Newer GLP-1 receptor agonists and obesity-diabetes

Peptides 100 (2018) 61–67

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Newer GLP-1 receptor agonists and obesity-diabetes Emily Brown, Daniel J. Cuthbertson, John P. Wilding

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T

Obesity & Endocrinology Research Group, Institute of Ageing and Chronic Disease, University of Liverpool, Liverpool, United Kingdom

A R T I C L E I N F O

A B S T R A C T

Keywords: Diabetes Obesity GLP-1 agonists Review

Obesity is a major risk factor for type 2 diabetes and may complicate type 1 diabetes. In parallel with the global epidemic of obesity, the incidence of type 2 diabetes is increasing exponentially. To reverse these alarming trends, weight loss becomes a major therapeutic priority in prevention and treatment of type 2 diabetes. Given that glucagon-like peptide-1 receptor agonists (GLP-1 RAs) improve glycaemic control and cause weight loss, they are receiving increasing attention for the treatment of diabetes-obesity. This review discusses current and emerging therapeutic options with GLP-1 RAs and considers the next generation of novel peptide co-agonists with the potential for improved therapeutic outcomes in obesity and type 2 diabetes.

1. Introduction We are seeing a rapid increase in the prevalence of obesity and associated type 2 diabetes. Although not all obese individuals will develop obesity-related complications, in people with established type 2 diabetes, the co-existence of obesity may contribute to the development of medical complications [1]. Subsequently there is a clinical need for anti-diabetic treatment with accompanied weight loss. Some existing glucose lowering treatments exacerbate weight gain (e.g. sulfonylureas, thiazolidinediones and insulin) but glucagon-like peptide-1 receptor agonists (GLP-1 RAs) concomitantly target weight loss and dysglycaemia. The consideration of GLP-1 RAs as anti-obesity drugs has increased the scientific and clinical interest in incretin therapy as the overlap between type 2 diabetes and obesity becomes increasingly relevant. 2. Incretin physiology and pathophysiology Hormonal and peptide signalling pathways between the gastrointestinal tract and other organs, particularly the brain, continue to provide important therapeutic targets for treatment of type 2 diabetes and more recently obesity. The development of incretin based therapies derived from the observations that oral glucose ingestion amplifies the insulin response compared to intravenous administration (the ‘incretin’ effect) [2]. The main incretin hormone, glucagon-like peptide 1 (GLP-1) is a derivative of the transcription product of proglucagon gene and is secreted from the L-cells of the small intestine. It exerts its effects by binding to GLP-1 receptors (GLP-1 Rs) belonging to the G proteincoupled receptor family. GLP-1 Rs are widely expressed, most

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abundantly within the pancreas, gut and the central nervous system but also in the heart, lungs, kidneys, vasculature and peripheral nervous system [3]. 3. BIOLOGICAL ACTIONS OF GLP-1 AND PATHOPHYSIOLOGY IN DIABETES AND OBESITY (Table 1) 3.1. The ‘incretin effect’ and metabolism The major known functions of GLP-1 are related to glucose metabolism, increasing pancreatic ß-cell insulin secretion (in a glucose dependent manner) and inhibiting hepatic glucose production via reduced α-cell glucagon secretion. A uniformly reduced incretin effect is seen in subjects with type 2 diabetes and obesity with reduced GLP-1 levels in the majority [4]. The pancreas remains responsive to GLP-1 but is no longer responsive to glucose-dependent insulinotropic polypeptide (GIP), which is the most likely reason for a reduced or absent incretin effect. Subsequently GLP-1 RAs have been a significant development in the pharmacological management of type 2 diabetes. Furthermore, GLP-1 upregulates the expression of glucokinase and glucose transporter genes involved in glucose metabolism and transport, improving whole body glucose disposal and insulin resistance [5–7]. A significant reduction in ß-cell volume is demonstrated in obese individuals with type 2 diabetes (63%) or pre-diabetes (40%) compared to healthy obese controls [8]. Animal studies have suggested that GLP-1 and GIP can increase ß-cell mass (regeneration and reduced apoptosis) [9] with findings of a small (n = 69) clinical study in type 2 diabetes demonstrating preservation of ß-cell function after 3 years of treatment with a short-acting GLP-1 RA [10,11]. Confirmation of this effect may

