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. Author manuscript; available in PMC: 2025 Apr 1.
Published in final edited form as: Br J Pharmacol. 2023 Nov 30;181(8):1153–1164. doi: 10.1111/bph.16278

Newer Pharmacological Interventions Directed at Gut Hormones for Obesity

Michael Camilleri 1, Andres Acosta 1
PMCID: PMC10947960  NIHMSID: NIHMS1942873  PMID: 37917871

Abstract

The objective is to review the newer pharmacological interventions for obesity, specifically single, dual, and triple incretin receptor agonists that are either available or in the pipeline for treatment of obesity. The three incretin receptor targets are glucagon like peptide-1 (GLP-1), glucose-dependent insulinotropic peptide (GIP), and glucagon. There are several approved single or dual incretin agonists which are administered subcutaneously daily (e.g., liraglutide) or weekly (e.g., semaglutide, dulaglutide, and exenatide QW), and experimental dual or triple incretin agonists. Other analogs of amylin, peptide YY, and oxyntomodulin, as well as a combination GLP1R agonist and GIPR antagonist are also being developed. Oral semaglutide (administered daily) is approved for type 2 diabetes and is on track for regulatory review for obesity. The review includes specifically perspectives on the effects of these mechanisms and pharmacological agents on gastric emptying which contribute to satiation and weight loss, in addition to the established evidence on effects on central mechanisms controlling appetite. In the future, it is anticipated that small molecule GLP-1 receptor agonists (e.g., oral danuglipron) will be developed. These pharmacological agents are having significant impact on glycemic control and obesity and their co-morbidities.

Graphical Abstract

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Introduction

The objective of this review is to evaluate the newer pharmacological agents available as interventions for the treatment of obesity. Nutrient intake is associated with important neurohormonal responses, and it is important to recognize the actions of the incretin hormones, glucagon like peptide-1 https://www.guidetopharmacology.org/GRAC/ObjectDisplayForward?objectId=249 and glucose-dependent insulinotropic peptide https://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=3542, as well as glucagon. One of the most convincing reasons to consider incretin treatment is the documentation of loss of endogenous incretin effects in patients with type 2 diabetes. The review will contrast the efficacy of incretins with that of prior drugs approved for treatment of obesity and will focus on the effects of single, dual, and triple incretin agonists that are either available or in the pipeline for treatment of obesity (Table 1). Several recently published reviews have addressed particularly the impressive metabolic effects of the gut hormone co-agonists (Nogueiras, Nauck, et al. 2023). With increased recognition of the role of gastric function in appetite and food intake and their modulation by pharmacological and bariatric interventions (Camilleri. 2023), the review incorporates a focus on the pharmacological effects of approved and experimental agents for obesity on gastric emptying to complement established effects on appetite.

Table 1.

Summary of single, dual, and triple incretin agonists and their route and frequency of administration

Incretin Agonists Single Dual Triple
Receptor target(s) GLP-1 GLP-1/GIP GLP-1/Glucagon GLP-1/GIP/glucagon
Administration
SQ daily multiple Exenatide
SQ daily single Lixisenatide Liraglutide Cotadutide
SQ weekly Albiglutide, Dulaglutide, Exenatide QW Semaglutide Tirzepatide BI 456906 Mazdutide (IBI362; LY3305677) Retatrutide (LY3437943)
Oral daily Semaglutide Danuglipron
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For review of the beneficial effects of these gut hormone agonists on major adverse cardiac events, the reader is referred to several systematic reviews that have documented benefits (Uneda, Kawaim, et al. 2021), even in patients with heart failure (Zhao, Liu, et al. 2023). Prior studies also addressed the effect of prior history of heart disease (D’Andrea, Kesselheim, et al. 2020), as well as age and race on the beneficial effects of GLP-1 agonists (Diallo, Carlos-Bolumbu, et al. 2022).

Lifestyle modification and diets have been the mainstay of treatments for obesity and have been incorporated into clinical practice guides for obesity and weight management. These recommendations include education and resources for the assessment of obesity including medical (e.g. cardiometabolic status), dietary and psychological evaluation, introduction of reduced calorie diet with physical activity and exercise, as well as behavioral programs to complement second level therapies using approved medications. The importance of weight loss maintenance and prevention of weight regain require careful health choices and behavioral changes in addition to regular physician or dietitian follow-up and community support. These principles were incorporated in the POWER Program recommended in 2017 by the American Gastroenterological Association (Acosta, Streett, et al. 2017), as well as other organizations such as The Obesity Society (Jensen, Ryan, et al. 2014). Unfortunately, the trends in obesity prevalence and cardiometabolic risk factors in U.S. adults with diabetes have continued to increase, as documented by the increases in class 1–3 obesity based on body mass index as well as the prevalence of central obesity between 1999 and 2020 (Hu, Ding, et al. 2023), and although being recommended by several societies, lifestyle interventions alone have not been sufficiently successful. For example, in the DIETFITS study of >600 obese adults, the average weight loss with low-fat or low-carbohydrate was about 6% over 12 months (Gardner, Trepanowski, et al. 2018). Such well-conducted studies of lifestyle intervention emphasize the importance of additional interventions.

