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.

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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 within some proliferator-​activated receptor (PPAR) agonists, existing classes (for example, new dipep­tidyl peptidase a GLUT4 facilitative transporter stimulator, a nuclear 4 inhibitors) as well as advances in devices or technol- factor-​κB (NF-​κB) inhibitor, a selective allosteric acti- ogies related to currently approved medications (for vator of LYN kinase, a nicotinic α7 receptor ligand, example, oral insulin and inhaled GLP1 receptor ago- a ghrelin analogue, a ghrelin–growth hormone (GH) nists). Importantly, advances in delivery devices and receptor agonist and an activin II-​B receptor modulator technologies for people with T2DM are expected to lead as well as a drug with an unknown mechanism of action to improved medication adherence and persistence for (imeglimin) (Table 4). both existing and emerging therapies. An example of such devices is ITCA650, a mini-osmotic​ pump capable Novel agents in development of continuous subcutaneous delivery of exenatide for up The year 2021 marks the 100th anniversary of the to 6 months21. discovery of insulin — the very first pharmacological Second, we excluded therapies tested for their other treatment for diabetes mellitus. Over those 100 years, physiological properties (for example, insulin sensitiza- 10 distinct classes of drugs have been approved by the tion but not glucose lowering), tested in disease states FDA for the treatment of T2DM, most of which were

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Oxyntomodulin Glucagon GLP1 receptor receptor agonists agonists Meglitinides Glucose Glucagon Sulphonylureas GLP1 GLUT1/2 receptor receptor

KATP channel GIPR GIPR (SUR1-Kir6.2)4 Glucokinase Glucokinase agonists activators

Glucose cAMP PKA metabolism ATP K+ GPCR119 Pro-insulin biosynthesis Mitochondrion GPCR119 agonists Piccolo Membrane RIM2 RAB3A depolarization Insulin EPAC2 Ca2+ Insulin granule IP3 PLC

L-type Ca2+ 2+ RAP1A Ca - dependent channel and calmodulin- dependent proteins GPCR40 PKC DAG Translocation agonists

GPCR40 Priming

Docking

Fig. 1 | Drugs that stimulate insulin secretion. Drug classes with new drugs in development are shown (blue ovals) as well as the pathways that they act on in β-cells​ to stimulate insulin secretion. New drugs include glucokinase activators (GKAs), which augment glucose-stimulated​ insulin secretion. Glucokinase (green oval) converts glucose into glucose-6-​ phophate. By contrast, G-protein-​ ​coupled receptor 40 (GPCR40) agonists act to increase free fatty acid-stimulated​ insulin secretion. New drugs that target the incretin axis are also under development, for example, dual and triple incretin mimetics, such as glucagon-​like peptide 1 (GLP1) receptor agonists with a glucose-dependent​ insulinotropic polypeptide receptor (GIPR) agonist and/or a glucagon receptor agonist, oxyntomodulin analogues, and G-protein-​ ​coupled receptor 119 (GPCR119) agonists. Drugs that act on the incretin axis stimulate glucose-dependent​ insulin secretion through cAMP signalling. Also shown are the established type 2 diabetes mellitus therapeutics sulfonylurea and meglitinide (orange ovals), which bind to SUR1 (part of the ATP-​sensitive Kir6.2 potassium channel), increase calcium influx and increase insulin secretion. Adapted from ref.106, Springer Nature Limited.

approved in the past 20 years22. Despite the explosion deficiency occurs when the pancreas makes insuffi- in therapeutic options for people with T2DM, the pipe- cient insulin, often in the context of insulin resistance. line for novel therapies in T2DM remains robust and Interestingly, of the >400 genetic associations with quite prolific. Companies developing each new therapy T2DM, the majority govern β-​cell function23. Genetic strive for theirs to be novel, first in class and better than, discovery has delivered novel mechanistic insights into or complimentary to, existing treatments. The goals of disease pathophysiology, including new ways to stim- novel therapies are to help patients reach their indi- ulate insulin secretion directly from β-​cells (Table 1; vidualized glycaemic targets while optimizing safety, Fig. 1). non-​glycaemic benefits and the prevention of compli- cations for individual patients who are at risk of specific Glucokinase activators. GKAs are a novel therapy that complications. directly targets β-​cells, with at least 11 drugs under development (one in phase III, four in phase II and six Drugs that directly target β-​cells in phase I clinical trials) (Table 1). Glucokinase, which Insulin deficiency is a defining feature of T2DM. facilitates the phosphorylation of glucose to glucose-6-​ Absolute insulin deficiency occurs when the pancreas phosphate, functions as the ‘glucose sensor’ of the body, no longer makes insulin, whereas a relative insulin maintaining plasma concentrations of glucose within a