Corresponding author at: Obesity & Endocrinology Research Group, Clinical Sciences Centre, University Hospital Aintree, Longmoor Lane, Liverpool, L9 7AL, United Kingdom. E-mail address: [email protected] (J.P. Wilding).

https://doi.org/10.1016/j.peptides.2017.12.009 Received 30 September 2017; Received in revised form 7 December 2017; Accepted 8 December 2017 0196-9781/ © 2017 Elsevier Inc. All rights reserved.

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heart rate, blood pressure and cardiac hemodynamic responses. GLP-1 use is associated with a fall in systolic blood pressure (2–3 mmHg) and a 2–3 beats per minute increase in heart rate [18]. GLP-1 may reduce blood pressure in several ways: improved endothelial function and vasodilation [19], diuresis and natriuresis [20], weight loss [21] and decreased sympathetic activity. The exact mechanism for the increased heart rate has not yet been fully elucidated but direct activation of GLP1R localised in myocytes of the sinoatrial node [22] and indirect regulation of the autonomic nervous system are mechanisms of interest. [23] Several studies have demonstrated that GLP-1 and GLP-1 RAs may be beneficial in patients with ischaemic cardiac injury or heart failure [24,25]. GLP-1 also decreases post-prandial triglycerides and free fatty acid levels [26].

Table 1 The multi-system physiological effects of GLP-1/GLP-1 RAs. Incretin effect and metabolism Insulin secretion ↑ Glucagon secretion ↓ ß-cell survival ↑ (?) (↓ ß-cell apoptosis and ↑ ß-cell proliferation) Hepatic glucose output ↓ Glycogen storage ↑ Glucose uptake ↑ Lipolysis ↓ Glucose uptake ↑

3.5. Renal effects Appetite and gastrointestinal effects

There is consistent evidence that improvement in glycaemic control reduces the risk of microalbuminuria and lowers progression to overt nephropathy in type 2 diabetes [27]. Beyond their effects on metabolic risk factors for kidney disease, there is also evidence for direct actions of GLP-1 in the kidney. GLP-1 and GLP-1 RA induces natriuresis and diuresis in both animals and humans [20,28]. In addition, by reducing (energy dependent) sodium intake in the proximal tubule, effects on renal hypoxia, tubulo-glomerular feedback and hyperfiltration may be anticipated and have been documented in some experimental models. [29]

Appetite ↓ Satiety ↑ Gastric emptying ↓ Gastrointestinal motility ↓

Cardiovascular and renal effects Blood pressure ↓ Heart rate ↑ Myocardial contractility ↑ Endothelial dependent vasodilation ↑ Cardioprotection ↑

4. GLP-1 Receptor agonists (GLP-1 RAs) Endogenous GLP-1 has a very short elimination half-life of < 1.5 min after intravenous administration due to rapid degradation by the ubiquitous enzyme, dipeptidyl peptidase (DPP4) [30]. Currently available GLP-1 RAs in Europe can be broadly classified as analogues of human GLP-1 with various structural modifications that prolong the agent’s half-life e.g. amino acid modifications (conferring resistance to the action of DPP4) or the addition of a fatty acid chain (liraglutide), albumin (albiglutide) or immunoglobulin (dulaglutide). Alternatively there are the exendin-based therapies (exenatide bd, lixisenatide, exenatide once weekly (QW)) (Fig. 1). Exendin-4 is a synthetic GLP-1 RA which was originally isolated from the venom of the Gila monster and shares 53% sequence homology with native GLP-1. In clinical practice GLP-1 RAs are referred to as short- (exenatide, lixisenatide) or longacting (liraglutide, exenatide QW, dulaglutide, albiglutide) based on their pharmacokinetic profile. Short-acting GLP-1 RAs display a marked ability to reduce gastric emptying, predominantly affecting post-prandial glucose excursions, whereas long-acting GLP-1 RAs have a more sustained glucose lowering effect and less effect on gastric emptying.

