Glycemic control a matter of life and death Linda Garcia Mellbin MD PhD Specialist in Cardiology & Internal medicine Dep of Cardiology Karolinska University Hospital /Karolinska Institutet
Mortality (%) The Swedish CCU registry 1995-2006 Time trends in 1-year mortality in patients with and without diabetes Diabetes Yes No 1995 1997 1999 2001 2003 2005 2007 (Norhammar et al Heart J 2007; 93:1577 ) (Norhammar et al data on file 2003-2006)
Admission glucose predicts mortality in MI patients without known diabetes Event free survival (%) 100 80 60 40 P-glucose median 7.4 mmol/l P-glucose > median 7.4 mmol/l 20 0 2P = 0.0029 (Log-Rank test) 0 3 6 9 12 15 18 21 24 27 months (Norhammar et al Diabetes Care 1999, 22: 1827)
Diabetes and cardiovascular disease The impact of increasing HbA1c in UKPDS Hazard ratio 10 1 0.5 Fatal and non-fatal MI P <0.0001 14% rise per 1% Fatal and non-fatal stroke P <0.035 12% rise per 1% Amputation/Death from PVD Heart failure Hazard ratio 10 1 0.5 P <0.0001 43% rise per 1% 5 6 7 8 9 10 HbA1 c (%) P <0.021 16% rise per 1% 5 6 7 8 9 10 (UKPDS Brit Med J 2000;321:405)
Linking dysglycemia to cardiovascular disease IGT Insulin resistance Postprandial hyperglycemia Oxidative stress Cardiovascular disease -cell impairment Diabetes mellitus (Ceriello & Motz Aterioscler Thromb Vasc Biol 2004;22:816)
Glycemic control Evidence for impact on cardiovascular events Any macrovascular Cardiac Peripheral Cerebrovascular with CAD Diabetes type 1 Diabetes type 2 Incidence Rate Ratio (Stettler C et al. Am Heart J 2006;152: 27)
Glycemic control Impact on cardiovascular events in type 1 diabetes Cumulative incidence of predefined cardiovascular events in the Diabetes Control and Complications Trial (DCCT-EDIC) CV death, MI or Stroke RR 57%; p=0.02 Years since entry At risk Intensive 705 686 640 118 Convent 721 694 637 96 (Nathan DM et al. New Engl J Med 2005;353: 264)
Glucose Lowering Intensity and CVD Trials in People with Dysglycemia Yrs from Dx -10-5 0 5 10 15 UKPDS DIGAMI 2 ACCORD ADVANCE VADT Microvascular complications Macrovascular complications High IFG &/or IGT Type 2 Diabetes (T2DM) Dysglycemia - - - - - - - - - - - - - - - - - - - - - - - (Adapted after Gerstein)
Intensive Glucose Lowering in Type 2 Diabetes UKPDS Extended study protocol Metformin n=279 n=309 Myocardial infarction Total mortality p=0.01 p=0.01-33% p=0.005-27% p=0.002 Conventional n=880 n=2118 Myocardial Infarction Total mortality p=0.052 p=0.44-15% p=0.01-13% p=0.007 SU+insulin (Holman et al New Engl J Med 2008;359:1577) 1977-1991 1997 2007
Glycemic control Patients with myocardial infarction and type 2 diabetes Long-term mortality in DIGAMI 1 Reduction in HbA1c 1% 0.7 0.6 0.5 Mortality Mean follow-up 3.4 years (1.6-5.6) Controls Intensive 0.4 0.3 0.2 0.1 0 RR = 0.72 [0.92-0.55] p = 0.011 Absolute reduction 11% 0 1 2 3 4 5 Year (Malmberg for DIGAMI study group Brit Med J 1997, 314:1512)
Event rate (%) DIGAMI 2 Death/reinfarction/stroke Suspect MI + Type 2 diabetes or B-glucose >11 mmol/l 45 40 35 30 25 20 15 10 5 0 Number at risk Group 1 Group 2 Group 3 (Malmberg et al Eur Heart J 2005;26:650) 0 Group 1 vs Group 3 HR = 1.22 (0.95-1.56) p = 0.115 474 473 367 381 299 317 254 261 202 225 154 170 87 91 306 241 214 175 145 119 80 Group 1 (insulin+insulin) Group 2 (insulin+conventional) Group 3 (conventional) 0.5 1.0 1.5 2.0 2.5 3.0 Years
