Retatrutide

Obesity pharmacotherapy reimagined: The era of multi-receptor agonists and next-generation metabolic modulators, perspectives and controversies.

Ioannis G Lempesis, Maria Dalamaga

Obesity affects over 2 billion adults globally, with projections indicating that nearly two-thirds of adults will be affected by 2050. Glucagon-like peptide-1 receptor agonists (GLP-1RAs) have transformed obesity treatment, achieving weight loss previously considered attainable only with bariatric surgery. However, GLP-1-based therapies have revealed important limitations, including weight loss plateaus, substantial inter-individual variability, and weight regain upon discontinuation, underscoring the need for next-generation approaches. Existing reviews have focused predominantly on approved GLP-1RAs, with limited synthesis of emerging multi-receptor agonists, oral formulations, and body composition-targeted agents, while guidance on treatment personalization and sequencing strategies remains limited. This review examines the evolving landscape of obesity pharmacotherapy beyond injectable GLP-1RAs. Oral GLP-1 agonists, including orforglipron, offer comparable efficacy to injectables while potentially improving global accessibility by eliminating cold-chain requirements and simplifying manufacturing. Multi-receptor agonists represent the most transformative developments: triple agonists such as retatrutide achieve weight reductions of 20-24%, while dual GLP-1/glucagon agonists like survodutide and mazdutide show strong efficacy with particular promise for metabolic-associated steatotic liver disease. Maridebart cafraglutide, combining GLP-1 agonism with glucose-dependent insulinotropic polypeptide (GIP) antagonism, enables once-monthly dosing. The amylin pathway has re-emerged through long-acting analogs (cagrilintide, eloralintide) and unimolecular co-agonists (amycretin), achieving weight reductions up to 24% via distinct neuroendocrine circuits. Body composition optimization through agents like bimagrumab addresses lean mass preservation during potent anorectic therapy. Personalized approaches, including setmelanotide for monogenic obesity, exemplify precision pharmacotherapy. Collectively, these advances signal a shift from appetite-centric weight loss toward integrated metabolic, neuroendocrine, and body-composition-focused disease modification. The next epoch of obesity pharmacotherapy will be defined by multi-receptor strategic combinations, targeted approaches to preserve lean mass, and personalized treatment algorithms. Critical priorities include phenotype-stratified trials, long-term safety surveillance, pediatric obesity research, and implementation science to ensure equitable global access. Balancing pharmacologic innovation with sustainable, equitable implementation remains the defining challenge ahead.

Childhood Obesity and Cardiac Risk in Youth: Emerging Challenges Toward 2050.

Nikunja Kishor Mishra

Pediatric obesity is increasing at an alarming rate, affecting over 381 million children worldwide and emerging as a critical public health issue. According to World Health Organization (WHO) 2016, 40% of adults are overweight and 13% are obese, highlighting obesity's persistence throughout life. Childhood obesity significantly heightens the risk of adult obesity and cardiovascular diseases (CVD) such as atherosclerosis and coronary artery disease, potentially leading to a global health crisis by 2050. Genetic predispositions identified through genome-wide association studies (GWAS) contribute to elevated body mass index (BMI), yet lifestyle factors reduced physical activity, prolonged screen time, and consumption of high-calorie, low-nutrient foods remain key drivers. This study aim is to explore the Real-world data (RWD) on childhood obesity from major countries, prevalence, risk factors, and cardiovascular consequences of pediatric obesity, evaluating public health initiatives, lifestyle interventions, and therapeutic strategies to address this growing concern. Data collected from PubMed, Scopus, and Springer databases reveal that childhood obesity is closely linked to hypertension, dysglycemia, dyslipidemia, and other cardiovascular disorders (heart attack, arrhythmias and stroke). The WHO Global Action Plan on Physical Activity 2018-2030 (GAPPA) emphasizes urgent preventive measures. Current management strategies include lifestyle modification, pharmacotherapy, and bariatric surgery. Glucagon-like peptide-1 (GLP-1) receptor agonists such as semaglutide and liraglutide are effective for weight management but commonly cause gastrointestinal adverse effects. The SURMOUNT-5 trial demonstrated superior weight-loss outcomes with tirzepatide, with a similar gastrointestinal safety profile. Emerging therapies including cagrilintide plus semaglutide, oral agents such as orforglipron and danuglipron, and the triagonist retatrutide may improve adherence and accessibility; however, these agents remain investigational and are currently under clinical evaluation. Despite promising advancements, gene therapy for pediatric obesity remains in the experimental phase. Overall, addressing childhood obesity requires multifaceted interventions combining public health initiatives, behavioral changes, and novel therapeutic strategies to mitigate cardiovascular risks and promote sustainable health outcomes.