Diuresis/natriuresis ↑

warrant earlier use of a GLP-1 RA in the treatment algorithm. 3.2. CNS effects on appetite GLP-1 is a physiological regulator of appetite and food intake with central GLP-1 Rs mediating reduced appetite and weight loss [12]. The physiological importance of endogenous GLP-1 in appetite and eating behaviour is supported by data showing that the systemic administration of GLP-1 to humans reduces food intake by strengthening satiety and reducing the motivation to eat [13] while blocking the GLP-1 receptor increases food intake in satiated rats [14]. We also know that variables other than caloric intake and satiety have profound effects on food intake such as the pleasurable properties of food and environmental factors. GLP-1 receptor activation has been shown to reduce the reward we get from food, which may prevent cravings and overeating when full [15].

4.1. Type 2 diabetes Clinical trials have reproducibly demonstrated that the GLP-1 RAs effectively lower blood glucose levels when used as monotherapy or in combination with other agents, with HbA1c reduction ranging from −0.8 to −1.9% (Table 2) [21,31,32].

3.3. Gastrointestinal motility GLP-1 has a profound inhibitory effect on gastric emptying [16] preventing the rapid entry of glucose into the systemic circulation, an important factor for postprandial glucose excursions [17]. Pharmacologically, short-acting GLP-1 RAs cause a marked reduction in gastric emptying, whereas long-acting agents display a degree of tachyphylaxis after sustained use [16].

4.2. Obesity Depending on the clinical trial, a weight loss of ∼3 kg is seen with GLP-1 RAs when used for treatment of type 2 diabetes. A meta-analysis of 21 trials of obese patients with or without type 2 diabetes treated with a GLP-1 RA (exenatide twice daily, exenatide QW or liraglutide up to 1.8 mg), demonstrated clinically relevant weight loss in patients with diabetes (−2.8 kg, −3.4 to −2.3; 18 trials) and without diabetes (−3.2 kg, −4.3 to −2.1; three trials) [21]. Limited head-to-head studies of GLP-1 RAs suggest that liraglutide is most effective for weight loss, whereas weight loss is somewhat less with albiglutide [33].

3.4. Cardiovascular effects Clinical and experimental studies suggest that GLP-1 may be cardioprotective beyond the benefits of improved glycaemic control. The underlying mechanism is uncertain but may be via favourable effects on 62

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Fig. 1. Structural modifications of available glucagon-like peptide-1 receptor agonists.

lower associated risk of diabetes. Whilst the study had a high withdrawal rate (∼50%), the magnitude of the ability to prevent progression to type 2 diabetes is consistent with other diabetes prevention studies [40].

Evidence suggests that GLP-1 RAs primarily lower body weight through loss of fat mass with reductions in subcutaneous and visceral fat [34]. They have been also shown to lower liver fat, partly dependent on weight-loss and partly on improvement in glycaemic control [34]. More recent evidence suggests they may even reverse/improve the histopathological changes in non-alcoholic steatohepatitis (NASH) [35]. Liraglutide 3.0 mg (Saxenda®; Novo Nordisk), as an adjunct to a reduced‐calorie diet and increased physical activity, has been approved for weight management in the USA, EU, and elsewhere. The Satiety and Clinical Adiposity Liraglutide Evidence (SCALE) in non-diabetic and diabetic people phase 3 clinical development programme investigated the safety and efficacy of liraglutide 3.0 mg (once daily subcutaneous injection). In this weight management programme subjects treated with liraglutide 3.0 mg experienced a dose-dependent weight loss ranging between 5.7% and 9.2% (6.0-8.8 kg) depending on the trial, whereas subjects treated with placebo (on diet and exercise alone) had a mean weight loss between 0.2% and 3.1% (0.2–3.0 kg) [36–38]. In the 3 year assessment of the SCALE Obesity and Prediabetes trial le Roux et al. examined whether 3.0 mg liraglutide reduced progression of type 2 diabetes in overweight or obese individuals with pre-diabetes [39]. A 4.6 kg placebo-subtracted weight loss reduction was observed with liraglutide (50% of patients lost > 5% weight). Regression from prediabetes to normoglycaemia was observed in 66% of individuals whilst on treatment with liraglutide (36% in placebo group) with a

