Retatrutide

Triple-Hormone-Receptor Agonist Retatrutide for Obesity - A Phase 2 Trial.

Retatrutide (LY3437943) is an agonist of the glucose-dependent insulinotropic polypeptide, glucagon-like peptide 1, and glucagon receptors. Its dose-response relationships with respect to side effects, safety, and efficacy for the treatment of obesity are not known. We conducted a phase 2, double-blind, randomized, placebo-controlled trial involving adults who had a body-mass index (BMI, the weight in kilograms divided by the square of the height in meters) of 30 or higher or who had a BMI of 27 to less than 30 plus at least one weight-related condition. Participants were randomly assigned in a 2:1:1:1:1:2:2 ratio to receive subcutaneous retatrutide (1 mg, 4 mg [initial dose, 2 mg], 4 mg [initial dose, 4 mg], 8 mg [initial dose, 2 mg], 8 mg [initial dose, 4 mg], or 12 mg [initial dose, 2 mg]) or placebo once weekly for 48 weeks. The primary end point was the percentage change in body weight from baseline to 24 weeks. Secondary end points included the percentage change in body weight from baseline to 48 weeks and a weight reduction of 5% or more, 10% or more, or 15% or more. Safety was also assessed. We enrolled 338 adults, 51.8% of whom were men. The least-squares mean percentage change in body weight at 24 weeks in the retatrutide groups was -7.2% in the 1-mg group, -12.9% in the combined 4-mg group, -17.3% in the combined 8-mg group, and -17.5% in the 12-mg group, as compared with -1.6% in the placebo group. At 48 weeks, the least-squares mean percentage change in the retatrutide groups was -8.7% in the 1-mg group, -17.1% in the combined 4-mg group, -22.8% in the combined 8-mg group, and -24.2% in the 12-mg group, as compared with -2.1% in the placebo group. At 48 weeks, a weight reduction of 5% or more, 10% or more, and 15% or more had occurred in 92%, 75%, and 60%, respectively, of the participants who received 4 mg of retatrutide; 100%, 91%, and 75% of those who received 8 mg; 100%, 93%, and 83% of those who received 12 mg; and 27%, 9%, and 2% of those who received placebo. The most common adverse events in the retatrutide groups were gastrointestinal; these events were dose-related, were mostly mild to moderate in severity, and were partially mitigated with a lower starting dose (2 mg vs. 4 mg). Dose-dependent increases in heart rate peaked at 24 weeks and declined thereafter. In adults with obesity, retatrutide treatment for 48 weeks resulted in substantial reductions in body weight. (Funded by Eli Lilly; ClinicalTrials.gov number, NCT04881760.).

Retatrutide-A Game Changer in Obesity Pharmacotherapy.

Obesity and type 2 diabetes mellitus (T2DM) are global health crises with significant morbidity and mortality. Retatrutide, a novel triple receptor agonist targeting glucagon-like peptide-1 (GLP-1), Glucose-Dependent Insulinotropic Polypeptide (GIP), and glucagon receptors, represents a groundbreaking advancement in obesity and T2DM pharmacotherapy. This review synthesizes findings from preclinical and clinical studies, highlighting retatrutide's mechanisms, efficacy, and safety profile. Retatrutide's unique molecular structure enables potent activation of GLP-1, GIP, and glucagon receptors, leading to significant weight reduction, improved glycemic control, and favorable metabolic outcomes. Animal studies demonstrate retatrutide's ability to delay gastric emptying, reduce food intake, and promote weight loss, with superior efficacy compared to other incretin-based therapies. Phase I and II clinical trials corroborate these findings, showing dose-dependent weight loss, reductions in Glycated Hemoglobin (HbA1c) levels, and improvements in liver steatosis and diabetic kidney disease. Common adverse effects are primarily gastrointestinal and dose-related. Ongoing Phase III trials, such as the TRIUMPH studies, aim to further evaluate retatrutide's long-term safety and efficacy in diverse patient populations. While retatrutide shows immense promise, considerations regarding cost and the quality of weight loss beyond BMI reduction warrant further investigation. Retatrutide heralds a new era in obesity and T2DM treatment, offering hope for improved patient outcomes.

Efficacy and Safety of GLP-1 Medicines for Type 2 Diabetes and Obesity.

The development of glucagon-like peptide 1 receptor agonists (GLP-1RA) for type 2 diabetes and obesity was followed by data establishing the cardiorenal benefits of GLP-1RA in select patient populations. In ongoing trials investigators are interrogating the efficacy of these agents for new indications, including metabolic liver disease, peripheral artery disease, Parkinson disease, and Alzheimer disease. The success of GLP-1-based medicines has spurred the development of new molecular entities and combinations with unique pharmacokinetic and pharmacodynamic profiles, exemplified by tirzepatide, a GIP-GLP-1 receptor coagonist. Simultaneously, investigational molecules such as maritide block the GIP and activate the GLP-1 receptor, whereas retatrutide and survodutide enable simultaneous activation of the glucagon and GLP-1 receptors. Here I highlight evidence establishing the efficacy of GLP-1-based medicines, while discussing data that inform safety, focusing on muscle strength, bone density and fractures, exercise capacity, gastrointestinal motility, retained gastric contents and anesthesia, pancreatic and biliary tract disorders, and the risk of cancer. Rapid progress in development of highly efficacious GLP-1 medicines, and anticipated differentiation of newer agents in subsets of metabolic disorders, will provide greater opportunities for use of personalized medicine approaches to improve the health of people living with cardiometabolic disorders.

Emerging pharmacotherapies for obesity: A systematic review.

The history of antiobesity pharmacotherapies is marked by disappointments, often entangled with societal pressure promoting weight loss and the prevailing conviction that excess body weight signifies a lack of willpower. However, categories of emerging pharmacotherapies generate hope to reduce obesity rates. This systematic review of phase 2 and phase 3 trials in adults with overweight/obesity investigates the effect of novel weight loss pharmacotherapies, compared to placebo/control or US Food and Drug Administration-approved weight loss medication, through searching Medline, Embase, and ClinicalTrials.gov (2012-2024). We identified 53 phase 3 and phase 2 trials, with 36 emerging antiobesity drugs or combinations thereof and 4 withdrawn or terminated trials. Oral semaglutide 50 mg is the only medication that has completed a phase 3 trial. There are 14 ongoing phase 3 trials on glucagon-like peptide-1 (GLP-1) receptor agonists (RAs) (ecnoglutide, orforglipron, and TG103), GLP-1 RA/amylin agonist (CagriSema), GLP-1/glucagon RAs (mazdutide and survodutide), GLP-1/glucose-dependent insulinotropic polypeptide and glucagon RA (retatrutide), dapagliflozin, and the combination sibutramine/topiramate. Completed phase 2 trials on incretin-based therapies showed a mean percent weight loss of 7.4% to 24.2%. Almost half of the drugs undergoing phase 2 trials are incretin analogs. The obesity drug pipeline is expanding rapidly, with the most promising results reported with incretin analogs. Data on mortality and obesity-related complications, such as cardio-renal-metabolic events, are needed. Moreover, long-term follow-up data on the safety and efficacy of weight maintenance with novel obesity pharmacotherapies, along with studies focused on underrepresented populations, cost-effectiveness assessments, and drug availability, are needed to bridge the care gap for patients with obesity. SIGNIFICANCE STATEMENT: Obesity is the epidemic of the 21st century. Except for the newer injectable medications, drugs with suboptimal efficacy have been available in the clinician's armamentarium for weight management. However, emerging alternatives of novel agents and combinations populate the current obesity therapeutic pipeline. This systematic review identifies the state and mechanism of action of emerging pharmacotherapies undergoing or having completed phase 2 and phase 3 clinical trials. The information provided herein furthers the understanding of obesity management, implying direct clinical implications and stimulating research initiatives.

LY3437943, a novel triple glucagon, GIP, and GLP-1 receptor agonist for glycemic control and weight loss: From discovery to clinical proof of concept.

With an increasing prevalence of obesity, there is a need for new therapies to improve body weight management and metabolic health. Multireceptor agonists in development may provide approaches to fulfill this unmet medical need. LY3437943 is a novel triple agonist peptide at the glucagon receptor (GCGR), glucose-dependent insulinotropic polypeptide receptor (GIPR), and glucagon-like peptide-1 receptor (GLP-1R). In vitro, LY3437943 shows balanced GCGR and GLP-1R activity but more GIPR activity. In obese mice, administration of LY3437943 decreased body weight and improved glycemic control. Body weight loss was augmented by the addition of GCGR-mediated increases in energy expenditure to GIPR- and GLP-1R-driven calorie intake reduction. In a phase 1 single ascending dose study, LY3437943 showed a safety and tolerability profile similar to other incretins. Its pharmacokinetic profile supported once-weekly dosing, and a reduction in body weight persisted up to day 43 after a single dose. These findings warrant further clinical assessment of LY3437943.

Efficacy and Safety of Glucagon-Like Peptide-1 Receptor Agonists for Weight Loss Among Adults Without Diabetes : A Systematic Review of Randomized Controlled Trials.