Pharmacologic Treatment of Metabolic Dysfunction-Associated Steatotic Liver Disease in the Context of Type 2 Diabetes.

Konstantinos Malandris, Konstantinos Charalampidis, Rohit Loomba +1 more

Metabolic dysfunction–associated steatotic liver disease (MASLD) is highly prevalent among individuals with type 2 diabetes (T2D). This review summarizes current evidence on the pharmacologic treatment of MASLD, with emphasis on agents currently approved for the management of T2D.

Retatrutide in type 2 diabetes mellitus and obesity: an overview.

Theodoros Panou, Evanthia Gouveri, Djordje S Popovic +1 more

Glucagon-like peptide-1 receptor agonists (GLP-1RAs) are increasingly used for T2DM and obesity.

Comparative Efficacy and Safety of Glucagon Receptor Agonists on Metabolic Outcomes: A Network Meta-Analysis of Randomised Controlled Trials.

Ayah Abulehia, Hazem Ayesh, Omar Ayesh +7 more

Glucagon receptor agonists (GRAs) are an emerging class of therapies for obesity and type 2 diabetes, demonstrating encouraging metabolic and weight-reducing effects. Several investigational GRA-based agents, including retatrutide, cotadutide, mazdutide, and survodutide, have reported promising results across early and mid-phase clinical trials. This comprehensive meta-analysis evaluates the efficacy and safety of these agents in individuals with type 2 diabetes, overweight, or obesity.

Engineered nutrient-stimulated hormonal multi-agonists for precision targeting of obesity and metabolic disorders.

Yun Kyung Cho, Chang Hee Jung

Obesity and its related metabolic comorbidities, including type 2 diabetes, metabolic dysfunction-associated steatotic liver disease, and cardiovascular disease, are increasingly recognized as heterogeneous and multisystemic disorders. Despite the significant benefits in glycemic control and weight loss exhibited by GLP-1 receptor agonists (GLP-1RAs), their limitations have initiated the development of engineered multi-agonist therapies targeting additional nutrient-stimulated hormonal (NUSH) pathways. Dual and triple peptide-based co-agonists combining glucagon-like peptide-1 (GLP-1) with glucose-dependent insulinotropic polypeptide (GIP), glucagon, amylin, or peptide YY have demonstrated superior metabolic efficacy in preclinical and clinical studies. Tirzepatide (GLP-1/GIP dual agonist), CagriSema (GLP-1/amylin dual agonist), and retatrutide (GLP-1/GIP/glucagon triple agonist) have achieved unprecedented levels of weight loss and glycemic improvement, with certain agents also demonstrating hepatic, cardiovascular, and inflammatory benefits. Non-peptidyl oral GLP-1RAs, such as orforglipron, offer novel formulation strategies to enhance treatment accessibility and adherence. Multi-agonist incretin-based therapies represent a paradigm shift in the management of obesity and metabolic diseases. These agents offer broad clinical utility beyond glucose lowering by mimicking the pleiotropic hormonal responses observed after bariatric surgery. These therapies are poised to emerge as key components of precision metabolic medicine. This review article explores the mechanistic basis, pharmacological characteristics, and clinical data supporting the use of engineered NUSH-based peptide therapies for obesity and its related metabolic disorders, with particular emphasis on recent progress in the development and clinical application of dual and triple agonists.

