1. Glycemic Control for myocardial infraction

2. Why??????

3. Introduction Patients with diabetes mellitus are at increased risk for myocardial infarction (MI) and diabetes was considered a coronary equivalent by the National Cholesterol Education Program Type 2 diabetic patients without a prior MI have the same risk of developing an MI as nondiabetic patients who have already had an MI

4. Introduction The proportion of type 2 diabetes is as high as 20–30% among patients admitted for acute myocardial infarction In the Swedish Register of Information and Knowledge about Swedish Heart Intensive Care Admission (RIKS-HIA) the relative risk for 1 year mortality among diabetic patients were 1.66, 1.42, and 1.34 for the age groups,65 years, 65–75years, and.75 years compared with those without diabetes.

5. Diabetes increases coronary mortality with and without a prior MI In a seven year follow up of 1059 subjects with type 2 diabetes and 1378 nondiabetics, diabetics with or without a prior myocardial infarction (MI) had a greater mortality from coronary disease compared to nondiabetics (42 versus 16 percent for those with a prior MI and 15 versus 2 percent for those without a prior MI. The rate of coronary death and fatal and nonfatal MI in diabetics without a prior MI was the same as in nondiabetics with a prior MI, providing part of the rationale for considering type 2 diabetes a coronary equivalent. Data from Haffner, SM, Lehto, S, Ronnemaa, T, et al, N Engl J Med 1998; 339:229.

6. Diabetics with a non-ST elevation ACS have a worse outcome than nondiabetics In the OASIS registry of 8013 patients with a non-ST elevation acute coronary syndrome (unstable angina or non Q- wave myocardial infarction), 21 percent had diabetes. After a two year follow-up, diabetic patients had a significantly higher combined event rate (cardiovascular death, new myocardial infarction, stroke, new heart failure) than nondiabetics (relative risk 1.56). Data from Malmberg, K, Yusuf, S, Gerstein, HC, et al. Circulation 2000; 102:1014.

7. Cumulative survival following intensive or conventional insulin treatment in the ICU Patients discharged alive from the ICU (panel A) and from the hospital (panel B) were considered to have survived. In both cases, the differences between the treatment groups were significant. Data from Van den Berghe, G, Wouters, P, Weekers, F, et al. Intensive insulin therapy in critically ill patients. N Engl J Med 2001; 345:1359.

8. Clinical trials in patients with myocardial infarction DIGAMI trial DIGAMI-2 trial HI-5 trial

9. DIGAMI In the DIGAMI trial, 620 diabetic patients with an acute MI were randomly assigned to an insulin-glucose infusion for 24 hours followed by subcutaneous insulin four times daily for ≥3 months or standard treatment with insulin therapy only if clinically indicated The target blood glucose level for patients was 126 to 196 mg/dL (7 to 10.9 mmol/liter). With respect to glycemic control, the following findings were noted: At randomization, the mean blood glucose was about 280 mg/dL (15.6 mmol/L). The blood glucose was significantly lower with intensive insulin at 24 hours (173 versus 211 mg/dL [9.6 versus 11.7 mmol/L]) and hospital discharge (148 versus 162 mg/dL [8.2 versus 9.0 mmol/L]) At randomization, the HbA1c was 8.1 percent. The reduction in HbA1c was significantly greater with intensive insulin therapy at three months (1.1 versus 0.4 percent) and one year (0.9 versus 0.4 percent).

10. Intensive insulin therapy reduces mortality in patients with diabetes after myocardial infarction The Diabetes Mellitus, Insulin Glucose Infusion in Acute Myocardial Infarction (DIGAMI) trial randomly assigned 620 diabetic patients to routine care (control group) or intensive therapy with a continuous insulin infusion. After an average followup of 3.4 years, the mortality in the control group was directly related to the admission blood glucose concentration (234 mg/dL [13 mmol/L], >234 to 297 mg/dL [13 to 16.5 mmol/L], and >297 mg/dL [16.5 mmol/L]) (p <0.001). The mortality in those treated with intensive insulin was significantly reduced (33 versus 44 percent in the control group) regardless of the blood glucose value at admission. Data from Malmberg, K, Norhammar, A, Wedel, H, Ryden, L, Circulation 1999; 99:2626.

11. HI-5 In this trial, 240 such patients were randomly assigned to conventional therapy or to an insulin/dextrose infusion to maintain the blood glucose between 72 and 180 mg/dL (4 and 10 mmol/L) for at least 24 hours. After 24 hours, the patients were managed with standard care by their own physicians with a recommend HbA1c of less than 7 percent. There was no difference in the primary end point of mortality in-hospital or at three or six months. The negative overall findings are consistent with those in the CREATE-ECLA trial of glucose- insulin-potassium therapy in over 20,000 patients. HI-5 was flawed by: 1)Small number of patient 2) lack of blinding 3) maintenance of glycemic control for only 24 hours 4) failure to attain a significant difference in mean 24-hour blood glucose between the intensive therapy and control groups.

12. DIGAMI 2

13. Aim To explore the impact of glucose lowering treatment on prognosis in diabetic patients with myocardial infarction.

14. Methods 1253 patients with established type 2 diabetes or an admission blood glucose11.0 mmol/L. Inculsion criteria: 1) Suspect acute myocardial infarction due to symptoms (chest pain.15 min during the preceding 24 h) 2)Recent ECG signs (new Q-waves and/or ST-segment deviations in 2 leads.

15. Methods They were randomized to one of three study arms receiving: 1) a 24 h insulin-glucose infusion followed by subcutaneous insulin-based long-term glucose control (n= 474); 2) the same initial treatment followed by standard glucose control (n =473) 3) glucose lowering treatment according to local practice (n=306).