Physiological Interactions of Nutrient Intake and Neurohormonal Responses

The entry of food in the upper gastrointestinal tract is associated with stimulation of afferent signals, predominantly involving vagal afferents whose nerve cell body is in the nodose ganglion, leading to activation of reflexes that ultimately stimulate vagal efferents from the dorsal motor vagus nucleus to stimulate physiological responses of the stomach as well as other upper gastrointestinal organs. These reflexes result in gastric accommodation through vagal cholinergic activation of intrinsic nitrergic and somatostatinergic neurons in the myenteric plexus, gastric motor stimulation leading to antral contractility, trituration of food, and antral pyloric duodenal coordination that facilitates gastric emptying. In addition, vagal afferents supply other upper gastrointestinal organs involved in digestion of nutrients including the gallbladder and pancreas, leading to the delivery of bile and pancreatic enzymes that are essential for digestion.

However, the arrival of nutrients in the upper gastrointestinal tract also results in the stimulation of several peptides or hormones that are intimately involved in the digestive process. Thus, the presence of osmotic and pH stimuli as well as fat results in secretion from the duodenal mucosa of the hormones, cholecystokinin and secretin, which leads to gallbladder and pancreatic exocrine secretion, but they also are associated with inhibition of vagal nerve reflexes resulting in inhibition of gastric contractility. Similarly, the presence of amino acids and carbohydrate in the upper gastrointestinal tract results in the release of gastrin from the stomach and glucose-dependent insulinotropic peptide from the proximal jejunum. The presence of monosaccharides and disaccharides in the upper gastrointestinal tract leads to the stimulation of release of glucagon like peptide-1 (GLP-1) from the intestinal mucosa and insulin from the pancreatic beta cells. Arrival of nutrients in the more distal small intestine and colon is associated with release of several hormones such as GLP-1, peptide tyrosine tyrosine (PYY), oxyntomodulin, and neurotensin (Camilleri 2015). Another hormone called insulin like peptide-5 (Insl5) is released from the distal colonic enteral endocrine cells, similar to the release of GLP-1 and PYY. However, in contrast to the latter hormones, plasma Insl5 levels are elevated during fasting or prolonged calorie restriction and decline with feeding (Grosse, Heffron, et al. 2014).

Effects of Endogenous Incretins

The endogenous incretins, GLP-1 and GIP, have significant effects on the gastrointestinal tract, central mechanisms controlling appetite, and pancreatic hormones. Thus, GLP-1 inhibits gastric emptying and motility, reduces appetite, increases insulin secretion as well as pancreatic β cell proliferation, and reduces glucagon secretion. GIP inhibits acid secretion and, like GLP-1, it increases insulin secretion and β cell proliferation in healthy humans, with markedly reduced insulinotropic effect in patients with type 2 diabetes (Nauck, Heimesaat, et al. 1993; Meier, Nauck, 2004). In acute administration studies, GIP does not influence appetite and food intake in human participants such as in those with type 2 diabetes receiving metformin and a long-acting GLP-1 receptor agonist (Bergmann, Gasbjerg, et al. 2020).

The rationale for exogenous incretin receptor agonists in type 2 diabetes is supported by the loss of effects of incretins in type 2 diabetes compared to those with normal glucose tolerance. Thus, in a systematic review and meta-analysis, Grespan et al. documented the marked reduction in effects of incretins calculated from insulin measurements in type 2 diabetes compared to normal glucose tolerance (Grespan, Guolo, et al. 2022).

Effects of Glucagon

Glucagon https://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=3785 also retards gastric emptying, reduces appetite, and increases insulin secretion at the concentrations present within the islets of Langerhans, signaling through GLP-1 (rather than glucagon) receptors on β cells. Glucagon is associated with increased thermogenesis and energy expenditure (Targher, Mantovani, et al. 2023).

