BARCELONA — Four widely prescribed oral sulfonylurea drugs are associated with significantly increased risk of all-cause mortality compared with metformin in type 2 diabetic patients having a history of MI, according to a comprehensive Danish national cohort study.
The study included all Danish adults with a prior MI who started on oral glucose-lowering monotherapy during 1997–2006. The conclusion: Glimepiride, glyburide, glipizide, and tolbutamide were associated with 33%–43% higher mortality risk than was metformin, Dr. Tina Ken Schramm said at the annual congress of the European Society of Cardiology.
In contrast, single-agent gliclazide and repaglinide had all-cause mortality risks similar to metformin.
“The clinical implication of this is that metformin, gliclazide, and repaglinide appear superior to other single-drug treatments received. We believe that metformin in general should be part of the treatment of type 2 diabetes to reduce mortality, but gliclazide and repaglinide may be good alternatives,” said Dr. Schramm of the Heart Center at Copenhagen University National Hospital, who reported no financial conflicts of interest.
Metformin deserves the nod as the first-line agent on the basis of the results of the landmark United Kingdom Prospective Diabetes Study, which convincingly established the drug as the safest glucose-lowering agent available, she added.
Out of the total Danish population of roughly 4.1 million, 107,870 type 2 diabetic individuals initiated monotherapy with a glucose-lowering agent during the 9-year study period. Among them were 9,135 with a prior MI, who formed the population for this study.
Glimepiride was the most widely prescribed of the glucose-lowering medications in Denmark, being used by 43% of subjects. Next came metformin (32%), glyburide (13%), glipizide and gliclazide (7% each), tolbutamide (6%), and repaglinide (2%). Acarbose was prescribed as monotherapy in only 44 patients nationwide—far too small a number to allow meaningful results. Similarly, the thiazolidinediones, which in Denmark are not recommended therapy in this clinical setting, were used too seldom to draw any conclusions, Dr. Schramm explained.
Metformin served as the comparator in determining all-cause mortality risks for the other oral glucose-lowering agents in a multivariate analysis adjusted for age, gender, years of diabetes, cardiovascular medications, and socioeconomic status.
Audience members asked if confounding was a potential issue in the study—that is, perhaps patients on drugs other than metformin were sicker, or had previously been on metformin but proved intolerant or unresponsive to it. Dr. Schramm replied that it's unlikely, since when she performed a subanalysis restricted to those patients starting their first-ever glucose-lowering agent the results were unchanged.
In a prior study, Dr. Schramm found that patients with diabetes had similar mortality risk to those who had experienced a myocardial infarction, at about 2.5-fold the risk in nondiabetics with no prior MI. In that 1997–2002 survey of Danish residents aged at least 30 years, she tracked 71,801 patients who had diabetes requiring glucose-lowering therapy and 79,575 who had a prior myocardial infarction study at baseline in 1997.
In both men and women, the risk for cardiovascular deaths were similar between groups. The age-adjusted hazard ratio for men with diabetes and no prior MI was 2.42, while that for nondiabetic men with a prior MI was 2.44, compared with nondiabetics without a prior MI as the reference. In women, those hazard ratios were 2.45 and 2.62, respectively, with the risk of cardiovascular death being significantly higher in the women with prior MI than in those with diabetes.
When the same analysis was performed for the composite of MI, stroke, and cardiovascular death, the risk was still markedly elevated in both groups, but again significantly higher in those with a prior MI than in those with diabetes only (HR 2.48 and 2.32 in men, and 2.71 and 2.48 in women).
The investigators concluded then that all patients over age 30 with diabetes who require glucose-lowering therapy should also receive intensive primary prevention for cardiovascular disease, regardless of other risk factors, sex, or type of diabetes mellitus (Circulation 2008;117:1945–54).
Dr. Schramm undertook the present study because most prior studies of oral glucose-lowering medications did not look beyond glucose-lowering efficacy in terms of outcomes, she said.
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