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      Glucagon-like peptide-1 receptor co-agonists for treating metabolic disease

      review-article
      Author(s): , ∗
      Publication date (Electronic):
      Journal: Molecular Metabolism
      Publisher: Elsevier
      Keywords: Diabetes, Obesity, Peptide, Receptor, Cardiovascular disease, Adipose tissue

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          Abstract

          Background

          Glucagon-like peptide-1 receptor (GLP-1R) agonists are approved to treat type 2 diabetes and obesity. They elicit robust improvements in glycemic control and weight loss, combined with cardioprotection in individuals at risk of or with pre-existing cardiovascular disease. These attributes make GLP-1 a preferred partner for next-generation therapies exhibiting improved efficacy yet retaining safety to treat diabetes, obesity, non-alcoholic steatohepatitis, and related cardiometabolic disorders. The available clinical data demonstrate that the best GLP-1R agonists are not yet competitive with bariatric surgery, emphasizing the need to further improve the efficacy of current medical therapy.

          Scope of review

          In this article, we discuss data highlighting the physiological and pharmacological attributes of potential peptide and non-peptide partners, exemplified by amylin, glucose-dependent insulinotropic polypeptide (GIP), and steroid hormones. We review the progress, limitations, and future considerations for translating findings from preclinical experiments to competitive efficacy and safety in humans with type 2 diabetes and obesity.

          Major conclusions

          Multiple co-agonist combinations exhibit promising clinical efficacy, notably tirzepatide and investigational amylin combinations. Simultaneously, increasing doses of GLP-1R agonists such as semaglutide produces substantial weight loss, raising the bar for the development of new unimolecular co-agonists. Collectively, the available data suggest that new co-agonists with robust efficacy should prove superior to GLP-1R agonists alone to treat metabolic disorders.

          Graphical abstract

          Highlights

          • •

            GLP-1 is a preferred partner for co-agonist development.

          • •

            Co-agonist combinations must exhibit improved weight loss beyond GLP-1 alone.

          • •

            Unimolecular coagonists must exhibit retained or improved cardioprotection.

          • •

            Obesity represents an optimal condition for the development of new GLP-1 co-agonists.

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          Most cited references133

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          Mechanisms of NAFLD development and therapeutic strategies

          Mary Rinella, Arun Sanyal, Scott Friedman … (2018)
          There has been a rise in the prevalence of nonalcoholic fatty liver disease (NAFLD), paralleling a worldwide increase in diabetes and metabolic syndrome. NAFLD, a continuum of liver abnormalities from nonalcoholic fatty liver (NAFL) to nonalcoholic steatohepatitis (NASH), has a variable course but can lead to cirrhosis and liver cancer. Here we review the pathogenic and clinical features of NAFLD, its major comorbidities, clinical progression and risk of complications and in vitro and animal models of NAFLD enabling refinement of therapeutic targets that can accelerate drug development. We also discuss evolving principles of clinical trial design to evaluate drug efficacy and the emerging targets for drug development that involve either single agents or combination therapies intended to arrest or reverse disease progression.
          Article 0 comments Cited 1268 times – based on 0 reviews     Review now
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            Liraglutide safety and efficacy in patients with non-alcoholic steatohepatitis (LEAN): a multicentre, double-blind, randomised, placebo-controlled phase 2 study.

            Matthew Armstrong, Piers Gaunt, Guruprasad P Aithal … (2016)
            Glucagon-like peptide-1 (GLP-1) analogues reduce hepatic steatosis, concentrations of liver enzymes, and insulin resistance in murine models of fatty liver disease. These analogues are licensed for type 2 diabetes, but their efficacy in patients with non-alcoholic steatohepatitis is unknown. We assessed the safety and efficacy of the long-acting GLP-1 analogue, liraglutide, in patients with non-alcoholic steatohepatitis.
            Article 0 comments Cited 528 times – based on 0 reviews     Review now
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              Bariatric Surgery versus Intensive Medical Therapy for Diabetes — 5-Year Outcomes