Central Effects of Incretins

GLP-1 receptors in the hypothalamus are involved in regulating food intake through processes that were associated with an increase in functional connectivity of the nucleus tract solitarius with the hypothalamus and thalamus, as well as direct stimulation of proopiomelanocortin and cocaine- and amphetamine-regulated transcript (POMC/CART)-expressing arcuate nucleus neurons and indirect inhibition of neuropeptide Y (NPY) and agouti-related peptide (AgRP) to increase measures of satiety and decrease hunger (Coveleskie, Kilpatrick, et al. 2017; Secher, Jelsing, et al. 2014). Eating behavior also modulates sensitivity to the central effects of GLP-1 receptor agonists. For example, there is an association between emotional eating scores and liraglutide-induced reductions in brain responses to food pictures after 10 days of treatment; after 12 weeks of treatment with liraglutide, baseline restraint eating scores were associated with greater GLP-1 receptor agonist-induced reductions in responses in the insula and caudate nucleus to pictures of foods or to the anticipation of chocolate milk (van Ruiten, Ten Kulve, et al. 2022).

In summary, the effects of GLP-1 receptor agonists in the brain-gut axis ultimately result in reducing food intake by enhancing postprandial satiety.

There is limited evidence regarding GIP effects on appetite centers based on studies in rodents which showed that certain somatostatinergic neurons in the hypothalamus express GIP receptors and react to activation of those receptors by decreasing food intake (Adriaenssens, Biggs, et al. 2019). GIP receptors have been identified in human hypothalamus (Farr, Sofopoulos, et al. 2016).

Overall, the central effects on appetite and food intake are the predominant mechanisms leading to weight loss. However, when formally and prospectively assessed over 16 weeks of treatment daily with SQ liraglutide, there was a significant association between degree of weight loss and slowing of gastric emptying of solids, particularly in patients with baseline acceleration of gastric emptying (Maselli, Atieh, et al. 2022). Moreover, analysis of the placebo-controlled trials of oral semaglutide (PIONEER 1, 4, 5, and 8) (Meier, Bardtrum, et al. 2023) demonstrated that gastrointestinal adverse effects contributed to a small proportion of the estimated treatment difference attributable to the oral GLP-1 agonist. To date, the relative contribution of delayed gastric emptying to weight loss with these classes of drugs has not been appropriately assessed, since the predominant method used to assess effects of gastric emptying in the literature has been the indirect plasma acetaminophen (paracetamol) method that assesses predominantly appraisal of liquid emptying. For example, early studies suggested that liraglutide SQ 1.8 or 3 mg for 5 weeks (van Can, Sloth, et al. 2014) and semaglutide SQ 2.4 mg for 20 weeks (Friedrichsen, Breitschaft, et al. 2021) did not delay overall gastric emptying based on the paracetamol method, whereas more recent studies based on scintigraphic measurement of radiolabeled scrambled egg in response to SQ liraglutide (up to 3.0 mg for 16 weeks) (Maselli, Atieh, et al. 2022) or of radiolabeled pancake in response to SQ semaglutide (1.0 mg for 12 weeks) (Jensterle, Ferjan, et al. 2023) showed marked and significant retardation of gastric emptying.

Chemical Structure of GLP-1 Receptor Agonists or Analogues

Chemical modulation of the structure of exendin 4 (a GLP-1 analog) has led to the development of agents with far greater half-life than the parent compound GLP-1 with its half-life of 2–3 minutes. Modifications to the structure include the removal of the site of degradation by dipeptidyl-peptidase IV (DPP4) in GLP-1 and addition of amino acids to the GLP-1 leading to the short-acting agents, exenatide and lixisenatide, which are associated with half-lives of around 3 hours. Furthermore, covalent conjugation with larger molecules such as human albumin (albiglutide), IgG4 Fc domain (dulaglutide), encapsulation into microspheres (exenatide QW), addition of C-16 fatty acid chain palmitoyl leading to non-covalent binding to albumin (liraglutide), introduction of a hydrophilic spacer, modification of the lysine in position 28, and C-18 fatty acid chain to mediate strong binding to albumin (semaglutide) lead to GLP-1 receptor agonists of longer half-life and daily or weekly administration via a subcutaneous route (Gentilella, Pechtner, et al. 2019).

Finally, an oral formulation of semaglutide was based on co-formulation with sodium N-8–2 hydroxy-benzoyl amino caprylate (SNAC) with circulating levels and biological efficacy including reduction in HbA1c and induction of nausea similar to that of subcutaneous semaglutide (Overgaard, Hertz, et al. 2021), although plasma levels with oral formulation will likely require higher oral doses such as 25 and 50 mg oral daily doses, as in recent clinical trials (Aroda, Aberle, et al. 2023). In the future, it is anticipated that oral small molecule GLP-1 receptor agonists will also be available with the added advantage that no interval will be required between drug intake and meal (Saxena, Gorman, et al. 2021).For example, daily oral orforglipron, a nonpeptide GLP-1 receptor agonist, at doses from 12 to 45 mg/day, was associated with weight reduction exceeding 10% at 36 weeks on average in patients with obesity without diabetes. Adverse events reported with orforglipron were similar to those with injectable GLP-1 receptor agonists (Wharton, Blevins, et al. 2023).

