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Glucagon-Like Peptide-1 Receptor Agonists in Type 2 Diabetes Mellitus and Cardiovascular Disease: The Past, Present, and Future

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Abstract

Type 2 diabetes mellitus (T2DM) is associated with high cardiovascular morbidity and mortality, and cardiovascular diseases are the leading causes of death and disability in people with T2DM. Unfortunately, therapies strictly aimed at glycemic control have poorly contributed to a significant reduction in the risk of cardiovascular events. On the other hand, randomized controlled trials have shown that five glucagon-like peptide-1 receptor agonists (GLP-1 RAs) and one exendin-based GLP-1 RA reduced atherosclerotic cardiovascular events in patients with diabetes at high cardiovascular risk. Furthermore, a meta-analysis including these six agents showed a reduction in major adverse cardiovascular events as well as all-cause mortality compared with placebo, regardless of structural homology. Evidence has also shown that some drugs in this class have beneficial effects on renal outcomes, such as preventing the onset of macroalbuminuria. In addition to lowering blood pressure, these drugs also favorably impacted on body weight in large randomized controlled trials as in real-world studies, a result considered a priority in T2DM management; these and other factors may justify the benefits of GLP-1 RAs upon the cardiovascular system, regardless of glycemic control. Finally, studies showed safety with a low risk of hypoglycemia and no increase in pancreatitis events. Given these benefits, GLP-1 RAs were preferentially endorsed in the guidelines of the European and American societies for patients with these conditions. This narrative review provides a current and comprehensive overview of GLP-1 RAs as cardiovascular and renal protective agents, far beyond their use as glucose-lowering drugs, supporting their effectiveness in treating patients with T2DM at high cardiovascular risk.

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Authors and Affiliations

  1. Postgraduate Program in Cardiology and Cardiovascular Sciences, Hospital de Clínicas de Porto Alegre, Universidade Federal do Rio Grande do Sul, School of Medicine, Rua Ramiro Barcelos 2350, Serviço de Fisiatria/Térreo, Porto Alegre, RS, 90470-260, Brazil

    Filipe Ferrari & Ricardo Stein

  2. Hospital de Clínicas de Porto Alegre, Porto Alegre, RS, Brazil

    Filipe Ferrari & Vítor M. Martins

  3. Pharmacology Department, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brazil

    Rafael S. Scheffel

  4. Endocrine Division, Hospital de Clínicas de Porto Alegre, Universidade Federal do Rio Grande do Sul, School of Medicine, Porto Alegre, RS, Brazil

    Rafael S. Scheffel

  5. Hospital Israelita Albert Einstein, São Paulo, SP, Brazil

    Raul D. Santos

  6. Lipid Clinic Heart Institute (InCor), Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo, São Paulo, SP, Brazil

    Raul D. Santos

  7. School of Medicine, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brazil

    Ricardo Stein

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  1. Filipe Ferrari
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  2. Rafael S. Scheffel
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  3. Vítor M. Martins
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  4. Raul D. Santos
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  5. Ricardo Stein
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Corresponding author

Correspondence to Ricardo Stein.

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Funding

This study was partially supported by the Hospital de Clínicas de Porto Alegre Research Incentive Fund (FIPE-HCPA), Porto Alegre, Brazil, and by the Coordination for the Improvement of Higher Education Personnel—Brazil (CAPES)—funding code 001. FF receives financial support from CAPES. RDS  is recipient of a Brazilian National Council for Scientific and Technological Development (CNPq) research scholarship (filing #303734/2018-3). RS receives research productivity funding from CNPq.  

Conflicts of interest

RDS has received honoraria related to consulting, research, and/or speaker activities from Abbott, Amgen, Aché, Amryt, AstraZeneca, Esperion, EMS, Kowa, Hypera, Merck, MSD, Novo Nordisk, Novartis, PTC, Pfizer, Roche, and Sanofi. Filipe Ferrari, Rafael S. Scheffel, Vítor M. Martins, and Ricardo Stein have no conflicts of interest that are directly relevant to the content of this article.

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Author contributions

Conception and design of the research; acquisition, analysis, and interpretation of the data; and writing of the manuscript: FF, RSS, VMM, RDS, RS. Critical revision of the manuscript for intellectual content: FF, RSS, RDS, RS.

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Ferrari, F., Scheffel, R.S., Martins, V.M. et al. Glucagon-Like Peptide-1 Receptor Agonists in Type 2 Diabetes Mellitus and Cardiovascular Disease: The Past, Present, and Future. Am J Cardiovasc Drugs 22, 363–383 (2022). https://doi.org/10.1007/s40256-021-00515-4

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