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narrow range (4–6 nM)24. The action of glucokinase is concentration of triglycerides27–30. Nevertheless, safety restricted to glucose-​sensitive and glucose-​responsive issues could be avoidable through careful patient tissues such as the liver and pancreas. As such, the GKAs selection31 and perhaps liver-​selective GKAs might in development have been designed to target both liver avoid the increased risk of hypoglycaemia; however, liver and pancreas (dual) or to be more specific, targeting safety will need to be clearly demonstrated32. only one tissue (selective)25. Glucokinase activation in the liver stimulates hepatic glucose uptake and inhib- G-​protein-​coupled receptor 40. GPCR40 (also known its hepatic glycogenolysis (Fig. 2), whereas glucokinase as free fatty acid receptor 1; FFAR1) agonists have gen- activation in the pancreatic β-​cell stimulates insulin erated considerable interest as a novel mechanism for secretion26. Dual GKAs can be further subdivided by direct β-cell​ stimulation. Agonists of GPCR40 act in the their enzyme kinetics, which can render them more or β-cell​ to induce free fatty acid (FFA)-stimulated​ insulin less potent to stimulate insulin secretion, thereby under- secretion33 and two agents have advanced into phase II scoring the customizability of the molecules. Historically, trials. These compounds act as cooperative, allosteric GKAs have not thrived in development, limited by their modulators of GPCR40 that rely on the ample circulat- lack of durability, risk of inducing hypoglycaemia, liver ing levels of FFAs to potentiate glucose-​dependent insu- toxicity and ability to cause an increase in the plasma lin secretion34. A previous GPCR40 agonist compound

Table 1 | Drugs that directly stimulate β-​cells Compound Mechanism of action Trial Results Ref. or clinical phase trial number GKAs HMS5552 Dual GKA (pancreas and liver); III 24 people with T2DM randomized 31,103 (dorzagliatin) GKA in pancreatic β-​cells to dorzagliatin 75 mg QD or BID for augments glucose-​stimulated 28 days; HbA1c –1.22% with QD and insulin secretion; GKA in liver –0.79% with BID

increases hepatic glucose 30,104 AZD1656 uptake; together, they maintain II 458 people with T2DM randomized plasma levels of glucose at to AZD1656 20 mg QD, 40 mg QD, 4–6 nM titrated from 10 mg to 140 mg QD, titrated from 20 mg to 200 mg QD, glipizide titrated from 5 mg to 20 mg

QD or placebo for 4 months; HbA1c –0.80% in the AZD1656 titrated groups but waned over time RO4389620 Ib 15 people with T2DM randomized 27,105 (piragliatin) to triple crossover of piragliatin 25 mg, 100 mg or placebo; glucose AUC during an OGTT at the 100 mg dose was less than that observed at the 25 mg dose, which was less than observed with placebo PSN-821 I No published data NCT01386099 DS-7309 I No published data NCT01862939, NCT01956305 PB-201 I No published data NCT03973515 BMS-820132 I No published data NCT01290575, NCT01105429 LY2608204 I Safety established in phase I trial NCT01247363 Globalagliatin I No published data NCT03414892, NCT03171623 PF04937319 Systemic partial GKA (weak II 639 people with T2DM randomized 32 pancreatic effects only) to PF04937319 50 mg QD or 100 mg

QD for 12 weeks; HbA1c –0.45% at 100 mg QD; PK/PD, safety and add-on​ studies appear promising GPCR40 agonists MK 8666 GPR40 is highly expressed in II 63 people with T2DM randomized 33 pancreatic β-cells;​ its activation to MK 8666 50 mg QD, 150 mg by fatty acids amplifies QD, 500 mg QD for 14 days; dose glucose-​dependent insulin dependent 31–54 mg/dl decrease secretion in fasting plasma glucose JTT-851 II No published data NCT01699737 AUC, area under the curve; BID, twice daily; GKA, glucokinase activator; GPCR40, G-protein-​ coupled​ receptor 40; OGTT, oral glucose tolerance test; PD, pharmacodynamics; PK, pharmacokinetics; QD, daily; T2DM, type 2 diabetes mellitus.

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Liver Islet

Oxyntomodulin Glucagon receptor GPCR119 agonists

Glucagon GIPR Glucagon receptor Glucagon agonists receptor antagonists DACRAs Glucose GLP1 Glucagon receptor antisense receptor oligonucleotide inhibitors Glucokinase GIPR Glucagon activators receptor Augmented insulin secretion Amylin GLUT1/2 receptor Increased Glucagon Adenylate amylin receptor mRNA cyclase secretion Glucokinase

β-Cell cAMP G-6-P Amylin

Insulin PKA Glycogen

• Glycogenolysis • Gluconeogenesis Hepatocyte

Glucagon Hepatic glucose secretion production

α-Cell

Fig. 2 | Drugs that decrease hepatic glucose production or increase hepatic glucose uptake. Glucagon receptor antagonists and antisense oligonucleotide inhibitors for the glucagon receptor both act directly on hepatocytes to decrease the hepatic glucose production stimulated by glucagon. By contrast, liver-selective​ glucokinase activators increase hepatic glucose uptake. Indirect effects on hepatic glucose metabolism are induced by drugs that act on β-​cells. For example, dual amylin–calcitonin receptor agonists (DACRAs) and drugs targeting the incretin axis (dual or triple incretin mimetics, oxyntomodulin analogues or G-protein-​ ​coupled receptor 199 (GPCR119) receptor agonists) induce insulin and/or amylin secretion, which inhibits glucagon secretion from α-cells.​ Decreased circulating levels of glucagon result in less induction of hepatic glucose production. G-6-​P, glucose 6-​phosphate; GIPR, glucose-​dependent insulinotropic polypeptide receptor; GLP1, glucagon-like​ peptide 1.