Comparison between Incretins and Non-Incretins Medications for Weight Loss and Glycemia

An earlier systematic review and network meta-analysis showed greater efficacy of incretin-modifying agents over other agents such as naltrexone-bupropion, locaserin, and orlistat. Comparable effects were noted for phentermine-topiramate and liraglutide (Khera, Murad, et al. 2016). A more recent systematic review and meta-analysis documented superiority of pharmacotherapy over lifestyle modification alone as documented for phentermine-topiramate, GLP-1 receptor agonists as a class, and naltrexone-bupropion; however, among the GLP-1 agonists, it was noted that there was greater percentage of body weight change with semaglutide (median -11.41%) compared to liraglutide (median -4.68%) and exenatide (median-3.72%) (Shi, Wang, et al. 2022) (Figure 1).

Figure 1. Summary of relative effects of weight-lowering drugs on benefit outcomes with certainty of evidence rated by the Grading of Recommendations Assessment, Development, and Evaluation criteria, including imprecision. The drugs were categorized according to being clearly or possibly better than lifestyle modification alone (the mean effect size exceeding or less than the MID and the 95% CI not crossing the MID threshold). The best, intermediate, and worst categories show whether the effect is clinically important or not. Bold text represents statistical significance.

Figure 1.

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MD=mean difference; MID=minimal important difference; OR=odds ratio; SMD=standardized mean difference. Adapted from Shi, Q., et al. (2022). Pharmacotherapy for adults with overweight and obesity: a systematic review and network meta-analysis of randomised controlled trials. Lancet, 399(10321), 259–269

Effects of Incretin Agonists Focusing on Mechanisms and Clinical Efficacy

The literature has amply documented the efficacy of incretin agonists on type 2 diabetes and obesity. The focus of this section is to review mechanisms and to highlight effects on glycemic control, weight loss, liver disease associated with obesity, and food intake regulation, gastric functions and appetite that are associated with weight loss.

Single Incretin Agonists

The short-acting GLP-1 agonist, exenatide, administered at a dose of 5 mcg subcutaneously twice daily for 30 days, was associated with marked retardation of gastric emptying; in addition, weight loss was pronounced in patients with documented acceleration of gastric emptying of solids at baseline, that is in patients whose gastric emptying T1/2 was less than 90 minutes (Acosta, Camilleri, et al. 2015).

The longer-acting GLP-1 agonist, liraglutide, administered once daily by subcutaneous injection and escalated to a maximum dose of 3 mg per day, was associated with significant weight loss as well as marked slowing of gastric emptying at 5 weeks and at 16 weeks of treatment. There was tachyphylaxis in the gastric emptying delay between 5 and 16 weeks, and there was an overall significant correlation between the amount of weight loss and the degree to which gastric emptying was delayed. Among patients with the fastest quartile gastric emptying at baseline, there was a significant correlation with weight loss in response to treatment with liraglutide (Maselli, Atieh, 2022). In the same study, liraglutide was noted to have additional effects on glycemic control, satiation, appetite, and fat mass without negatively impacting lean body mass (Kadouh, Chedid, et al. 2020). The degree of weight loss with the 3 mg per day liraglutide dose was associated with the degree of prolongation of gastric emptying of solids at 5 weeks, the baseline gastric emptying prior to treatment, and, as would be expected, the kilocalorie intake during an ad libitum meal at the end of 16 weeks of treatment (Sannaa, Dilmaghani, et al. 2023). It has been estimated that the degree of gastric emptying delay may contribute around 20% of the variance in weight loss in response to liraglutide based on the correlation coefficients observed between degree of gastric emptying delay and weight loss (Jalleh, Rayner, et al. 2022). Post-hoc analysis of the data from 67 patients treated with liraglutide for 16 weeks showed that liraglutide was associated with significant gastric emptying delay in 57% (39/67) of patients with obesity, but tachyphylaxis restored normal gastric emptying in 19/39 so that gastric emptying delay was persistent in 30% at 16 weeks. The factors predisposing to such delay and for its spontaneous resolution remain unclear (Camilleri, Carlson, et al. 2023)

Based on a systematic review and meta-analysis and network meta-analysis of the different GLP-1 receptor agonists, it was documented that the most efficacious medication was semaglutide 2.4 mg, followed by semaglutide less than 2.4 mg subcutaneously each week, and liraglutide greater than 1.8 mg subcutaneously each day (Vosoughi, Atieh, et al. 2021). It is important to note that the adverse event profile is similar for these three medications. In addition, as the meta-analysis of these large clinical trials documented, there was greater efficacy with GLP-1 agonists in terms of weight loss in nondiabetic participants compared to patients with type 2 diabetes, with the most evident comparisons based on treatment with daily subcutaneous liraglutide and weekly subcutaneous semaglutide (Vosoughi, Roghani, et al. 2022).

