Cardiovascular outcomes of antidiabetes medications by race/ethnicity: A systematic review and meta-analysis

https://doi.org/10.1016/j.jdiacomp.2021.107980Get rights and content

Highlights

  • Cardiovascular safety of antidiabetes agents was shown for all racial/ethnic groups.

  • Significant cardiovascular risk reduction only in White and Asian participants.

  • Cardiovascular effects in Blacks and subjects from other groups need more investigations.

Abstract

Background

The consistency of cardiovascular risk reduction by antidiabetes medications across racial and ethnic groups remains unclear. The aim of this study was to analyze racial/ethnic patterns in the results of cardiovascular outcomes trials of antidiabetes medications in people with type 2 diabetes.

Method

PubMed and Cochrane library databases were searched from the inception dates to December 2020. Cardiovascular outcome trials in type 2 diabetes that randomized participants to antidiabetes medication or control treatment and reported results by race/ethnic groups or region were included.

Results

A total of 19 studies were included in this meta-analysis. Among White participants, treatment with antidiabetes medications significantly decreased the risk of composite cardiovascular outcomes when compared with placebo treatment (OR = 0.88, 95% CI 0.83–0.94, p < 0.05). Among Asian participants, antidiabetes medications also significantly decreased the risk of composite cardiovascular outcomes when compared with control treatment (OR = 0.80, 95% CI 0.74–0.86, p < 0.05). A similar pattern was found when analyzing the effects of antidiabetes medications vs. control treatment in other racial/ethnic groups comprising mostly Hispanics and Pacific Islanders (OR = 0.87, 95% CI 0.78-0.98, p < 0.05). However, among Black participants, treatment with antidiabetes medications resulted in nominal but non-significant decreases in the composite cardiovascular outcomes when compared with control treatment (OR = 0.84, 95% CI 0.62–1.14, p = 0.26).

Conclusions

The present meta-analysis showed cardiovascular safety of antidiabetes medications in people with type 2 diabetes from all racial/ethnic groups studied; however, significant composite cardiovascular risk reductions were demonstrated only in White and Asian participants. To determine whether antidiabetes drugs confer consistent cardiovascular benefits in Black and other racial/ethnic participants requires more investigations in the future.

Introduction

Racial and ethnic disparities in the risk factors, prevalence and complications of type 2 diabetes mellitus (T2DM) have been widely reported.1., 2, 3, 4, 5 For example, the National Health and Nutrition Examination Survey (NHANES) estimates show approximately 2-fold or higher prevalence of diagnosed T2DM in African Americans, Hispanic Americans, Asian Americans and American Indians, compared with non-Hispanic white Americans.1,6,7 Other reports have indicated that Asians tend to develop T2DM at a younger age and lower body mass index when compared with White or African populations.8,9

The quality of glycemic control and clinical consequences of the microvascular complications of diabetes, such as retinopathy, amputation, and kidney disease, have also been reported to show ethnic/racial disparities.4,10,11 The disparities in microvascular complications can be eliminated with equal access to care and optimal glycemic control.12,13

Unlike microvascular complications, which can be prevented by optimal glycemic control, the approach to the prevention of cardiovascular disease (CVD) requires targeting all modifiable cardiovascular risk factors along with glucose control.14,15 Analysis of data from 1,344,899 patients in an insured population followed from 2002 to 2012 showed that Blacks, Latinos, and Asians had lower risk of coronary heart disease (CHD) across all risk categories, compared with Whites.16 However, despite having a lower prevalence of CHD and less atherogenic lipid profile, Blacks have a higher CHD mortality rate compared with Whites.17, 18, 19 The age-adjusted CHD death rates per 100,000 were 132.3 for non-Hispanic White men versus 146.5 for non-Hispanic Black men, and 67.9 for non-Hispanic White women versus 85.4 for non-Hispanic Black women.18

Landmark randomized controlled clinical trials of aggressive glycemic control failed to demonstrate reduction in CVD events in people with T2DM, during the active follow-up period.20., 21., 22 However, other more recent studies have tested specific antidiabetes medications (rather than glucose control, per se) for the pre-specified primary outcome of major adverse cardiovascular events (MACE). Several of these cardiovascular outcomes trials (CVOTs) of antidiabetes medications have been completed and the results show variability among classes of glucose-lowering agents in their effects on CVD events. Furthermore, enrollment of subjects into the CVOTs does not appear to reflect any attempt at ensuring racial/ethnic balance in the study populations. Consequently, the data from the individual CVOTs do not provide full insight into the efficacy of the study medications across racial/ethnic groups. Given the potential for interplay among prevalent CVD risk factors, genetic background, socioeconomic factors, and other variables, in determining outcomes of the CVOTs in different racial/ethnic groups, we conducted a meta-analysis to explore consistency of results from CVOTs across race/ethnicity.