in development (fasiglifam, also called TAK 875) showed been associated with increased de novo lipogenesis glucose-​lowering properties in phase IIa clinical trials; and subsequent hepatic steatosis36. Furthermore, nat- however, considerable liver toxicity in phase III trials urally occurring polymorphisms in the glucokinase led to the termination of its development programme35. regulatory protein have been associated with elevated Hence, continued vigilance towards safety will dominate plasma levels of triglyceride, FFAs and VLDL cho- the development of its successors as it is unclear how lesterol in humans37–39. By contrast, studies in animal these new molecules differ from fasiglifam. models show that the liver toxicity seen with GPCR40 agonists seems to be mediated through disrupted bile Potential for liver toxicity. The liver toxicity associated acid homeostasis40,41. Taking the liver toxicity data with drugs that stimulate insulin secretion directly from with GKAs and GPCR40 agonists together, it is clear β-​cells is worth contemplating. Of note, both glucoki- that directly stimulating insulin secretion from the nase and GPCR40 are expressed in the liver as well as β-​cell using drugs that also have actions in the liver in β-​cells. In humans, naturally occurring mutations could lead to untoward alterations in pathways of lipid leading to hepatic glucokinase overexpression have metabolism.

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Table 2 | Drugs that utilize the incretin axis Compound Mechanism of action Trial Results Ref. or clinical phase trial number Multi-​site receptor agonists for GLP1, GIP and/or glucagona AVE2268 GLP1–GIP–glucagon I No published data NCT00361738 triple receptor agonist HM12460A GLP1–GIP–glucagon I No published data NCT01724814, triple receptor agonist NCT03332836 LY3298176 GLP1–GIP dual receptor III 318 people with T2DM randomized to 44 (tirzepatide) agonist tirzepatide 1 mg Q week, 5 mg Q week, 10 mg Q week, 15 mg Q week, dulaglutide 1.5 mg Q

week or placebo for 26 weeks; HbA1c –1.06%, –1.73%, –1.89%, –1.94%, –1.21%, –0.06%, respectively SAR425899 GLP1–glucagon dual II PK/PD established in 36 people with T2DM 46 receptor agonist MEDI0382 GLP1–glucagon dual IIa MEDI0382 lowered glucose AUC during a NCT03596177 , receptor agonist MTT versus placebo; PK/PD, safety, add-on​ NCT03555994, established in phase I trial NCT03550378, NCT03745937 , NCT03385369, NCT02548585, NCT03341013, NCT03444584, NCT03645421, NCT03244800, NCT03235050, NCT04515849, NCT04208620 Oxyntomodulin analogueb OPK88003 This oxyntomodulin II No published data NCT03406377 analogue has the potential actions of a GLP1–glucagon dual receptor agonist GPCR119 agonist MBX-2982 GPCR119 is highly I No published data NCT01035879

expressed in the human 47,48 DS-8500a gastrointestinal tract II 99 people with T2DM randomized to (small intestinal L cells) DS-8500a 10 mg QD, 75 mg QD or placebo for 28 days; 24 h mean weighted glucose and pancreas (β-​cells); the stimulation of measurements decreased by 0.74 mmol/l GPCR119 has the and 1.05 mmol/l for 10 mg and 75 mg doses, potential to promote respectively, relative to placebo glucose-​dependent insulin secretion AUC, area under the curve; GIP, glucose-​dependent insulinotropic polypeptide; GLP1, glucagon-like​ peptide 1; GPCR119, G-protein-​ coupled​ receptor 119; MTT, meal tolerance test; PD, pharmacodynamics; PK, pharmacokinetics; QD, daily; Q week, dosed once per week; T2DM, type 2 diabetes mellitus. aGLP1 is secreted by the L cells in the small bowel in response to nutrient ingestion. Modulated through a complex neural plexus, it augments glucose-dependent​ insulin secretion, suppresses glucagon and induces satiety, resulting in weight loss. GIP is secreted by intestinal K cells with food ingestion, has the potential to augment insulin secretion and has been found to be deficient in people with T2DM. Glucagon has lipolytic and thermogenic capabilities. The glucose-raising​ effects of glucagon are constrained when used in combination with GLP1. bOxyntomodulin, like GLP1 and glucagon, is a peptide product derived from the post-translational​ modification of preproglucagon. It is secreted by the enteroendocrine cells of the small intestine in response to nutrient ingestion and has been shown in vitro to be a natural chimera, binding and activating both the GLP1 receptor and the glucagon receptor.