4.3. Type 1 diabetes Few high quality studies have assessed the safety and efficacy of GLP-1 RA treatment, alongside insulin therapy, in patients with type 1 diabetes. The Lira-1 study evaluated the efficacy and safety of liraglutide as add-on to insulin treatment in overweight patients with type 1 diabetes [41]. Whilst no additional effect on HbA1c was demonstrated, reductions in weight (−6.8 kg) and insulin requirements were seen in the liraglutide arm. Whilst not contraindicated in type 1 diabetes, its prescription in this group of patients should be on an individual basis, with careful consideration of the risks and benefits. There may be a subgroup of patients (e.g. overweight/obese with type 1 diabetes) in which a GLP-1 RA, adjunct to insulin, would produce the most benefit but at present limited data is available.

Table 2 Comparative clinical and structural characteristics of glucagon-like peptide-1 receptor agonists. GLP-1 RA

Properties

% amino acid homology to native GLP-1

T 1/2

Dosing

Reductions in HbA1c (%)

Reduction in body weight (kg)

Exenatide Lixisenatide Exenatide-QW

39 AA peptide 44 AA derivative of exenatide Encapsulated in biodegradable polymer microspheres C-16 fatty acid to lys26, non-covalent bond to albumin GLP-1 dimer bound to albumin GLP-1 RA peptide fused to IgG4 molecule

53 ∼53 53

2.4 h 4h 96 h

5–10mcg bd 10–20mcg od 2 mg weekly

0.8–1.2 1.3–2.7 1.3–1.9

1–3 1.3–2.7 2–3.7

97

12 h

1.2mg–1.8 mg od

0.8–1.5

2–3

95 90

6–8 days 90 h

30–50 mg weekly 0.75–1.5 mg weekly

0.7–1 0.78–1.5

0.8–1.1 0.8–2.5

Liraglutide Albiglutide Dulaglutide

AA, amino acid; Lys, lysine; bd, twice daily; od, once daily; T1/2, half-life; QW, once weekly

63

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5. Emerging GLP-1 therapies for obesity/diabetes

in glycaemic control due to related calorie restriction and weight loss; however, improvements can be seen well in advance of any weight loss. There is intense interest in the mechanisms through which bariatric surgery works, which are complex, but changes in circulating gut hormones and neuroendocrine signalling play a significant role and have been the focus of much interest [52]. Whilst some mechanistic studies report that bariatric surgery likely works though GLP-1 signalling [53], in animal models, GLP-1 signalling is not necessary to recapitulate the weight loss effects of bariatric surgery [54]. GLP-1 is just one product of the preproglucagon gene: others, including oxyntomodulin and glucagon, also have anoretic effects. Other gut hormones, such as cholecystokinin (CKK), peptide YY(3–36) and pancreatic polypeptide (PP) reduce food intake. In contrast ghrelin, is orexigenic i.e. promotes hunger. Combination therapies and hybrid molecules that act on multiple receptors seems likely to maximise beneficial outcomes. Examples of hybrid molecules in which two or more peptides are joined together into a single molecule have mostly been aimed at three key peptide hormone receptors: GLP-1, glucosedependent insulinotropic polypeptide (GIP) and glucagon receptors [55–57]. Classically GLP-1 and glucagon have been thought to oppose each other in controlling glucose control. In preclinical animal studies of obesity/diabetes a glucagon/GLP-1 co-agonist improved glucose tolerance, hepatic fat and body weight compared to GLP-1 on its own [57]. More recently Finan et al. examined a unimolecular tri-agonist (GLP-1R, GIPR and glucagon) in animal models of type 2 diabetes and obesity demonstrating a potent reversal of diet-induced obesity with improved insulin resistance and hepatic steatosis [55]. At present the data is too preliminary to predict clinical effectiveness but these hybrid peptides seem promising.

