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Clinical Drug Investigation

, Volume 38, Issue 6, pp 491–501 | Cite as

Cardiovascular Mortality of Oral Antidiabetic Drugs Approved Before and After the 2008 US FDA Guidance for Industry: A Systemic Review and Meta-Analysis

  • Rashmi Goyat
  • Pragya Rai
  • Jongwha Chang
  • Charles D. Ponte
  • Xi Tan
Systematic Review

Abstract

Background

Both diabetes and antidiabetic drugs (ADDs) increase the risk for cardiovascular (CV) diseases. Due to the increasing concern about CV safety associated with ADDs, the US FDA revised regulatory guidelines in 2008 to include CV safety as an endpoint.

Objective

The objective of the current study was to conduct a systematic review with meta-analysis to compare CV mortality of oral ADDs approved before and after the FDA’s 2008 guidance.

Methods

Three electronic databases (PubMed, Scopus, and the Clinical Trial Registry) were searched to retrieve studies published up to 24 February 2017. Randomized clinical trials were included in this study if they (1) were published in the English language; (2) included adults with type 2 diabetes mellitus with or without CV risk factors, who were taking at least one oral antidiabetic drug; and (3) had at least one study outcome as CV mortality. Meta-analysis was performed using a random-effects model. Small-study effects were accessed using funnel plot symmetry. The primary outcome was CV mortality.

Results

We found that there was no significant increase in CV mortality for drugs approved before and after 2008. The overall odds ratio (OR) and the upper bound of the two-sided 95% confidence interval (CI) for all drugs approved after 2008 (OR 0.74, 95% CI 0.52–1.07) were lower than the overall OR for all drugs approved before 2008 (OR 1.03, 95% CI 0.89–1.19). In addition, the upper bounds of the two-sided 95% CI for both groups of drugs before and after 2008 were below 1.3. Empagliflozin, which was approved after the guidance, was significantly associated with a reduction in CV mortality.

Conclusion

The 2008 FDA guidance appears to have a positive impact on CV risk assessment of recently marketed drugs for the management of diabetes.

Notes

Compliance with Ethical Standards

Funding

No funding was received to conduct this study.

Conflicts of interest

Rashmi Goyat, Pragya Rai, Jongwha Chang, Charles D. Ponte, and Xi Tan declare no conflicts of interest.

Supplementary material

40261_2018_639_MOESM1_ESM.pdf (722 kb)
Supplementary material 1 (PDF 722 kb)

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Copyright information

© Springer International Publishing AG, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Department of Pharmaceutical Systems and Policy, School of PharmacyWest Virginia UniversityMorgantownUSA
  2. 2.Department of Pharmacy Practice, School of PharmacyUniversity of TexasEl PasoUSA
  3. 3.Department of Clinical Pharmacy, School of PharmacyWest Virginia UniversityMorgantownUSA

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