Retatrutide Shows Multiple Metabolic Benefits in Diet-Induced Obese MASH Mouse and Hamster Models.

François Briand, Camille Le Cudennec, Estelle Grasset +4 more

Our aim was to evaluate the efficacy of the triple glucagon, GIP, and GLP-1 receptor agonist retatrutide in diet-induced obese MASH mouse and hamster models, two preclinical models that we routinely use for assessing new therapies targeting obesity.

Incretin-Based Dual and Triple Agonists in Overweight or Obese Individuals: A Systematic Review and Meta-Analysis.

Zhi Hong Chan, Abdousamad Said Omar, Kieran Gill +11 more

Incretin-based dual and triple agonists have emerged as effective options for obesity management, offering enhanced weight loss through multi-receptor agonism. However, data on their efficacy and safety remain limited. We conducted a systematic review and meta-analysis to evaluate the efficacy and safety of these emerging agents. A comprehensive literature search was conducted using PubMed, the Cochrane Library, and Google Scholar from inception to June 2025 to identify randomized controlled trials evaluating tirzepatide, retatrutide, or mazdutide in obese adults. Clinical outcomes were assessed using the random-effects model and pooled as mean differences (MDs) or risk ratios (RRs) with 95% confidence intervals (CIs). A total of 10 randomized controlled trials, including 3236 participants, were analyzed. Incretin polyagonists significantly reduced body weight compared to placebo (MD -11.47; 95% CI: -14.00 to -8.95). Significant reductions were also observed in waist circumference (MD -9.40; 95% CI: -11.91 to -6.89), glycated hemoglobin (MD -0.96; 95% CI: -1.16 to -0.75), and fasting plasma glucose (MD -26.89 mg/dL; 95% CI: -33.48 to -20.30). However, the use of dual and triple agonists was associated with a higher risk of any adverse events (AEs) (RR 1.13; 95% CI: 1.08-1.19), including gastrointestinal AEs (nausea, vomiting, diarrhea, constipation), AEs leading to withdrawal (RR 1.96; 95% CI: 1.17-3.30), and hypoglycemic episodes (RR 3.08; 95% CI: 1.61-5.89). No significant difference was found in serious AEs (RR 0.87; 95% CI: 0.65-1.14). In conclusion, incretin-based polyagonists were associated with significant weight reduction and improved metabolic outcomes compared to placebo.

Efficacy and Safety of Retatrutide in the Treatment of Diabetes and/or Obesity Comorbid with Chronic Kidney disease: a Systematic Review and Meta-Analysis.

Kumari Pallavi, Anshuman Chandra, Keshav Kumar +4 more

There are still substantial clinical challenges in treating patients who come with type 2 diabetes and/or obesity in addition to chronic kidney disease (CKD). Retatrutide, an innovative agent, represents a potential advancement in therapy; however, its performance and safety profile specifically in a CKD population are not fully determined yet. This meta-analysis and systematic review sought to consolidate existing research on the use of retatrutide in this comorbid patient group. A comprehensive literature search identified relevant randomized controlled trials for inclusion. Reductions in glycated hemoglobin (HbA1c) and body weight were the primary goals for evaluating effectiveness, whereas adverse events were used to evaluate safety. Eight studies were included in the present research work. A significant mean reduction in HbA1c of -1.04% (95% CI -1.42 to -0.67) and a noticeable loss in weight, reaching up to -24.2%, were both linked with retatrutide treatment. A subgroup analysis indicated that the glycemic benefits were dose-dependent, with lower doses (≤8 mg) demonstrating a greater HbA1c reduction (-1.39%) than higher doses (≥12 mg, -0.65%). Furthermore, secondary analyses pointed toward possible renoprotective effects, evidenced by a reduction in albuminuria. The safety profile is primarily characterized by gastrointestinal adverse events, which is anticipated for this drug class. In conclusion, retatrutide exhibits strong efficacy for improving glucose levels and promoting weight loss in patients with diabetes, obesity and CKD, displaying a distinctive dose-response pattern where lower doses may be more effective for glycemic control. Its potential for kidney protection is promising, though clinicians should be mindful of managing gastrointestinal tolerability.