Recent randomized controlled trials (RCTs) have investigated glucagon-like peptide-1 receptor agonists (GLP-1 RAs) and dual or triple co-agonists for weight loss among adults with overweight or obesity and without diabetes. To assess the efficacy and safety of GLP-1 RAs and co-agonists for the treatment of obesity among adults without diabetes. MEDLINE, Embase, and Cochrane CENTRAL from inception to 4 October 2024. Placebo-controlled RCTs in otherwise healthy participants with overweight or obesity. The primary outcome was change in relative or absolute body weight from baseline to maximum on-treatment follow-up. Safety outcomes included death, serious adverse events (SAEs), any adverse events (AEs), and gastrointestinal AEs. A total of 26 RCTs comprising 15 491 participants (72% female; mean body mass index, 30 to 41 kg/m2; mean age, 34 to 57 years) and 12 agents (3 commercially available agents [liraglutide, semaglutide, and tirzepatide] and 9 premarket agents for long-term weight management) were included. Treatment ranged from 16 to 104 weeks (median, 43 weeks). Compared with placebo, tirzepatide (15 mg once weekly) resulted in weight loss of up to 17.8% (95% CI, 16.3% to 19.3%) after 72 weeks of therapy; semaglutide (2.4 mg once weekly), up to 13.9% (CI, 11.0% to 16.7%) after 68 weeks; and liraglutide (3.0 mg once daily), up to 5.8% (CI, 3.6% to 8.0%) after 26 weeks. Retatrutide (12 mg once weekly) produced greater weight loss of up to 22.1% (CI, 19.3% to 24.9%) after 48 weeks; other novel single and combination GLP-1 agents were also efficacious to varying degrees. Although AEs were frequent (GLP-1 RA vs. placebo: 80% to 97% vs. 63% to 100%), the majority were gastrointestinal-related (47% to 84% vs. 13% to 63%, respectively), most commonly nausea, vomiting, diarrhea, and constipation. AEs requiring treatment discontinuation (0% to 26% vs. 0% to 9%, respectively) and SAEs (0% to 10% vs. 0% to 12%, respectively) were rare. No head-to-head RCTs were available. Heterogeneity prevented meta-analysis. GLP-1 RAs and co-agonists are efficacious for weight loss, with reported safety concerns predominantly gastrointestinal in nature, when used among adults with overweight or obesity and without diabetes. None. (PROSPERO: CRD42024505558).

Incretin-Based Weight Loss Pharmacotherapy: Can Resistance Exercise Optimize Changes in Body Composition?

This narrative review highlights the degree to which new antiobesity medications based on gut-derived nutrient-stimulated hormones (incretins) cause loss of lean mass, and the importance of resistance exercise to preserve muscle. Glucagon-like peptide 1 receptor agonists (GLP-1RA) induce substantial weight loss in randomized trials, effects that may be enhanced in combination with glucose-dependent insulinotropic polypeptide (GIP) receptor agonists. Liraglutide and semaglutide (GLP-1RA), tirzepatide (GLP-1 and GIP receptor dual agonist), and retatrutide (GLP-1, GIP, and glucagon receptor triple agonist) are peptides with incretin agonist activity that induce ∼15-24% weight loss in adults with overweight and obesity, alongside beneficial impacts on blood pressure, cholesterol, blood glucose, and insulin. However, these agents also cause rapid and significant loss of lean mass (∼10% or ∼6 kg), comparable to a decade or more of aging. Maintaining muscle mass and function as humans age is crucial to avoiding sarcopenia and frailty, which are strongly linked to morbidity and mortality. Studies indicate that supervised resistance exercise training interventions with a duration >10 weeks can elicit large increases in lean mass (∼3 kg) and strength (∼25%) in men and women. After a low-calorie diet, combining aerobic exercise with liraglutide improved weight loss maintenance compared with either alone. Retaining lean mass during incretin therapy could blunt body weight (and fat) regain on cessation of weight loss pharmacotherapy. We propose that tailored resistance exercise training be recommended as an adjunct to incretin therapy to optimize changes in body composition by preserving lean mass while achieving fat loss.

Retatrutide, a GIP, GLP-1 and glucagon receptor agonist, for people with type 2 diabetes: a randomised, double-blind, placebo and active-controlled, parallel-group, phase 2 trial conducted in the USA.

According to current consensus guidelines for type 2 diabetes management, bodyweight management is as important as attaining glycaemic targets. Retatrutide, a single peptide with agonist activity at the glucose-dependent insulinotropic polypeptide (GIP), GLP-1, and glucagon receptors, showed clinically meaningful glucose-lowering and bodyweight-lowering efficacy in a phase 1 study. We aimed to examine the efficacy and safety of retatrutide in people with type 2 diabetes across a range of doses. In this randomised, double-blind, double-dummy, placebo-controlled and active comparator-controlled, parallel-group, phase 2 trial, participants were recruited from 42 research and health-care centres in the USA. Adults aged 18-75 years with type 2 diabetes, glycated haemoglobin (HbA1c) of 7&#xb7;0-10&#xb7;5% (53&#xb7;0-91&#xb7;3 mmol/mol), and BMI of 25-50 kg/m2 were eligible for enrolment. Eligible participants were treated with diet and exercise alone or with a stable dose of metformin (&#x2265;1000 mg once daily) for at least 3 months before the screening visit. Participants were randomly assigned (2:2:2:1:1:1:1:2) using an interactive web-response system, with stratification for baseline HbA1c and BMI, to receive once-weekly injections of placebo, 1&#xb7;5 mg dulaglutide, or retatrutide maintenance doses of 0&#xb7;5 mg, 4 mg (starting dose 2 mg), 4 mg (no escalation), 8 mg (starting dose 2 mg), 8 mg (starting dose 4 mg), or 12 mg (starting dose 2 mg). Participants, study site personnel, and investigators were masked to treatment allocation until after study end. The primary endpoint was change in HbA1c from baseline to 24 weeks, and secondary endpoints included change in HbA1c and bodyweight at 36 weeks. Efficacy was analysed in all randomly assigned, except inadvertently enrolled, participants, and safety was assessed in all participants who received at least one dose of study treatment. The study is registered at ClinicalTrials.gov, NCT04867785. Between May 13, 2021, and June 13, 2022, 281 participants (mean age 56&#xb7;2 years [SD 9&#xb7;7], mean duration of diabetes 8&#xb7;1 years [7&#xb7;0], 156 [56%] female, and 235 [84%] White) were randomly assigned and included in the safety analysis (45 in the placebo group, 46 in the 1&#xb7;5 mg dulaglutide group, and 47 in the retatrutide 0&#xb7;5 mg group, 23 in the 4 mg escalation group, 24 in the 4 mg group, 26 in the 8 mg slow escalation group, 24 in the 8 mg fast escalation group, and 46 in the 12 mg escalation group). 275 participants were included in the efficacy analyses (one each in the retatrutide 0&#xb7;5 mg group, 4 mg escalation group, and 8 mg slow escalation group, and three in the 12 mg escalation group were inadvertently enrolled). 237 (84%) participants completed the study and 222 (79%) completed study treatment. At 24 weeks, least-squares mean changes from baseline in HbA1c with retatrutide were -0&#xb7;43% (SE 0&#xb7;20; -4&#xb7;68 mmol/mol [2&#xb7;15]) for the 0&#xb7;5 mg group, -1&#xb7;39% (0&#xb7;14; -15&#xb7;24 mmol/mol [1&#xb7;56]) for the 4 mg escalation group, -1&#xb7;30% (0&#xb7;22; -14&#xb7;20 mmol/mol [2&#xb7;44]) for the 4 mg group, -1&#xb7;99% (0&#xb7;15; -21&#xb7;78 mmol/mol [1&#xb7;60]) for the 8 mg slow escalation group, -1&#xb7;88% (0&#xb7;21; -20&#xb7;52 mmol/mol [2&#xb7;34]) for the 8 mg fast escalation group, and -2&#xb7;02% (0&#xb7;11; -22&#xb7;07 mmol/mol [1&#xb7;21]) for the 12 mg escalation group, versus -0&#xb7;01% (0&#xb7;21; -0&#xb7;12 mmol/mol [2&#xb7;27]) for the placebo group and -1&#xb7;41% (0&#xb7;12; -15&#xb7;40 mmol/mol [1&#xb7;29]) for the 1&#xb7;5 mg dulaglutide group. HbA1c reductions with retatrutide were significantly greater (p<0&#xb7;0001) than placebo in all but the 0&#xb7;5 mg group and greater than 1&#xb7;5 mg dulaglutide in the 8 mg slow escalation group (p=0&#xb7;0019) and 12 mg escalation group (p=0&#xb7;0002). Findings were consistent at 36 weeks. Bodyweight decreased dose dependently with retatrutide at 36 weeks by 3&#xb7;19% (SE 0&#xb7;61) for the 0&#xb7;5 mg group, 7&#xb7;92% (1&#xb7;28) for the 4 mg escalation group, 10&#xb7;37% (1&#xb7;56) for the 4 mg group, 16&#xb7;81% (1&#xb7;59) for the 8 mg slow escalation group, 16&#xb7;34% (1&#xb7;65) for the 8 mg fast escalation group, and 16&#xb7;94% (1&#xb7;30) for the 12 mg escalation group, versus 3&#xb7;00% (0&#xb7;86) with placebo and 2&#xb7;02% (0&#xb7;72) with 1&#xb7;5 mg dulaglutide. For retatrutide doses of 4 mg and greater, decreases in weight were significantly greater than with placebo (p=0&#xb7;0017 for the 4 mg escalation group and p<0&#xb7;0001 for others) and 1&#xb7;5 mg dulaglutide (all p<0&#xb7;0001). Mild-to-moderate gastrointestinal adverse events, including nausea, diarrhoea, vomiting, and constipation, were reported in 67 (35%) of 190 participants in the retatrutide groups (from six [13%] of 47 in the 0&#xb7;5 mg group to 12 [50%] of 24 in the 8 mg fast escalation group), six (13%) of 45 participants in the placebo group, and 16 (35%) of 46 participants in the 1&#xb7;5 mg dulaglutide group. There were no reports of severe hypoglycaemia and no deaths during the study. In people with type 2 diabetes, retatrutide showed clinically meaningful improvements in glycaemic control and robust reductions in bodyweight, with a safety profile consistent with GLP-1 receptor agonists and GIP and GLP-1 receptor agonists. These phase 2 data also informed dose selection for the phase 3 programme. Eli Lilly and Company.

