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  • Review Article
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Novel therapies with precision mechanisms for type 2 diabetes mellitus

Nature Reviews Endocrinology volume 17, pages 364–377 (2021)Cite this article

Subjects

Abstract

Type 2 diabetes mellitus (T2DM) is one of the greatest health crises of our time and its prevalence is projected to increase by >50% globally by 2045. Currently, 10 classes of drugs are approved by the US Food and Drug Administration for the treatment of T2DM. Drugs in development for T2DM must show meaningful reductions in glycaemic parameters as well as cardiovascular safety. Results from an increasing number of cardiovascular outcome trials using modern T2DM therapeutics have shown a reduced risk of atherosclerotic cardiovascular disease, congestive heart failure and chronic kidney disease. Hence, guidelines have become increasingly evidence based and more patient centred, focusing on reaching individualized glycaemic goals while optimizing safety, non-glycaemic benefits and the prevention of complications. The bar has been raised for novel therapies under development for T2DM as they are now expected to achieve these aims and possibly even treat concurrent comorbidities. Indeed, the pharmaceutical pipeline for T2DM is fertile. Drugs that augment insulin sensitivity, stimulate insulin secretion or the incretin axis, or suppress hepatic glucose production are active in more than 7,000 global trials using new mechanisms of action. Our collective goal of being able to truly personalize medicine for T2DM has never been closer at hand.

Key points

  • Type 2 diabetes mellitus (T2DM) is one of the greatest health crises of our time, and the number of people with T2DM is projected to increase by >50% globally by 2045.

  • Despite our extensive armamentarium of current drug treatments for T2DM, >7,000 trials are registered around the world, many looking at ‘novel’ drug targets.

  • Mechanisms of action for novel drugs in the pipeline for T2DM include directly targeting β-cells, targeting the incretin axis, directly or indirectly affecting glucose metabolism in the liver, and increasing insulin sensitivity.

  • In our judgement, compounds with the most promise include dual-acting and triple-acting incretin mimetics owing to their glucose-lowering capacity, non-glycaemic benefits and safety.

  • The bar has been raised for novel therapies under development for T2DM; new therapies are now expected to prevent cardiovascular and renal complications independent of and in addition to their ability to decrease the plasma concentrations of glucose.

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Fig. 1: Drugs that stimulate insulin secretion.
Fig. 2: Drugs that decrease hepatic glucose production or increase hepatic glucose uptake.
Fig. 3: Drugs that improve insulin sensitivity.

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Authors and Affiliations

  1. University of Colorado Anschutz Medical Campus, Aurora, CO, USA

    Leigh Perreault

  2. Diabetes Research Institute, University of Miami, Miami, FL, USA

    Jay S. Skyler

  3. Dallas Diabetes Research Center at Medical City, Dallas, TX, USA

    Julio Rosenstock

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The authors contributed equally to all aspects of the article.

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Correspondence to Leigh Perreault.

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Competing interests

L.P. has received personal fees for speaking and/or consulting from Novo Nordisk, Sanofi, Boehringer-Ingelheim, AstraZeneca, Janssen, Merck and UpToDate. J.S.S. has been an advisor to Abvance Therapeutics, Adocia, Avotres, Boehringer-Ingelheim, Dance Biopharm/Aerami Therapeutics, Immunomolecular Therapeutics, Intrexon/ActoBiotics, Novo-Nordisk, Oramed, Orgenesis, Sanofi, Tolerion and Viacyte. J.S.S. is a member of the Board of Directors of Dexcom, Intarcia and Applied Therapeutics. J.R. has consulted for Applied Therapeutics, Boehringer Ingelheim, Eli Lilly, Intarcia, Janssen, Lexicon, Novo Nordisk, Sanofi, and Oramed and has received grant/research support from AstraZeneca, Boehringer Ingelheim, Eli Lilly, Genentech, GlaxoSmithKline, Intarcia, Janssen, Lexicon, Merck, Novo Nordisk, Pfizer, Sanofi and Oramed.

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Nature Reviews Endocrinology thanks the anonymous, reviewer(s) for their contribution to the peer review of this work.

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PubMed: https://pubmed.ncbi.nlm.nih.gov/

US National Institute of Health Clinical Trials Database: www.clinicaltrials.gov

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Perreault, L., Skyler, J.S. & Rosenstock, J. Novel therapies with precision mechanisms for type 2 diabetes mellitus. Nat Rev Endocrinol 17, 364–377 (2021). https://doi.org/10.1038/s41574-021-00489-y

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