Intense metabolic control by means of insulin in patients with diabetes mellitus and acute myocardial infarction (DIGAMI 2): effects on mortality and morbidity
This review may be edited
Posted By: Laurie Hall
Posted Date: 9/9/2005
Title: Intense metabolic control by means of insulin in patients with diabetes mellitus and acute myocardial infarction (DIGAMI 2): effects on mortality and morbidity
Authors: Malmberg, K., et al
Reference: Eur Heart J, 2005. 26(7): p. 650-61
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Abstract: AIMS: Patients with diabetes have an unfavourable prognosis after an acute myocardial infarction. In the first DIGAMI study, an insulin-based glucose management improved survival. In DIGAMI 2, three treatment strategies were compared: group 1, acute insulin-glucose infusion followed by insulin-based long-term glucose control; group 2, insulin-glucose infusion followed by standard glucose control; and group 3, routine metabolic management according to local practice.
METHODS AND RESULTS: DIGAMI 2 recruited 1253 patients (mean age 68 years; 67% males) with type 2 diabetes and suspected acute myocardial infarction randomly assigned to groups 1 (n=474), 2 (n=473), and 3 (n=306). The primary endpoint was all-cause mortality between groups 1 and 2, and a difference was hypothesized as the primary objective. The secondary objective was to compare total mortality between groups 2 and 3, whereas morbidity differences served as tertiary objectives. The median study duration was 2.1 (interquartile range 1.03-3.00) years. At randomization, HbA1c was 7.2, 7.3, and 7.3% in groups 1, 2, and 3, respectively, whereas blood glucose was 12.8, 12.5, and 12.9 mmol/L, respectively. Blood glucose was significantly reduced after 24 h in all groups, more in groups 1 and 2 (9.1 and 9.1 mmol/L) receiving insulin-glucose infusion than in group 3 (10.0 mmol/L). Long-term glucose-lowering treatment differed between groups with multidose insulin (> or =3 doses/day) given to 15 and 13% of patients in groups 2 and 3, respectively compared with 42% in group 1 at hospital discharge. By the end of follow-up, HbA1c did not differ significantly among groups 1-3 ( approximately 6.8%). The corresponding values for fasting blood glucose were 8.0, 8.3, and 8.6 mmol/L. Hence, the target fasting blood glucose for patients in group 1 of 5-7 mmol/L was never reached. The study mortality (groups 1-3 combined) was 18.4%. Mortality between groups 1 (23.4%) and 2 (22.6%; primary endpoint) did not differ significantly (HR 1.03; 95% CI 0.79-1.34; P=0.831), nor did mortality between groups 2 (22.6%) and 3 (19.3%; secondary endpoint) (HR 1.23; CI 0.89-1.69; P=0.203). There were no significant differences in morbidity expressed as non-fatal reinfarctions and strokes among the three groups.
CONCLUSION: DIGAMI 2 did not support the fact that an acutely introduced, long-term insulin treatment improves survival in type 2 diabetic patients following myocardial infarction when compared with a conventional management at similar levels of glucose control or that insulin-based treatment lowers the number of non-fatal myocardial reinfarctions and strokes. However, an epidemiological analysis confirms that the glucose level is a strong, independent predictor of long-term mortality in this patient category, underlining that glucose control seems to be an important part of their management.
Are the Results Valid?
1. Was the assignment of patients to treatments randomized? ( Was allocation concealment maintained?)
Yes! They state that the computer-based randomization was centralized to the study coordinating office.
2. Were all patients who entered the trial properly accounted for and attributed at its conclusion?
2a. Was followup complete?
Yes. All patients were followed up for a minimum of six months, and the maximum time of follow up was three years.
2b. Were patients analyzed in the groups to which they were randomized?
Yes. There were 474 patients in group 1 (insulin-glucose infusion + subcutaneous insulin), 473 patients in group 2 (insulin-glucose infusion + standard glucose control) and 306 patients in group 3 (routine management according to local practice) at randomisation and the same number reported in the mortality and mortality analyses.
3. Were patients, health workers, and study personnel blind to treatment?
There is no mention of attempting to keep patients and health workers blinded to allocations, although it sounds like the outcome assessment was blinded. They state that ‘an independent committee comprising three experienced cardiologist adjudicated all events blindly’.
4. Were the groups similar at the start of the trial?
All baseline characteristics appear to be similar across the three groups except for previous history of myocardial infarction (36.5% grp 1, 35.1% grp 2 and 27.5% grp 3) and treatment with nitrates on admission (26.8% grp 1, 22.6% grp 2 and 18.6% grp 3). This had something to do with the slow recruitment and the way they applied the randomisation algorithm. Comparisons were done both for crude and adjusted HRs.
5. Aside from the experimental intervention, were the groups treated equally?
Yes. The authors stated that the use of concomitant treatment was uniform across all three groups and based on international guidelines for acute MI.
What are the Results?
1. How large was the treatment effect?
The primary objective was to compare outcomes between treatment groups 1 and 2. To this end, the authors present Kaplan-Meier survival curves, which assess 'time to mortality'. The authors should report 'time to mortality' (not mortality rates) to be consistent with the analysis they actually carried out. The authors report hazard ratios (HR).
  • There was no significant difference between Group 1 and Group 2(HR 1.03; 95% CI 0.79-1.34; P=0.831.
  • There was no significant difference between Group 1 and Group 3(HR 1.23; CI 0.89-1.69; P=0.203)
  • 2. How precise was the estimate of the treatment effect?
    See above.
    Will the Results Help Me In Caring For My Patients?
    1. Can the results be applied to my patient care?
    This trial stopped recruitment early due to slow recruitment which meant that the power of the study was decreased to ~50%. It is very difficult to draw inferences from such a low powered negative study.
    2. Were all clinically important outcomes considered?
    They reported mortality and morbidity in the form of stroke and myocardial reinfarction. They also reported surrogate outcomes such as fasting blood glucose and glycated haemoglobin.
    Side effects (such as hypoglycaemia) were also reported.
    Costs and workload are not reported.
    3. Are the likely treatment benefits worth the potential harms and costs?

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