Review
Extraglycemic effects of glp-1-based therapeutics: Addressing metabolic and cardiovascular risks associated with type 2 diabetes

https://doi.org/10.1016/j.diabres.2012.11.009Get rights and content

Abstract

Context

To examine whether widespread tissue expression of the glucagon-like peptide (GLP)-1 receptor supports the possibility of differential effects of GLP-1-based therapeutics on cardiac function, blood pressure, food intake, gastric emptying, and other regulatory activities. GLP-1 receptor agonists (RAs) have demonstrated pleiotropic effects on overweight/obesity, hypertension, dyslipidemia, and cardiovascular (CV) disease. Food-regulatory effects have been demonstrated in preclinical and clinical trials, including reduced gastric motility and food intake leading to body weight reductions. Native GLP-1 and GLP-1 RAs have demonstrated cardioprotective effects in preclinical models.

Evidence acquisition

Using PubMed, we performed a search of the recent literature on GLP-1 and GLP-1 RAs.

Evidence synthesis

Preliminary clinical data indicate native GLP-1 has beneficial effects on endothelial cell function and vascular inflammation. Native GLP-1 and GLP-1 RAs have demonstrated renoprotective and antihypertensive effects, and reductions in lipid parameters. The GLP-1 RA liraglutide has also demonstrated positive effects on such markers of endothelial dysfunction as tumor necrosis factor-α and plasminogen activator inhibitor-1.

Conclusion

Preliminary data suggest GLP-1 RAs could benefit type 2 diabetes patients at risk for CV comorbidities. Additional studies are needed to confirm the extraglycemic and extrapancreatic effects and determine whether outcomes will translate into beneficial effects for patient care.

Introduction

Glucagon-like peptide (GLP)-1, secreted by intestinal L cells, and glucose-dependent insulinotropic polypeptide (GIP), secreted by intestinal K cells, are incretin hormones rapidly released after meals [1]. In patients with type 2 diabetes, incretin-mediated, glucose-dependent insulin secretion is significantly reduced by decreased GLP-1 secretion and altered action of GIP [2]. Incretin-based treatment targets restoration of the insulinotropic response using either GLP-1 receptor agonists (RAs) or dipeptidyl peptidase (DPP-4) inhibitors. The long-acting GLP-1 RAs exenatide and liraglutide have mechanisms of action distinct from the DPP-4 inhibitors, resulting in differential efficacy [1], [3]. GLP-1 RAs supplement endogenous secretion of GLP-1 and result in pharmacologic levels of receptor activity [4]. Alternatively, the efficacy of DPP-4 inhibitors depends on endogenous secretion of GLP-1 as they inhibit the degradation of endogenous GLP-1 and GIP and result in more physiologic levels of receptor stimulation [3].

GLP-1 research has focused mainly on its insulinotropic and glucagon-lowering actions [1], [5], and less on its extrapancreatic effects. There are now emerging data regarding possible cardiovascular (CV), cardioprotective, and central nervous system (CNS) effects [6]. GLP-1 receptors are widely expressed in various cell types. They have been localized in rodent cardiac myocytes, endothelial cells, and vascular smooth muscle cells; and in regions of the CNS regulating an array of homeostatic functions over and above glucoregulation [7]. Such wide-ranging receptor expression has implications for the differential actions of incretin therapeutics in the treatment of type 2 diabetes. Accordingly, recent in vitro, preclinical and clinical investigations have demonstrated direct and indirect effects of GLP-1 RAs on cardiac contractility, cardiac output, blood pressure (BP), cardioprotection, gastric motility, feeding behavior, satiety, and other systemic regulatory responses (Fig. 1) [7], [8]. This review discusses the extraglycemic effects of the endogenous incretin hormone GLP-1, and analyzes available clinical and preclinical data on GLP-1-based pharmacotherapy.

Section snippets

Gastrointestinal system and CNS effects

GLP-1 receptors are found in regions of the CNS that regulate gastric motility, satiety, feeding behavior and food choice; suggesting that GLP-1 plays an important role in regulating appetite and body weight [9], [10], [11]. In normal weight or obese subjects, and in people with diabetes, GLP-1 inhibits food intake and promotes satiety [12], [13], often resulting in weight loss. Study results in Göttingen minipigs indicate that the long-acting GLP-1 RA, liraglutide, may also have potent actions

Clinical implications

The pleiotropic effects of GLP-1 RAs may benefit patients with type 2 diabetes who also often have co-morbidities, including obesity, dyslipidemia, hypertension and cardiovascular disease. Rising mortality rates in patients with type 2 diabetes with comorbid adiposity and CV disease underscore the need to address all salient risk factors. Clinical trials have examined effects of GLP-1 analogs on body weight, BP, and other CV risk markers (Table 1, Table 2, Table 3).

Conclusions

New research suggests pleiotropic effects of GLP-1 beyond its glucose-dependent potentiation of insulin and suppression of glucagon secretion, including direct and indirect cardioprotective actions, BP reduction, improvements in lipids, neuroprotective effects, and positive effects on satiety and food intake with associated weight reduction. Evidence-based medicine dictates that effective management of type 2 diabetes should integrate a comprehensive program of lifestyle intervention and

Funding

Funding to support the preparation of this manuscript was provided by Novo Nordisk Inc. This manuscript was prepared according to the International Society for Medical Publication Professionals’ “Good Publication Practice for Communicating Company-Sponsored Medical Research: the GPP2 Guidelines.” The authors received no honorarium or payment for their authorship of this review.

Disclosure

ESH has served as an advisory board member and consultant to Amarin Corporation, PLC; Amylin Pharmaceuticals, Inc.; Janssen Pharmaceuticals, Inc.; Merck & CO. Inc. and Gilead Sciences, Inc. In addition, ESH has served on Data Safety Monitoring Boards for GI Dynamics, Inc.; Theracos, Inc. and Takeda Pharmaceuticals U.S.A, Inc.; is a member of the Merck speakers bureau; and has received research grant support from Amylin and Eli Lilly and Company.

Conflict of interest

SH declares she has no conflict of interest.

Acknowledgements

The authors wish to thank Robert McCarthy, Ph.D., and Patricia Abramo of AdelphiEden Health Communications, and Lynanne McGuire, Ph.D., of MedVal Scientific Information Services, LLC, for providing medical writing and editorial services.

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