5.1. Long-acting GLP-1 RAs There has been increasing interest in the development of long-acting GLP-1 RAs in order to maximise clinical outcomes. Semaglutide is a GLP-1 RA which permits once-weekly subcutaneous administration due to its extended half-life. For the semaglutide molecule the principal mechanism of protraction is strong albumin binding facilitated by a large fatty acid chain attached to the lysine in position 26 [42]. The large phase 3 clinical programme assessing efficacy and safety of semaglutide (SUSTAIN) in type 2 diabetes has been completed. The semaglutide phase 2 dose-finding trial in subjects with type 2 diabetes showed a clear dose-dependent response on HbA1c and weight over 12 weeks of treatment with semaglutide 1.6 mg/week providing a reduction in HbA1c by up to 1.7% and an absolute weight loss of 4.82 kg vs 1.18 kg in the placebo group. Direct comparison with liraglutide (up to 1.8 mg) was made as a secondary end-point. Semaglutide appeared to be more efficacious for weight loss than liraglutide (2.6 kg) [42]. Preliminary results from the phase 2 clinical trial with once-daily semaglutide investigating safety and efficacy of weight loss in people with obesity have also been reported. In the trial 957 people with obesity were randomised to semaglutide (0.05–0.4 mg/day) or placebo for 52 weeks. A weight loss of up to 17.8 kg was observed corresponding to an estimated 13.8% weight loss vs 2.3% achieved in the placebo group [43]. To avoid the requirement for subcutaneous injection, with the potential to improve compliance, different delivery methods of GLP-1 RA are being explored with the formulation of oral semaglutide currently in phase 3 development. This formulation is combined with the absorption enhancer SNAC (sodium N-[8-(2-hydroxybenzoyl)amino] caprylate), causing a localised increase in pH, enabling a higher solubility and protection from enzymatic degradation [44].

6. Safety and tolerability 6.1. Adverse effects and safety concerns

5.2. GLP-1 RAs and sodium–glucose co-transporter 2 inhibitors (SGLT2i)

GLP-1 RAs demonstrate similar class-specific adverse effects, the most common being gastrointestinal upset (nausea, vomiting and diarrhoea). These are usually mild and transient [16]. As with all protein-based pharmaceuticals, subjects treated with GLP-1 RAs may develop mild immunogenic and allergic reactions, with limited effect on clinical efficacy [58,59]. Whilst focusing on cardiovascular outcomes, adverse events were also reported in the recent large-scale cardiovascular outcome trials for GLP1-RAs. In SUSTAIN-6, higher than expected rates of diabetic retinopathy complications occurred in the semaglutide group, and were seen very early in the trial [60]. The authors acknowledge an association between rapid glucose lowering and worsening of retinopathy in patients with type 1 diabetes [61]. Smaller retrospective studies have also shown this in patients with type 2 diabetes [62] but a direct effect of semaglutide cannot be ruled out. Another safety question that is frequently raised is whether or not GLP-1 RAs are linked to an increased risk of pancreatitis and or pancreatic carcinoma. Concerns have not been fully justified partly arising from a lack of plausible mechanistic data and partly because of insufficient evidence from randomised controlled trials (RCTs) [63], with data from the cardiovascular outcome trials providing some reassurance. Similarly, the increased incidence of C-cell hyperplasia and medullary thyroid carcinoma which was noticed in rodent studies [64] has not been demonstrated in large scale human studies with monitoring of serum calcitonin levels [65].