16. Methods Treatment Group 1 and 2 were initially treated with a glucose–insulin infusion aiming at blood glucose between 7–10 mmol/L as fast as possible and to be continued until stable normoglycemia and at least for 24 h. Group 1 : the infusion was followed by multidose, subcutaneous insulin, short- and intermediate long-acting, targeting a fasting blood glucose between 5-7 mmol/L, and non- fasting,10 mmol/L. Group 2 : there was no specified treatment goals in this group. Group 3: the choice of glucose lowering treatment left to the discretion of the responsible

17. Methods Concomitant treatment: The protocol stated that the use of concomitant treatment should be as uniform as possible and according to evidence-based international guidelines for acute myocardial infarction

18. Methods Laboratory investigations Blood glucose was obtained at each follow-up visit to be reported as locally analysed whole blood glucose in mmol/L. visits were scheduled after 3, 6, 9, and 12 months and thereafter every sixth month. All patients were followed for a minimum of 6 months, whereas the maximum time of follow-up was 3 years.

19. Methods Definitions Myocardial infarction was diagnosed according to the joint ESC and ACC recommendations. A re-infarction was defined as an event 72 h from the index infarction. Stroke was defined as unequivocal signs of focal or global neurological deficit of sudden onset and vascular origin, lasting 24 h.

20. Methods Definitions Updated blood glucose was defined as the average value of all fasting glucose values. The first was recorded at the day of hospital discharge and subsequent values at each visit until that preceding an event or at the end of follow-up.

21. Statistics The Cox proportional hazards model was the basis for the main analyses. Proportional hazards models are a sub-class of survival model in statistics. Covariate is a variable that is possibly predictive of the outcome under study

22. Statistics the following covariates, recorded at the time for hospital admission, remained significant: 1)age 2)smoking habits 3)previous myocardial infarction 4) previous congestive heart failure 5) Creatinine at randomization 6) sex 7)Percutaneous transluminal coronary angioplasty (PTCA) or coronary artery bypass grafting (CABG) before randomization, and also during the hospitalization.

23. Results Characteristics at baseline The total DIGAMI 2 cohort consisted of 1253 patients with type 2 diabetes of whom 1181 (94%), the present population, were discharged alive. The median study duration was 2.1 (inter-quartile range 1.03–3.00) years, and no patient was lost to follow-up. The median time of follow-up was 2.1 years (mean 2.0+0.9) for patients on insulin and 2.5 years (mean2.1+0.9) for the remaining patients Newly detected diabetes, defined as of duration,1 year, was seen in 251 of the 1181 patients (21%)

24. Results Treatment At the time for discharge,436 patients were treated with oral glucose lowering agents, 268(61%) with sulphonylureas, 200 (46%) metformin, and 9 (2%)acarbos. At discharge, 690 patients (58%) were on insulin while176 (15%) did not receive any pharmacological glucose lowering treatment. A total of 173 (15%) patients were on a combination of various glucose lowering agents.

25. Results Mortality and morbidity During follow-up, 206 of the 1181 patients died while 162 and 54 had non-fatal myocardial infarction or stroke respectively. The impact of glucose lowering drugs on cardiovascular events was analysed in three steps.

26. Results Mortality and morbidity The first compared all different glucose lowering therapies (insulin, oral, or no pharmacological) with each other as regards cardiovascular events. The likelihood to develop a non-fatal myocardial reinfarction or stroke was significantly lower in patients on metformin while sulphonylureas did not relate to morbidity.

27. Results Mortality and morbidity Insulin was not associated with all cause or cardiovascular mortality but with an increased proportion of non-fatal reinfarction or stroke.

28. Results Mortality and morbidity Finally, a third analysis compared all patients that were randomized to and discharged with new insulin according to the study protocol

29. Discussion The important message from this epidemiological analysis of the DIGAMI 2 trial is that the agent used for long-term glucose control may play a considerable role for the development of future non-fatal cardiovascular events. Chronic insulin was associated with an increased number while metformin was beneficial and sulphonylureas neutral in this respect.

30. Discussion Updated blood glucose was preferred as a measure of glycemic control partly because a total of 253 HbA1c analyses were reported as missing while the information on blood glucose was complete. Glucose was an independent and strong predictor of mortality, indeed stronger than HbA1c in the DIGAMI 2 trial

31. Discussion Sulphonylureas did not relate to mortality and morbidity. Since the original report by the University Group Diabetes Programme The use of sulphonylureas has been questioned and claimed to increase cardiovascular mortality, especially in patients at a high cardiovascular risk.

32. Discussion Glucose lowering by means of metformin did not influence mortality but was related to a lower proportion of non-fatal cardiovascular events. It is not unlikely that the lower incidence of non- fatal cardiovascular events in metformin treated patients in DIGAMI 2 may reduce mortality during extended follow-up.

33. Discussion The most surprising finding was the increase in non-fatal cardiovascular events seen with the use of insulin compared with oral glucose lowering agents or life-style measures only.

34. Discussion The present finding contrasts the results of DIGAMI 1 in which insulin based glucose control improved long-term mortality. An important difference between the two DIGAMI trials is that the first succeeded in getting a significantly better glucose control in the insulin-based treatment arm, whereas glucose control was similar with oral glucose lowering agents and insulin in the latter

35. Conclusions The present observations make it important to further study the impact of insulin in a randomized study design and to search for other pharmacological glucose lowering agents.

36. Conclusions Controlling for confounders including updated blood glucose, there was no significant difference in mortality between sulphonylureas,metformin, and insulin. The risk of non-fatal myocardial infarction or stroke was higher in patients on insulin treatment while metformin seemed to be protective. Whether this difference will translate into increased mortality can only be answered by more extensive periods of follow-up.

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