Using Real-World Data to Predict Findings of an Ongoing Phase IV Cardiovascular Outcome Trial: Cardiovascular Safety of Linagliptin Versus Glimepiride
Abstract
OBJECTIVE Using real-world data (RWD) from three U.S. claims data sets, we aim to predict the findings of the CARdiovascular Outcome Trial of LINAgliptin Versus Glimepiride in Type 2 Diabetes (CAROLINA) comparing linagliptin versus glimepiride in patients with type 2 diabetes (T2D) at increased cardiovascular risk by using a novel framework that requires passing prespecified validity checks before analyzing the primary outcome.
RESEARCH DESIGN AND METHODS Within Medicare and two commercial claims data sets (May 2011–September 2015), we identified a 1:1 propensity score–matched (PSM) cohort of T2D patients 40–85 years old at increased cardiovascular risk who initiated linagliptin or glimepiride by adapting eligibility criteria from CAROLINA. PSM was used to balance >120 confounders. Validity checks included the evaluation of expected power, covariate balance, and two control outcomes for which we expected a positive association and a null finding. We registered the protocol (NCT03648424, ClinicalTrials.gov) before evaluating the composite cardiovascular outcome based on CAROLINA’s primary end point. Hazard ratios (HR) and 95% CIs were estimated in each data source and pooled with a fixed-effects meta-analysis.
RESULTS We identified 24,131 PSM pairs of linagliptin and glimepiride initiators with sufficient power for noninferiority (>98%). Exposure groups achieved excellent covariate balance, including key laboratory results, and expected associations between glimepiride and hypoglycemia (HR 2.38 [95% CI 1.79–3.13]) and between linagliptin and end-stage renal disease (HR 1.08 [0.66–1.79]) were replicated. Linagliptin was associated with a 9% decreased risk in the composite cardiovascular outcome with a CI including the null (HR 0.91 [0.79–1.05]), in line with noninferiority.
CONCLUSIONS In a nonrandomized RWD study, we found that linagliptin has noninferior risk of a composite cardiovascular outcome compared with glimepiride.
Footnotes
This article contains Supplementary Data online at http://care.diabetesjournals.org/lookup/suppl/doi:10.2337/dc19-0069/-/DC1.
See accompanying article, p. 2161.
- Received January 10, 2019.
- Accepted June 14, 2019.
- © 2019 by the American Diabetes Association.
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