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Exploring heterogeneities of cardiovascular efficacy and effectiveness of SGLT2 inhibitors in patients with type 2 diabetes: an umbrella review of evidence from randomized clinical trials versus real-world observational studies

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Abstract

Purpose

We aimed to explore possible contributors to discrepancies between randomized controlled trials (RCTs) and real-world observational studies (OS) in cardiovascular benefits of sodium-glucose cotransporter 2 (SGLT2) inhibitors in type 2 diabetes (T2D) patients.

Methods

We searched PubMed and EMBASE to identify meta-analyses of RCTs and OS on cardiovascular effects of SGLT2 inhibitors in T2D patients. Cardiovascular outcomes included major adverse cardiovascular events (MACE), myocardial infarction (MI), stroke, cardiovascular mortality (CVM), all-cause mortality (ACM), hospitalization for heart failure (HHF), and atrial fibrillation (AF). We examined the summary relative risk (RR) and 95% confidence interval (CI) for each endpoint from meta-analyses of RCTs.

Results

We identified and included 15 eligible meta-analyses, 13 for RCTs and 2 for OS, with moderately strong evidence. The results revealed a significant discrepancy between RCTs and OS for MI (RR, 95% CI 1.05, 0.82–1.38; I = 91.5% versus odds ratio (OR), 95% CI 0.77, 0.73–0.81; I = 15.0%), stroke (RR, 95% CI 0.99, 0.76–1.29; I = 93.4% versus OR, 95% CI 0.75, 0.72–0.78; I = 23.0%), and AF (RR, 95% CI 0.72, 0.62–0.85; I = 0.0% versus OR, 95% CI 0.92, 0.83–1.02; I = 0.0%).

Conclusion

OS presented significant benefits of SGLT2 inhibitors both on primary and secondary preventions of MACE, MI, stroke, ACM, CVM, and HHF; RCTs did not. Given the spectrum of T2D patient characteristics and the strength of overall evidence, our review underscored the importance of constant integration of all available information and critical interpretation of all inconsistencies to optimize evidence-based diabetes care.

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Availability of data and materials

The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.

Abbreviations

SGLT2 :

Sodium-glucose cotransporter 2

T2D :

Type 2 diabetes

FDA :

Food and Drug Administration

CVD :

Cardiovascular disease

RCTs :

Randomized clinical trials

RWE :

Real-world evidence

OS :

Observational studies

CV :

Cardiovascular

PRISMA :

Preferred Reporting Items for Systematic Reviews and Meta-Analyses

CI :

Confidence interval

MACE :

Major adverse cardiovascular events

MI :

Myocardial infarction

ACM :

All-cause mortality

CVM :

CV-specific mortality

HHF :

Hospitalization for heart failure

AF :

Atrial fibrillation

RR :

Relative risk

AMSTAR :

A MeaSurement Tool to Assess systematic Reviews

GRADE :

Grading of Recommendations, Assessment, Development and Evaluation

OR :

Odds ratio

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Author information

Authors and Affiliations

  1. Department of Epidemiology, Indiana University Richard M. Fairbanks School of Public Health, IN, Indianapolis, 46202, USA

    Bojung Seo & Yiqing Song

  2. Cardiology Professional Services of Berkshire Medical Center, 777 North St, MB, Pittsfield, 01201, USA

    Jialin Su

Authors
  1. Bojung Seo
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Contributions

Seo, BJ has collected and analyzed/interpreted the data and drafted the manuscript. Song, Y has made substantial contributions to the design of this study, interpreted the data, and substantively revised the manuscript with a wide range of clinical and epidemiologic expertise. Su, J has made some contributions to the study conception and data interpretation from cardiological perspectives and reviewed the manuscript.

Corresponding author

Correspondence to Yiqing Song.

Ethics declarations

Ethics approval

Not applicable, since this study is an umbrella review that used published data of meta-analyses. Thus, we did not collect deeply personal, sensitive, or confidential information from participants, but just used publicly accessible documents as evidence. Therefore, there was no need to seek an institutional ethics approval and gain any consent to participate before commencing this study.

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Not applicable, our manuscript does not contain data from any individual person.

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The authors declare no competing interests.

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Seo, B., Su, J. & Song, Y. Exploring heterogeneities of cardiovascular efficacy and effectiveness of SGLT2 inhibitors in patients with type 2 diabetes: an umbrella review of evidence from randomized clinical trials versus real-world observational studies. Eur J Clin Pharmacol 78, 1205–1216 (2022). https://doi.org/10.1007/s00228-022-03327-w

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  • DOI: https://doi.org/10.1007/s00228-022-03327-w

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