Mortality Associated with Metformin Versus Sulfonylurea Initiation: A Cohort Study of Veterans with Diabetes and Chronic Kidney Disease

Abstract

Background: For patients with type 2 diabetes and chronic kidney disease (CKD), high-quality evidence about the relative benefits and harms of oral glucose-lowering drugs is limited.

Objective: To evaluate whether mortality risk differs after the initiation of monotherapy with either metformin or a sulfonylurea in Veterans with type 2 diabetes and CKD.

Design: Observational, national cohort study in the Veterans Health Administration (VHA).

Participants: Veterans who received care from the VHA for at least 1 year prior to initiating monotherapy treatment for type 2 diabetes with either metformin or a sulfonylurea between 2004 and 2009.

Main measures: Metformin and sulfonylurea use was assessed from VHA electronic pharmacy records. The CKD-EPI equation was used to estimate glomerular filtration rate (eGFR). The outcome of death from January 1, 2004, through December 31, 2009, was assessed from VHA Vital Status files.

Key results: Among 175,296 new users of metformin or a sulfonylurea monotherapy, 5121 deaths were observed. In primary analyses adjusted for all measured potential confounding factors, metformin monotherapy was associated with a lower mortality hazard ratio (HR) compared with sulfonylurea monotherapy across all ranges of eGFR evaluated (HR ranging from 0.59 to 0.80). A secondary analysis of mortality risk differences favored metformin across all eGFR ranges; the greatest risk difference was observed in the eGFR category 30-44 mL/min/1.73m² (12.1 fewer deaths/1000 person-years, 95% CI 5.2-19.0).

Conclusions: Initiation of metformin versus a sulfonylurea among individuals with type 2 diabetes and CKD was associated with a substantial reduction in mortality, in terms of both relative and absolute risk reduction. The largest absolute risk reduction was observed among individuals with moderately-severely reduced eGFR (30-44 mL/min/1.73m²).

Keywords: chronic kidney disease; diabetes; mortality.

Figure 1

Eligibility criteria and sample size.

Figure 2

Association between initiation of metformin or sulfonylurea monotherapy and mortality among Veterans by eGFR category in subgroups, Veterans Health Administration, 2004–2009. Abbreviations: BMI, body mass index; CHF, congestive heart failure; CVD, cardiovascular disease; eGFR, estimated glomerular filtration rate. Adjusted for the baseline covariates listed in Table 1.

Figure 3

FDA labeling updates for metformin-containing products, April 2016.

Figure 4

Kaplan–Meier curves for survival among metformin and sulfonylurea monotherapy users, unadjusted.

Figure 5

Kaplan–Meier curves for survival among metformin and sulfonylurea monotherapy users by eGFR category, unadjusted.