Drugs that utilize the incretin axis of drugs that act on the incretin axis is further amplified The indirect stimulation of β-cells​ is achievable through by the ability of incretins to induce weight loss42. drugs that affect the incretin axis (Table 2; Fig. 2). By defi- nition, incretin hormones (for example, GLP1 and GIP) Dual-​acting or triple-​acting incretin mimetics. are hormones secreted by enteroendocrine cells in the Importantly and unlike GKAs and GPCR40 agonists, gastrointestinal tract in response to the oral ingestion of insulin secretion invoked by incretin mimetics is glu- nutrients. These hormones act to decrease the plasma cose dependent; that is, the plasma concentrations of concentrations of glucose by mediating delayed gastric glucose must be elevated or rising for insulin secretion emptying, augmenting insulin secretion and suppressing to be stimulated. GLP1 receptor agonists have been glucagon secretion. Of note, the glucose-​lowering ability used in T2DM care for the past 15 years to decrease

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plasma concentrations of glucose and body weight43 and, rather than the supplementation of GLP1 and GIP is from 2016, to provide protection from cardiovascular being tested using analogues of GPCR119; one drug disease13,14. Expanded use of the incretin axis includes is in phase I trials and another is in phase II47,48. the development of molecules that act as both GLP1 The well-established​ ability of glucagon to stimulate receptor agonists and GIP receptor agonists and/or as hepatic glucose production makes it a counterintuitive glucagon receptor agonists. Such dual or triple agonist choice as a treatment for T2DM. The rationale for inte- drugs aim to achieve even greater efficacy for glucose grating the pharmacology of GLP1 and glucagon relies lowering, greater body weight loss and perhaps greater upon the action of GLP1 to restrain the hyperglycae- cardiovascular protection in patients with T2DM than mic effect of glucagon while adding a centrally medi- provided by single agonists. ated anorectic action to synergize with the lipolytic and In addition to their role in treating T2DM, dual-​ thermogenic capabilities of glucagon with the aim to acting or triple-​acting agonists have the potential substantially decrease body weight49. to attain independent indications for obesity, sleep apnoea, renal insufficiency, non-​alcoholic fatty liver Oxyntomodulin analogues. Oxyntomodulin, like GLP1 disease (NAFLD) and non-​alcoholic steatohepatitis in and glucagon, is a peptide product derived from the people with or without T2DM. Currently, drugs in clin- post-​translational modification of preproglucagon. ical trials include one dual-​acting GLP1–GIP receptor Oxyntomodulin is secreted by the enteroendocrine agonist in phase III44, two dual-​acting GLP1–glucagon cells of the small intestine in response to nutrient inges- receptor agonists in phase II45,46, and two triple-​acting tion and has been shown in vitro to be a natural chi- GLP1–GIP–glucagon receptor agonists in phase I trials mera, binding and activating both GLP1 and glucagon (Table 2). The clinical rationale for combining these receptors50. The dual stimulation of GLP1 and gluca­ dual-​acting or triple-acting​ peptides is mainly to poten- gon receptors is currently being tested for T2DM using

tiate the weight loss effects as it is unlikely that the HbA1c an analogue of oxyntomodulin (one drug in phase II reductions observed will be much greater than the trials)50. Similar to dual-​acting GLP1–glucagon recep- 1.5% or even 2% that have already been achieved with tor agonists, oxyntomodulin exerts its glucoregulatory compounds like semaglutide (approved) or tirzepatide actions independent of but in addition to considerable (phase III), respectively. In addition, the stimulation weight loss50.

Table 3 | Drugs that modulate hepatic glucose metabolism Compound Mechanism of action Trial Results Ref. or clinical phase trial number Glucagon receptor antagonist LGD-6972 Inhibits glucagon action II PK/PD established 54 REMD-477 I–II No published data NCT02455011 Antisense oligonucleotide inhibitor for the glucagon receptor ISIS-449884 (GCGRRx) Inhibits hepatic glucagon II Three phase II randomized, 55 receptor expression and double-​blind studies exposed hepatic glycogenolysis people with T2DM to ISIS-449884 50–200 mg SC

weekly for 13–26 weeks; HbA1c –0.9% to 2.0% with the various doses and a dose-dependent​ increase in transaminases was observed DACRAs KBP-042 Calcitonin stimulates II No published data NCT03230786 amylin secretion; amylin KBP089 lowers glucose levels I No published data NCT03907202 through delayed gastric emptying and suppressing glucagon secretion GKAs PF-04991532 Liver-​selective GKA; GKA II PK/PD, safety established in NCT01129258, in liver increases hepatic T2DM NCT01469065, glucose uptake NCT01336738, NCT01338870, NCT01369602 GK1-399 (formerly Liver-​selective GKA II No published data NCT01474083, TTP399) NCT02405260, NCT01474083 DACRA, dual amylin–calcitonin receptor agonist; GKA, glucokinase activator; PD, pharmacodynamics; PK, pharmacokinetics; SC, subcutaneous; T2DM, type 2 diabetes mellitus.

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The therapeutic potential of the incretin axis. Whether incretin axis is not only being pursued for the treatment by a new dual or triple agonist therapy or by established of T2DM but also for the treatment of NAFLD and non-​ GLP1 receptor agonists, the utilization of the incre- alcoholic steatohepatitis51,52. Without question, the sub- tin axis holds particular promise for the treatment of stantial weight loss observed with these novel therapies T2DM and its common comorbidities. As mentioned is responsible for much of their metabolic benefits and previously, the indirect, glucose-dependent​ stimulation probably extends to non-metabolic​ benefits as well (for of insulin secretion avoids the hypoglycaemia and dis- example, improvements in sleep apnoea and mobility). rupted lipid metabolism that are seen with GKAs and Furthermore, expanded use of the incretin axis for ther- GPCR40 agonists. By contrast, expanded use of the apeutic purposes has provided unique insights into the

