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Glucagon-Like Peptide-1 Receptor Agonists and Cardiovascular Risk Reduction in Type 2 Diabetes Mellitus: Is It a Class Effect?

  • Diabetes and Cardiovascular Disease (ND Wong, Section Editor)
  • Published:
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Abstract

Purpose of Review

Mimetics and analogs that extend the half-life of native glucagon-like peptide-1 (GLP-1), i.e., glucagon-like peptide-1 receptor agonists (GLP-1 RAs), at therapeutic doses, are indicated as adjuncts to diet and exercise, to improve glycemic control in adults with type 2 diabetes mellitus (T2DM). In patients with T2DM, GLP-1 RAs not only affect improvements in impaired beta cell and alpha cell function, suppress appetite, and induce weight loss but also possess multiple cardiovascular protective properties that potentially have a beneficial impact on atherosclerotic cardiovascular disease (ASCVD) morbidity and mortality.

Recent Findings

Required to demonstrate CV safety, compared to standard-of-care antidiabetic therapies, GLP-1 RAs have revealed statistically significant non-inferiority (p < 0.001), among CV outcome trials (CVOTs) thus far completed. Once-daily liraglutide and once-weekly semaglutide demonstrated significant superiority (p = 0.01 and p = 0.02, respectively), reducing 3-point composite major adverse cardiovascular events (MACE) in extreme risk secondary prevention adults with T2DM. Once-weekly exenatide demonstrated only a non-significant (p = 0.06) favorable trend for CV superiority, possibly due to in-trial mishaps, including placebo drop-ins with other CV protective medications. The short half-life lixisenatide was neutral (p = 0.81) in reducing MACE, most likely due to ineffective once-daily dosing. Structural differences among GLP-1 mimetics and analogs may explain potency differences in both A1C reduction and weight loss that may parallel important cardiovascular protective properties of the GLP-1 RA class.

Summary

Significant superiority in reducing 3-point composite MACE in adults with T2DM with GLP-1 RAs has been limited to liraglutide and semaglutide. Careful attention to within-trial drop-in of cardioprotective antidiabetic agents assuring equipoise between placebo and investigational product groups might demonstrate significant MACE risk reduction with once-weekly exenatide. Maintenance of 24-h circulating levels, by an alternative administration method, may resurrect lixisenatide as a cardioprotective agent. Before a GLP-1 RA bioequivalence “class effect” claim for composite MACE risk reduction superiority can be fully discussed, we are obliged to wait for the pending results of CVOTs with other GLP-1 RAs, particularly albiglutide and dulaglutide, where steric hindrance may potentially inhibit full mimicry of pharmacologic GLP-1.

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Abbreviations

ARR:

Absolute risk reduction

BMI:

Body mass index

CKD:

Chronic kidney disease

CVD:

Cardiovascular disease

CVOTs:

CV (safety) outcome trials

DPP-4:

Dipeptidyl peptidase-4

FDA:

Food and Drug Administration

GLP-1 RAs:

Glucagon-like peptide-1 receptor agonists

HR:

Hazard ratio

MACE:

Major adverse cardiovascular events

NF-MI:

Non-fatal myocardial infarction

NNH:

Number needed to harm

NNT:

Number needed to treat

PEP:

Primary endpoint

RCTs:

Randomized clinical trials

RRR:

Relative risk reduction

T2DM:

Type 2 diabetes mellitus

UA:

Unstable angina

ELIXA:

Evaluation of Lixisenatide in Acute Coronary Syndrome

EXSCEL:

Effect of Once Weekly Exenatide On Cardiovascular Outcome in Type 2 Diabetes’

FREEDOM-CVO:

Cardiovascular outcome safety study of ITCA 650, an injection-free exenatide osmotic mini-pump delivery system

HARMONY:

Trial of the effect of albiglutide on major adverse cardiovascular (CV) events in patients with T2DM and established CV disease

LEADER:

Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Outcome Results

REWIND:

Researching cardiovascular Events with a Weekly Incretin in Diabetes

SUSTAIN-6:

Trial to Evaluate Cardiovascular and Other Long-term Outcomes with Semaglutide in Subjects with Type 2 Diabetes

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Authors and Affiliations

  1. West Anaheim Medical Center, Department of Medicine, OPTI-West, 3033 West Orange Ave, Anaheim, CA, 92804, USA

    Yixing Li

  2. Dept. of Medicine, Div. Endocrinology, Diabetes & Metabolism, University California, Irvine, School of Medicine, Irvine, CA, USA

    Paul D. Rosenblit

  3. Diabetes Out-Patient Clinic, UCI Medical Center, Orange, CA, USA

    Paul D. Rosenblit

  4. Diabetes / Lipid Management & Research Center, 18821 Delaware St., Suite 202, Huntington Beach, CA, 92648, USA

    Paul D. Rosenblit

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  1. Yixing Li
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Correspondence to Paul D. Rosenblit.

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Yixing Li declares that he has no conflicts of interest.

Paul D. Rosenblit reports the following: Clinical Research Trial site for Amgen, AstraZeneca, Boehringer Ingelheim, Bristol-Myers-Squib, Glaxo SmithKline, Ionis, Lexicon, Novo Nordisk, and Sanofi; Speaking/Teaching Honoraria from Akcea, Amgen, Janssen, Novo Nordisk, and Merck; and Advisory Board Honoraria from Akcea, Amarin, Amgen, Novo Nordisk, and Sanofi-Regeneron.

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Li, Y., Rosenblit, P.D. Glucagon-Like Peptide-1 Receptor Agonists and Cardiovascular Risk Reduction in Type 2 Diabetes Mellitus: Is It a Class Effect?. Curr Cardiol Rep 20, 113 (2018). https://doi.org/10.1007/s11886-018-1051-2

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