Oral antidiabetic treatment in patients with coronary disease: Time‐related increased mortality on combined glyburide/metformin therapy over a 7.7‐year follow‐up

Abstract

Background: A sulfonylurea —usually glyburide—plus metformin constitute the most widely used oral antihyperglycemic combination in clinical practice. Both medications present undesirable cardiovascular effects. The issue whether the adverse effects of each of these pharmacologic agents may be additive and detrimental to the prognosis for coronary patients has not yet been specifically addressed. Hypothesis: This study was designed to examine the survival in type 2 diabetics with proven coronary artery disease (CAD) receiving a combined glyburide/metformin antihyperglycemic treatment over a long‐term follow‐up period. Methods: The study sample comprised 2,275 diabetic patients, aged 45–74 years, with proven CAD, who were screened but not included in the bezafibrate infarction prevention study. In addition. 9,047 nondiabetic patients with CAD represented a reference group. Diabetics were divided into four groups on the basis of their therapeutic regimen: diet alone (n = 990), glyburide (n = 953), metformin (n = 79), and a combination of the latter two (n = 253). Results: The diabetic groups presented similar clinical characteristics upon recruitment. Crude mortality rate after a 7.7‐year follow‐up was lower in nondiabetics (14 vs. 31.6%, p<0.001). Among diabetics, 720 patients died: 260 on diet (mortality 26.3%). 324 on glyburide (34%), 25 on metformin alone (31.6%), and 111 patients (43.9%) on combined treatment (p<0.000001). Time‐related mortality was almost equal for patients on metformin and on combined therapy over an intermediate follow‐up period of 4 years (survival rates 0.80 and 0.79, respectively). The group on combined treatment presented the worst prognosis over the long‐term follow‐up, with a time‐related survival rate of 0.59 after 7 years, versus 0.68 and 0.70 for glyburide and metformin, respectively. After adjustment to variables for prognosis, the use of the combined treatment was associated with an increased hazard ratio (HR) for all‐cause mortality of 1.53 (95% confidence interval [CI] 1.20–1.96), whereas glyburide and metformin alone yielded HR 1.22 (95% CI 1.02–1.45) and HR 1.26 (95% CI 0.81–1.96), respectively. Conclusions: We conclude that after a 7.7‐year follow‐up, monotherapy with either glyburide or metformin in diabetic patients with CAD yielded a similar outcome and was associated with a modest increase in mortality. However, time‐related mortality was markedly increased when a combined glyburide/metformin treatment was used.

Comment on: Evans JMM, Ogston SA, Emslie-Smith A, Morris AD (2006) Risk of mortality and adverse cardiovascular outcomes in type 2 diabetes: a comparison of patients treated with sulfonylureas and metformin. Diabetologia 49:930–936

“…Likewise, in the University Related Diabetes Project, cardiovascular mortality was 12.7% in the tolbutamide monotherapy group, as compared with 4.9% in the placebo-treated diabetic group [2]-an unadjusted risk of 2.6. In another study, the adjusted risk of mortality was 2.1 with tolbutamide or chlorpropamide monotherapy, and 1.3 with glibenclamide (known as glyburide in the USA and Canada) monotherapy [3], similar to the figure of 1.22 reported for glibenclamide monotherapy in a recent study [4]. With regard to cardiovascular mortality, monotherapy with glibenclamide was associated with a significant adjusted risk of 1.37 [3].…”

“…In this trial, approximately one-third of the patients given conventional treatment were using glibenclamide or chlorpropamide. In a fourth trial, mortality was increased 1.53-fold in patients given the combination of glibenclamide and metformin [4].…”

Type of preadmission glucose-lowering treatment and prognosis among patients hospitalised with myocardial infarction: a nationwide follow-up study

“…Another study showed no differences in longterm (>3 years) survival rate between patients treated with sulfonylureas prior to MI and those receiving any other glucose-lowering treatments (diet, insulin or metformin and/or acarbose) [6]. Further, in agreement with our finding, an increased mortality rate has also previously been found among users of combination therapy (sulfonylureas and metformin) when compared with patients treated with diet, whereas no increased mortality rate was found among users of the drugs in monotherapy [14].…”

“…Data regarding outcome in cardiac patients using various types of glucose-lowering drugs are sparse and conflicting [3][4][5][6][7][8][9][10][11][12][13][14], and the existing studies have some limitations, including small and often nonrepresentative samples and shortcomings in the data analysis.…”

Risk of mortality and adverse cardiovascular outcomes in type 2 diabetes: a comparison of patients treated with sulfonylureas and metformin

“…Another worrying result was a 96% increase in diabetes-related deaths in sulfonylureatreated patients with addition of metformin [6]. Observational studies have shown increased risks associated with a combination of metformin and sulfonylureas, but have been unable to account fully for underlying differences between patients in different therapy groups [7,8]. In contrast, a more recent study found no increased risk of mortality among patients who were prescribed sulfonylureas and metformin in combination, compared with those prescribed either drug as monotherapy [9].…”