Another interesting observation from an analysis of more than 24,000 randomized patients who received GLP-1 receptor agonists is that the risk difference of nausea was associated with the absolute excess weight loss compared to placebo (Vosoughi, Roghani, et al. 2022). This raises the question as to whether gastrointestinal adverse effects contribute to the weight loss in response to GLP-1 receptor agonists. This was formally addressed in an analysis conducted post hoc in the placebo-controlled trials of oral semaglutide in patients with type 2 diabetes. That analysis showed that effects other than gastrointestinal adverse effects were responsible for the weight loss, with a minor contribution attributable to the gastrointestinal adverse effects (Meier, Bardtrum, et al. 2023). Oral daily semaglutide was also demonstrated to be almost as efficacious as subcutaneous liraglutide up to 1.8 mg per day in a randomized, controlled trial (Pratley, Amod, et al. 2019). The doses of 25 and 50 mg of oral semaglutide resulted in weight loss over 68 weeks’ administration (Aroda, Aberle, et al. 2023) as had been reported for SQ semaglutide 2.4 mg (Davies, Faerch, et al. 2021).

In the future, it is anticipated that small molecule GLP-1 receptor agonists will be developed for the same indications, specifically, glycemic control and obesity. For example, danuglipron is an oral small molecule GLP-1 receptor agonist with comparable efficacy to injectable peptide GLP-1 receptor agonists in a humanized model. In patients with type 2 diabetes receiving metformin, administration of danuglipron was associated with mild adverse effects such as nausea, dyspepsia, and vomiting (Saxena, Gorman, et al. 2021). A study conducted in Japanese patients with type 2 diabetes showed significant reduction in glycemia and body weight (Ono, Furihata, et al. 2023). Patients with type 2 diabetes showed a significant reduction in glycemia and body weight at 16 weeks (Saxena, Frias, et al. 2023).

Despite the positive effects on glycemic control and weight loss during treatment with GLP-1 receptor agonists, several trials have documented weight regain and cardiometabolic effects on withdrawal of medication, as shown for example with subcutaneous semaglutide (Wilding, Batterham, et al. 2022). These observations suggest the need for chronic management of obesity and diabetes with incretins, as these medications control the disease but do not revert the pathogenesis of the disease. Further studies are needed to understand the length of therapy when successful weight loss and glycemic control are achieved.

Dual Incretin Agonists

Several dual incretin agonists are either available for prescription or in development. The dual incretin (GLP-1/GIP) agonist, tirzepatide, administered subcutaneously weekly, was efficacious in ameliorating glycemic control (HbA1c) and body weight in patients with type 2 diabetes. This medication was approved for prescription and marketing for type 2 diabetes in 2022, and it is on fast track for consideration for treatment of obesity. Clinical trials have also shown significant weight loss even reaching 20.9% mean change in body weight or mean weight reduction of 11.2 kg with the 15 mg dose (Jastreboff, Aronne, 2022; Frias, Davies, et al. 2021). Moreover, the 15 mg dose reduced fat mass, calorie intake, and appetite in adults with type 2 diabetes when administered for 28 weeks. In this study, although energy intake and satiety effects were similar with semaglutide 1mg and tirzepatide 15 mg, the latter had a significantly greater effect on fat mass change from baseline relative to the effect on fat mass with semaglutide (Heise, DeVries, et al. 2023). The beneficial effects of tirzepatide may be partly related to its effects on gastric emptying, since there was a significant reduction in the maximum concentration of acetaminophen during the first 4 hours after ingestion; this reflects the gastric emptying of liquids and, as with gastric emptying of solids with liraglutide, there appeared to be tachyphylaxis in the reduction of maximum concentration of acetaminophen after 3 weeks of administration relative to the second day of tirzepatide intake (Urva, Coskun, et al. 2020). Tirzepatide was also associated with reduction in visceral and abdominal adipose tissue in patients with type 2 diabetes in comparison with treatment with insulin degludec (Gastaldelli, Cusi, et al. 2022). Three systematic reviews and meta-analyses have been published in 2023, documenting the weight loss benefits of tirzepatide (Lin, Yu, et al. 2023; Tan, Pan, et al. 2023; Rohani, Malekpour Alamdari, et al. 2023), with one drawing attention to the need for vigilance regarding gastrointestinal advere effects (Lin, Yu, et al. 2023).