Blood glucose over time by treatment group mmol/l 20 18 16 14 12 10 8 6 4 2 0 * Baseline 24 h 3 6 12 18 24 30 36 months No Group 1 469 454 329 313 295 228 197 144 114 Group 2 469 452 331 320 304 219 195 151 108 Group 3 304 282 214 199 184 154 125 98 77 Group 1 Group 2 Group 3 (Malmberg, Rydén et al Eur Heart J 2005;26:650) 28/07/2010 12
DIGAMI 2 Effect of different glucose lowering treatments after hospital discharge 1 = Mortality; 2= CV-mortality; 3 = Death, nonfatal MI or stroke; 4 = nonfatal MI or stroke Metformin Sulphonylureas Insulin HR 95% CI 0.91 (0.61 1.34) 0.93 (0.60 1.43) 0.78 (0.58 1.04) 0.63 (0.42 0.95) 1.08 (0.78 1.50) 1.15 (0.82 1.64) 0.93 (0.73 1.20) 0.81 (0.57 1.14) 1.12 (0.83 1.51) 1.05 (0.75 1.46) 1.42 (1.13 1.78) 1.73 (1.26 2.37) No glucose lowering drug 1.12 0.89 (0.61 (0.76 1.64) 1.31) 1.19 0.84 (0.55 (0.78 1.82) 1.29) 0.96 1.04 (0.77 (0.71 1.30) 1.41) 0.84 1.19 (0.78 (0.55 1.28) 1.83) (Mellbin et al Eur Heart J 2008;29:166)
DIGAMI 2 Effect of different glucose lowering treatments after hospital discharge 1 = Mortality; 2= CV-mortality; 3 = Death, nonfatal MI or stroke; 4 = nonfatal MI or stroke Metformin Sulphonylureas Insulin HR 95% CI 0.91 (0.61 1.34) 0.93 (0.60 1.43) 0.78 (0.58 1.04) 0.63 (0.42 0.95) 1.08 (0.78 1.50) 1.15 (0.82 1.64) 0.93 (0.73 1.20) 0.81 (0.57 1.14) 1.12 (0.83 1.51) 1.05 (0.75 1.46) 1.42 (1.13 1.78) 1.73 (1.26 2.37) No glucose lowering drug 1.12 0.89 (0.61 (0.76 1.64) 1.31) 1.19 0.84 (0.55 (0.78 1.82) 1.29) 0.96 1.04 (0.77 (0.71 1.30) 1.41) 0.84 1.19 (0.78 (0.55 1.28) 1.83) (Mellbin et al Eur Heart J 2008;29:166)
DIGAMI 2 Effect of different glucose lowering treatments after hospital discharge 1 = Mortality; 2= CV-mortality; 3 = Death, nonfatal MI or stroke; 4 = nonfatal MI or stroke Metformin Sulphonylureas Insulin HR 95% CI 0.91 (0.61 1.34) 0.93 (0.60 1.43) 0.78 (0.58 1.04) 0.63 (0.42 0.95) 1.08 (0.78 1.50) 1.15 (0.82 1.64) 0.93 (0.73 1.20) 0.81 (0.57 1.14) 1.12 (0.83 1.51) 1.05 (0.75 1.46) 1.42 (1.13 1.78) 1.73 (1.26 2.37) No glucose lowering drug 1.12 0.89 (0.61 (0.76 1.64) 1.31) 1.19 0.84 (0.55 (0.78 1.82) 1.29) 0.96 1.04 (0.77 (0.71 1.30) 1.41) 0.84 1.19 (0.78 (0.55 1.28) 1.83) (Mellbin et al Eur Heart J 2008;29:166)
DIGAMI 2 Effect of newly instituted insulin treatment n=317; 245 randomised to insulin = 77%; adjusted HR % 25 20 Insulin No Insulin Mortality % 25 20 Insulin No Insulin New MI/Stroke 15 15 10 10 5 HR=1.09 (0.74 1.61) p=0.6631 5 HR=1.95 (1.35 2.82) p=0.0004 0 er at risk sulin No Insulin Insulinn Number at risk 0 0 1 2 3 Years 0 1 2 3 Years Number at risk 489 317 401 261 299 187 No Insulin 143 Insulin 96 489 367 266 125 317 220 147 73 (Mellbin et al Eur Heart J 2008;29:166)
DIGAMI 2 longterm follow-up Effect of different glucose lowering treatments after hospital discharge n=1073 (Mellbin et al. Unpublished data)
DIGAMI 2 Insulin and cancer Causes of death in DIGAMI 2 Group 1 2 3 Malignances 16 (3.4) 5 (1.1) 2 (0.7) Group 1 vs group 2, P = 0.016; group 1 vs. group 3, p=0.011; group 2 vs. group 3, p = 0.471 (Malmberg, Rydén et al Eur Heart J 2005;26:650)