Insulin Liver Muscle GH–ghrelin Ghrelin PTP1B antisense co-agonist analogue oligonucleotide Glucagon LYN kinase inhibitors Insulin Glucagon Glucose activator receptor receptor GLUT2 GLUT4

GH receptor PTP1B mRNA ATP cAMP LYN kinase γ β

PIP2 PTP1B IRS1/2 PI3K ↓ G6Pase αq Mitochondrion Translocation PIP3 ↓ FBPase

PKB PDK1/2 Pyruvate ATP:AMP PLC GLUT4 LKB facilitative Synaptic AMPK transporter stimulator vesicle

ACC Glucose uptake mTORC1 MAPK cascade

• Gluconeogenesis Transcription of genes ↑ Glucose uptake, Ca2+ influx • Lipid synthesis involved in energy metabolism and • Lactate production storage and expenditure glycolysis Endoplasmic reticulum

PPAR agonists

PPARs RXR

Hepatocyte or muscle cell

Fig. 3 | Drugs that improve insulin sensitivity. Several new drugs are in action of these drugs is not fully understood but they are thought to development that improve insulin sensitivity through various mechanisms increase endoplasmic reticulum calcium influx, thereby stimulating of action. For example, the antisense oligonucleotide inhibitor specific for physiological IGF1 production in the liver, which in turn increases insulin protein tyrosine phosphatase 1B (PTP1B) mRNA disinhibits insulin signalling action. Not shown on the figure are agents that target fibroblast growth by reducing the translation of the negative regulator PTP1B. Furthermore, factor 21 (FGF21) or inhibit diacylglycerol acetyl transferase 1 (DGAT1) and novel peroxisome proliferator-activated​ receptor (PPAR) agonists are being microsomal triglyceride transfer protein (MTP). These drugs all act as developed that stimulate the transcription of genes involved in energy presumed insulin sensitizers through altering lipid metabolism. In addition, storage and expenditure. In skeletal muscle, a selective allosteric activator an agent targeting the type II B activin receptor is also thought to be an of LYN kinase and a glucose transporter type 4 (GLUT4) facilitative insulin sensitizer through an unknown mechanism. Anti-​inflammatory transporter stimulator both act to increase the translocation of GLUT4 to agents, including a nuclear factor-​κB (NF-​κB) inhibitor and agent that the plasma membrane. Finally, a ghrelin analogue and ghrelin–growth upregulates the nicotinic α7 receptor, are also in development. Adapted hormone (GH) receptor agonist have been developed; the mechanism of from ref.106, Springer Nature Limited.

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Table 4 | Drugs that improve insulin sensitivity Compound Mechanism of action Trial Results Ref. or clinical phase trial number Antisense oligonucleotide inhibitor for PTP1B mRNA ISIS 113715 PTP1B has been shown to be a negative III 92 people with T2DM randomized to ISIS 83

(IONIS-​PTP-1BRx) regulator of insulin and leptin signalling; 113715 200 mg SC Q week or placebo for the inhibition of PTP1B enhances insulin 26 weeks; HbA1c –0.44% with ISIS 113715 and leptin action FGF21 analogue LY2405319 FGF21 has been shown to improve whole I 47 people with T2DM randomized to 66 body insulin sensitivity, enhance insulin LY2405319 at 3 mg, 10 mg or 20 mg QD for secretion while suppressing glucagon 28 days; LY2405319 lowered LDL-​cholesterol, secretion, inhibit hepatic lipogenesis, triglycerides, fasting insulin and body weight and increase energy expenditure via the while increasing adiponectin but little effect activation of brown adipose tissue on plasma concentrations of glucose was observed SRT2379 I No published data NCT01018628 SAR425899 I No published data NCT03414736, NCT02973321, NCT02411825 DGAT1 inhibitor PF-04620110 Inhibits the acetylation of diacylglycerol I PK/PD established in T2DM NCT01298518 to triacylglycerol; the ectopic deposition of triacylglycerol has been linked to insulin resistance Enterocytic MTP inhibitor KD026 (SLx-4090) Inhibits the production of apo B II No published data NCT02434744, containing lipoproteins in the gut; NCT00871936, by-products​ stimulate insulin signalling NCT02434744 independent of the insulin receptor Novel PPAR agonists CS038 (chiglitazar) Dual PPARα/γ agonist; intranuclear III No published data NCT02173457 , transcription factors that lower plasma NCT02121717 levels of triglycerides and differentiate preadipocytes into mature adipocytes, respectively T0903131 (formerly Partial PPARγ agonist; weak intranuclear I 367 people with T2DM randomized to NCT00952445, INT-131; besylate) transcription factor that differentiates T0903131 0.5 mg, 1 mg, 2 mg or 3 mg QD NCT00631007 pre-adipocytes​ into mature adipocytes versus placebo for 24 weeks; dose-dependent​