Gut hormones and appetite regulation.

Various gut hormones interact with the brain through delicate communication, thereby influencing appetite and subsequent changes in body weight. This review summarizes the effects of gut hormones on appetite, with a focus on recent research. Ghrelin is known as an orexigenic hormone, whereas glucagon-like peptide-1 (GLP-1), glucose-dependent insulinotropic polypeptide (GIP), cholecystokinin (CCK), postprandial peptide YY (PYY), and oxyntomodulin (OXM) are known as anorexigenic hormones. Recent human studies have revealed that gut hormones act differently in various systems, including adipose tissue, beyond appetite and energy intake, and even involve in high-order thinking. Environmental factors including meal schedule, food contents and quality, type of exercise, and sleep deprivation also play a role in the influence of gut hormone on appetite, weight change, and obesity. Recently published studies have shown that retatrutide, a triple-agonist of GLP-1, GIP, and glucagon receptor, and orforglipron, a GLP-1 receptor partial agonist, are effective in weight loss and improving various metabolic parameters associated with obesity. Various gut hormones influence appetite, and several drugs targeting these receptors have been reported to exert positive effects on weight loss in humans. Given that diverse dietary and environmental factors affect the actions of gut hormones and appetite, there is a need for integrated and largescale long-term studies in this field.

What is the pipeline for future medications for obesity?

Obesity is a chronic disease associated with increased risk of obesity-related complications and mortality. Our better understanding of the weight regulation mechanisms and the role of gut-brain axis on appetite has led to the development of safe and effective entero-pancreatic hormone-based treatments for obesity such as glucagon-like peptide-1 (GLP-1) receptor agonists (RA). Semaglutide 2.4&#x2009;mg once weekly, a subcutaneously administered GLP-1 RA approved for obesity treatment in 2021, results in 15-17% mean weight loss (WL) with evidence of cardioprotection. Oral GLP-1 RA are also under development and early data shows similar WL efficacy to semaglutide 2.4&#x2009;mg. Looking to the next generation of obesity treatments, combinations of GLP-1 with other entero-pancreatic hormones with complementary actions and/or synergistic potential (such as glucose-dependent insulinotropic polypeptide (GIP), glucagon, and amylin) are under investigation to enhance the WL and cardiometabolic benefits of GLP-1 RA. Tirzepatide, a dual GLP-1/GIP receptor agonist has been approved for glycaemic control in type 2 diabetes as well as for obesity management leading in up to 22.5% WL in phase 3 obesity trials. Other combinations of entero-pancreatic hormones including cagrisema (GLP-1/amylin RA) and the triple agonist retatrutide (GLP-1/GIP/glucagon RA) have also progressed to phase 3 trials as obesity treatments and early data suggests that may lead to even greater WL than tirzepatide. Additionally, agents with different mechanisms of action to entero-pancreatic hormones (e.g. bimagrumab) may improve the body composition during WL and are in early phase clinical trials. We are in a new era for obesity pharmacotherapy where combinations of entero-pancreatic hormones approach the WL achieved with bariatric surgery. In this review, we present the efficacy and safety data for the pipeline of obesity pharmacotherapies with a focus on entero-pancreatic hormone-based treatments and we consider the clinical implications and challenges that the new era in obesity management may bring.

Retatrutide for the treatment of obesity, obstructive sleep apnea and knee osteoarthritis: Rationale and design of the TRIUMPH registrational clinical trials.

Retatrutide, a novel synthetic molecule, is a triple agonist activating the glucose-dependent insulinotropic polypeptide, glucagon-like peptide-1 and glucagon receptors. The TRIUMPH clinical development program evaluates its safety and efficacy concurrently for the treatment of obesity and two related complications-obstructive sleep apnea (OSA) and knee osteoarthritis (OA). A novel basket trial design simultaneously evaluates retatrutide treatment across these multiple adiposity-related disease states. TRIUMPH consists of four Phase 3, multicenter, randomized, double-blind studies assessing weekly subcutaneous retatrutide compared to placebo, in conjunction with healthy diet and physical activity in over 5800 participants. The four trials consist of two weight management basket trials (TRIUMPH-1 and TRIUMPH-2) with OSA and/or OA protocols nested within the weight management trial; one weight management trial in a population with CVD (TRIUMPH-3); and one stand-alone OA trial (TRIUMPH-4). The primary endpoint for weight management is percent change in body weight, for OSA is change in Apnea-Hypopnea Index and for knee OA includes change in the Western Ontario and McMaster Universities Osteoarthritis Index pain subscale score. The basket trial permits independent analysis of weight management, OSA and OA studies with type I error rate controlled at &#x3b1;&#x2009;=&#x2009;0.05, split between the overarching weight management and each basket trial. By recruiting participants with shared disease exposures, the TRIUMPH program will assess the safety and efficacy of retatrutide for the treatment of adults with obesity and two of its common complications-OSA and OA.

Triple hormone receptor agonist retatrutide for metabolic dysfunction-associated steatotic liver disease: a randomized phase 2a trial.

Retatrutide is a novel triple agonist of the glucose-dependent insulinotropic polypeptide, glucagon-like peptide 1 and glucagon receptors. A 48-week phase 2 obesity study demonstrated weight reductions of 22.8% and 24.2% with retatrutide 8 and 12&#x2009;mg, respectively. The primary objective of this substudy was to assess mean relative change from baseline in liver fat (LF) at 24&#x2009;weeks in participants from that study with metabolic dysfunction-associated steatotic liver disease and &#x2265;10% of LF. Here, in this randomized, double-blind, placebo-controlled trial, participants (n&#x2009;=&#x2009;98) were randomly assigned to 48&#x2009;weeks of once-weekly subcutaneous retatrutide (1, 4, 8 or 12&#x2009;mg dose) or placebo. The mean relative change from baseline in LF at 24&#x2009;weeks was -42.9% (1&#x2009;mg), -57.0% (4&#x2009;mg), -81.4% (8&#x2009;mg), -82.4% (12&#x2009;mg) and +0.3% (placebo) (all P&#x2009;<&#x2009;0.001 versus placebo). At 24&#x2009;weeks, normal LF (<5%) was achieved by 27% (1&#x2009;mg), 52% (4&#x2009;mg), 79% (8&#x2009;mg), 86% (12&#x2009;mg) and 0% (placebo) of participants. LF reductions were significantly related to changes in body weight, abdominal fat and metabolic measures associated with improved insulin sensitivity and lipid metabolism. The ClinicalTrials.gov registration is NCT04881760 .

The power of three: Retatrutide's role in modern obesity and diabetes therapy.

The increasing prevalence of obesity and type 2 diabetes mellitus has resulted in a significant challenge to public health throughout the globe. It required the development of novel therapeutic approaches. Retatrutide is a groundbreaking triple agonist that targets glucagon receptors, gastric inhibitory polypeptide, and glucagon-like peptide-1. Retatrutide's complex mechanism of action involves a synergistic interaction among these receptors, resulting in increased insulin secretion, improved glucose homeostasis, and refined appetite modulation. Clinical trials in phases 1 to 3 have demonstrated significant efficacy, highlighted by significant reductions in body weight and favorable glycemic control outcomes. Additionally, retatrutide shows promise in mitigating cardiovascular risk factors and addressing metabolic dysfunction-associated steatotic liver disease. However, careful attention is required to delineate its long-term safety profile, explore its potential in special populations, unravel its adjunctive therapeutic roles, and elucidate its mechanisms in pediatric cohorts. As a transformative therapeutic modality, retatrutide represents a beacon of hope, signifying transformative changes in the management landscape of obesity and type 2 diabetes mellitus (T2DM), and warranting continued exploration and refinement in clinical practice. This narrative review examines the therapeutic potential of retatrutide in the management of obesity and T2DM.

Weight management treatment in obesity.

Obesity is a chronic and relapsing disease associated with medical complications and mortality. Our improved understanding of the relevance of the gut-brain axis in regulating appetite and body weight has encouraged research into nutrient-stimulated gastroenteropancreatic hormones as a new therapeutic arsenal for the treatment of people living with obesity. Beyond the necessary lifestyle changes, this new era with second-generation drugs has been able to achieve weight loss of 15-25%, close to that of bariatric surgery. Glucagon-like peptide-1 (GLP-1) receptor agonists (RA), used as weekly injectable monotherapy or daily oral (semaglutide), achieve weight loss of 15-17%, with a good safety profile. The synergistic combination with other hormones (such as glucose-dependent insulinotropic polypeptide (GIP), glucagon, or amylin) will allow to increase weight loss, as well as improve cardiometabolic variables. Tirzepatide (a dual GLP-1/GIP receptor agonist) achieves weight loss of up to 22.5% at the highest doses. In this same range of weight loss, it is expected that it can be achieved with the combination of Cagrisema (cagrilintide 2.4mg plus semaglutide 2.4mg), combinations of GLP-1 RAs - glucagon agonists or with the triple combination of GLP-1 RAs-GIP-Glucagon (Retatrutide). In this review, we will examine the efficacy and safety of the drugs marketed and others under ongoing clinical trials for the treatment of persons with obesity, as well as the main challenges faced by both healthcare professionals and patients in maintaining long-term treatment.