IUPHAR review: From foe to friend: Repurposing glucagon to treat obesity and type 2 diabetes.

Andrew J Elmendorf, Mostafa Yousefian, Il-Man Kim +3 more

The epidemics of metabolic disease, in the form of obesity and type 2 diabetes, are a growing public health concern. However, incretin-based therapeutics have transformed our ability to address these diseases. While this current generation of incretin analogues show weight regain upon cessation of treatment, the amount of which can depend on the treatment and patient, iterative advancements may improve weight loss durability in the long term. In this review, we discuss the development of glucagon like peptide-1 receptor (GLP-1R) agonists and GLP-1R/ glucose-dependent insulinotropic polypeptide receptor (GIPR) co-agonists, and how future generations will leverage this strategy. We focus our review on glucagon receptor (GCGR) agonism, which has recently been combined with both GLP-1R and GLP-1R/GIPR agonism to generate dual (e.g. survodutide, cotatutide, mazdutide, etc) and triple agonists (e.g. retatrutide, etc) for improved body weight loss via energy expenditure stimulation. We rely on largely pre-clinical evidence for action because clinical data is extremely limited for GCGR agonism. Herein, we review mechanisms by which glucagon receptor agonists act to increase energy expenditure. Finally, we discuss future improvements to incretin-based therapeutics, and how they can include strategies that target the GCGR. The purpose of this review is to discuss mechanisms by which GCGR agonism can reduce body weight and put them in the context of the combination with incretin receptor agonists. Mechanistic data has only currently been evaluated in preclinical rodent models and evidence for similar processes in humans is limited. We also provide perspectives about how treatments can improve for future advancement of obesity treatment.

Medical Management of Obesity: A Comprehensive Review of Food and Drug Administration (FDA)-Approved and Investigational Therapies.

Syed S Raza, Zarshal Zakir, Ahmad Hashmat +2 more

The global rise in obesity has accelerated both clinical and pharmaceutical innovation in antiobesity pharmacotherapy. This narrative review synthesizes current evidence on Food and Drug Administration-approved medications and emerging investigational agents that are shaping clinical practice. We summarize mechanisms of action, pivotal efficacy data, safety profiles, indications, prescribing guidance, and key uncertainties. Approved long-term agents, orlistat, phentermine/topiramate, naltrexone/bupropion, liraglutide, semaglutide, and tirzepatide, differ in mechanism, weight-loss magnitude, and safety considerations. Semaglutide and tirzepatide have redefined expectations for pharmacological weight loss, while next-generation drugs, such as oral glucagon-like peptide 1 receptor agonists (e.g., orforglipron) and multireceptor agonists (e.g., retatrutide), show even greater efficacy in early studies. Common safety concerns include gastrointestinal effects, gallbladder events, pancreatitis risk, thyroid C-cell tumor warnings, teratogenicity, and cost barriers. Appropriate patient selection depends on body mass index, comorbidities, contraindications, and treatment goals, with close monitoring throughout therapy. Long-term data on cardiovascular outcomes and posttreatment weight durability are emerging. Future research should prioritize direct comparative trials, real-world effectiveness, long-term safety, and strategies to improve access and adherence. This review offers clinicians a concise, evidence-based guide for obesity pharmacotherapy and outlines key research priorities as the treatment landscape rapidly evolves.

Harnessing GLP-1 Receptor Agonists for Obesity Treatment: Prospects and Obstacles on the Horizon.

Riad Mohammed Abdelrahman, Taha Hussein Musa, Ismail Adam Arbab +6 more

Obesity has emerged as a pressing global health challenge, and therapies based on glucagon-like Peptide 1 receptor agonists (GLP-1RAs) have transformed its management. Currently, liraglutide, semaglutide, and tirzepatide are FDA-approved for obesity treatment, while other agents are used off-label. These drugs not only provide unprecedented efficacy and acceptable safety in weight reduction and glycemic control for patients with obesity and Type 2 diabetes but also hold promise in broader indications, including neurodegenerative disorders, fatty liver disease, dyslipidemia, atherosclerosis, and cardiovascular conditions.

