Glycemic control a matter of life and death

Transcription

1 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

2 Mortality (%) The Swedish CCU registry Time trends in 1-year mortality in patients with and without diabetes Diabetes Yes No (Norhammar et al Heart J 2007; 93:1577 ) (Norhammar et al data on file )

3 Admission glucose predicts mortality in MI patients without known diabetes Event free survival (%) P-glucose median 7.4 mmol/l P-glucose > median 7.4 mmol/l P = (Log-Rank test) months (Norhammar et al Diabetes Care 1999, 22: 1827)

4 Diabetes and cardiovascular disease The impact of increasing HbA1c in UKPDS Hazard ratio Fatal and non-fatal MI P < % rise per 1% Fatal and non-fatal stroke P < % rise per 1% Amputation/Death from PVD Heart failure Hazard ratio P < % rise per 1% HbA1 c (%) P < % rise per 1% (UKPDS Brit Med J 2000;321:405)

5 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)

6 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)

7 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 Convent (Nathan DM et al. New Engl J Med 2005;353: 264)

8 Glucose Lowering Intensity and CVD Trials in People with Dysglycemia Yrs from Dx UKPDS DIGAMI 2 ACCORD ADVANCE VADT Microvascular complications Macrovascular complications High IFG &/or IGT Type 2 Diabetes (T2DM) Dysglycemia (Adapted after Gerstein)

9 Intensive Glucose Lowering in Type 2 Diabetes UKPDS Extended study protocol Metformin n=279 n=309 Myocardial infarction Total mortality p=0.01 p= % p= % p=0.002 Conventional n=880 n=2118 Myocardial Infarction Total mortality p=0.052 p= % p= % p=0.007 SU+insulin (Holman et al New Engl J Med 2008;359:1577)

10 Glycemic control Patients with myocardial infarction and type 2 diabetes Long-term mortality in DIGAMI 1 Reduction in HbA1c 1% Mortality Mean follow-up 3.4 years ( ) Controls Intensive RR = 0.72 [ ] p = Absolute reduction 11% Year (Malmberg for DIGAMI study group Brit Med J 1997, 314:1512)

11 Event rate (%) DIGAMI 2 Death/reinfarction/stroke Suspect MI + Type 2 diabetes or B-glucose >11 mmol/l 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 ( ) p = Group 1 (insulin+insulin) Group 2 (insulin+conventional) Group 3 (conventional) Years

12 Blood glucose over time by treatment group mmol/l * Baseline 24 h months No Group Group Group Group 1 Group 2 Group 3 (Malmberg, Rydén et al Eur Heart J 2005;26:650) 28/07/

13 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 ( ) 0.93 ( ) 0.78 ( ) 0.63 ( ) 1.08 ( ) 1.15 ( ) 0.93 ( ) 0.81 ( ) 1.12 ( ) 1.05 ( ) 1.42 ( ) 1.73 ( ) No glucose lowering drug (0.61 ( ) 1.31) (0.55 ( ) 1.29) (0.77 ( ) 1.41) (0.78 ( ) 1.83) (Mellbin et al Eur Heart J 2008;29:166)

14 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 ( ) 0.93 ( ) 0.78 ( ) 0.63 ( ) 1.08 ( ) 1.15 ( ) 0.93 ( ) 0.81 ( ) 1.12 ( ) 1.05 ( ) 1.42 ( ) 1.73 ( ) No glucose lowering drug (0.61 ( ) 1.31) (0.55 ( ) 1.29) (0.77 ( ) 1.41) (0.78 ( ) 1.83) (Mellbin et al Eur Heart J 2008;29:166)

15 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 ( ) 0.93 ( ) 0.78 ( ) 0.63 ( ) 1.08 ( ) 1.15 ( ) 0.93 ( ) 0.81 ( ) 1.12 ( ) 1.05 ( ) 1.42 ( ) 1.73 ( ) No glucose lowering drug (0.61 ( ) 1.31) (0.55 ( ) 1.29) (0.77 ( ) 1.41) (0.78 ( ) 1.83) (Mellbin et al Eur Heart J 2008;29:166)

16 DIGAMI 2 Effect of newly instituted insulin treatment n=317; 245 randomised to insulin = 77%; adjusted HR % Insulin No Insulin Mortality % Insulin No Insulin New MI/Stroke HR=1.09 ( ) p= HR=1.95 ( ) p= er at risk sulin No Insulin Insulinn Number at risk Years Years Number at risk No Insulin 143 Insulin (Mellbin et al Eur Heart J 2008;29:166)

17 DIGAMI 2 longterm follow-up Effect of different glucose lowering treatments after hospital discharge n=1073 (Mellbin et al. Unpublished data)

18 DIGAMI 2 Insulin and cancer Causes of death in DIGAMI 2 Group 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 = (Malmberg, Rydén et al Eur Heart J 2005;26:650)

19 2009 Sep;52(9): Insulin Dangerous or not?

20 Possible effects of insulin and metformin Possible negative effects of insulin Proatherogenic effect Insulin-IGF-1 axis Survival and proliferation of malignant cells Hypoglycemia

21 Insulin and endothelium Healthy Insulin PI3K pathway NO Vasodilatation Antiatherosclerotic

22 Insulin and endothelium Healthy Insulin Insulin resistence/diabetes Insulin PI3K pathway MAPK pathway ET-1 NO Vasodilatation Antiatherosclerotic Vasoconstriction Proaterosclerotic

23 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

24 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)

25 Intensive Glucose Lowering in Type 2 Diabetes ACCORD and ADVANCE HbA1c(%) HbA1c (%) Glycemia trial (n=10 251) HbA1c <6.0% vs HbA1c % 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)

26 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 ) 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 ) p=0.01 Intensive (Gerstein et al. NEJM 2008;358:2545) (Patel et al. NEJM 2008;358: 2560) Time of follow up (months)

27 Glycemic control Meta-analysis of 5 prospective randomised trials (intensive vs standard) n= Mean HbA1c difference 0.9% Non-fatal MI (17% reduction) All cause mortality 0.83 ( ) 1.02 ( ) (Ray K et al. Lancet 2009;373:1765)

28 Primary outcome subgroup analyses Subgroup Patient Events no no (Gerstein et al. NEJM 2008;358:2545)

29 Glucose lowering drugs GI Sulphonylurea Incretins Alfaglucosidase inhibitors Incretins Insulin Pancreas Insulin Metformin TZD Liver Metformin TZD Glucose Muscle and adipose tissue

30 Glucose Lowering Strategies/Drugs and CVD Trials in People with Dysglycemia Yrs from Dx 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)

31 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)

32 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)

33 Future Establish if metabolic modulation/control is beneficial or not in CAD Determine target glucose levels New treatment options New tools

34 Thank you!