Triple Agonism Based Therapies for Obesity.

Glucagon-like peptide 1 (GLP-1) receptor agonists (RA) have transformed obesity and type 2 diabetes (T2D) management. Tirzepatide, the first dual GLP-1/glucose-dependent insulinotropic polypeptide (GIP) RA approved for both conditions, has paved the way for next-generation incretin-based therapies. Among these, triple agonists targeting GLP-1, GIP, and glucagon receptors represent a promising next step. This review outlines the rationale for their development and summarizes clinical trial data, focusing on retatrutide, the most advanced candidate. Retatrutide is the first triple agonist (acting on GLP-1/GIP/glucagon receptors) with published phase 2 data in people with obesity as well as in people with T2D. Retatrutide achieved up to 24.2% mean weight loss after 48 weeks in individuals with obesity and 16.9% in those with T2D after 36 weeks. In the T2D study, HbA1c improved by 2.2%, with 82% of participants reaching HbA1c&#x2009;&#x2264;&#x2009;6.5%. Retatrutide also improved multiple cardiometabolic parameters, including blood pressure, lipids, waist circumference, and liver fat (82% reduction in hepatic steatosis). Gastrointestinal symptoms were the most common side effects; no major safety concerns were observed. A comprehensive phase 3 program is ongoing to evaluate efficacy, safety, and cardiovascular/renal outcomes in people with obesity and/or T2D. Other unimolecular triple agonists and combination regimens involving tirzepatide with additional mono agonists are also in development. Retatrutide, a triple agonist now in phase 3 trials, has the potential to become the most effective pharmacological treatment for obesity while also offering substantial benefits in T2D management and other cardiometabolic risk factors.

Pharmacological Treatment of Binge Eating Disorder and Frequent Comorbid Diseases.

Binge eating disorder (BED) is the most common specific eating disorder (ED). It is frequently associated with attention deficit hyperactivity disorder (ADHD), depression, bipolar disorder (BD), anxiety disorders, alcohol and nicotine use disorder, and obesity. The aim of this narrative review was to summarize the evidence for the pharmacological treatment of BED and its comorbid disorders. We recommend the ADHD medication lisdexamfetamine (LDX) and the antiepileptic and antimigraine drug topiramate for the pharmacological treatment of BED. However, only LDX is approved for the treatment of BED in some countries. Medications to treat diseases frequently comorbid with BED include atomoxetine and LDX for ADHD; citalopram, fluoxetine, sertraline, duloxetine, and venlafaxine for anxiety disorders and depression; aripiprazole for manic episodes of BD; lamotrigine, lirasidone and lumateperone for depressive episodes of BD; naltrexone for alcohol use disorder; bupropion for nicotine use disorder; and liraglutide, semaglutide, and the combination of bupropion and naltrexone for obesity. As obesity is a frequent health consequence of BED, weight gain-inducing medications, such as the atypical antipsychotics olanzapine or clozapine, the novel antidepressant mirtazapine and tricyclic antidepressants, and the mood stabilizer valproate should be avoided where possible. It is currently unclear whether the novel and promising glucagon, glucose-dependent insulinotropic polypeptide (GIP), and glucagon-like peptide 1 (GLP-1) receptor agonists like tirzepatide and retatrutide help with BED and its comorbidities. However, these compounds have been reported to reduce binge eating in individuals with obesity or overweight.

The impact of weight loss on fat-free mass, muscle, bone and hematopoiesis health: Implications for emerging pharmacotherapies aiming at fat reduction and lean mass preservation.

Similar to bariatric surgery, incretin receptor agonists have revolutionized the treatment of obesity, achieving up to 15-25&#xa0;% weight loss in many patients, i.e., at a rate approaching that achieved with bariatric surgery. However, over 25&#xa0;% of total weight lost from both surgery and pharmacotherapy typically comes from fat-free mass, including skeletal muscle mass, which is often overlooked and can impair metabolic health and increase the risk of subsequent sarcopenic obesity. Loss of muscle and bone as well as anemia can compromise physical function, metabolic rate, and overall health, especially in older adults. The myostatin-activin-follistatin-inhibin system, originally implicated in reproductive function and subsequently muscle regulation, appears to be crucial for muscle and bone maintenance during weight loss. Activins and myostatin promote muscle degradation, while follistatins inhibit their activity in states of negative energy balance, thereby preserving lean mass. Novel compounds in the pipeline, such as Bimagrumab, Trevogrumab, and Garetosmab-which inhibit activin and myostatin signaling-have demonstrated promise in preventing muscle loss while promoting fat loss. Either alone or combined with incretin receptor agonists, these medications may enhance fat loss while preserving or even increasing muscle and bone mass, offering a potential solution for improving body composition and metabolic health during significant weight loss. Since this dual therapeutic approach could help address the challenges of muscle and bone loss during weight loss, well-designed studies are needed to optimize these strategies and assess long-term benefits. For the time being, considerations like advanced age and prefrailty may affect the choice of suitable candidates in clinical practice for current and emerging anti-obesity medications due to the associated risk of sarcopenia.

Seven glucagon-like peptide-1 receptor agonists and polyagonists for weight loss in patients with obesity or overweight: an updated systematic review and network meta-analysis of randomized controlled trials.

This study aimed to provide evidence-based support and a reference for the efficacy and safety of seven glucagon-like peptide-1 (GLP-1) receptor agonists and polyagonists for weight loss in patients with obesity or overweight through a network meta-analysis. Relevant randomized controlled trials (RCTs) with an intervention duration of at least 16&#xa0;weeks assessing seven GLP-1 receptor agonists and polyagonists (mazdutide, 6 or 4.5&#xa0;mg; retatrutide, 12 or 8&#xa0;mg; tirzepatide, 15 or 10&#xa0;mg; liraglutide, 3.0&#xa0;mg; semaglutide, 2.4&#xa0;mg; orforglipron, 45 or 36&#xa0;mg; and beinaglutide, 0.2&#xa0;mg) in patient with obesity or overweight was searched using three databases (Cochrane Library, PubMed, and Embase) from creation to August 30, 2024. The primary outcome was the percentage change in body weight from baseline. Secondary outcomes included changes in waist circumference, hemoglobin A1c, and fasting plasma glucose level from baseline; adverse events, serious adverse events, adverse event withdrawal, and hypoglycemic events. We conducted a frequentist random-effects network meta-analysis to analyze the data extracted from the RCTs using Stata 16.1 software. Twenty-seven RCTs of seven GLP-1 receptor agonists and polyagonists and 15,584 patients were included in the network meta-analysis. In terms of efficacy, compared with placebo, retatrutide 12&#xa0;mg (-22.10&#xa0;% in body weight and&#xa0;-&#xa0;17.00&#xa0;cm in waist circumference), retatrutide 8&#xa0;mg (-20.70&#xa0;% and&#xa0;-&#xa0;15.90&#xa0;cm), and tirzepatide 15&#xa0;mg (-16.53&#xa0;% and&#xa0;-&#xa0;13.23&#xa0;cm) were the three most efficacious treatments for reducing body weight and waist circumference. However, these treatments were less effective in patients with type 2 diabetes mellitus (T2DM). In addition, patients with a high body mass index (BMI) or longer treatment cycles exhibited significantly greater weight loss than those with a low BMI or shorter treatment cycles. In terms of safety, patients without T2DM had a higher incidence of adverse events than those with T2DM. None of the interventions increased the incidence of serious adverse or hypoglycemic events (&#x2c2;54&#xa0;mg/dL). There was no significant difference in the incidence of adverse event withdrawal for all interventions in head-to-head comparisons. In addition, disparities in race, BMI, and treatment cycles did not significantly increase the incidence of adverse events. Finally, the sensitivity and publication bias analyses indicated that the basic analysis results were reliable. Retatrutide (both doses) and tirzepatide exhibited superior efficacy compared to other GLP-1 receptor agonists and polyagonists in reducing body weight and waist circumference. Patients without T2DM, those with a high BMI, and individuals undergoing longer treatment cycles demonstrated significantly greater weight loss and reductions in waist circumference. Dual or triple receptor agonists (GLP-1 plus glucose-dependent insulinotropic polypeptide and/or Glucagon receptor) are more effective for weight loss than GLP-1 receptor agonists.

Efficacy and safety of retatrutide, a novel GLP-1, GIP, and glucagon receptor agonist for obesity treatment: a systematic review and meta-analysis of randomized controlled trials.

Retatrutide is a novel triple agonist targeting the receptors of glucagon-like peptide 1 (GLP-1), gastric inhibitory polypeptide (GIP), and glucagon. We sought to assess the efficacy and safety of retatrutide in obese patients with or without diabetes. PubMed, Scopus, Web of Science, and Cochrane databases were searched from inception until May 2024. Eligible studies comprised randomized controlled trials that compared retatrutide with placebo in obese patients. We excluded studies on healthy populations, non-English texts, single-arm studies, animal studies, and abstracts. RevMan software (version 5.4) was used for analysis, with subgroup evaluation by dose (4&#xa0;mg, 8&#xa0;mg, 12&#xa0;mg). Three randomized controlled trials, encompassing 878 patients, satisfied our inclusion criteria. Retatrutide significantly reduced body weight (mean difference [MD]: -14.33%), body mass index (MD: -5.38), waist circumference (MD: -10.51&#xa0;cm), fasting plasma glucose (MD: -23.51&#xa0;mg/dL), hemoglobin A1c (MD: -0.91%), and systolic and diastolic blood pressure (MD: -9.88&#xa0;mm Hg and -3.88&#xa0;mm Hg, respectively), all with P values < 0.00001. No significant difference in adverse events was observed between the groups (relative risk: 1.11, P&#x2009;=&#x2009;0.24). Retatrutide demonstrated significant improvements in body weight and metabolic outcomes among adults with obesity and had an appropriate safety profile. However, additional large and long-term trials are required to establish these results.