Perceived benefits of treatment for obesity with retatrutide: A qualitative study of patients in a phase 2 clinical trial.

Iris A Goetz, Chisom Kanu, Anastasia Hoover +5 more

Retatrutide, an agonist of glucose-dependent insulinotropic polypeptide, glucagon-like peptide-1, and glucagon receptors, is in development for the treatment of obesity. We interviewed participants exiting a phase 2 trial to understand the impact of retatrutide on eating behaviors, physical aspects, emotions, and lifestyle.

Appetite, eating attitudes, and eating behaviours during treatment with retatrutide in adults with type 2 diabetes: Results of a phase 2 study.

Chisom Kanu, Kristina S Boye, Jiat Ling Poon +6 more

To determine whether adults with type 2 diabetes (T2D) treated with retatrutide report greater changes in self-reported appetite, dietary restraint, and disinhibition compared to placebo or dulaglutide and to examine associations with weight change.

Glucagon-like peptide-1 receptor analogues and beyond: emerging obesity pharmacotherapies.

Kaivalya Abburi, Eka Melson, Alexander D Miras +1 more

Obesity is a chronic disease associated with multiple health risks. Multimodal treatments including lifestyle interventions, pharmacotherapies and bariatric surgery should be the standard of care for obesity management. Bariatric surgery remains the most effective treatment yielding to sustainable weight loss (WL) of about 20-30%. Having understood better the role of the gut-brain axis on appetite, the field of obesity pharmacotherapy has been advancing rapidly. The recent approvals for glucagon-like peptide-1 (GLP-1) receptor agonist (RA) semaglutide 2.4 mg and the dual GLP-1 and glucose-dependent insulinotropic polypeptide (GIP) agonist tirzepatide as treatments for obesity have raised the bar for WL efficacy for the emerging obesity pharmacotherapies. Combining GLP-1 RA and other entero-pancreatic hormones including GIP, glucagon or amylin receptor agonists (RAs) as well as GIP receptor antagonists have shown promising data in early phases of clinical trials, with some progressing to phase III clinical trials. Notably, the combinations of GLP-1 RA, GIP and glucagon RA (retatrutide) have shown WL efficacy closing on to that observed in bariatric surgery. While entero-pancreatic hormone-based therapies have been the centre of attention for obesity pharmacotherapies, non- entero-pancreatic hormone treatments also hold promise. In this review, we present the future pharmacotherapies for weight management in people with obesity, focusing on entero-pancreatic hormone-based molecules.

Weight management treatment in obesity.

Miguel A Rubio-Herrera, Sara Mera-Carreiro

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.

The Effects of Glucagon-Like Peptide-1 (GLP-1) Receptor Agonists on Polycystic Ovarian Syndrome: A Scoping Review.

Mia Hudanich, Shannon N Smith, Amanda Marino +1 more

Polycystic ovarian syndrome (PCOS) is the most common endocrinopathy in reproductive-aged women worldwide; however, treatment modalities often lack cohesion due to its multifactorial pathophysiology. PCOS is suspected of inducing insulin resistance. Research has explored the use of newly developed incretin mimetics as standard therapy for insulin resistance in insulin-dependent tissues associated with PCOS. The aim of this review was to explore the classes of incretin mimetics, such as glucagon-like peptide-1 (GLP-1) receptor agonists or semaglutide, dual agonists of the GLP-1 receptor and gastric inhibitory peptide (GIP) or tirzepatide, and a new triple agonist, or retatrutide (which is currently seeking Food and Drug Administration (FDA) approval), and their suggested benefits as a treatment for PCOS. A literature review was conducted using EBSCO Medline and PubMed following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. All three classes of incretin mimetics showed significant improvement in weight loss and insulin sensitivity when compared to traditional pharmacological management with metformin and estradiol-progesterone combination pills in patients with PCOS. The added upregulation of GIP in dual-acting and triple-acting agonists, such as tirzepatide and retatrutide, respectively, resulted in greater reductions in weight loss and insulin sensitivity when compared to medications that acted at the GLP-1 receptor alone. Some research demonstrated symptom improvements specific to PCOS presentation, such as dysmenorrhea and the classic dysmorphic ovarian morphology. Further research is warranted to determine the exact mechanism behind how incretin mimetics may improve the hormonal dysregulation in patients with PCOS, as well as how to best use these medications in conjunction with the current standard of care treatments.