HbA1c –0.3% to –1.0% in T0903131 Other mechanisms DS-1150b GLUT4 facilitative transporter stimulator; I No published data NCT02004678 improves insulin signalling CAT-1004 (edasalonexent) Anti-​inflammatory I No published data NCT01511900 MLR-1023 (tolimidone) Selective allosteric activator of LYN I No published data NCT03279263, kinase; improves insulin signalling NCT02317796 TC-6987 Nicotinic α7 receptor ligand; II No published data NCT01293669 anti-​inflammatory AZP-531 (livoletide) Ghrelin analogue; inhibits food intake 1 No published data NCT02040012 and induces weight loss TH-9507 (tesamorelin Ghrelin–GH receptor agonist; 2 53 people with T2DM randomized to TH-9507 NCT01264497 or Egrifta) GH-releasing​ hormone analogue; 1 mg or 2 mg SC QD or placebo for 12 weeks; 74 decreases visceral adipose tissue no difference in HbA1c was observed accumulation S707106 Unknown mechanism of action 2 No published data NCT01154348, NCT01240759 Bimagrumab Type II-B​ activin receptor modulator; 2 No published data NCT03005288 activates muscle growth (ref.80) DGAT1, diacylglycerol acetyl transferase 1; FGF21, fibroblast growth factor 21; GH, growth hormone; MTP, microsomal triglyceride transfer protein; PD, pharmacodynamics; PK, pharmacokinetics; PPAR, peroxisome proliferator-activated​ receptor; PTP1B, protein tyrosine phosphatase 1B; QD, daily; Q week, dosed once per week; SC, subcutaneous; T2DM, type 2 diabetes mellitus.

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complex interplay between diet, enteroendocrine cells tissue-​selective but could be designed to be so. Proven and the microbiome in human health and disease53. safety with DACRAs would strengthen this hypothesis, Collectively, the knowledge to be gained from and the particularly if neither hypoglycaemia nor liver toxicity therapeutic potential of the incretin axis is vast. are observed. The development of partial and/or tissue-​ selective glucagon receptor antagonists might prove a Drugs targeting metabolism in the liver worthy pursuit. Plasma levels of glucose can be decreased using thera- peutics that target glucose metabolism in the liver. These Drugs that improve insulin sensitivity agents can target the liver directly, either by modulating Perhaps the greatest need for new therapies in T2DM the action of glucagon in hepatocytes to reduce hepatic falls in the area of insulin sensitization and the glucose production or by activating glucokinase to approaches of the pharmaceutical industry to meeting increase glucose uptake by hepatocytes. Alternatively, this need could not be more diverse. Unfortunately, most these drugs can reduce glucagon secretion from islets, of these approaches to date do not seem particularly thereby indirectly reducing hepatic glucose production promising for decreasing levels of glucose in patients (Table 3; Fig. 2). with T2DM (Table 4; Fig. 3).

Antagonizing glucagon action. Whether endogenous Targeting FGF21. Considerable interest has been or exogenous, glucagon induces hepatic glycogenolysis shown in FGF21, a hepatokine that activates the NAD-​ leading to a rapid increase in plasma concentrations of dependent protein deacetylase sirtuin 1 (three drugs are glucose. Thus, it is conceivable that blocking the actions currently in phase I trials) (Table 4). FGF21 is thought of glucagon might lead to improved glucose control. to be an insulin sensitizer through its ability to mitigate As a single agent, glucagon action in patients with T2DM FFA-induced​ insulin resistance60. Collectively, investiga- must be antagonized so as to not exacerbate hypergly- tions have revealed FGF21 as a stimulator of fatty acid caemia. Indeed, this strategy is being approached in a oxidation, particularly in the liver, that increases the number of ways; for example, two drugs that are direct production of ketone bodies and inhibits lipogenesis61,62. glucagon receptor antagonists are currently in phase II Despite reports of circulating levels of FGF21 being trials54. Furthermore, RNA interference gene therapy has higher in people with any combination of T2DM63, been utilized for this purpose through the creation of NAFLD64 or obesity than in individuals without these an antisense oligonucleotide inhibitor for the glucagon conditions, people treated with FGF21 analogues show receptor (one drug is in a phase II trial)55. The use of weight loss65. Nevertheless, a proof-​of-​concept study antisense RNA antagonizes the action of glucagon by in people with T2DM treated with FGF21 analogues blocking the transcription of the gene that encodes the observed a decrease in the plasma levels of lipids but glucagon receptor. not in plasma concentrations of glucose66. Another strategy to indirectly target the hepatic actions of glucagon involves the use of a DACRA (one Inhibitors of DGAT1 and MTP. One inhibitor of DGAT1 drug is in a phase I trial and another is in a phase II trial) is currently in phase I trials and one inhibitor of MTP (Table 3). The rationale for DACRAs stems from using is in phase II trials. The rationale for developing these the action of calcitonin to stimulate the amylin recep- agents lies in the assumption that altering lipid metabo- tor on β-cells​ leading to the co-secretion​ of amylin and lism will favourably affect glucose metabolism. However, insulin. Amylin itself decreases blood concentrations preclinical studies have yet to show that this scenario of glucose by delaying gastric emptying56 as well as by is the case67,68 and there might be reason to suspect inhibiting post-​prandial glucagon secretion57. Although that a glucose-​lowering ability by these drugs will not each agent in this group has demonstrated promise in be demonstrated after all. For example, the inhibition decreasing levels of glucose in humans, their specific of DGAT1 might indeed decrease the tissue accumu- effect on suppressing hepatic glucose production, per se, lation of triacylglycerol (aka triglyceride); however, is presumptive and is yet to be clearly proven. it does so at the expense of an increased tissue accumu- lation of diacylglycerol, which is a far more inflamma- Safety issues. Unfortunately, an increase in hepatic tory, insulin de-sensitizing​ lipid than triacylglycerol69,70. steatosis and blood biomarkers of liver injury (transam- Moreover, MTP acts in the liver and intestine to pre- inases) have been reported in clinical trials with the vent the transfer of triglycerides to other apo-​B con- antisense oligonucleotide inhibitor as well as after direct taining lipoproteins, thereby reducing post-​prandial antagonism of the glucagon receptor58,59. These safety hypertriglyceridaemia71,72. Nevertheless, a link is lack- concerns have led to the abandonment of a number of ing between decreasing plasma levels of triglycerides and compounds in development (for example, Bay 27-9955, insulin sensitization and/or decreases in plasma levels of MK-0893, MK-3577 and LY-24090215). Most note- glucose in humans73. worthy is that the inhibition of hepatic glycogenolysis, whether by glucagon antagonism, GKAs or GPCR40 Targeting the GH receptor. Speculation exists as to agonists, increases hepatic de novo lipogenesis. The whether the adverse effects of GH on glucose metabo- physiological nature of this response is predictable but lism might be offset by its anabolic action as well as by its could be avoidable, for example, by developing tissue-​ ability to stimulate the production of insulin-like​ growth selective drugs that avoid the liver. To date, gluca- factor 1 in the liver. The gastric-​derived peptide, ghre- gon receptor antagonists in development are not lin, is an endogenous ligand for GH-​releasing hormone