Retatrutide.

Effects of once-weekly subcutaneous retatrutide on weight and metabolic markers: A systematic review and meta-analysis of randomized controlled trials.

To assess the effects of once-weekly subcutaneous retatrutide on weight and metabolic markers and the occurrence of side effects in patients with overweight, obesity and/or type 2 diabetes (T2D). PubMed, Embase, Cochrane Library, and ClinicalTrials.gov databases were systematically searched for placebo-controlled, randomized clinical trials (RCTs) published up until February 23, 2024. Weighted mean differences (WMDs) for continuous outcomes and risk ratios (RRs) for binary endpoints were computed, with 95&#xa0;% confidence intervals (CIs). A total of three studies were included, comprising 640 patients, of whom 510 were prescribed retatrutide. Compared with placebo, retatrutide significantly reduced body weight (WMD -10.66&#xa0;kg; 95&#xa0;% CI -17.63, -3.69), body mass index (WMD -4.53&#xa0;kg/m2; 95&#xa0;% CI -7.51, -1.55), and waist circumference (WMD -6.61&#xa0;cm; 95&#xa0;% CI -13.17, -0.05). In addition, retatrutide significantly increased the proportion of patients who achieved a weight reduction of &#x2265;5&#xa0;% (RR 2.92; 95&#xa0;% CI 2.17-3.93), &#x2265;10&#xa0;% (RR 9.32; 95&#xa0;% CI 4.56-19.06), &#x2265;15&#xa0;% (RR 18.40; 95&#xa0;% CI 6.00-56.42), and &#x2265;20&#xa0;% (RR 16.61; 95&#xa0;% CI 4.17-66.12). In this meta-analysis, the use of once-weekly subcutaneous retatrutide was associated with a significant reduction in body weight and improvement of metabolic markers in patients with overweight, obesity and/or T2D, compared with placebo, with an increase in non-severe gastrointestinal and hypersensitivity adverse events. Phase 3 RCTs are expected to shed further light on the efficacy and safety of once-weekly subcutaneous retatrutide over the long term.

LY3437943, a novel triple GIP, GLP-1, and glucagon receptor agonist in people with type 2 diabetes: a phase 1b, multicentre, double-blind, placebo-controlled, randomised, multiple-ascending dose trial.

Treating hyperglycaemia and obesity in individuals with type 2 diabetes using multi-receptor agonists can improve short-term and long-term outcomes. LY3437943 is a single peptide with agonist activity for glucagon, glucose-dependent insulinotropic polypeptide (GIP), and glucagon-like peptide 1 (GLP-1) receptors that is currently in development for the treatment of type 2 diabetes and for the treatment of obesity and associated comorbidities. We investigated the safety, pharmacokinetics, and pharmacodynamics of multiple weekly doses of LY3437943 in people with type 2 diabetes in a 12-week study. In this phase 1b, proof-of-concept, double-blind, placebo-controlled, randomised, multiple-ascending dose trial, adults (aged 20-70 years) with type 2 diabetes for at least 3 months, a glycated haemoglobin A1c (HbA1c) value of 7&#xb7;0-10&#xb7;5%, body-mass index of 23-50 kg/m2, and stable bodyweight (<5% change in previous 3 months) were recruited at four centres in the USA. Using an interactive web-response system, participants were randomly assigned to receive once-weekly subcutaneous injections of LY3437943, placebo, or dulaglutide 1&#xb7;5 mg over a 12-week period. Five ascending dose cohorts were studied, with randomisation in each cohort such that a minimum of nine participants received LY3437943, three received placebo, and one received dulaglutide 1&#xb7;5 mg within each cohort. The top doses in the two highest dose cohorts were attained via stepwise dose escalations. The primary outcome was to investigate the safety and tolerability of LY3437943, and characterising the pharmacodynamics and pharmacokinetics were secondary outcomes. Safety was analysed in all participants who received at least one dose of study drug, and pharmacodynamics and pharmacokinetics in all participants who received at least one dose of study drug and had evaluable data. This trial is registered at ClinicalTrials.gov, NCT04143802. Between Dec 18, 2019, and Dec 28, 2020, 210 people were screened, of whom 72 were enrolled, received at least one dose of study drug, and were included in safety analyses. 15 participants had placebo, five had dulaglutide 1&#xb7;5 mg and, for LY3437943, nine had 0&#xb7;5 mg, nine had 1&#xb7;5 mg, 11 had 3 mg, 11 had 3/6 mg, and 12 had 3/6/9/12 mg. 29 participants discontinued the study prematurely. Treatment-emergent adverse events were reported by 33 (63%), three (60%), and eight (54%) participants who received LY3437943, dulaglutide 1&#xb7;5 mg, and placebo, respectively, with gastrointestinal disorders being the most frequently reported treatment-emergent adverse events. The pharmacokinetics of LY3437943 were dose proportional and its half-life was approximately 6 days. At week 12, placebo-adjusted mean daily plasma glucose significantly decreased from baseline at the three highest dose LY3437943 groups (least-squares mean difference -2&#xb7;8 mmol/L [90% CI -4&#xb7;63 to -0&#xb7;94] for 3 mg; -3&#xb7;1 mmol/L [-4&#xb7;91 to -1&#xb7;22] for 3/6 mg; and -2&#xb7;9 mmol/L [-4&#xb7;70 to -1&#xb7;01] for 3/6/9/12 mg). Placebo-adjusted sHbA1c also decreased significantly in the three highest dose groups (-1&#xb7;4% [90% CI -2&#xb7;17 to -0&#xb7;56] for 3 mg; -1&#xb7;6% [-2&#xb7;37 to -0&#xb7;75] for 3/6 mg; and -1&#xb7;2% [-2&#xb7;05 to -0&#xb7;45] for 3/6/9/12 mg). Placebo-adjusted bodyweight reduction with LY3437943 appeared to be dose dependent (up to -8&#xb7;96 kg [90% CI -11&#xb7;16 to -6&#xb7;75] in the 3/6/9/12 mg group). In this early phase study, LY3437943 showed an acceptable safety profile, and its pharmacokinetics suggest suitability for once-weekly dosing. This finding, together with the pharmacodynamic findings of robust reductions in glucose and bodyweight, provides support for phase 2 development. Eli Lilly and Company.

Advancements in pharmacological treatment of NAFLD/MASLD: a focus on metabolic and liver-targeted interventions.

In the present narrative review, we have summarized evidence on the pharmacological treatment of non-alcoholic fatty liver disease (NAFLD)/metabolic dysfunction-associated steatotic liver disease (MASLD). We start by reviewing the epidemiology of the condition and its close association with obesity and type 2 diabetes. We then discuss how randomized-controlled trials are performed following guidance from regulatory agencies, including differences and similarities between requirements of the US Food and Drug Administration and the European Medicine Agency. Difficulties and hurdles related to limitations of liver biopsy, a large number of screening failures in recruiting patients, as well as unpredictable response rates in the placebo group are evaluated. Finally, we recapitulate the strategies employed for potential drug treatments of this orphan condition. The first is to repurpose drugs that originally targeted T2DM and/or obesity, such as pioglitazone, glucagon-like peptide 1 receptor agonists (liraglutide and semaglutide), multi-agonists (tirzepatide and retatrutide), and sodium-glucose transporter 2 inhibitors. The second is to develop drugs specifically targeting NAFLD/MASLD. Among those, we focused on resmetirom, fibroblast growth factor 21 analogs, and lanifibranor, as they are currently in Phase 3 of their clinical trial development. While many failures have characterized the field of pharmacological treatment of NAFLD/MASLD in the past, it is likely that approval of the first treatments is near. As occurs in many chronic conditions, combination therapy might lead to better outcomes. In the case of non-alcoholic steatohepatitis, we speculate that drugs treating underlying metabolic co-morbidities might play a bigger role in the earlier stages of disease, while liver-targeting molecules will become vital in patients with more advanced disease in terms of inflammation and fibrosis.

Effects of retatrutide on body composition in people with type 2 diabetes: a substudy of a phase 2, double-blind, parallel-group, placebo-controlled, randomised trial.