Strategic Design of Triple GLP-1R/GCGR/GIPR Agonists with Varied Receptor Potency: Achieving Comparable Glycemic and Weight Reduction Effects.

Shuang Wang, Yun Liu, Zhiming Yan +8 more

Triple activation of the glucagon-like peptide 1 receptor (GLP-1R), the GIP receptor (GIPR), and the glucagon receptor (GCGR) is an innovative strategy for treating obesity and diabetes. We report the rational design of triple GLP-1R/GCGR/GIPR agonists, featuring potent GLP-1R and GCGR activity with weaker GIPR activation. Using sequence analysis, molecular dynamics simulations, docking, and amino acid optimization, we developed xGLP-1-based triagonists, with xGLP/GCG/GIP-32 exhibiting a unique activation profile. It shows superior weight loss effects compared to tirzepatide and similar metabolic efficacy to retatrutide, despite significantly less potent GIPR activity. Preliminary mechanistic studies revealed that xGLP/GCG/GIP-32 exhibits biased agonism toward the GIPR and GCGR. These activity data suggest it may not be imperative to focus solely on potent activation of all three receptors. Especially for triple agonists with receptor-biased agonism, there may be room to explore optimal receptor activation ratios.

Saving muscle while losing weight: A vital strategy for sustainable results while on glucagon-like peptide-1 related drugs.

Maja Cigrovski Berkovic, Lana Ruzic, Vjekoslav Cigrovski +1 more

Obesity affects over 1 billion people worldwide and is linked to more than 230 health complications, with cardiovascular disease being a leading cause of mortality. Losing 5%-10% of body weight is considered clinically significant for improving health. This weight loss can be achieved through pharmacotherapy, including glucagon-like peptide 1 (GLP-1) receptor agonists, GLP-1/glucose-dependent insulinotropic peptide dual receptor agonists, and GLP-1/glucose-dependent insulinotropic peptide/glucagon triple receptor agonists (such as semaglutide, tirzepatide, and retatrutide, respectively). While much of the weight loss comes from fat mass, these treatments also result in the loss of lean mass, including muscle. This loss of muscle may contribute to difficulties in maintaining weight over the long term and can lead to sarcopenia. Therefore, the focus of new anti-obesity treatments should be primarily on reducing fat mass while minimizing the loss of muscle mass, ideally promoting muscle gain. Research focusing on human myocytes has identified more than 600 myokines associated with muscle contraction, which may play a crucial role in preserving both muscle mass and function. We explored the potential of new anti-obesity agents and their combinations with incretin-based therapies to achieve these outcomes. Further studies are needed to better understand the functional implications of lean mass expansion during weight loss and weight maintenance programs.

Efficacy and safety of incretin co-agonists: Transformative advances in cardiometabolic healthcare.

