Review of DIGAMI 2

Effect of three treatment strategies for hyperglycemia in patients with Type 2 diabetes and acute myocardial infarction

European Heart Journal, Volume 26, Issue 7, 2005, 650–661

Background  Patients with diabetes have a higher risk of death after myocardial infarction than those without diabetes. There are many possible reasons for this difference. One may be that diabetic patients have detrimental responses during the acute phase of MI. In the DIGAMI 1 trial, patients with diabetes and AMI were randomized to intensive glucose control via IV insulin or standard care. Although the primary endpoint of all-cause mortality at 3 months was not statistically significant, the 1-year mortality was reduced by 30% in the IV-insulin group.  The DIGAMI 1 trial had lower than expected mortality which led to wide confidence intervals.

The hypothesis of the DIGAMI 2 trial was early and continued insulin-based metabolic control is a key to mortality reduction in patients with diabetes and AMI.

Patients Eligible patients with type 2 diabetes or an admission blood glucose > 198 mg/dl who were admitted to participating CCU were eligible if they had suspected AMI due to symptoms (chest pain >15 min during the preceding 24 h) and/or recent ECG signs (new Q-waves and/or ST-segment deviations in two or more leads). Exclusion criteria were inability to cope with insulin treatment or to receive information on the study; residence outside the hospital catchment area; participation in other studies.

Baseline Characteristics The trial recruited 1253 patients (mean age 68 years; 67% males) with type 2 diabetes and suspected acute myocardial infarction. At hospital discharge, approximately 85% of patients fulfilled the diagnosis of MI. Nearly half of these were STEMI. The remaining patients had unstable angina. The mean duration of diabetes was 8 years but about 20% of patients had diabetes of less than one year duration. Almost a third of patients had had a previous MI. Thirty percent of patients were on some form of insulin treatment before randomization. At randomization, HbA1c was 7.2, 7.3, and 7.3% in groups 1, 2, and 3, respectively.  The three groups were well matched in most respects, however, there were significantly fewer previous Mis and trend towards fewer patients with HTN, DM and HF in group 3.

Evidence-based treatments for MI was extensive in all groups. Nearly all eligible patients had acute revascularization.

Trial procedures DIGAMI 2 was carried out in 44 centers in Sweden, Finland, Norway, and Denmark. It had three treatment arms: a 24 h insulin–glucose infusion followed by a subcutaneous insulin-based long-term glucose control (group 1); a 24 h insulin–glucose infusion followed by standard glucose control (group 2), and, routine metabolic management according to local practice (group 3).

The authors attempted to balance randomization and simulate the DIGAMI 1 trial by communicating baseline variables before randomization—which was based on an algorithm that included prognostic markers from the first DIGAMI trial. The goal was to improve the ability to compare the two DIGAMI trials. During the first 24 h, blood glucose was followed according to the infusion protocol in groups 1 and 2 and at the discretion of the attending physician in charge in group 3 (standard care).

In groups 1 and 2, glucose-lowering treatment was initiated with a glucose–insulin infusion with the objective to decrease blood glucose as fast as possible and keep it between 126 and 180 mg/dl.  The infusion lasted until stable normoglycemia and at least for 24 h. In group 1, subcutaneous insulin was initiated at the cessation of the infusion. The treatment goal for patients in group 1 was a fasting blood glucose level of 90–126 mg/dl and a non-fasting level of <180 mg/dl. Apart from the initial insulin–glucose infusion given to patients in group 2, the glucose-lowering treatment in groups 2 and 3 was at the discretion of the responsible physician and according to local routines.

Endpoints: The primary objective of DIGAMI 2 was to compare total mortality between treatment groups 1 and 2 during the time of follow-up. A secondary objective was to compare the total mortality between groups 2 and 3, and a tertiary objective to compare morbidity, such as non-fatal reinfarction, congestive heart failure, and stroke, among the three groups.

The estimated 2-year mortality was close to 35% in group 3; however, adjusted to 30% to correct for time-trends in mortality. It was assumed that the mortality would be lowered to 17% in group 1 and 23% in group 2 corresponding to a mortality reduction of 25% between each of three treatment strategies. These assumptions would require a sample size of 1150 patients in groups 1 and 2 and 700 patients in group 3 for a two-tailed test with an alpha-value of 0.05 and a power of at least 85%

DIGAMI 2 planned to enroll 3000 patients but the trial was terminated prematurely due to slow enrollment. The authors write that it was a truly investigator-initiated trial with a low budget.

Results: The median study duration was 2.1 years. Blood glucose was significantly reduced after 24 hours in all groups, but more in groups 1 and 2 (164 and 164 mg/dl) than in group 3 (180 mg/dl). HbA1c did not differ significantly among groups 1–3 (∼6.8%) at the end of follow-up.

Hypoglycemia (glucose < 54 mg/dl) was more frequent during the initial 24 hours in Group 1 (12.7%) and Group 2 (9.6%) than Group 3 (1%).

After 2 years of follow-up, the Kaplan–Meier estimated mortality was 23.4% among patients in group 1 compared with 21.2% in group 2 (HR=1.03; 95% CI=0.79–1.34; P=0.832). The corresponding proportion in group 3 was 17.9% (group 1 vs. 3: HR=1.26, CI=0.92–1.72; P=0.157). The adjusted HR for the slight imbalance in previous diseases between groups 1 and 3 was 1.19 (CI=0.86–1.64; P=0.29). The comparison of mortality between groups 2 and 3 yielded a hazard ratio of 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: Insulin infusion and tight glycemic control in the acute phase post myocardial infarction did not improve mortality or cardiovascular outcomes.

The authors used many words to explain why DIGAMI 2 did not confirm DIGAMI 1. They mentioned factors such as a) the lower-than-expected power (due to early termination), b) the fact that group 1 did not achieve its strict goal of glucose lowering, c) that there were crossovers wherein 14% of patients in Group 3 received insulin-glucose infusions against protocol, and d) that overall mortality in all groups was lower than expected. It seemed to us that the nonsignificant effect on mortality came as a surprise.

Our conclusion, however, is that DIGAMI 2 enrolled more patients with broader entry criteria and in the setting of excellent baseline care, more aggressive glucose-lowering therapy did not reduce death rate.

The lessons of these 2 trials will be repeated in coming trials. That is, caution is warranted in smaller trials with large effect sizes, and, as baseline care improves, it becomes harder to show incremental benefit of new therapies—especially aggressive ones.

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Editor note:

Link to an article on the importance of stress induced hyperglycemia: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3672537/