Retatrutide, a glucose-dependent insulinotropic polypeptide, glucagon-like peptide-1, and glucagon receptor agonist, has demonstrated robust glucose and bodyweight reductions in participants with type 2 diabetes. This substudy assessed percent change from baseline to week 36 in total body fat mass versus placebo and dulaglutide. This phase 2, double-blind, parallel-group, placebo-controlled, randomised controlled trial was done in 42 medical centres in the USA. Eligible participants were adults aged 18-75 years with type 2 diabetes, HbA1c of 7&#xb7;0-10&#xb7;5%, stable bodyweight, and BMI of 25-50 kg/m2. Eligible participants were randomly assigned in a 2:2:2:1:1:1:1:2 ratio to once-weekly subcutaneous placebo, dulaglutide 1&#xb7;5 mg, or retatrutide 0&#xb7;5 mg, 4 mg (2 mg initial dose), 4 mg (4 mg initial dose), 8 mg (2 mg initial dose), 8 mg (4 mg initial dose), or 12 mg. The prespecified primary substudy endpoint was percent change from baseline to week 36 in total fat mass, as measured by dual-energy X-ray absorptiometry (DXA). Regression methods with on-treatment data before study drug discontinuation from all randomly assigned participants with non-missing DXA scans were included in efficacy analysis. All participants who received at least one dose of study drug were included in the safety analysis population. The completed trial is registered with ClinicalTrials.gov, NCT04867785. Between May 13, 2021 and June 13, 2022, 534 participants were screened for inclusion into the main study. 253 were excluded and 281 participants were enrolled and randomly assigned to the main study. Of the main study participants, 189 participants were enrolled to the body composition substudy (29 in the placebo group, 32 in the retatrutide 0&#xb7;5 mg group, 31 in the retatrutide 4 mg groups [pooled], 33 in the retatrutide 8 mg group [pooled], 30 in the retatrutide 12 mg group, and 34 in the dulaglutide 1&#xb7;5 mg group). Of these, 155 had a baseline DXA scan and 103 completed treatment and both baseline and week 36 DXA scans. 105 (56%) of 189 participants were female and 84 (44%) were male. 160 (85%) of 189 participants were White, 24 (13%) were Black, and five (3%) were Asian. Percent reduction from baseline in total fat mass was 4&#xb7;9% (SE 1&#xb7;4%) with retatrutide 0&#xb7;5 mg, 15&#xb7;2% (3&#xb7;2%) with retatrutide 4 mg (pooled), 26&#xb7;1% (2&#xb7;5%) with retatrutide 8 mg (pooled), 23&#xb7;2% (3&#xb7;0%) with retatrutide 12 mg, 2&#xb7;6% (1&#xb7;6%) with dulaglutide, and 4&#xb7;5% (1&#xb7;2%) with placebo. Least squares mean change from baseline in total fat mass compared to placebo was -0&#xb7;4 (95% CI -4&#xb7;0 to 3&#xb7;2, p=0&#xb7;83 with retatrutide 0&#xb7;5 mg, -10&#xb7;7 (-17&#xb7;2 to -4&#xb7;2, p=0&#xb7;0013) with retatrutide 4 mg (pooled), -21&#xb7;6 (-27&#xb7;1 to -16&#xb7;1, p<0&#xb7;0001) with retatrutide 8 mg (pooled), and -18&#xb7;7 (-25&#xb7;1 to -12&#xb7;3, p<0&#xb7;0001) with retatrutide 12 mg. Adverse events were similar between groups. Serious adverse events occurred in two (7%) of 29 participants in the placebo group, two (6%) of 32 participants in the retatrutide 0&#xb7;5 mg group, zero of 31 participants in the retatrutide 4 mg group, three (9%) of 33 participants in the retatrutide 8 mg group, one (3%) of 30 participants in the retatrutide 12 mg group, and zero of 34 participants in the dulaglutide group. Gastrointestinal events were the most frequently reported adverse events, and no deaths were reported. In adults with type 2 diabetes, retatrutide significantly improved total body fat mass reduction compared with placebo and dulaglutide. The proportion of lean mass loss to weight loss was similar to other obesity treatments. These findings could provide reassurance that a greater proportion of lean mass is not lost with retatrutide despite the overall increased weight loss. The study was funded by Eli Lilly and Company.

Incretin triple agonist retatrutide (LY3437943) alleviates obesity-associated cancer progression.

Medical therapeutics for weight loss are changing the landscape of obesity but impacts on obesity-associated cancer remain unclear. We report that in pre-clinical models with significant retatrutide (RETA, LY3437943)-induced weight loss, pancreatic cancer engraftment was reduced, tumor onset was delayed, and progression was attenuated resulting in a 14-fold reduction in tumor volume compared to only 4-fold reduction in single agonist semaglutide-treated mice. Despite weight re-gain after RETA withdrawal, the anti-tumor benefits of RETA persisted. Remarkably, RETA-induced protection extends to a lung cancer model with 50% reduced tumor engraftment, significantly delayed tumor onset, and mitigated tumor progression, with a 17-fold reduction in tumor volume compared to controls. RETA induced immune reprogramming systemically and in the tumor microenvironment with durable anti-tumor immunity evidenced by elevated circulating IL-6, increased antigen presenting cells, reduced immunosuppressive cells, and activation of pro-inflammatory pathways. In sum, our findings suggest that patients with RETA-mediated weight loss may also benefit from reduced cancer risk and improved outcomes.

Novel GLP-1-based Medications for Type 2 Diabetes and Obesity.

The approvals of semaglutide and tirzepatide have set new benchmarks in the treatment of type 2 diabetes and obesity. Building on their success, novel glucagon-like peptide-1 (GLP-1)-based therapeutics are rapidly advancing. These next-generation agents engage not only GLP-1 receptors but also those for other gastro-entero-pancreatic hormones such as glucose-dependent insulinotropic polypeptide (GIP), glucagon, amylin, and peptide YY to enhance energy uptake, storage, and expenditure through synergistic mechanisms. Both GIP receptor agonism and antagonism, particularly in combination with GLP-1 receptor agonism, have shown promise. Maridebart cafraglutide, combining GLP-1 receptor agonism with GIP receptor antagonism, exemplifies this innovative approach. Glucagon coagonists like survodutide and mazdutide have demonstrated significant weight loss and improved glycemic control. Amylin-based agents, including CagriSema (cagrilintide + semaglutide) and amycretin, enhance satiety and glycemic outcomes through complementary actions. Further innovation is seen in triple agonists such as retatrutide, which targets GIP, GLP-1, and glucagon receptors to amplify metabolic effects. Meanwhile, the emergence of orally active small-molecule GLP-1 receptor agonists like danuglipron and orforglipron, which are resistant to enzymatic degradation, marks a major advance in patient-friendly drug delivery. This review explores the mechanisms, clinical development, and therapeutic potential of these novel agents, excluding already approved drugs like liraglutide, semaglutide, and tirzepatide. We highlight how multireceptor agonists and oral GLP-1-based therapies may reshape the future landscape of obesity and type 2 diabetes treatment by offering more effective and better-tolerated options.

Efficacy and Safety of GLP-1 Receptor Agonists, Dual Agonists, and Retatrutide for Weight Loss in Adults With Overweight or Obesity: A&#xa0;Bayesian NMA.

To compare the efficacy and safety of GLP-1 receptor agonists (GLP-1RAs), dual agonists (GLP-1RAs/GIP or GCGR), and retatrutide (GLP-1/GIP/glucagon) for weight loss in adults with overweight or obesity. We conducted a systematic review and Bayesian network meta-analysis (NMA) of 19 randomized controlled trials (RCTs) including 29,506 adults (BMI &#x2265;&#x2009;25&#x2009;kg/m2), assessing liraglutide, semaglutide, survodutide, tirzepatide, retatrutide, and placebo. Outcomes included mean weight loss, achievement of &#x2265;&#x2009;5%, &#x2265;&#x2009;10%, and &#x2265;&#x2009;15% weight loss, waist circumference (WC), BMI, and adverse events (AEs) at &#x2265;&#x2009;36&#x2009;weeks. Subgroup and meta-regression analyses evaluated the impact of diabetes status, sex, age, and BMI. Retatrutide and dual agonists achieved equivalent mean weight loss (-11.0&#x2009;kg), surpassing GLP-1RAs (-9.0&#x2009;kg), with retatrutide excelling at achieving &#x2265;&#x2009;15% weight loss (OR 54.6). Dual agonists and GLP-1RAs followed (OR 16.4 and 9.0, respectively). Retatrutide had the highest AE risk. Meta-regression showed type 2 diabetes mellitus (T2DM) reduced weight loss by 4.338&#x2009;kg for GLP-1RAs and 5.016&#x2009;kg for dual agonists, with enhanced outcomes in female-dominant or high-BMI cohorts. Retatrutide offers superior weight loss efficacy but with a higher AE risk. Dual agonists provide a favorable efficacy-safety balance. Personalized treatment selection based on patient characteristics is recommended.

Efficacy and safety of retatrutide for the treatment of obesity: a systematic review of clinical trials.

Obesity is a major public health issue linked to various health complications. Retatrutide, a triple agonist peptide targeting the glucagon receptor, GIP receptor, and GLP-1 receptor, shows promise in addressing this&#xa0;need. This systematic review assessed the safety and efficacy of retatrutide for obesity treatment using available clinical trial data. We conducted a comprehensive search of databases, including PubMed, Cochrane and ClinicalTrials.gov, from their inception until March 15, 2025 following PRISMA guidelines. Three articles were included in this systematic review, screening a total of 1,082 patients, with 691 randomly assigned to groups. The average age of participants was 54.26&#xa0;&#xb1;&#xa0;9.9 years, consisting of 335 men (48&#x202f;%) and 356 women (52&#x202f;%). Retatrutide was administered to 510 participants, while 130 received a placebo. The 12&#x202f;mg dosage of retatrutide showed the most significant reductions in body weight, body mass index, and waist circumference. It also led to a higher percentage of patients achieving weight losses of&#xa0;&#x2265;5&#x202f;, 10, 15, and 20&#x202f;%. Gastrointestinal adverse effects were the most commonly reported. Weekly subcutaneous injections of retatrutide in obese patients resulted in significant weight loss and metabolic improvements compared to a placebo.

The promise of glucagon-like peptide 1 receptor agonists (GLP-1RA) for the treatment of obesity: a look at phase 2 and 3 pipelines.

