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      Antihyperglycemic Treatment in Diabetics with Coronary Disease: Increased Metformin-Associated Mortality over a 5-Year Follow-Up


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          Mortality rates are considerably higher in chronic ischemic heart disease (IHD) patients with non-insulin-dependent diabetes mellitus (NIDDM) than in those who are nondiabetics. The relationship between different types of antihyperglycemic pharmacological therapy and mortality rate in this NIDDM population is uncertain. We aimed to examine the survival in NIDDM patients with IHD using various types of oral antidiabetic treatments over a 5-year follow-up period. The study sample comprised 11,440 patients with a previous myocardial infarction and/or stable anginal syndrome, aged 45–74 years, who were screened, but not included in the Bezafibrate Infarction Prevention study. Among them, 9,045 were nondiabetics and 2,395 diabetics. The diabetic patients were divided into four groups on the basis of their therapeutic regimen at screening: diet alone (n = 990), sulfonylureas (n = 1,041), metformin (n = 78) and a combination of a sulfonylurea and metformin (n = 266). All NIDDM groups were similar with regard to age, gender, hypertension, smoking, heart failure, angina and prior myocardial infarction. Crude mortality rate was lower in the nondiabetic group (11.21 vs. 21.8%; p < 0.001). In the diabetic group, mortality was 18.5% for patients on diet alone, 22.5% for those on sulfonylureas, 25.6% for patients on metformin, and 31.6% for the combined sulfonylurea/metformin group (p < 0.01). When analyzing age-adjusted mortality rate and actuarial survival curves, the lowest mortality was found in patients on diet alone and the highest in patients on metformin (alone or in combination with sulfonylureas). After adjustment for variables connected with long-term prognosis, the use of metformin was associated with increased relative risk (RR) for all-cause mortality of 1.42 (95% CI 1.10–1.85), whereas the use of sulfonylureas alone was not [RR 1.11 (95% CI 0.90–1.36)]. NIDDM patients with IHD using metformin, alone or in combination with sulfonylureas, exhibited a significantly increased mortality. Until the results of problem-oriented prospective studies on oral control of NIDDM will be available, alternative therapeutic approaches should be investigated in these patients.

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          Efficacy of metformin in patients with non-insulin-dependent diabetes mellitus. The Multicenter Metformin Study Group.

          Sulfonylurea drugs have been the only oral therapy available for patients with non-insulin-dependent diabetes mellitus (NIDDM) in the United States. Recently, however, metformin has been approved for the treatment of NIDDM. We performed two large, randomized, parallel-group, double-blind, controlled studies in which metformin or another treatment was given for 29 weeks to moderately obese patients with NIDDM whose diabetes was inadequately controlled by diet (protocol 1: metformin vs. placebo; 289 patients), or diet plus glyburide (protocol 2: metformin and glyburide vs. metformin vs. glyburide; 632 patients). To determine efficacy we measured plasma glucose (while the patients were fasting and after the oral administration of glucose), lactate, lipids, insulin, and glycosylated hemoglobin before, during, and at the end of the study. In protocol 1, at the end of the study the 143 patients in the metformin group, as compared with the 146 patients in the placebo group, had lower mean (+/- SE) fasting plasma glucose concentrations (189 +/- 5 vs. 244 +/- 6 mg per deciliter [10.6 +/- 0.3 vs. 13.7 +/- 0.3 mmol per liter], P < 0.001) and glycosylated hemoglobin values (7.1 +/- 0.1 percent vs. 8.6 +/- 0.2 percent, P < 0.001). In protocol 2, the 213 patients given metformin and glyburide, as compared with the 210 patients treated with glyburide alone, had lower mean fasting plasma glucose concentrations (187 +/- 4 vs. 261 +/- 4 mg per deciliter [10.5 +/- 0.2 vs. 14.6 +/- 0.2 mmol per liter], P < 0.001) and glycosylated hemoglobin values (7.1 +/- 0.1 percent vs. 8.7 +/- 0.1 percent, P < 0.001). The effect of metformin alone was similar to that of glyburide alone. Eighteen percent of the patients given metformin and glyburide had symptoms compatible with hypoglycemia, as compared with 3 percent in the glyburide group and 2 percent in the metformin group. In both protocols the patients given metformin had statistically significant decreases in plasma total and low-density lipoprotein cholesterol and triglyceride concentrations, whereas the values in the respective control groups did not change. There were no significant changes in fasting plasma lactate concentrations in any of the groups. Metformin monotherapy and combination therapy with metformin and sulfonylurea are well tolerated and improve glycemic control and lipid concentrations in patients with NIDDM whose diabetes is poorly controlled with diet or sulfonylurea therapy alone.
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            Plasma homocysteine levels and mortality in patients with coronary artery disease.

            Elevated plasma homocysteine levels are a risk factor for coronary heart disease, but the prognostic value of homocysteine levels in patients with established coronary artery disease has not been defined. We prospectively investigated the relation between plasma total homocysteine levels and mortality among 587 patients with angiographically confirmed coronary artery disease. At the time of angiography in 1991 or 1992, risk factors for coronary disease, including homocysteine levels, were evaluated. The majority of the patients subsequently underwent coronary-artery bypass grafting (318 patients) or percutaneous transluminal coronary angioplasty (120 patients); the remaining 149 were treated medically. After a median follow-up of 4.6 years, 64 patients (10.9 percent) had died. We found a strong, graded relation between plasma homocysteine levels and overall mortality. After four years, 3.8 percent of patients with homocysteine levels below 9 micromol per liter had died, as compared with 24.7 percent of those with homocysteine levels of 15 micromol per liter or higher. Homocysteine levels were only weakly related to the extent of coronary artery disease but were strongly related to the history with respect to myocardial infarction, the left ventricular ejection fraction, and the serum creatinine level. The relation of homocysteine levels to mortality remained strong after adjustment for these and other potential confounders. In an analysis in which the patients with homocysteine levels below 9 micromol per liter were used as the reference group, the mortality ratios were 1.9 for patients with homocysteine levels of 9.0 to 14.9 micromol per liter, 2.8 for those with levels of 15.0 to 19.9 micromol per liter, and 4.5 for those with levels of 20.0 micromol per liter or higher (P for trend=0.02). When death due to cardiovascular disease (which occurred in 50 patients) was used as the end point in the analysis, the relation between homocysteine levels and mortality was slightly strengthened. Plasma total homocysteine levels are a strong predictor of mortality in patients with angiographically confirmed coronary artery disease.
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              Lactic acidosis in patients with diabetes treated with metformin.


                Author and article information

                S. Karger AG
                September 1999
                24 September 1999
                : 91
                : 3
                : 195-202
                aCardiac Rehabilitation Institute and bBezafibrate Infarction Prevention Coordinating Center, Neufeld Cardiac Research Institute, Chaim Sheba Medical Center, affiliated to the Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
                6909 Cardiology 1999;91:195–202
                © 1999 S. Karger AG, Basel

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                Page count
                Figures: 2, Tables: 3, References: 37, Pages: 8
                Clinical Pharmacology


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