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Novel Therapies with Precision Mechanisms for Type 2 Diabetes Mellitus

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Novel Therapies with Precision Mechanisms for Type 2 Diabetes Mellitus REVIEWS Novel therapies with precision mechanisms for type 2 diabetes mellitus Leigh Perreault 1 ✉ , Jay S. Skyler2 and Julio Rosenstock3 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. Formal diagnostic criteria for diabetes mellitus were speculation that some agents, such as thiazolidinedi- first introduced by the National Diabetes Data Group ones, might actually increase cardiovascular risk10. On in 1979 (REF.1) and by the World Health Organization in account of these concerns, in 2008, the FDA mandated 1980 (REF.2). Expanded and refined over time, plasma glu- cardiovascular safety studies be conducted for all new cose thresholds for diagnosis remain in diagnostic criteria medications approved for lowering plasma levels of glu- today based on their predictive value for microvascular cose in patients with T2DM. Knowledge gained from the disease, specifically retinopathy1. Furthermore, land- cardiovascular outcome trials of these newer agents has mark trials have convincingly demonstrated a reduction considerably expanded our understanding of T2DM and in incidence of microvascular disease with decreasing what can be done for patients. Specifically, glucagon- like levels of plasma glucose in both type 1 diabetes melli- peptide 1 (GLP1) receptor agonists and sodium– tus and type 2 diabetes mellitus (T2DM)3–7. Altogether, glucose cotransporter 2 (SGLT2) inhibitors exert desir- diabetes mellitus is largely conceived as a disease of ele- able ‘off- target’ non- glycaemic effects (for example, vated blood concentrations of glucose. The reduction reductions in body weight and blood pressure), have 8 1University of Colorado in HbA1c remains a central focus of care as well as the improved safety profiles (for example, no incidences of Anschutz Medical Campus, benchmark used by the FDA to approve pharmaceuticals hypoglycaemia, as compared with insulin and sulfony- Aurora, CO, USA. that lower plasma concentrations of glucose. lureas), reduce the risk of atherosclerotic cardiovascular 2Diabetes Research Institute, Nevertheless, much ado has been made about how disease and hospitalization for heart failure, and slow University of Miami, Miami, to safely decrease plasma concentrations of glucose in the progression of diabetic kidney disease11–17. These FL, USA. people with T2DM, with health- care providers citing beneficial effects are all in addition to their ability to 3 Dallas Diabetes Research concerns over the potential for hypoglycaemia and decrease plasma concentrations of glucose. Interestingly, Center at Medical City, 8,9 Dallas, TX, USA. weight gain and, most notably, cardiovascular safety . SGLT2 inhibitors can also reduce the number of hospi- 18,19 ✉e- mail: leigh.perreault@ The latter point arose from interventional randomized talizations for heart failure in people without T2DM . cuanschutz.edu controlled trials in patients with T2DM, which repeat- This finding suggests that the cardiovascular benefits are https://doi.org/10.1038/ edly showed a failure to reduce cardiovascular risk by provided by a mechanism that is independent from the s41574-021-00489- y decreasing plasma levels of glucose4–7, together with glucose- lowering effects. 364 | JUNE 2021 | VOLUME 17 www.nature.com/nrendo 0123456789();: REVIEWS Key points that indirectly affect glycaemia (for example, anti-obesity therapies) or used for complications related to T2DM. • Type 2 diabetes mellitus (T2DM) is one of the greatest health crises of our time, and Third, we excluded preclinical, non- human phase the number of people with T2DM is projected to increase by >50% globally by 2045. evaluations or therapies that failed to meet their • Despite our extensive armamentarium of current drug treatments for T2DM, >7,000 safety and/or efficacy end points (that is, terminated trials are registered around the world, many looking at ‘novel’ drug targets. development programmes). Outcomes provided to • Mechanisms of action for novel drugs in the pipeline for T2DM include directly ClinicalTrials.gov and publications available on PubMed targeting β- cells, targeting the incretin axis, directly or indirectly affecting glucose were used to corroborate the phase and status of trials, metabolism in the liver, and increasing insulin sensitivity. whenever possible. • In our judgement, compounds with the most promise include dual- acting and Thus, this Review focuses on the identification of triple- acting incretin mimetics owing to their glucose- lowering capacity, potentially novel pharmaceuticals for T2DM that are non- glycaemic benefits and safety. in active or completed clinical trials and conducted in • The bar has been raised for novel therapies under development for T2DM; new people with T2DM, with decreasing HbA levels as the therapies are now expected to prevent cardiovascular and renal complications 1c primary outcome, specifically for the purpose of meeting independent of and in addition to their ability to decrease the plasma concentrations of glucose. regulatory approval. Identified novel mechanisms of action In pursuit of precision medicine, guidelines for peo- Once the aforementioned criteria were applied, we iden- ple with T2DM are now principally focused on reaching tified 43 compounds with highly novel mechanisms of individualized glycaemic targets, while optimizing safety, action in development for T2DM. Collectively, their non- glycaemic benefits, and the prevention of micro- glucose- lowering mechanisms could be grouped into vascular and macrovascular complications for individual four over- arching physiological effectors of diabetes patients who are at risk of specific complications20. Novel mellitus. First are drugs that stimulate insulin secre- therapies in development will not only need to show tion directly from β- cells (Fig. 1). These include both meaningful reductions in glycaemic parameters but pancreas- selective and pancreas–liver dual- activating will need added value to meet these increased standards. glucokinase activators (GKAs) and G- protein- coupled Furthermore, to be competitive against the current ther- receptor 40 (GPCR40) agonists (Table 1). Second are apies in use, new drugs must distinguish themselves with drugs that utilize the incretin axis (Figs 1,2). These include additional attributes such as contributing to increased agonists of the GLP1 receptor and glucose- dependent weight loss, having no increased risk for hypoglycaemia, insulinotropic polypeptide (GIP) receptor, GLP1–gluca- or utilizing improved drug delivery systems and routes gon receptor agonists, triple GLP1–GIP–glucagon of administration that might decrease the frequency of receptor agonists, oxyntomodulin, and agonists of use. This Review generates a comprehensive list of the G- protein- coupled receptor 119 (GPCR119) (Table 2). novel therapies for T2DM currently in development and Third are drugs that directly or indirectly decrease discusses their potential for improving care for patients. hepatic glucose production or increase hepatic glucose uptake (Fig. 2). These drugs include glucagon receptor Review criteria antagonists, antisense oligonucleotide inhibitors specific To compile the most comprehensive list of promising, for glucagon receptor mRNA, dual amylin–calcitonin novel therapies for T2DM, the US National Institute receptor agonists (DACRAs) and liver- selective GKAs of Health Clinical Trials database was searched from (Table 3). Fourth and finally are drugs that improve November 26, 2019, to March 31, 2020, using the condi- insulin sensitivity (Fig. 3). These include an antisense tion or disease term ‘type 2 diabetes’. This query yielded oligonucleotide inhibitor for protein tyrosine phos- 7,484 registered trials worldwide, which were examined phatase 1B (PTP1B) mRNA, fibroblast growth factor 21 individually. The following three exclusion criteria were (FGF21) analogues, a diacylglycerol acetyl transferase 1 applied. First, we excluded drugs in existing classes. (DGAT1) inhibitor and an enterocytic microsomal tri- Therapies considered ‘novel’ were any medical phar- glyceride transfer protein (MTP) inhibitor. Additional maceutical therapy not currently approved for T2DM. drugs in this category include novel selective peroxi- Hence, we excluded new drugs in development
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