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Metformin and heart failure–related outcomes in patients with or without diabetes: a systematic review of randomized controlled trials

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Abstract

Metformin is considered a safe anti-hyperglycemic drug for patients with type 2 diabetes (T2D); however, information on its impact on heart failure–related outcomes remains inconclusive. The current systematic review explored evidence from randomized clinical trials (RCTs) reporting on the impact of metformin in modulating heart failure–related markers in patients with or without T2D. Electronic databases such as MEDLINE, Cochrane Library, and EMBASE were searched for eligible studies. Included studies were those assessing the use of metformin as an intervention, and also containing the comparison group on placebo, and all articles had to report on measurable heart failure–related indices in individuals with or without T2D. The modified Downs and Black checklist was used to evaluate the risk of bias. Overall, nine studies met the inclusion criteria, enrolling a total of 2486 patients. Although summarized evidence showed that metformin did not affect left ventricular function, this antidiabetic drug could improve myocardial oxygen consumption concomitant to reducing prominent markers of heart failure such as n-terminal pro-brain natriuretic peptide and low-density lipoprotein levels, inconsistently between diabetic and nondiabetic patients. Effective modulation of some heart failure–related outcomes with metformin treatment was related to its beneficial effects in ameliorating insulin resistance and blocking pro-inflammatory markers such as the aging-associated cytokine CCL11 (C-C motif chemokine ligand 11). Overall, although such beneficial effects were observed with metformin treatment, additional RCTs are necessary to improve our understanding on its modulatory effects on heart failure–related outcomes especially in diabetic patients.

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Data availability

Data related to search strategy, study selection, and extraction items will be made available upon request after the manuscript is published.

Abbreviations

AMPK:

5′ AMP-activated protein kinase

CAD:

coronary artery disease

CCL11:

C-C motif chemokine ligand 11

CVDs:

cardiovascular diseases

LVEF:

left ventricular ejection fraction

NT-proBNP:

n-terminal pro-brain natriuretic peptide

RCTs:

randomized controlled trials

T2D:

type 2 diabetes

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Acknowledgments

BB Nkambule is a University of KwaZulu-Natal Developing Research Innovation, Localisation and Leadership in South Africa (DRILL) fellow. DRILL, is a NIH D43 grant (D43TW010131) awarded to UKZN in 2015 to support a research training and induction program for early career academics. The content hereof is the sole responsibility of the authors and do not necessarily represent the official views of the funders.

Funding

This work was supported in part by baseline funding from the Biomedical Research and Innovation Platform of the South African Medical Research Council (SAMRC) and the National Research Foundation (Grant number 117829). PV Dludla was partially supported as a Post-Doctoral Fellow by funding from the SAMRC through its division of Research Capacity Development under the Intra-Mural Postdoctoral Fellowship Programme from funding received from the South African Treasury.

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Authors and Affiliations

  1. Biomedical Research and Innovation Platform, South African Medical Research Council, Tygerberg, 7505, South Africa

    Phiwayinkosi V. Dludla, Rabia Johnson, Kwazi B. Gabuza, Christo J. F. Muller & Johan Louw

  2. Department of Life and Environmental Sciences, Polytechnic University of Marche, 60131, Ancona, Italy

    Phiwayinkosi V. Dludla, Sonia Silvestri, Patrick Orlando & Luca Tiano

  3. School of Laboratory Medicine and Medical Sciences, College of Health Sciences, University of KwaZulu-Natal, Durban, 4000, South Africa

    Tawanda M. Nyambuya, Vuyolwethu Mxinwa, Kabelo Mokgalaboni & Bongani B. Nkambule

  4. Department of Health Sciences, Faculty of Health and Applied Sciences, Namibia University of Science and Technology, Windhoek, 9000, Namibia

    Tawanda M. Nyambuya

  5. Division of Medical Physiology, Faculty of Health Sciences, Stellenbosch University, Tygerberg, 7505, South Africa

    Rabia Johnson, Sithandiwe E. Mazibuko-Mbeje & Christo J. F. Muller

  6. Department of Biochemistry, Faculty of Natural and Agricultural Sciences, North-West University, Mmabatho, 2745, South Africa

    Sithandiwe E. Mazibuko-Mbeje

  7. Department of Biochemistry and Microbiology, University of Zululand, KwaDlangezwa, 3880, South Africa

    Christo J. F. Muller & Johan Louw

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  1. Phiwayinkosi V. Dludla
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Contributions

PVD, TMN, BBN: concept and original draft. VM, KM: data extraction and study appraisal. PVD, TMN, RJ, SS, PO, SEM-M, KBG, VM, KM, LT, CJF, JL, BBN: writing and final approval of the manuscript.

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Correspondence to Phiwayinkosi V. Dludla.

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The content hereof is the sole responsibility of the authors and do not necessarily represent the official views of the SAMRC or the funders.

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The authors declare no conflict of interest.

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This is a review of already published studies and thus it does not require ethical approval.

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Dludla, P.V., Nyambuya, T.M., Johnson, R. et al. Metformin and heart failure–related outcomes in patients with or without diabetes: a systematic review of randomized controlled trials. Heart Fail Rev 26, 1437–1445 (2021). https://doi.org/10.1007/s10741-020-09942-y

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