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receptor. GH receptor agonism can be achieved either insulin receptor substrate 1 in insulin-responsive​ tissues, directly using a GH–ghrelin receptor co-​agonist74 (one which in return phosphorylates LYN kinase, suggesting drug in phase II trials) or indirectly using a pure ghre- a regulatory feedback loop between LYN kinase and lin analogue75 (one drug in phase I trials) (Table 4). The insulin receptor activation84. Interestingly, the insulin potentiation of GH via ghrelin is unlikely to thrive in secretagogue, glimepiride, harbours extra pancreatic development as a treatment for T2DM owing to the ina- action as an insulin sensitizer through the activation bility of this mechanism to induce weight loss76,77 and of LYN kinase; however, glimepiride is associated with blunting of glucose-stimulated​ insulin secretion78. hypoglycaemia85. By contrast, hypoglycaemia has not The anabolic action of GH might be better achieved been reported with the upregulation of insulin sig- with a more direct approach such as type II-​B activin nalling in peripheral tissues by other compounds that receptor modulation (one drug in phase II trials). specifically target LYN kinase currently in development. Blockade of the type II-​B activin receptor inhibits the actions of natural ligands that negatively regulate skeletal PPAR agonists. The pipeline also revisits PPAR ago- muscle growth, thereby leading to a preservation and nists, striving to improve their efficacy and safety, either even expansion of lean mass79. Bimagrumab, a monoclo- through dual PPARα–PPARγ agonism86 (one drug in nal antibody that inhibits the activin type II receptor, was phase III trials) or through partial dual PPARα–PPARγ shown in 2021 to increase lean mass, decrease fat mass agonism (one drug in phase I trials) (Table 4). PPARα 80 and improve HbA1c in adults with T2DM . Although the agonists inhibit hepatic lipoprotein C-III​ expression and precise mechanism of action remains largely unknown, subsequent VLDL production, making them useful as it is clear that the anabolic action of bimagrumab is single agents for decreasing plasma levels of triglyceride distinct from GH and harbours favourable effects on (for example, gemfibrozil and fenofibrate are approved glucose metabolism. for this indication). PPARγ agonists act as intranuclear transcription factors that improve insulin sensitivity Strategies that target inflammation. Insulin resistance is by expanding subcutaneous adipose tissue depots and widely regarded as a pro-​inflammatory state, although inducing the differentiation of pre-​adipocytes into it is unclear whether a unidirectional causative pathway mature adipocytes (for example, rosiglitazone and pio- exists or whether insulin resistance and inflammation glitazone)87. Contemporary clinical trials have eased are simply associated. Approaches targeting inflam- historic concerns over the cardiovascular safety of mation are attractive for their widespread benefits some PPARγ single agonists88. However, thus far, none on diabetes-​related complications but are too early in of the dual PPARα–PPARγ agonists has followed suit development to understand their efficacy and safety with numerous development programmes halted owing in T2DM. For example, the TINSAL trials (Targeting to renal and cardiovascular concerns (for example, Inflammation Using Salsalate in Type 2 Diabetes) exten- aleglitazar89, muraglitazar90 and tesaglitazar91). sively explored the role of the anti-​inflammatory agent Altogether, pharmaceuticals in development for salsalate as a treatment for T2DM. Results from these tri- T2DM mainly directly or indirectly exploit one of the

