Mortality outcomes of different sulphonylurea drugs: the results of a 14-year cohort study of type 2 diabetic patients

Abstract

Objective: Available data about mortality of type 2 diabetic patients treated with different sulphonylureas are scarce and contradictory. Design: We evaluated the associations between all-cause and cause-specific mortality and treatments with different sulphonylureas in a retrospective cohort of type 2 diabetic patients from a diabetes clinic. Methods: All 1277 patients treated with sulphonylureas during 1996-1997 were enrolled: 159 patients were treated with tolbutamide, 977 glibenclamide and 141 gliclazide. The baseline data (centralised laboratory parameters, anthropometric data and presence of chronic complications) were abstracted from the clinical records. Information on vital status was collected from demographic files after 14-year follow-up. Adjusted hazard ratios (HR) were estimated with Cox (all-cause mortality) or Fine and Gray models (cause-specific mortality), including several potential confounders. Results: Five hundred and fifty-six patients died during the follow-up: 262 from cardiovascular causes, 158 from cancer and 136 from other causes. When compared with the glibenclamide users, the gliclazide and tolbutamide users showed a significantly lower cancer mortality (HRZ0.30; 95% CI 0.16-0.55, and HRZ0.48; 95% CI 0.29-0.79 respectively). These results were strongly confirmed in the 555 patients on sulphonylurea monotherapy. None of the patients who were treated with gliclazide monotherapy died from cancer during the follow-up, and the patients on tolbutamide treatment exhibited a lower cancer mortality than the glibenclamide users (HRZ0.40; 95% CI 0.22-0.71). Data did not change after stratification for the duration of sulphonylurea treatment from diabetes diagnosis to the study enrolment. Conclusions: Cancer mortality was markedly reduced in the patients on gliclazide and tolbutamide treatment. These results suggest additional benefits for these drugs beyond their blood glucoselowering effect and strongly advocate for further investigation.

The Use of Glyburide Compared With Other Sulfonylureas and the Risk of Cancer in Patients With Type 2 Diabetes

“…glibenclamide) (2,6,13). These findings are supported by biological evidence, as glyburide seems to cause the production of reactive oxygen species (ROS), which is a well-known pro-oncogenic factor (14).…”

“…However, this observed increased risk may have been exaggerated by timelag bias (24) because glyburide users had longer diabetes duration than gliclazide users (13.2 vs. 7.7 years, respectively) (2). Similarly, time-lag bias was likely present in another study reporting strong decreased risks with gliclazide and tolbutamide compared with glyburide (13). As for the studies reporting decreased risks, the use of glyburide in one was associated with a 17% decreased risk of prostate cancer, with similar decreased risks observed with all other antidiabetic drugs (17).…”

“…Overall, these studies produced conflicting findings, with three reporting increased risks ranging from 150 to 250% (2,6,13) and two reporting decreased risks ranging from 20 to 50% (16,17). The discrepancy between these studies is likely due to important methodological shortcomings.…”

“…Although several observational studies have investigated the association between sulfonylureas and cancer incidence or cancer-related mortality (3)(4)(5)(6)(7)(8)(9)(10)(11)16,17,22,23), only five focused on glyburide and cancer-related outcomes (2,6,13,16,17). Overall, these studies produced conflicting findings, with three reporting increased risks ranging from 150 to 250% (2,6,13) and two reporting decreased risks ranging from 20 to 50% (16,17).…”

“…To date, the few observational studies that have specifically assessed the association between glyburide and cancer risk had a number of methodological shortcomings, such as time-related biases (2,13,16) and confounding by indication (17). Thus, given the widespread use of glyburide and continued concerns regarding its safety, we conducted a populationbased cohort study to determine whether the use of glyburide compared with other second-generation sulfonylureas is associated with an increased risk of cancer in patients with type 2 diabetes.…”