Elsevier

American Heart Journal

Volume 240, October 2021, Pages 73-80
American Heart Journal

Clinical Investigations
Regional variation of effects of new antidiabetic medications in cardiovascular outcome trials

https://doi.org/10.1016/j.ahj.2021.06.001Get rights and content

Background

In international trials, glucagon-like protein-1 receptor agonists (GLP-1RAs) and sodium-glucose cotransporter-2 inhibitors (SGLT2Is) were effective in improving cardiovascular (CV) outcomes.

Methods

We assessed the effect of GLP-1RAs and SGLT2Is treatment effect on CV endpoints by geographical region in multiple international trials using random effects weighted least squares meta-regressions.

Results

The estimated effects of both SGLT2Is and GLP-1RAs on major adverse CV events (MACE) in North America (SGLT2Is n = 12,399, HR 0.90, 95% CI 0.81-1.01; GLP-1RAs n = 12,515, HR 0.95, 95% CI 0.83- 1.09) and in Europe (SGLT2Is n = 19,435, HR 0.93, 95% CI 0.85-1.02; GLP-1RAs n = 22,812, HR 0.88, 95% CI 0.79-0.99) were numerically lower but not statistically different to the rest of the world (ROW) (SGLT2Is n = 15,127, HR 0.83, 95% CI 0.75-0.92, p-value for interaction 0.26; GLP-1RAs n = 17,494, HR 0.82, 95% CI 0.73-0.92, p-value for interaction 0.28). Effects of SGLT2Is on heart failure readmission or CV death varied significantly by region (P = 0.0094). The effect of SGLT2Is was significantly smaller in Europe (n = 18,653, HR 0.86, 95% CI 0.78-0.95) than in the ROW (n = 12,463, HR 0.68, 95% CI 0.61-0.76, P = 0.0024). The smaller effect in North America (n = 9776, HR 0.76, 95% CI 0.66-0.87) did not differ significantly from that in the ROW (P = 0.2370).

Conclusion

The effects of SGLT2Is on HF events are larger in the ROW. Further analyses and studies are needed to better elucidate the differential effects of SGLTIs and GLP-1RAs by geographical regions.

Section snippets

Methods

We searched PubMed for clinical trials of SGLT2 inhibitors and of GLP-1 receptor agonists assessing effects on CV and/or renal outcomes and included large (>1,000 patients) phase 3 randomized placebo-controlled trials that reported outcomes by region. Terms used for search are given in Supplementary Table 1. We have further compared our review findings with two other metanalysis of SGLT2Is and GLP1RAs.19, 20

Estimated effects by geographic region were available for 14 of 15 trials identified.

Results

Treatment effects on each of the outcomes by geographical region for SGLT2Is in each of the studies is presented in Table 1 and for GLP1RAs in Table 2. Summaries of the available results across all studies are presented in Table 3.

Discussion

The current analysis suggests that there may be some geographical variation with regard to the effects of SGLT2 inhibitors and GLP-1 receptor agonists on cardiovascular outcomes. The point estimates for the effects on several CV outcomes are lower in North America and Europe, not reaching statistical significance in these regions, while for all endpoints, the effects of both SGLT2Is and GLP-1RAs in the rest of the world were large and significant (Figure 1). However, except for the effects of

Limitations and conclusion

The current analysis is limited by the public data available on the effects of SGLT2Is and GLP1RAs by geographical region. The availability of more granular data would allow examination of treatment effect moderation by specific countries and even states, as well as exploration of associations with markers of reduced application of standard of care. However, all analyses will be limited by the extent to which standard of care therapy is assessed in the individual trials. Given that prior

Author contribution

Conceptualization: GC, BAD. Investigation: GC, BAD, CE, SS. Formal analysis: BAD, CE, SS. Drafting of manuscript: GC, BAD. All authors reviewed, edited, and approved the final version of the article.

Competing Interests

None.

Funding

None.

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