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Glucagon-Like Peptide-1 Receptor Agonists and Cardiovascular Risk Reduction in Type 2 Diabetes Mellitus: Is It a Class Effect?
Curr Cardiol Rep. 2018 09 26; 20(11):113.CC

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. 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.

Authors+Show Affiliations

West Anaheim Medical Center, Department of Medicine, OPTI-West, 3033 West Orange Ave, Anaheim, CA, 92804, USA.Dept. of Medicine, Div. Endocrinology, Diabetes & Metabolism, University California, Irvine, School of Medicine, Irvine, CA, USA. pdrosenblit@yahoo.com. Diabetes Out-Patient Clinic, UCI Medical Center, Orange, CA, USA. pdrosenblit@yahoo.com. Diabetes / Lipid Management & Research Center, 18821 Delaware St., Suite 202, Huntington Beach, CA, 92648, USA. pdrosenblit@yahoo.com.

Pub Type(s)

Journal Article
Review

Language

eng

PubMed ID

30259238

Citation

Li, Yixing, and Paul D. Rosenblit. "Glucagon-Like Peptide-1 Receptor Agonists and Cardiovascular Risk Reduction in Type 2 Diabetes Mellitus: Is It a Class Effect?" Current Cardiology Reports, vol. 20, no. 11, 2018, p. 113.
Li Y, Rosenblit PD. Glucagon-Like Peptide-1 Receptor Agonists and Cardiovascular Risk Reduction in Type 2 Diabetes Mellitus: Is It a Class Effect? Curr Cardiol Rep. 2018;20(11):113.
Li, Y., & Rosenblit, P. D. (2018). Glucagon-Like Peptide-1 Receptor Agonists and Cardiovascular Risk Reduction in Type 2 Diabetes Mellitus: Is It a Class Effect? Current Cardiology Reports, 20(11), 113. https://doi.org/10.1007/s11886-018-1051-2
Li Y, Rosenblit PD. Glucagon-Like Peptide-1 Receptor Agonists and Cardiovascular Risk Reduction in Type 2 Diabetes Mellitus: Is It a Class Effect. Curr Cardiol Rep. 2018 09 26;20(11):113. PubMed PMID: 30259238.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Glucagon-Like Peptide-1 Receptor Agonists and Cardiovascular Risk Reduction in Type 2 Diabetes Mellitus: Is It a Class Effect? AU - Li,Yixing, AU - Rosenblit,Paul D, Y1 - 2018/09/26/ PY - 2018/9/28/entrez PY - 2018/9/28/pubmed PY - 2019/10/23/medline KW - Cardiovascular disease KW - ELIXIR KW - EXSCEL KW - Glucagon-like peptide-1 KW - HARMONY KW - LEADER KW - REWIND KW - Receptor agonists (GLP-1 RAs) KW - SUSTAIN-6 KW - Type 2 diabetes mellitus (T2DM) SP - 113 EP - 113 JF - Current cardiology reports JO - Curr Cardiol Rep VL - 20 IS - 11 N2 - 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. 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. SN - 1534-3170 UR - https://www.unboundmedicine.com/medline/citation/30259238/Glucagon_Like_Peptide_1_Receptor_Agonists_and_Cardiovascular_Risk_Reduction_in_Type_2_Diabetes_Mellitus:_Is_It_a_Class_Effect L2 - https://dx.doi.org/10.1007/s11886-018-1051-2 DB - PRIME DP - Unbound Medicine ER -