              Philip Schauer, Deepak Bhatt, John Kirwan … (2017)
              Background Long-term results from randomized, controlled trials that compare medical therapy with surgical therapy in patients with type 2 diabetes are limited. Methods We assessed outcomes 5 years after 150 patients who had type 2 diabetes and a body-mass index (BMI; the weight in kilograms divided by the square of the height in meters) of 27 to 43 were randomly assigned to receive intensive medical therapy alone or intensive medical therapy plus Roux-en-Y gastric bypass or sleeve gastrectomy. The primary outcome was a glycated hemoglobin level of 6.0% or less with or without the use of diabetes medications. Results Of the 150 patients who underwent randomization, 1 patient died during the 5-year follow-up period; 134 of the remaining 149 patients (90%) completed 5 years of follow-up. At baseline, the mean (±SD) age of the 134 patients was 49±8 years, 66% were women, the mean glycated hemoglobin level was 9.2±1.5%, and the mean BMI was 37±3.5. At 5 years, the criterion for the primary end point was met by 2 of 38 patients (5%) who received medical therapy alone, as compared with 14 of 49 patients (29%) who underwent gastric bypass (unadjusted P=0.01, adjusted P=0.03, P=0.08 in the intention-to-treat analysis) and 11 of 47 patients (23%) who underwent sleeve gastrectomy (unadjusted P=0.03, adjusted P=0.07, P=0.17 in the intention-to-treat analysis). Patients who underwent surgical procedures had a greater mean percentage reduction from baseline in glycated hemoglobin level than did patients who received medical therapy alone (2.1% vs. 0.3%, P=0.003). At 5 years, changes from baseline observed in the gastric-bypass and sleeve-gastrectomy groups were superior to the changes seen in the medical-therapy group with respect to body weight (-23%, -19%, and -5% in the gastric-bypass, sleeve-gastrectomy, and medical-therapy groups, respectively), triglyceride level (-40%, -29%, and -8%), high-density lipoprotein cholesterol level (32%, 30%, and 7%), use of insulin (-35%, -34%, and -13%), and quality-of-life measures (general health score increases of 17, 16, and 0.3; scores on the RAND 36-Item Health Survey ranged from 0 to 100, with higher scores indicating better health) (P<0.05 for all comparisons). No major late surgical complications were reported except for one reoperation. Conclusions Five-year outcome data showed that, among patients with type 2 diabetes and a BMI of 27 to 43, bariatric surgery plus intensive medical therapy was more effective than intensive medical therapy alone in decreasing, or in some cases resolving, hyperglycemia. (Funded by Ethicon Endo-Surgery and others; STAMPEDE ClinicalTrials.gov number, NCT00432809 .).
              Article 0 comments Cited 528 times – based on 0 reviews     Review now
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                Author and article information

                Contributors
                Daniel J. Drucker
                Journal
                Journal ID (nlm-ta): Mol Metab
                Journal ID (iso-abbrev): Mol Metab
                Title: Molecular Metabolism
                Publisher: Elsevier
                ISSN (Electronic): 2212-8778
                Publication date PMC-release: 25 September 2020
                Publication date Collection: April 2021
                Publication date (Electronic): 25 September 2020
                Volume: 46
                Electronic Location Identifier: 101090
                Affiliations
                [1]Lunenfeld-Tanenbaum Research Institute, Department of Medicine, Mt. Sinai Hospital, Toronto, Ontario, M5G 1X5 Canada
                Author notes
                [∗ ]Corresponding author. Mt. Sinai Hospital, 600 University Ave., TCP5-1004, Mailbox 49, Toronto, Ontario, M5G 1X5 Canada. drucker@ 123456lunenfeld.ca
                Article
                Publisher Item ID: S2212-8778(20)30164-2 Publisher ID: 101090
                DOI: 10.1016/j.molmet.2020.101090
                PMC ID: 8085566
                PubMed ID: 32987188
                SO-VID: 89c67b21-3ed9-417a-b7d4-9466bcee00ee
                Copyright © © 2020 The Author(s)
                License:

                This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

                History
                Date received : 28 August 2020
                Date revision received : 13 September 2020
                Date accepted : 17 September 2020
                Categories
                Subject: Review

                Keywords: diabetes,obesity,peptide,receptor,cardiovascular disease,adipose tissue
                Data availability:
                Keywords: diabetes, obesity, peptide, receptor, cardiovascular disease, adipose tissue

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