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Using Real-World Data to Predict Findings of an Ongoing Phase IV Cardiovascular Outcome Trial: Cardiovascular Safety of Linagliptin Versus Glimepiride.

Authors
  • Patorno, Elisabetta1
  • Schneeweiss, Sebastian1
  • Gopalakrishnan, Chandrasekar2
  • Martin, David3
  • Franklin, Jessica M1
  • 1 Division of Pharmacoepidemiology and Pharmacoeconomics, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA.
  • 2 Division of Pharmacoepidemiology and Pharmacoeconomics, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA [email protected]
  • 3 Office of Medical Policy, Center for Drug Evaluation and Research, U.S. Food and Drug Administration, Silver Spring, MD.
Type
Published Article
Journal
Diabetes care
Publication Date
Dec 01, 2019
Volume
42
Issue
12
Pages
2204–2210
Identifiers
DOI: 10.2337/dc19-0069
PMID: 31239281
Source
Medline
Language
English
License
Unknown

Abstract

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. 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. 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. In a nonrandomized RWD study, we found that linagliptin has noninferior risk of a composite cardiovascular outcome compared with glimepiride. © 2019 by the American Diabetes Association.

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