Nevertheless, it is still unclear how GIP agonism contributes to the therapeutic benefit of the dual GLP-1/GIP agonist, since exogenous GIP has little effect on glycemic control in patients with type 2 diabetes (Nauck, Heimesaat, et al. 1993), there is limited evidence for its effect on appetite (Bergmann, Gasbjerg, et al. 2020), and, as detailed below, AMG-133, a GLP-1 receptor agonist and GIP receptor antagonist, also results in weight loss. This paradox is discussed in greater detail in other reviews (Campbell, 2021; Nauck, Quast, et al., 2021) with two independent hypotheses being, first, that antagonism of the GIPR may enhance GLP-1R activity, and second, chronic GIPR agonism may produce desensitization and ultimately loss of GIPR activity that mimics antagonism (Campbell, 2021). Indeed, mouse genetic studies showed that loss of function alleles and GIP overexpression both protect from high-fat diet–induced weight gain, suggesting that both agonists and antagonists may be feasible approaches for the treatment of obesity (Killion, Lu, et al. 2020). Given that antagonist antibodies against the GIP receptor promote weight loss when combined with GLP-1 in both obese mice and non-human primates (Lu, Chen, et al. 2021), Holst asked the rhetorical question: What combines best with GLP-1 for obesity treatment: GIP receptor agonists or antagonists? (Holst. 2021). These interesting questions are the subject of ongoing research, particularly with the recent discovery of a potent GIP receptor antagonist that is also effective in human systems (Yang, Gelfanov, et al. 2022) and the demonstration that the selective GIP receptor antagonist, GIP(3–30)NH2, is biologically active since it reduced postprandial insulin secretion in patients with type 2 diabetes (Stensen, Gasbjerg, et al. 2021).

Cotadutide is a dual incretin agonist (GLP-1/glucagon) that was efficacious in improving glycemic control and reducing body weight in obese patients with type 2 diabetes (Nahra, Wang, et al. 2021). Efficacy was also documented using mechanistic studies that evaluated the changes in blood glucose following a mixed meal tolerance test as well as changes in body weight, and improvements in lipid profile, transaminase levels, propeptide of type III collagen level, fibrosis-4 index, and nonalcoholic fatty liver disease fibrosis score. In the same study, gastric emptying of solid food was assessed using 13C-octanoate breath test; the study documented marked slowing of gastric emptying which persisted during 50 days of administration of cotadutide dual (GLP-1/glucagon) agonist, and reverted to normal at 28 days follow-up (Parker, Robertson, et al. 2020).

Pemvidutide (ALT-801), also a GLP-1/glucagon receptor dual agonist, has been tested in a mouse model of NASH and caused significant reductions in body weight (approximately 25%), plasma ALT, AST, plasma total cholesterol and liver triglycerides/total cholesterol, in addition to improving liver steatosis, with greater reductions compared to semaglutide and elafibranor. ALT-801 also significantly reduced the inflammation marker galectin-3 and the fibrosis marker collagen type 1 alpha 1 compared to vehicle, and significantly improved composite NASH compared to the active controls (Nestor, Parkes, et al. 2022). Pemvidutide also improved weight and cardiometabolic risk factors in overweight/obese participants (Klein, Nestor, et al. 2022).

Another dual (GLP-1/glucagon) incretin agonist, BI456906, was also shown to reduce body weight relative to baseline and to reduce gastric emptying of liquids based on plasma acetaminophen measurement (Jungnik, Arrubla Martinez, et al. 2023). A recent report also documented weight loss in Japanese men, and the degree of weight loss appeared to be dose related between 1.8 mg and 4.8 mg, each administered once weekly (Yazawa, Ishida, et al. 2023).

A third experimental dual (GLP-1/glucagon) incretin agonist, mazdutide (IBI362 or LY3305677), has been tested at escalated doses of 3, 4.5, and 6 mg in Chinese patients in 12-week trials compared to placebo, and it has been documented that this results in Hb improvement in HbA1c and reduced body weight in type 2 diabetes, and in reduced body weight in obesity (Jiang, Pang, et al. 2022; Ji, Jiang, et al. 2021). Mazdutide has also been shown to be safe and efficacious at the 9 and 10 mg doses in Chinese adults with overweight and obesity in a placebo-controlled, multiple-ascending-dose trial (Ji, Gao, et al. 2022).

Combination GLP1R Agonist and GIPR Antagonist

Several dual incretin agonists are also in development and are regarded as experimental at present. Unlike the GLP-1/GIP co-agonists, AMG-133 is a GLP-1 receptor agonist and GIP receptor antagonist. The GIPR antagonist component reduces body weight through reduction in food intake as well as inducing improvement in fat cell metabolic function (Hammoud, Drucker 2023). Interestingly, the mouse model of GIPR knockout is resistant to diet-induced obesity mediated by an increase in energy expenditure (Hansotia, Maida, et al. 2007). AMG-133 is currently under evaluation in a phase 2 clinical trial (Clinical Trials.gov NCT05669599).