2009 Sep;52(9):1699-708 Insulin Dangerous or not?
Possible effects of insulin and metformin Possible negative effects of insulin Proatherogenic effect Insulin-IGF-1 axis Survival and proliferation of malignant cells Hypoglycemia
Insulin and endothelium Healthy Insulin PI3K pathway NO Vasodilatation Antiatherosclerotic
Insulin and endothelium Healthy Insulin Insulin resistence/diabetes Insulin PI3K pathway MAPK pathway ET-1 NO Vasodilatation Antiatherosclerotic Vasoconstriction Proaterosclerotic
Possible effects of insulin and metformin Possible negative effects of insulin Proatherogenic effect Insulin-IGF-1 axis Survival and proliferation of malignant cells Hypoglycemia Possible beneficial effects of metformin AMPK
Thiazolidinediones Dangerous or not? Pioglitazone (Actos ) Meta-analysis of randomized trials (19 trials, n=16 390) Treatment duration: 4 mo 3.4 years Death, Myocardial infarction, Stroke January 25, 2008 (EMEA) Rosiglitazone (Avandia ) Meta-analysis of randomized trials (4 trials, n=14 291) Treatment duration: 1 4 years Myocardial infarction New warning: the use of rosiglitazon in patients with ischaemic heart disease and/or peripheral arterial disease is not recommended. New contradiction: rosiglitazon may not be used in patients with an acute coronary syndrome as the safety and efficacy of rosiglitazon has not been demonstrated in clinical studies for this patient group. Hazard Ratio (95% CI) (Lincoff et al. JAMA 2007;298:1180) (Singh et al. JAMA 2007;298:1189) Relative Risk (95% CI)
Intensive Glucose Lowering in Type 2 Diabetes ACCORD and ADVANCE HbA1c(%) HbA1c (%) Glycemia trial (n=10 251) HbA1c <6.0% vs HbA1c 7.0-7.9% Standard Severe hypoglycemia: 1.0 vs 3.1 %/yr Intensive Time of follow up (years) Glycemia trial (n=11 140) HbA1c 6.5% vs local guidelines Severe hypoglycemia: 0.4 vs 0.7 %/yr Standard Intensive (Gerstein et al. NEJM 2008;358:2545) (Patel et al. NEJM 2008;358: 2560) Time of follow up (months)
Intensive Glucose Lowering in Type 2 Diabetes ACCORD and ADVANCE Cumulative incidence (%) Pateints with events (%) Primary outcome (MI,stroke,CV death) Follow-up median 3.4 years Drugs: Insulin 77% vs 55% Rosiglitazone 90% vs 58% HR 0.90 (CI 0.78-1.04) P=0.16 Standard Intensive Time of follow up (years) Follow-up: median 5 years Drugs: Insulin 41% vs 24 % Rosiglitazone 17% vs 11% Combined major macro- and microvasc events Standard HR 0.90 (CI 0.82-0.98) p=0.01 Intensive (Gerstein et al. NEJM 2008;358:2545) (Patel et al. NEJM 2008;358: 2560) Time of follow up (months)
Glycemic control Meta-analysis of 5 prospective randomised trials (intensive vs standard) n=33 040 Mean HbA1c difference 0.9% Non-fatal MI (17% reduction) All cause mortality 0.83 (0.75-0.93) 1.02 (0.87-1.19) (Ray K et al. Lancet 2009;373:1765)
Primary outcome subgroup analyses Subgroup Patient Events no no (Gerstein et al. NEJM 2008;358:2545)
Glucose lowering drugs GI Sulphonylurea Incretins Alfaglucosidase inhibitors Incretins Insulin Pancreas Insulin Metformin TZD Liver Metformin TZD Glucose Muscle and adipose tissue
Glucose Lowering Strategies/Drugs and CVD Trials in People with Dysglycemia Yrs from Dx -10-5 0 5 10 15 NAVIGATOR ACE TECOS PROACTIVE RECORD BARI 2D ORIGIN ALECARDIO TIDE Microvascular complications Macrovascular complications High IFG &/or IGT Type 2 Diabetes (T2DM) Dysglycemia - - - - - - - - - - - - - - - - - - - - - - - (Adapted after Gerstein)
ADA Standards of Medical Care in Diabetes 2010 General goal of HbA1c < 7% for macrovascular risk reduction Lower HbA1C goals (without adverse effects/significant hypoglycemia) Short duration of diabetes Long life expectancy No significant CVD Less stringent A1C goals History of severe hypoglycemia Limited life expectancy Advanced microvascular or macrovascular complications Extensive comorbid conditions Longstanding diabetes (when general goal is difficult to attain) (Diabetes Care 2010:33;S11)
ADA and EASD consesus 1. Well-validated core therapies At diagnosis: Lifestyle + Metformin Lifestyle + Metformin + Basal insulin Lifestyle + Metformin + Sulfonylurea Lifestyle + Metformin + Intensive insulin STEP 3 STEP 1 STEP 2 2. Less wellvalidated therapies Lifestyle + Metformin + Pioglitazone Lifestyle + Metformin + GLP-1 agonist Lifestyle + Metformin + Pioglitazone + Sulfonylurea Lifestyle + Metformin + Basal insulin (Nathan et al. Diabetes Care 2009;32:193)
Future Establish if metabolic modulation/control is beneficial or not in CAD Determine target glucose levels New treatment options New tools
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