als demonstrated HbA1c reduction but also raised safety original ‘triumvirate’ of defects, that is, impaired insu- concerns that precluded the introduction of salsalate lin secretion, reduced insulin sensitivity and increased to the market as an anti-​diabetic agent81,82. New com- hepatic glucose production, described in T2DM many pounds in the pipeline include a drug in phase I trials years ago92. One agent in phase III clinical trials is that inhibits NF-​κB as well as a drug in phase II imeglimin, a tetrahydrotriazine-​containing oxidative trials that upregulates the nicotinic α7 receptor (Table 4). phosphorylation blocker that might attend to the entire The anti-​inflammatory mechanisms of action of these triumvirate: stimulating insulin secretion, improving compounds in development clearly differ from that of insulin sensitivity and reducing hepatic glucose pro- salsalate (inhibiting NF-κB​ or activating the nicotinic α7 duction through the enhancement of mitochondrial receptor ligand versus inhibiting cyclooxygenase) but are bioenergetics93–96. However, the data remain highly also likely to exert systemic effects. controversial.

Revisiting existing strategies. Remaining novel com- Future directions pounds in development for insulin sensitization for the In reviewing the 7,484 trials registered in ClinicalTrials.gov purpose of decreasing blood concentrations of glucose that were generated using the key word ‘type 2 diabe- in T2DM reminisce on existing themes. One approach tes’, 43 novel therapies were identified. Through unique seeks to upregulate insulin signalling in peripheral tis- mechanisms of action that directly stimulate insulin sues by inhibiting dephosphorylation of the insulin secretion in the β-cell,​ utilize the incretin axis, suppress receptor using an antisense oligonucleotide inhibitor for hepatic glucose production and/or improve insulin sen- PTP1B mRNA (one drug in phase III trials)83. A second sitivity, several recurring themes dominate the potential approach seeks to completely bypass glucose dependency of these novel therapies to move into clinical care. First, by stimulating the translocation of the insulin-dependent​ clinical trials continue to reveal important safety signals, glucose facilitative transporter (GLUT4) directly (one most notably liver toxicity. Given the exquisite ability of drug in phase I trials) (Table 4). A third strategy aims at the human body to shift substrate utilization and storage, the indirect potentiation of insulin action through the it is clearly important to recognize that the mechanism allosteric activation of LYN kinase (one drug in phase I by which one decreases plasma concentrations of glu- trials) (Fig. 3). Activated LYN kinase can phosphorylate cose in T2DM is probably as important as the absolute

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decrease achieved. For example, drugs in development patient characteristics, risk of complications and expo- that block hepatic glucose output decrease plasma lev- sure to glucose-​lowering medications97. Several genetic els of glucose at the expense of hepatic steatosis. Future variants and genetic risk scores were differentially compounds could avoid these issues if designed to be associated with the clusters; however, they were not tissue selective. Second, dual and triple agonist thera- examined for their independent association with com- pies harbour the potential to minimize adverse effects plications or drug exposure. Of note, genetic variabil- as smaller doses can be used and the different agonists ity has been shown to alter the responses of patients to can also exert synergistic effects with each other. This sulfonylureas99, metformin100 and thiazolidinediones101, advantage is best exemplified by compounds in develop- suggesting that the same might be true for the newer and ment that utilize the incretin axis. Incretin-​induced insu- emerging medical therapies. Most importantly, future lin secretion is indirect and glucose dependent, thereby studies could unveil genetic predictors of patients with avoiding unnecessary hypoglycaemia while invoking the an improved response to a glucose-​lowering medication gut microbiome and its metabolites to diversify the drug as well as of patients who are likely to have complications response53. Most certainly, therapies that facilitate weight prevented by such medications. Fortunately, comprehen- loss will treat much more than T2DM. sive modelling approaches are under way102 to bring this collective science from the bench to the bedside. Precision mechanisms As the treatments for T2DM continue to diversify, our Conclusions ability to deliver precision health care is becoming real- Novel therapies currently in development for the treat- ized; drugs with different mechanisms of action can be ment of T2DM directly stimulate insulin secretion in combined to produce the best possible treatment out- the β-​cell, utilize the incretin axis, suppress hepatic glu- comes in individual patients. Undoubtedly, guidelines cose production and/or improve insulin sensitivity via will continue to integrate emerging data that focus on unique mechanisms of action. In our judgement, com- reaching individualized glycaemic targets while optimiz- pounds with the most promise — by virtue of validated ing safety, non-​glycaemic benefits, and the prevention mechanisms of action and advancement in clinical trials of microvascular and macrovascular complications for by meeting preliminary efficacy and safety end points individual patients at risk of specific complications20. — include dual-​acting GLP1–GIP receptor agonists, To achieve these aims, considerable work is under way to dual-​acting GLP1–glucagon receptor agonists, and predict which patients are most likely to benefit from the perhaps triple-acting​ GLP1–GIP–glucagon receptor ago- various non-glycaemic​ effects and prevention of specific nists and oxyntomodulin. Each is fully expected to attain complications. individualized glycaemic targets while optimizing safety, Revelations have come from both clinical biomarkers off-target​ benefits and the prevention of complications, and phenotyping97, as well as from pharmacogenomics98. thereby fuelling hope that they might also treat a host of For example, one data-​driven cluster analysis of nearly obesity-​related complications beyond T2DM. 9,000 people with new-​onset T2DM identified five rep- licable phenotypic clusters with substantially different Published online 4 May 2021

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