Triple Incretin Agonist

An experimental triple incretin agonist, retatrutide, acts on glucagon, GIP, and GLP-1 receptors. This is currently under investigation for the indication of chronic weight loss. It has been shown to be more potent at the human GIP receptor and less potent at the glucagon and GLP-1 receptors compared to native or endogenous peptides. The estimated half-time is approximately 6 days and this supports administration once per week (Coskun, Urva, et al. 2022). In healthy participants, this medication was associated with body weight reduction as well as reduced appetite scores over 6 weeks of treatment (Coskun, Urva, et al. 2022). In phase 1B and phase 2, double-blind, placebo-controlled or active comparator studies conducted in patients with type 2 diabetes using ascending doses of retatrutide, there were significant improvements in glycemic control, HbA1c and body weight (Urva, Coskun, et al. 2022; Rosenstock, Frias, et al. 2023). In adults with obesity, retatrutide treatment for 48 weeks resulted in substantial reductions in body weight, reaching 24% in the 12mg dose group (Jastreboff, Kaplan, et al. 2023). Retatrutide also slows gastric emptying of liquids based on the acetaminophen test (Urva, O’Farrell, et al. 2023).

Actions of Incretin Receptor Agonists on Liver Disease

Given the impact of metabolic or nonalcoholic fatty liver disease on health and need for liver transplantation, it is important to note the potential of novel approaches to treat obesity and its impact on NAFLD, as in an algorithm for risk stratification in patients with NAFLD/NASH developed by the American Gastroenterological Association, the American Diabetes Association, and The Obesity Society. The algorithm makes specific recommendations regarding the application of lifestyle intervention, introduction of liver directed pharmacotherapy in the presence of fibrosis stages II or III, or cirrhosis, and the approach to concomitant treatment of diabetes which includes the use of pioglitazone as well as GLP-1 receptor agonists (Kanwal, Shubrook, et al. 2021).

The use of incretin agonists is supported by the observation in a systematic review and meta-analysis showing that, in 8 trials conducted in 468 patients, treatment with liraglutide, exenatide, or dulaglutide was associated with reduced transaminases, intrahepatic adipose, and visceral fat (Zhu, Xu, et al. 2021). Experimental studies also showed reduced hepatic fibrosis in mouse models of NASH (Boland, Laker, et al. 2020) as documented for example with the experimental GLP-1/2-Fc fusion compound (Kim, Park, et al. 2022), and the reduction in hepatic fibrosis in both mouse models of NASH and in humans with overweight or obesity and type 2 diabetes with the experimental dual incretin agonist, cotadutide (Nahra, Wang, et al. 2021).

Obesity-associated liver diseases respond to tirzepatide as documented with reductions in AST, ALT, and apoptosis and fibrosis markers (Hartman, Sanyal, et al. 2020). Tirzepatide also reduced liver AST and adipose tissue in the abdomen in patients with type 2 diabetes compared to insulin gludec (Gastaldelli, Cusi, et al. 2022).

Other Agents

Amylin Analogs

Amylin, a 37-amino acid peptide with an estimated half-life of 13 minutes, is released with insulin from beta cells in the pancreas and induces its satiating effect via both the homoeostatic and hedonic regions of the brain (Mietlicki-Baase, Hayes 2014). Amylin and analogs such as pramlintide (which differs from amylin by 3 proline substitutions and has a half-life of 20−45 minutes) also regulate glucose levels (Hermann, Frias, et al. 2013) and slow gastric emptying through inhibition of vagal function (Vella, Lee, et al. 2002; Samsom, Szarka, et al. 2000). Cagrilintide is a long-acting, lipidated, albumin-binding, stable agonist of the amylin receptor; its extended half-life results from addition of an N-terminal C20 fatty acid. It is now being developed in combination with the GLP-1 agonist, semaglutide, to achieve sustained weight loss in persons with overweight and obesity (D’Ascanio, Mullally, et al. 2023). Cagrilintide, 0.3–4.5 mg for 26 weeks, showed dose-dependent, clinically meaningful weight loss as an adjunct to lifestyle interventions in adults with overweight or obesity (Lau, Erichsen, et al. 2021). Concomitant treatment with cagrilintide and semaglutide, 2·4 mg SQ weekly, was well tolerated with an acceptable safety profile in a phase 1B trial with mean estimated treatment differences at 20 weeks of treatment being 6, 7.2, and 7.2% for 1, 2.4 and 4.5 mg cagrilintide compared to placebo, with all treatments combined with the same semaglutide dose (Enebo, Berthelsen, et al. 2021). The latter study also included pharmacokinetics and showed half-life of 159–195 h, with a median tmax of 24–72 h which would be consistent with weekly administration of the amylin agonist (Enebo, Berthelsen, et al. 2021). A more recent phase 2 study has also confirmed efficacy of combination cagrilintide with semaglutide leading to 15.6% weight reduction at 32 weeks relative to baseline, and with greater weight loss than each component alone (Frias, Deenadayalan, et al. 2023).