Sowrabha Bhat, Cornelius J Fernandez, Vijaya Lakshmi +1 more

The ground-breaking development of the incretin agonists by manipulation of the incretin system, including the gut hormones glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), as well as the pancreatic hormone glucagon, has led to the emergence of promising pharmacotherapy for metabolic health. The GLP-1 receptor agonists (GLP-1RAs), namely liraglutide, dulaglutide, albiglutide, exenatide, and semaglutide, have been found to have beneficial effects on glycated hemoglobin, weight, lipid profile, and liver fat and thereby improving cardiometabolic health. Other drugs of the same group in development include Orforglipron, which has a high weight loss efficacy (-15% weight reduction). Long-acting GLP-1RAs in trials are Ecnoglutide, Efpeglenatide, TG103, and Visepegenatide. Many of these have cardiovascular benefits in terms of reduction in MACE (Non-fatal MI, Non-fatal stroke, and mortality). Tirzepatide is a dual GIP/GLP-1RA, the first drug of the group to be approved for diabetes and obesity with remarkably lower gastrointestinal side effects compared to GLP-1 monoagonists. The dual GLP-1/glucagon co-agonists cause tremendous weight loss due to the synergistic action. Most drugs in this class are long-acting and developed for once-weekly administration. The revolutionary triple agonists at the GLP-1, GIP, and Glucagon receptors have demonstrated the highest achievable weight loss with pharmacotherapy. Retatrutide and Efocipegtrutide belong to this novel group of drugs. The newer drugs in the broad category of incretin co-agonists include the GLP-1/amylin receptor agonist like CagriSema and Amycretin, oral GLP-1 agonists other than semaglutide, and the peptide YY/GLP-1 receptor dual agonists. The profound biochemical and weight loss outcomes associated with incretin co-/poly-agonists are expected to translate into outstanding cardiometabolic benefits, the theme of this evidence review.

Decreases in circulating ANGPTL3/8 concentrations following retatrutide treatment parallel reductions in serum lipids.

Yi Wen, Deven Lemen, Yanzhu Lin +10 more

The aim of this study was to determine if retatrutide, a triple agonist of glucose-dependent insulinotropic polypeptide (GIP) receptor, glucagon-like peptide 1 (GLP-1) receptor and glucagon (GCG) receptor, may lower serum triglyceride (TG) and low-density lipoprotein cholesterol (LDL-C) levels in part by decreasing circulating concentrations of the angiopoietin-like protein 3/8 complex (ANGPTL3/8).

Effect of Incretin-Based Therapies on Blood Pressure: A Systematic Review and Meta-Analysis.

Christian Basile, Aurora Merolla, Costantino Mancusi +7 more

Hypertension and obesity frequently coexist and synergistically increase cardiovascular (CV) risk. Incretin-based therapies with glucagon-like peptide-1 receptor agonists (GLP-1-RAs), gastric inhibitory polypeptide (GIP)/GLP1-RAs, and glucagon/GIP/GLP-1RAs lead to substantial weight loss. However, their antihypertensive efficacy and safety profile have not been comprehensively quantified. Our study aimed to evaluate the effects of incretin-based therapies on office systolic blood pressure (BP) (SBP), diastolic BP (DBP), all-cause mortality, and key safety outcomes, i.e., hypoglycemia and pancreatitis episodes, in adults with overweight or obesity.

Triple Agonism Based Therapies for Obesity.

Jonathan Goldney, Malak Hamza, Farhaana Surti +2 more

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.

Review: Special Issue: Real-world evidence on the use of GLP1 receptor agonists: Emerging concepts in obesity management: focus on glucagon receptor agonist combinations.

Sarah L Anderson

The global rise in obesity and its associated health risks has driven the need for more effective pharmacological treatments. Glucagon receptor (GCGR)-based multi-agonist drugs are emerging as promising treatments for obesity, with several in advanced stages of clinical development. Agents like mazdutide, pemvidutide, survodutide and retatrutide have demonstrated the ability to trigger significant weight loss in earlier phase trials, often surpassing the amount of weight loss obtained with existing therapies. Their potential to address obesity-related comorbidities, including type 2 diabetes mellitus and cardiovascular disease, positions them as important additions to future obesity treatment guidelines. As these GCGR-based multi-agonists advance through clinical trials, their impact on obesity management may be substantial, particularly for patients who have not achieved success with current medications or lifestyle interventions. Some are also being evaluated for cardiovascular outcomes, highlighting their relevance in populations at high risk with overweight and obesity. Key considerations as these drugs move forward in development to eventual approval include cost, access and long-term safety. This article is part of the Real-world evidence on the use of GLP1 receptor agonists Special Issue: https://www.drugsincontext.com/special_issues/real-world-evidence-on-the-use-of-glp1-receptor-agonists.

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

Saurav Misra, Ravi Kant Narayan, Manmeet Kaur

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 need.