak postprandial capillary plasma glucose† <180 mg/dl* (<10.0 mmol/l) ADA. V. Diabetes Care. Diabetes Care 2011;34(suppl 1):S19. ADA. V. Diabetes Care. Diabetes Care 2011;34(suppl 1):S21. Table 10. Recommendations: Glycemic Goals in Adults (3) • Conversely, less stringent A1C goals may be appropriate for patients with –History of severe hypoglycemia, limited life expectancy, advanced microvascular or macrovascular complications, extensive comorbid conditions – Those with longstanding diabetes in whom the general goal is difficult to attain despite diabetes selfmanagement education, appropriate glucose monitoring, and effective doses of multiple glucose lowering agents including insulin (C) ADA. V. Diabetes Care. Diabetes Care 2011;34(suppl 1):S19. ADA recommendations ADA JANV 2010 Avoid TZD treatment In patients with symptomatic heart failure (C) Metformin use in patients with stable CHF Indicated if renal function is normal Should be avoided in unstable or hospitalized patients with CHF (C) Effets du GLP-1 POST PRANDIAL GLYCEMIA AND CVD • Acarbose: CVD: - 49 % STOP-NIDDM Trial demonstrated that, in subjects with IGT, acarbose treatment was effective in reducing the risk of type 2 diabetes. • It also suggested that it was associated with a reduction in hypertension and cardiovascular disease (HR 0,62 p< 0,004). JAMA 2003 Recommendations: Hypertension/Blood Pressure Control Goals • A goal systolic blood pressure <130 mmHg is appropriate for most patients with diabetes (C) • Based on patient characteristics and response to therapy, higher or lower systolic blood pressure targets may be appropriate (B) • Patients with diabetes should be treated to a diastolic blood pressure <80 mmHg (B) ADA. VI. Prevention, Management of Complications. Diabetes Care 2011;34(suppl 1):S27. Recommendations: Hypertension/Blood Pressure Control • Pharmacologic therapy for patients with diabetes and hypertension – Pair with a regimen that includes either an ACE inhibitor or angiotensin II receptor blocker – to achieve blood pressure targets – Thiazide diuretic should be added to those with estimated GFR ≥30 ml x min/1.73 m2 – calcium channel blockers – Beta-blockers If past ACS ADA. VI. Prevention, Management of Complications. Diabetes Care 2011;34(suppl 1):S27. Recommendations: Dyslipidemia/Lipid Management Screening • In adults with low-risk lipid values • LDL cholesterol <100 mg/dl • HDL cholesterol >50 mg/dl • Triglycerides <150 mg/dl) • In individuals with overt CVD – Lower LDL cholesterol goal of <70 mg/dl (1.8 mmol/l), using a high dose of a statin, (B) ADA. VI. Prevention, Management of Complications. Diabetes Care 2011;34(suppl 1):S29. Statins: Reduction in 10-Year Risk of Major CVD* in Patients with Diabetes Secondary Prevention Relative risk reduction Absolute risk reduction LDL cholesterol reduction, mg/dl (%) Statin dose and comparator Risk reduction 4S-DM1 Simvastatin 20-40 mg vs. placebo 85.7 to 43.2% 50% 42.5% 186 to 119 (36%) ASPEN2 Atorvastatin 10 mg vs. placebo 39.5 to 24.5% 34% 12.7% 112 to 79 (29%) Simvastatin 40 mg vs. placebo 43.8 to 36.3% 17% 7.5% 123 to 84 (31%) Pravastatin 40 mg vs. placebo 40.8 to 35.4% 13% 5.4% 136 to 99 (27%) Atorvastatin 80 mg vs. 10 mg 26.3 to 21.6% 18% 4.7% 99 to 77 (22%) Studyref. HPS-DM3 CARE-DM4 TNT-DM5 *Endpoints=CHD death, nonfatal MI ADA. VI. Prevention, Management of Complications. Diabetes Care 2011;34(suppl 1):S30. Table 11. Recommendations: Antiplatelet Agents (3) • Use aspirin therapy (75–162 mg/day) – Secondary prevention strategy in those with diabetes with a history of CVD (A) • For patients with CVD, documented aspirin allergy – Clopidogrel (75 mg/day) should be used (B) • Combination therapy with ASA (75–162 mg/day) and clopidogrel (75 mg/day) – Reasonable for up to a year after an acute coronary syndrome (B) ADA. VI. Prevention, Management of Complications. Diabetes Care 2011;34(suppl 1):S31. Recommendations: Coronary Heart Disease Treatment (1) • To reduce risk of cardiovascular events in patients with known CVD, use – ACE inhibitor* (C) – Aspirin* (A) – Statin therapy* (A) • In patients with a prior MI – Beta-blockers should be continued for at least 2 years after the event (B) ADA. VI. Prevention, Management of Complications. Diabetes Care 2011;34(suppl 1):S32. Recommendations: Nephropathy • To reduce risk or slow the progression of nephropathy –Optimize glucose control (A) –Optimize blood pressure control (A) Screening the other complications +++and the other cardio vascular risks ADA. VI. Prevention, Management of Complications. Diabetes Care 2011;34(suppl 1):S33. ADA Recommendations: • Smoking : Advise all patients not to smoke (A) • Include smoking cessation counseling and other forms of treatment as a routine component of diabetes care (B) Physical Activity : Advise people with diabetes to perform at least 150 min/week of moderate-intensity aerobic physical activity (50-70% of maximum heart rate) (A) Diabetes Self-Management Education Life style ADA. VI. Prevention, Management of Complications. Diabetes Care 2011;34(suppl 1):S32. Clinical Case • Mr M, 65 year- old -man Diabetes since 11 years : metformin : 2000 mg/day, glibenclamide: 10 mg/day Hypertension since 4 years : nifedipine : 40 mg/day Smoking : 10 cigaretts / day Chest pain ICU Diagnosis: acute MI : ST + Glycemia: 13 mmol/l, Hb A1c: 9%, TRP positive, creatinin: 1OO µmol/l, LDLc: 1.4 g/l, Tg: 1.1 g/l, HDL c: 0.5 g/l What do you recommend ? Clinical Case • Diabetes : • metformin : 2000 mg/day, • Stop glibenclamide: 10 mg/day and switch on gliclazide, glimepiride or insulin Hypertension: stop nifedipine : SRAA blocker and Betablockers Antiplatelet Agents +++ Lipids : statins stop smoking Education and screening of the other complications and risks • MI : ST + : cardilogist recommends? Conclusion • Diabetes Mellitus is associated with adverse cardiovascular prognosis. • DM have added risk of cardiovascular mortality after ACS. •PRIMARY Common conditions with type 2 ANDcoexisting SECONDARY diabetes (e.g., hypertension, dyslipidemia) are PREVENTION clear risk factors for CVD • Perspectives: how to reduce the mortality of patients with DM and ACS to a rate comparable to patients without DM?