Peptide Tyrosine-Tyrosine (PYY) and Oxyntomodulin

PYY 3–36 https://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=1517 is associated with reduced food/energy intake, modulation of brain appetite centers (such as nucleus accumbens and orbitofrontal cortex) and appetite in humans, though these effects were more prominent with co-administration of GLP-17–36 amide or GLP-1 (De Silva, Salem, et al. 2011; Schmidt, Gregersen, et al. 2014). Infusions of PYY3–36 at pharmacological doses resulted in reduced food intake (Degen, Oesch, et al. 2005); similarly, SQ injections of PYY3–36 reduced appetite and energy intake, but significant nausea was also induced (Sloth, Davidsen, et al. 2007). On the other hand, oral administration of glucagon-PYY3–36 did not significantly affect food intake in healthy male subjects (Steinert, Poller, et al. 2010).

Oxyntomodulin (which is a natural GLP-1 co-agonist) had significant effects on energy intake in humans (Cohen, Ellis, et al. 2003) and reduced weight and energy intake when administered SQ in a randomized, controlled trial (Wynne, Park, et al. 2006; Wynne, Park, et al. 2005). PYY3–36 and oxyntomodulin may reduce food intake (Field, Wren, et al. 2010).

A tripeptide hormone infusion approach suggests further energy intake restraint with the “GOP” combination of GLP-1, oxyntomodulin, and PYY (Behary, Alessimii, et al. 2023) in addition to metabolomic and glycemic effects (Tan, Behary, et al. 2017; Behary, Tharakan, et al. 2019; Jones, Sands, et al. 2022). Further randomized, controlled trials are needed with these promising other agents.

Conclusion

While it is evident that diet and lifestyle changes are required for all patients with obesity, advances in pharmacological approaches suggest that drug treatment should be considered if weight loss has not exceeded 5% of body weight or glycosylated hemoglobin has not dropped by 1% or more. Among the non-incretin agents, the most effective medication for obesity is phentermine-topiramate. Nevertheless, the new pharmacological agents targeting increasing mechanisms greatly impact obesity as well as its cardiometabolic and hepatic complications. It must be acknowledged that stopping all anti-obesity medications, including GLP-1 agents, results in weight regain as well as reversal of the beneficial effects on cardiometabolic function. Therefore, it is of paramount importance to use the success observed during efficacious pharmacological treatment of obesity to establish longer-term diet and lifestyle changes, and possibly additional pharmacological or other bariatric interventions, to impact this disease. In addition, given the multiple manifestations of obesity in gastrointestinal and hepatic diseases, as well as the fact that many of the novel approaches in addition to interventions with bariatric procedures target the gastrointestinal tract, it is strongly recommended that gastroenterologists and hepatologists should be treating obesity (Camilleri, El-Omar 2023).

Nomenclature of Targets and Ligands

Key protein targets and ligands in this article are hyperlinked to corresponding entries in https://www.guidetopharmacology.org and are permanently archived in the Concise Guide to PHARMACOLOGY 2021/22 (Alexander et al., 2021).

Acknowledgements

Funding:

Andres Acosta is supported by grant K23-DK114460 from National Institutes of Health.

Footnotes

Conflicts of interest: Michael Camilleri is a stockholder in Phenomix Sciences and serves as a consultant to Kallyope (with consulting fee paid to his employer, Mayo Clinic).

Andres Acosta is a stockholder in Gila Therapeutics, and Phenomix Sciences; he served on as a consultant for Rhythm Pharmaceuticals, General Mills, Nestle, Boehringer Ingelheim, Currax, Amgen, Bausch Health, RareDiseases.

Authors’ contributions:

Michael Camilleri: Literature review, primary author

Andres Acosta: Co-author

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Hyperlinks

  1. glucagon like peptide-1. https://www.guidetopharmacology.org/GRAC/ObjectDisplayForward?objectId=249.
  2. glucose-dependent insulinotropic peptide. https://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=3542.
  3. Glucagon. https://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=3785.
  4. PYY3–36. https://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=1517.

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