Myocardial infarction and diabetes mellitus : studies on glucose lowering therapies and novel risk markers based on observations from the DIGAMI 2 trial

Abstract

Background: Patients with myocardial infarction (MI) and type 2 diabetes (T2DM) and have a poor prognosis. Hyperglycemia is an independent risk predictor. The best tools for glucose control are debated. Important is identification of biomarkers to gain further pathophysiological insights and new therapeutic possibilities.

Aims: In patients with acute MI and T2DM: 1. Explore the prognostic impact of hypoglycemia during hospitalization for MI; 2. Study the prognostic impact of glucose lowering treatment; 3. Investigate the relation between Copeptin and IGFBP-1 and their prognostic impact; and 4. Characterize MBL geno- and phenotypes and to investigate their prognostic importance.

Study population: This thesis is based on epidemiological reports from the DIGAMI 2 trial comprising 1253 patients with T2DM and acute MI. DIGAMI 2 was a randomized trial with the primary aim to compare three glucose lowering strategies testing the hypothesis that insulin-based metabolic control reduces mortality.

Hypoglycemia during hospitalization for acute MI: Hypoglycemic episodes were recorded in 153 patients (symptomatic = 45). Patients with hypoglycemia were older, had a longer duration of T2DM, a lower body weight and more often a history of heart failure. The mortality and cardiovascular morbidity did not differ between patients with or without hypoglycemia besides that patients who were symptomatic were at increased risk of death. This higher risk disappeared after adjustment for confounding factors.

Glucose lowering treatment and prognosis: During the initial follow-up of 2.3 years the adjusted hazard ratio (HR) for non-fatal MI and stroke, in patients discharged alive (n=1181), was 1.73 (95% CI 1.26 2.37; p =0.0007) with insulin treatment, 0.81 (95% CI 0.57 1.14; p = 0.23) with sulphonylureas and 0.63 (95% CI 0.42 0.95; p = 0.03) with metformin. None of the glucose lowering treatments influenced mortality. The odds ratio for insulin on non-fatal cardiovascular events was 1.90 (95% CI 1.38-2.63; p=<0.0001) without influencing mortality after an extended follow-up period of 4.1 years. Metformin was associated with a lower mortality and a lower risk of death of malignancies. There were no difference in total or cardiovascular mortality between the randomized treatment groups but the risk of dying of malignancies was highest in patients randomized to long-term insulin.

Novel risk markers and prognosis: Copeptin, a surrogate marker for vasopressin, was associated with IGFBP-1 (r = 0.53; p<0.001) in 393 patients participating in the biochemical program of DIGAMI 2. Both biomarkers were predictors of events (cardiovascular death, MI and stroke) in univariate analyses. In the final statistical model, adjusting for age and renal function, copeptin was the only independent predictor (HR 1.35; 95% CI: 1.16-1.57; p<0.001). Serum (S)-MBL, an activator of the complement system, was determined in 387 and MBL genotypes in 287 patients. Fifty four percent had high coding (median S-MBL=2658 ìg/l; IQR 1715 3829) and 46% low coding MBL genotype (median S-MBL=373ìg/l; IQR 100-765). S-MBL did not predict events. The risk of events was lower in patients with high genotype and S-MBL above median for their genotype (HR 0.49; 95%CI 0.26-0.92; p= 0.026) than among patients with low genotype and S-MBL below median for their genotype. This relation did, however, only reach borderline significance in adjusted analyses.

Conclusions: Hypoglycemia during hospitalization is not an independent risk factor for mortality and cardiovascular morbidity in patients with T2DM and MI. It is more prevalent in patient at high risk for other reasons. Glucose lowering agents seem to impact cardiovascular morbidity, mortality and deaths from malignancies, a finding that deserves further evaluation. Copeptin may explain at least some of the prognostic impact ofIGFBP-1 in these patients an observation that may open for new therapeutic attempts. MBL did not have a significant impact on prognosis.