GLP-1-based therapies have changed the treatment of overweight/obesity. Liraglutide 3.0&#x2009;mg daily, the first GLP-1 RA approved for treatment of overweight, induced a weight loss of 6-8%, Semaglutide 2.4&#x2009;mg once weekly improved weight loss to about 12-15%, while the dual GIP/GLP-1 receptor agonist tirzepatide once weekly has induced a weight loss of about 20% in obese people without diabetes. This review describes results obtained with GLP-1 mono-agonists, GLP-1/GIP dual agonists, GLP-1/glucagon co-agonists, and the triple agonist retatrutide (GIP/GLP-1/glucagon), which have shown beneficial effect both on body weight and steatotic liver disease. A combination of semaglutide (a GLP-1 agonist) and cagrilintide (a long-acting amylin analogue) for weekly administration is currently in phase III development, and so is oral semaglutide and several non-peptide small molecule GLP-1 agonists for oral administration. The adverse events with the GLP-1-based therapies are primarily gastrointestinal and include nausea, vomiting, obstipation, or diarrhea, which often can be mitigated by slow up titration. The GLP-1-based therapies will change the treatment of obesity and its comorbidities including steatotic liver disease in the future. Outstanding question is maintenance of the weight loss, possibly pharmacological treatment needs to be life-long.

Efficacy and safety of retatrutide, a GIP, GLP-1, and glucagon receptor agonist, in people with type 2 diabetes and inadequate glycaemic control with diet and exercise (TRANSCEND-T2D-1): a double-blind, randomised, phase 3 trial.

Retatrutide is a GIP, GLP-1, and glucagon triple hormone receptor agonist, under clinical development for type 2 diabetes, obesity, and related complications. We aimed to assess the efficacy and safety of retatrutide as a monotherapy in people with type 2 diabetes that is inadequately controlled by diet and exercise alone. In this 40-week, phase 3, randomised, double-blind, placebo-controlled trial at 48 sites in the USA, Mexico, and India, we recruited adults (aged &#x2265;18 years) with type 2 diabetes that is inadequately controlled by diet and exercise alone, glycated haemoglobin (HbA1c) between 7&#xb7;0% and 9&#xb7;5% (53-80 mmol/mol), and BMI of at least 23 kg/m2. Participants were randomly assigned (1:1:1:1) to receive retatrutide (4 mg, 9 mg, or 12 mg) or placebo by once-weekly subcutaneous injection. The primary endpoint was the change in HbA1c concentration from baseline to week 40. A key secondary endpoint was the percentage change in bodyweight from baseline to week 40. This trial is registered with ClinicalTrials.gov, NCT06354660, and is completed. Between April 10, 2024, and April 21, 2025, 930 participants were screened and 537 (296 [55%] female and 241 [45%] male) were randomly assigned: 134 to retatrutide 4 mg, 133 to retatrutide 9 mg, 136 to retatrutide 12 mg, and 134 to placebo. Baseline mean age was 48&#xb7;8 years (SD 12&#xb7;1), mean HbA1c concentration was 7&#xb7;9% (SD 1&#xb7;1), mean duration of diabetes was 2&#xb7;5 years (SD 4&#xb7;4), and mean BMI was 35&#xb7;8 kg/m2 (SD 7&#xb7;0). 490 (91%) participants completed the treatment period on study drug and 504 (94%) completed the study. For the treatment regimen estimand, the mean change from baseline in HbA1c concentration was -1&#xb7;69% (SE 0&#xb7;11) with retatrutide 4 mg, -1&#xb7;86% (0&#xb7;10) with 9 mg, and -1&#xb7;94% (0&#xb7;08) with 12 mg, versus -0&#xb7;81% (0&#xb7;12) with placebo, resulting in estimated treatment differences versus placebo of -0&#xb7;88% (95% CI -1&#xb7;18 to -0&#xb7;59) with retatrutide 4 mg, -1&#xb7;04% (-1&#xb7;32 to -0&#xb7;76) with 9 mg, and -1&#xb7;12% (-1&#xb7;39 to -0&#xb7;85) with 12 mg (all p<0&#xb7;0001). The mean percentage change from baseline in bodyweight was -11&#xb7;5% (SE 0&#xb7;7) with retatrutide 4 mg, -13&#xb7;9% (0&#xb7;8) with 9 mg, and -15&#xb7;3% (0&#xb7;8) with 12 mg, versus -2&#xb7;6% (0&#xb7;5) with placebo. The most frequent adverse events with retatrutide were generally mild to moderate gastrointestinal events, which subsided over time. Study intervention discontinuations due to adverse events were 2-5% with retatrutide and 0% with placebo. No severe hypoglycaemia was reported. Two deaths occurred during the study, both in the retatrutide 4 mg group and unrelated to the study drug. Retatrutide showed significant improvements in glycaemic control and bodyweight reduction as a monotherapy in adults with type 2 diabetes that is inadequately controlled with diet and exercise alone, with an adverse event profile consistent with molecules with GLP-1 agonist activity, supporting its potential as an effective treatment for type 2 diabetes. Eli Lilly and Company.

Multifunctional incretin peptides in therapies for type 2 diabetes, obesity and associated co-morbidities.

Recent studies with peptide-based incretin therapies have focussed mainly on the glucagon-like peptide-1 (GLP-1) receptor agonist semaglutide and the dual agonist tirzepatide that engages receptors for GLP-1 and glucose-dependent insulinotropic polypeptide (GIP). Randomised clinical trials and 'real-world' studies have confirmed the marked glucose-lowering and weight-lowering efficacy of these agents across diverse populations. These include different ethnic groups, young and elderly individuals with and without diabetes and/or overweight or obesity. Recent studies have also confirmed protections against the development and progression of cardiovascular and renal diseases that are additive to the benefits conferred by improved control of blood glucose and body weight. Emerging evidence suggests that incretin therapies could additionally ameliorate fatty liver disease, chronic inflammation, sleep apnea and possibly degenerative bone disorders and cognitive decline. New incretin-based peptide therapies in development include a long-acting glucagon receptor agonist (LY3324954), dual GLP-1/glucagon receptor agonists (survodutide, pemvidutide, mazdutide, G49), triple GLP-1/GIP/glucagon receptor agonists (retatrutide, efocipegtrutide), a combination of semaglutide with the amylin analogue cagrilintide (CagriSema), a unimolecular GLP-1/amylin receptor dual agonist (amycretin), and a GIP receptor antibody with GLP-1 receptor agonism (MariTide). The creation of multi-targeting incretin-based synthetic peptides provides opportunities for improved management of type 2 diabetes and obesity as well as new therapeutic approaches to an expanding list of associated co-morbidities. The aim of the review is to acquaint the reader with developments in the field from 2023 to the present (February 2025).

Efficacy of GLP-1 Receptor Agonist-Based Therapies on Cardiovascular Events and Cardiometabolic Parameters in Obese Individuals Without Diabetes: A Meta-Analysis of Randomized Controlled Trials.

The cardioprotective effects of glucagon-like peptide-1 receptor agonist (GLP-1RA)-based therapies in nondiabetic individuals with overweight or obesity remain underexplored. This meta-analysis evaluates their impact on cardiovascular events and metabolic parameters in this population. A meta-analysis was conducted using PubMed, Embase, Cochrane, and Web of Science databases from inception to June 18, 2024. Eligible studies were randomized controlled trials (RCTs) enrolling nondiabetic adults with overweight or obesity. These studies compared GLP-1RA-based therapies with placebo and reported cardiovascular events and metabolic parameters. A total of 29 RCTs involving 9 GLP-1RA-based drugs and 37&#x2009;348 eligible participants were included. Compared to placebo, GLP-1RA-based therapies significantly reduced the risk of total cardiovascular events (relative risk: 0.81, 95% confidence interval [CI]: [0.76, 0.87]), major adverse cardiovascular events (0.80, [0.72, 0.89]), myocardial infarction (0.72, [0.61, 0.85]), and all-cause mortality (0.81, [0.71, 0.93]). No significant differences were observed in cardiovascular death or stroke. Additionally, GLP-1RA-based therapies were associated with significant reductions in some cardiometabolic parameters. Among GLP-1RA-based therapies, orfroglipron demonstrated strong benefits in reducing systolic blood pressure (mean difference: -7.10&#x2009;mmHg, 95% CI: [-11.00, -2.70]). Tirzepatide induced the greatest reduction in body mass index (-6.50&#x2009;kg/m2, [-7.90, -5.10]) and hemoglobin A1c concentrations (-0.39%, [-0.52, -0.26]). Retatrutide and semaglutide were most effective in improving lipid profiles and reducing C-reactive protein levels (-1.20&#x2009;mg/dL, [-1.80, -0.63]), respectively. In nondiabetic individuals with overweight or obesity, GLP-1RA-based therapies significantly reduce cardiovascular events and improve cardiometabolic parameters. These findings underscore the potential for individualized GLP-1RA-based therapies targeting cardiovascular risk factors.

Efficacy of GLP-1-based Therapies on Metabolic Dysfunction-associated Steatotic Liver Disease and Metabolic Dysfunction-associated Steatohepatitis: A Systematic Review and Meta-analysis.

