Abstract

Background

Clinical trials often compare hypoglycemic medications on the basis of glycemic control but do not examine long-term outcomes (e.g., mortality). This study demonstrates an alternative approach to lengthening clinical trials to assess these long-term outcomes.

Objective

To use observational quasi-experimental methods using instrumental variables (IVs) to compare the effect of two hypoglycemic medications, sulfonylureas (SUs) and thiazolidinediones (TZDs), on long-term outcomes.

Methods

This study used administrative data from the Veterans Health Administration and Medicare from 2000 to 2010. The study population included US veterans dually enrolled in Medicare who received a prescription for metformin and then initiated SUs or TZDs. Patients could either continue on or discontinue metformin after the initiation of the second agent. Treatment was defined as starting either a SU or a TZD. Local variations in SU prescribing rates were used as instruments in IV models to control for selection bias. Survival models predicted all-cause mortality, ambulatory care sensitive condition hospitalizations, and stroke or heart attack (acute myocardial infarction).

Results

Starting on SUs compared to TZDs significantly increased the likelihood of experiencing mortality and ACSC hospitalization. The estimated hazard ratio for the effect of starting on SUs compared to TZDs was 1.50 (95% confidence interval [CI] 1.09–2.09) for all-cause mortality, 1.68 (95% CI 1.31–2.15) for ambulatory care sensitive condition hospitalization, and 1.15 (95% CI 0.80–1.66) for acute myocardial infarction or stroke.

Conclusions

Our findings suggest increased risk of major adverse events associated with SUs as a second-line agent. Quasi-experimental IV methods may be an important alternative to lengthening clinical trials to assess long-term outcomes.