Impact of Oral Antihyperglycemic Therapy on All-Cause Mortality Among Patients With Diabetes in the Veterans Health Administration

Abstract

OBJECTIVE -The objective of this analysis was to evaluate the impact of several classes of oral antihyperglycemic therapy relative to sulfonylurea monotherapy on all-cause mortality among a cohort of patients with diabetes from the Veterans Health Administration (VHA). RESEARCH DESIGN AND METHODS-A retrospective cohort study using data obtained from the VHA Diabetes Epidemiology Cohort was used. Users of oral antihyperglycemic therapy were classified into the following cohorts: sulfonylurea monotherapy, metformin monotherapy, metformin plus sulfonylurea, thiazolidinedione (TZD) use alone or in combination with other oral agents (TZD users), and no drug therapy. All-cause mortality was the outcome of interest. Multivariate mixed models incorporating a propensity score to account for imbalance among cohorts were used to estimate drug effects on mortality with associated 95% CIs.RESULTS -A total of 39,721 patients with diabetes were included in the study. Adjusted odds ratios and 95% CIs for all-cause mortality were 0.87 (0.68 -1.10) for metformin monotherapy users, 0.92 (0.82-1.05) for metformin plus sulfonylurea users, and 1.04 (0.75-1.46) for TZD users, relative to sulfonylurea monotherapy users.CONCLUSIONS -We did not find any significant drug effect on all-cause mortality for any oral treatment cohorts relative to sulfonylurea oral monotherapy. Diabetes Care 30:1689-1693, 2007T he most influential study designed to assess long-term microvascular and macrovascular outcomes in patients with type 2 diabetes was the U.K. Prospective Diabetes Study (UKPDS). It was specifically designed to assess the effects of intensive glycemic control versus a more liberal treatment target on the cardiovascular and microvascular complications of type 2 diabetes (1,2). Despite several shortcomings (3), the UKPDS answered the question of whether intensive blood glucose control is beneficial for people with type 2 diabetes and found that it definitely is, especially with regard to microvascular complications (2). However, the UKPDS was less conclusive regarding the impact of specific oral antihyperglycemic treatments targeting a lower A1C level on the risk of macrovascular complications and all-cause mortality. Furthermore, thiazolinediones (TZDs) were not available during the time period of the UKPDS.Since the publication of the primary findings from the UKPDS, several observational studies conducted in Europe and Canada have assessed the effect of diabetes drug treatment on mortality but have produced conflicting results (4 -8). A commonality across most of the observational studies conducted to date is that it has been difficult to draw conclusions because of the high potential for confounding by indication (i.e., the tendency for patients with more severe disease both to be exposed to more aggressive therapy and to be more likely to experience an adverse outcome). The direct effect of drug exposure also has been difficult to ascertain because many of the long-term studies assessed drug exposure only once and then assessed mortal...

Oral hypoglycaemic agents, insulin resistance and cardiovascular disease in patients with type 2 diabetes

“…It cannot be concluded from the literature whether combination therapy with metformin and SU has harmful effects, as indicated by the UKPDS (13,(25)(26)(27). At present, the international guidelines recommend combination therapy when monotherapy fails (4).…”

“…Observational studies have yielded conflicting results of combined intervention with metformin and insulin secretagogues with respect to the risk of CVD (25,26). A recently published meta-analysis indicates an increased frequency of CVD by combined intervention with metformin and insulin secretagogues compared with diet or monotherapy (27).…”

Mortality risk with sulphonylureas compared to metformin

“…Other observational data comparing sulphonylureas with metformin have also supported the observation that sulphonylureas are associated with a higher risk of mortality as a class [56][57][58], and glipizide, glimepriride, tolbutamide and glibenclamide specifically [59]. Conversely, a retrospective study using data from VHA Diabetes Epidemiology Cohort found that the risk of all-cause mortality was not significantly different for metformin monotherapy and sulphonylurea monotherapy [adjusted odds ratio (OR) 0.87; 95% CI 0.68-1.10] [60]. In addition, a meta-analysis of available data from randomized, controlled trials (RCTs) did not find that metformin had a statistically significant effect on all-cause mortality.…”

Combination therapy with sulfonylureas and metformin and the prevention of death in type 2 diabetes: a nested case‐control study

“…1 These unexpected findings have been the subject of much debate, 2 and have led to the publication of several observational studies in recent years. [3][4][5][6][7][8][9][10][11] Despite the number of observational studies published to date, there is great discordance between their results. Whereas in some studies the use of the combination of sulfonylureas and metformin was associated with an increased risk of all-cause mortality, 3,5,8,11 others found no association, 6,9 while some found protective effects.…”

“…[3][4][5][6][7][8][9][10][11] Despite the number of observational studies published to date, there is great discordance between their results. Whereas in some studies the use of the combination of sulfonylureas and metformin was associated with an increased risk of all-cause mortality, 3,5,8,11 others found no association, 6,9 while some found protective effects. 4,7,10 A recent meta-analysis of these studies found that combination therapy of sulfonylur-eas and metformin significantly increased the risk of the composite endpoint of cardiovascular diseaserelated hospitalizations or mortality, but not for allcause mortality.…”