Until recently there was limited evidence on the combination of GLP-1 RAs and the sodium–glucose co-transporter 2 inhibitors (SGLT2i) despite potentially good rationale to do so. In brief it is anticipated that addition of a GLP-1 RA can overcome the potentially (mal)adaptive compensatory responses that occur with SGLT2i alone (increased hepatic glucose production due to hyperglucagonaemia and possible compensatory changes in appetite) in particular the observations that GLP-1 RAs can potently inhibit appetite, and reduce hepatic (endogenous) glucose production. DURATION-8 considered combination therapy with dapagliflozin and exenatide QW on a background of metformin demonstrating a 2% reduction in HbA1c and a weight loss of 3.4 kg after 28 weeks administration [45]. Mechanistic studies are underway to determine the wider benefits of this combination [46]. 5.3. Peptide combinations Combinations of GLP-1 RAs with long-acting insulin are currently available as IdegLira (insulin degludec and liraglutide) and iGlarLixi (insulin glargine and lixisenatide) and are administered as a single daily subcutaneous injection. Basal insulin delivers sustained insulin throughout the day, targeting fasting glucose levels, whereas GLP-1 RAs stimulate glucose-dependent insulin secretion, inhibit glucose-dependent glucagon secretion, and increase satiety. With both agents the glycaemic improvement is superior to their components with the supplementary benefits of weight loss, and no increased risk of hypoglycaemia versus basal insulin [47–49]. The effect of weight loss on reversal of type 2 diabetes is highlighted by several key areas of evidence, in particular studies examining remission of type 2 diabetes after calorie restriction and bariatric surgery [50,51]. In theory all bariatric surgery procedures cause improvements

6.2. Cardiovascular outcome trials The increase in heart rate seen with GLP-1 RAs, theoretically, represents a safety concern, but increased heart rate does not appear to increase the cardiovascular risk of individuals with type 2 diabetes with (or at high risk of) cardiovascular disease. At this time, there are four 64

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3-pt MACE 3-pt MACE T2DM, high risk T2DM T2DM with prior CV events and or known CV risks 9400 ∼9600 HARMONY REWIND

EXSCEL

Albiglutide Dulaglutide

3-pt MACE T2DM with prior CV events and or known CV risks 14000 Exenatide QW

3-pt MACE 3297 Semaglutide

a

SUSTAIN−6a

4-pt MACE

T2DM, acute coronary event within 180 days prior to randomisation T2DM, high risk T2DM 6068 Lixisenatide ELIXAa

LEADER

MACE = major adverse cardiovascular event. 3-point MACE = composite of cardiovascular death and non-fatal myocardial infarction and stroke. 4-point MACE = 3-point MACE plus hospitalisation for another specified cardiovascular event. a Studies for which the results have already been reported.

2018 2019

Completed

Increased risk of diabetic retinopathy in semaglutide arm Considers the primary prevention of cardiovascular events Completed

Completed

Reduction in all-cause mortality in liraglutide arm Completed

HR 0.87 =;95% CI 0.78-0.97; P = 0.01 for superiority HR 1.02 =;95% CI 0.89-1.17 P < 0.01 for non-inferiority HR 0.74 =;95% CI 0.58-0.95 P = 0.02 for superiority HR 0.91 =;95% CI 0.83-1.00 P < 0.01 for non-inferiority Ongoing Ongoing 3-pt MACE T2DM, high risk T2DM 9340 Liraglutide

Primary outcome History n Drug

a

Study

Table 3 Cardiovascular outcome trials with glucagon-like peptide-1 receptor agonists.