Section snippets

Data sources and searches

This study was conducted according to standard guidelines for conducting and reporting systematic reviews (PRISMA checklist). We searched PubMed (Medline), the Cochrane Central Register of Controlled Trials (CENTRAL), and Embase for randomized control trials (RCTs) from inception until December 2020.

Study selection

The inclusion criteria were (1) type 2 diabetes cardiovascular outcome trials; (2) studies that reported prespecified cardiovascular events in the active treatment and control groups by

Included studies

Through the search, we identified 719 records. As is shown in Fig. 1, finally 19 studies were included in the quantitative synthesis. Of the included studies, 17 were placebo-controlled and 2 studies compared the test medications against active agents (Table S2). The primary outcomes were MACE in 15 placebo-controlled studies; of the other 4 studies, the primary outcomes were hospitalization for heart failure in 2 studies and renal events in the other 2 studies. The antidiabetes medications

Discussion

Our meta-analysis of 19 RCTs of antidiabetes medications that prespecified cardiovascular outcomes and provided adequate pertinent data showed that the overall event rates did not differ significantly among participants from the different racial/ethnic groups. The latter finding probably reflects the inclusion criteria that targeted high-risk patients with type 2 diabetes for enrollment in the CVOTs.

However, when comparing the effects of antidiabetes medication versus placebo- or active-control

Conclusion

In conclusion, the present meta-analysis shows that the aggregate point estimates and confidence intervals for the numerous agents that have been tested in CVOTs reached statistical significance for reduction of composite cardiovascular outcomes only in White and Asian participants, who together represented 85.98% of the 136,178 participants enrolled in those trials. For Blacks and other racial/ethnic groups (who together represented 14.02% of the enrollment), the meta-analysis showed general

Abbreviations

    AGI

    alpha glucosidase inhibitor

    CENTRAL

    the Cochrane Central Register of Controlled Trials

    CHD

    coronary heart disease

    CI

    confidence interval

    CVD

    cardiovascular disease

    DPP-4

    dipeptidyl-peptidase-4

    GLP-1RA

    glucagon-like peptide-1 receptor analog

    MACE

    major adverse cardiovascular events

    NHANES

    National Health and Nutrition Examination Survey

    OR

    odd ratio

    PPAR

    peroxisome proliferation activated receptor

    RCT

    randomized control trial

    SGLT2i

    sodium glucose cotransporter 2 inhibitor

    T2DM

    type 2 diabetes mellitus

Ethics approval and consent to participate

No applicable.

Consent for publication

No applicable.

Availability of data and materials

Data of all the clinical trials included in this meta-analysis could be reached from the published manuscripts.

Funding

This study was supported by National Natural Science Foundation of China (No. 81970708 and No. 81970698) and was also funded by Lilly China company. SD-J is supported, in part, by a grant from the National Institutes of Health (R01 DK067269). The funding sources had no role in the study design, data collection or analysis, decision to publish, or preparation of the manuscript.

CRediT authorship contribution statement

LJ and XC conceived and designed the study. XC and CL assisted with the methods. XC, CL and WY did the data analysis. XC, CL and LJ drafted the manuscript. SD-J discussed study concept, reviewed and revised manuscript. All authors assisted with interpretation, commented on drafts of the manuscript, and approved the final version. LJ is the guarantor and attests that all listed authors meet authorship criteria and that no others meeting the criteria have been omitted.

Declaration of competing interest

Linong Ji has received fees for lecture presentations and consulting fees from AstraZeneca, Merck, Novartis, Novo Nordisk, Lilly, Roche, Sanofi-Aventis and Takeda, and grants/research support from AstraZeneca, Merck, Novartis, Novo Nordisk and Sanofi-Aventis; S.D.-J. has led clinical trials for AstraZeneca, Novo Nordisk, Inc., and Boehringer Ingelheim; has received consulting fees from AstraZeneca, Boehringer Ingelheim, Janssen, Merck & Co. Inc., and Sanofi; and has equity interests in Jana

Acknowledgements

We thank doctors, nurses and technicians for their practical work during the study at Department of Endocrinology and Metabolism in Peking University People's Hospital.

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