New therapies are urgently needed for the treatment of metabolic dysfunction-associated steatotic liver disease (MASLD) and metabolic dysfunction-associated steatohepatitis (MASH). We conducted this systematic review and meta-analysis to evaluate the therapeutic effects of glucagon-like peptide-1 receptor agonists (GLP-1RAs) on MASLD/MASH. We searched PubMed, Embase, and Cochrane Library databases to identify randomized controlled trials (RCTs) that compared GLP-1RAs with placebo or active agents with respect to the efficacy in patients with MASLD/MASH. The effects of GLP-1RAs on liver fat content (LFC) by imaging, liver histology, serum liver enzymes, and noninvasive fibrosis indexes [Fibrosis-4, nonalcoholic fatty liver disease fibrosis score, cytokeratin 18, procollagen III, and liver stiffness) were evaluated. Mean differences and risk ratios with 95% confidence intervals were pooled using a random-effect model. Twenty-five RCTs involving 2600 patients who used GLP-1RAs including liraglutide, exenatide, dulaglutide, semaglutide, tirzepatide, efinopegdutide, survodutide, and retatrutide were included. Overall, GLP-1RAs treatment for a median of 24 weeks demonstrated a significant reduction in LFC by 5.21%, with retatrutide displaying the most obvious treatment effects. GLP-1RAs treatment induced significant histological improvements in steatosis, hepatocellular ballooning, and lobular inflammation but nonsignificantly improved fibrosis, with the evidence for tirzepatide more robust than that for semaglutide and liraglutide. GLP-1RAs treatment significantly decreased serum alanine aminotransferase, aspartate aminotransferase, and &#x3b3;-glutamyl transferase compared with control. GLP-1RAs also significantly improved liver stiffness, with semaglutide displaying the most obvious treatment effect. No drug-related adverse effects involving the liver were observed. GLP-1RAs decreased liver fat deposition and improved histological steatosis, hepatocellular ballooning, and lobular inflammation, without worsening of fibrosis in MASLD and MASH.

Beyond weight loss: multisystem benefits of obesity medications.

Obesity is increasingly managed with medications as disease-modifying therapies, reflecting its role as a gateway disease driving metabolic, cardiovascular, reproductive, neuropsychiatric, and mechanical conditions. This Review synthesises evidence from randomised controlled trials and high-quality meta-analyses on approved and late-stage investigational obesity medications, including phentermine-topiramate, naltrexone-bupropion, glucagon-like peptide-1 (GLP-1) receptor agonists (eg, liraglutide, semaglutide, subcutaneously and orally), and newer GLP-1 receptor agonist-based agents (eg, tirzepatide, survodutide, mazdutide, retatrutide, cagrilintide-semaglutide, and amycretin). We evaluated the effects of obesity medications across major obesity-related conditions, including type 2 diabetes, metabolic dysfunction-associated steatotic liver disease, chronic kidney disease, heart failure, cardiovascular disease, obstructive sleep apnoea syndrome, polycystic ovary syndrome (recently named polyendocrine metabolic ovarian syndrome), osteoarthritis, muscle mass, depression, quality of life, and food cravings, along with binge-eating disorders, substance use disorders, and neurodegenerative diseases. Overall, GLP-1-based and multiagonist therapies show beneficial effects across these comorbid conditions. While many benefits of obesity medications are mediated by weight loss, accumulating evidence indicates important weight loss-independent effects, particularly with GLP-1 receptor agonist-based therapies. A broader understanding of these pleiotropic effects is essential to inform personalised obesity management and optimise long-term clinical outcomes.

Recent advances in the treatment of type 2 diabetes mellitus using new drug therapies.

Several recent advances provide multiple health benefits to individuals with type 2 diabetes mellitus (T2DM). Pharmacological therapy is governed by person-centered factors, including comorbidities and treatment goals. Adults with T2DM who have an established/high risk of atherosclerotic cardiovascular disease, heart failure, and/or chronic kidney disease, require a treatment regimen that includes agents that are proven to reduce cardiorenal risk. Weight management plays a key role in reducing glucose for patients with T2DM. A glucose-reduction treatment regimen must consider weight management. Sodium glucose co-transporter 2 (SGLT2) inhibitors reduce the risk of heart failure, cardiovascular and renal events. Glucagon-like peptide-1 (GLP-1) receptor agonists allow better control of glycemia, promote weight loss and reduce the risk of cardiovascular events. Newer Glucose-dependent insulinotropic polypeptide (GIP) and GLP-1 dual agonist, which activate GIP and GLP-1 receptors improve glycemic control and promote greater weight loss than GLP-1 receptor agonists. Several novel drugs are in the clinical development phase. This review pertains to recent advances in pharmacological management of type 2 diabetes.

Triple-Hormone-Receptor Agonist Retatrutide for Obesity. Reply.

Efficacy of Tirzepatide, Retatrutide, and Semaglutide for Weight Loss in Obese Individuals Without Diabetes.

Comparison of the effects of Liraglutide, Tirzepatide, and Retatrutide on diabetic kidney disease in db/db mice.

To assess and compare the therapeutic efficacy of Liraglutide, Tirzepatide, and Retatrutide in treating diabetic kidney disease (DKD) in db/db mice. Db/db mice were administered intraperitoneal injections of Liraglutide (10 nmol/kg), Tirzepatide (10 nmol/kg), and Retatrutide (10 nmol/kg) for 10 weeks. Subsequently, we assessed the effectiveness of these three drugs in controlling blood glucose levels, reducing weight, and improving serum biochemical indicators and DKD. Additionally, we measured and compared the renal inflammation and fibrosis indexes. Meanwhile, the content of intestinal metabolite butyrate was compared to reflect the regulatory effects of these three drugs on gut microbiota. Retatrutide demonstrated superior effectiveness in reducing weight and improving renal function in db/db mice compared to Liraglutide and Tirzepatide. Additionally, it markedly suppressed the expression of pro-inflammatory cytokines (TNF-&#x3b1;, caspase-1, and NLRP3) and pro-fibrotic factors (fibronectin, &#x3b1;-SMA, and collagen I) in the kidneys of mice. Furthermore, Retatrutide substantially enhanced liver function, reduced triglyceride levels, cholesterol levels, low-density lipoprotein cholesterol, elevated high-density lipoprotein cholesterol, and increased the content of intestinal metabolite butyrate in db/db mice when compared to the other two drugs. Unfortunately, despite its ability to lower blood glucose levels, Retatrutide did not outperform the other two drugs. In contrast, Tirzepatide exhibited better effects on lowering blood glucose, weight loss, lipid reduction, and improvement of DKD compared to Liraglutide. Retatrutide and Tirzepatide were significantly effective in improving DKD, controlling blood glucose and body weight. Retatrutide was the most effective in improving DKD and body weight, while Tirzepatide was the most effective in controlling blood glucose. Inhibiting the expression of inflammatory factors and fibrosis mediators and regulating intestinal microbiota may be the potential mechanisms of these two drugs to delay the progression of DKD.

A review of an investigational drug retatrutide, a novel triple agonist agent for the treatment of obesity.

Obesity is one of the critical public health problems in our society. It leads to various health conditions, such as type 2 diabetes mellitus, cardiovascular disease, hypertension, dyslipidaemia, and non-alcoholic fatty liver disease. With the rising incidence of obesity, there is a growing demand for new therapies which can effectively manage body weight and improve health. Currently under development, multi-receptor agonist drugs may offer a promising solution to meet this unmet medical need. Retatrutide is a novel triple receptor agonist peptide that targets the glucagon receptor (GCGR), glucose-dependent insulinotropic polypeptide receptor (GIPR), and glucagon-like peptide-1 receptor (GLP-1R). This novel drug has the potential to treat metabolic abnormalities associated with obesity as well as diseases resulting from it due to its distinct mechanism of action. The Phase III trial of this pipeline drug for treating type 2 diabetes mellitus, non-alcoholic fatty liver disease, and obesity started on August 28, 2023. The results of a Phase II clinical trial have demonstrated significant weight reduction in overweight and obese adults. Specifically, the trial reported an average weight loss of 17.5% and 24.4% at 24 and 48 weeks, respectively. These findings hold promise for the development of effective weight loss interventions in this population group. There is a need for more phase III studies to provide sufficient clinical evidence for the effectiveness of retatrutide, as current evidence is limited to phase II studies and has yet to prove its worth in a larger population. Here, we aimed to provide an overview of retatrutide's safety and effectiveness in treating obesity.

[Glucagon-like peptide-1 receptor agonists: a new pharmacological treatment option for psychiatric illnesses?].

Albiglutide, dulaglutide, exenatide, liraglutide, lixisenatide, orforglipron and semaglutide are glucagon-like peptide&#x2011;1 (GLP-1) receptor agonists. Tirzepatide targets not only GLP&#x2011;1 but also glucose-dependent insulinotropic peptide (GIP) receptors and retatrutide is a&#xa0;triple GLP&#x2011;1, GIP and glucagon receptor agonist. The GLP&#x2011;1 receptor agonists increase insulin release but suppress glucagon release. They slow down the emptying of the stomach and thus prevent blood sugar spikes. They reduce appetite and food intake. In the brain GLP&#x2011;1 receptor agonists lead to a&#xa0;better glycemic control and they appear to have anti-inflammatory and neuroprotective effects. It has been reported that GLP&#x2011;1 receptor agonists reduce oxidative stress and apoptosis, lower the risk of ischemia and promote neurogenesis. The GLP&#x2011;1 receptor agonists can also influence dopaminergic signal transduction in the nucleus accumbens. Therefore, they could modify the effect of cocaine, alcohol and nicotine. Preliminary investigations provide indications of the therapeutic benefits of GLP&#x2011;1 receptor agonists for people with dementia, eating disorders, psychopharmacologically induced weight gain, depression, anxiety and substance use disorders. Typical accompanying adverse reactions are gastrointestinal side effects, such as nausea, vomiting, diarrhea, eructation and gastroesophageal reflux. More severe side effects include pancreatitis, allergic reactions, renal function disorders and possibly an increased risk of thyroid cancer.