Primary outcome results

Estimated end date

Additional comments

E. Brown et al.

published cardiovascular safety outcome trials for the GLP-1 agents: once weekly exenatide (EXSCEL), liraglutide (LEADER), lixisenatide (ELIXA) and semaglutide (SUSTAIN-6) (Table 3). Whilst lixisenatide and once weekly exenatide did not significantly alter the rate of major cardiovascular events compared to placebo [66,67], GLP-1 RAs liraglutide and semaglutide showed improvements in cardiovascular and renal outcomes [60,68]. In the LEADER trial, 9340 patients at high risk of cardiovascular events were randomised to either liraglutide or placebo. Liraglutide reduced the risk for the combined primary outcome of cardiovascular death, myocardial infarction, or stroke by 13% (13.0% versus 14.9%; HR, 0.87; 95% CI, 0.78–0.97). The slow separation of events in LEADER and SUSTAIN-6 suggests effects on the progression of atherosclerosis. The different results seen between these studies is not entirely understood but may be explained by the individual pharmacological profiles of each agent or simply trial design. Head to head trials would be required to resolve these questions. 7. Discussion With the rising prevalence of obesity and associated type 2 diabetes attention has rightly been directed towards treatment strategies that promote weight loss. GLP-1 RAs have become a successful treatment for type 2 diabetes and obesity with effective glucose control and modest weight loss. Their potential cardiovascular benefits are also receiving increasing focus and may lead to use earlier in the disease process, at least for those with pre-existing cardiovascular disease. Despite their success, even with the development of longer-acting agents, we still see a heterogeneity in response to treatment, both in terms of weight loss and HbA1c reduction. This may reflect a number of factors e.g. pharmacokinetics, that results in different drug exposure at the same dose (e.g. depending on body size), or other patient factors (biological and non-biological) that might alter response. There have been some small advances in this area with studies attempting to explain the heterogeneity, particularly weight change, by stratification of weight loss: ‘responders’ (who have lost ≥5% of their initial body weight) and ‘non-responders’ (who have lost ≤5% of their initial body weight) [69,70]. It is perhaps not surprising that early response to a weight loss intervention can predict long‐term weight loss. The future in obesity and type 2 diabetes management clearly involves combination treatments that mimic the benefits of bariatric surgery with glycaemic benefit, control of appetite and weight loss. The hope is that the combination of gut hormone analogues will have additive or even synergistic effects in improving glycaemic control and reducing caloric intake and subsequently weight loss. At present we are some way off from this reality with only a few examples of novel peptide co-agonists demonstrating proof of concept. It does however seem highly likely that the next decade will deliver significant advances in combination therapies for obesity and associated type 2 diabetes. Funding No specific grant from any funding agency in the public, commercial or not-for-profit sectors was received for this work. Conflicts of interest JW has acted as a consultant, received institutional grants and given lectures on behalf of pharmaceutical companies developing or marketing medicines used for the treatment of diabetes and obesity, specifically AstraZeneca, Boehringer Ingelheim, Janssen Pharmaceuticals, Lilly, Novo Nordisk, Orexigen, Sanofi & Takeda. DJC has competing interests with AstraZeneca, Boehringer Ingelheim, Janssen Pharmaceuticals, Lilly & Novo Nordisk. JCGH has acted as a consultant for Orexigen and Novo Nordisk. EB has no conflicts of interest to declare. EB is a Clinical Research Fellow funded by AstraZeneca. 65

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Author contributions

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All authors contributed to the writing of the manuscript and agreed on the final version. Glossary CCK DPP4 GIP GLP-1 GLP1R NASH PP PYY RCT SCALE SNAC

Cholecystokinin Dipeptidyl peptidase Gastric inhibitory peptide Glucagon like peptide-1 Glucagon like peptide-1 receptor Non-alcoholic steatohepatitis Pancreatic polypeptide Peptide YY Randomised controlled trial Satiety and clinical adiposity liraglutide evidence SGLT2i sodium-glucose co-transporter 2 inhibitor Sodium N-[8-(2-hydroxybenzoyl)amino] caprylate

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