Published Research
Efficacy and safety of co-administered cagrilintide and semaglutide versus semaglutide alone in adults with overweight or obesity with or without type 2 diabetes in Japan and Taiwan (REDEFINE 5): a multicentre, randomised, active-controlled, phase 3a trial.
Yamauchi T, Becker NP, Hagemann CA, Huang KC, Kiyosue A, et al. — 2026
BACKGROUND: The combination of cagrilintide and semaglutide has been shown in global studies to induce reductions in bodyweight. We assessed the efficacy and safety of a fixed-dose combination of cagrilintide 2·4 mg and semaglutide 2·4 mg versus semaglutide 2·4 mg for weight management in an east Asian population. METHODS: This double-blind, parallel-group, phase 3a trial (REDEFINE 5) was conducted across 21 sites (community, hospital) in Japan and one site in Taiwan. We included participants aged at least 18 years with a BMI of at least 27 kg/m and at least two obesity-related complications, or with a BMI of at least 35 kg/m and at least one obesity-related complication (per the Japan Society for the Study of Obesity guidelines), with or without type 2 diabetes. Participants were randomly assigned (1:1) to once-weekly subcutaneous injections of cagrilintide-semaglutide or semaglutide (both escalated to 2·4 mg), plus lifestyle intervention, for 68 weeks. Randomisation was done centrally using an interactive web response system and stratified according to planned CT scan, BMI of at least 35 kg/m, and type 2 diabetes status. Participants, site staff, investigators, and study funder were all masked to active study treatments. The primary endpoint was relative change in bodyweight from baseline to week 68. Efficacy analyses were done in all participants who underwent randomisation, using the trial product estimand (ie, assuming the treatment was taken as intended, regardless of dose) as the primary estimand. Missing data at week 68 were imputed. Safety analyses were done in all participants who underwent randomisation and received at least one dose of trial product. This trial is registered with ClinicalTrials.gov (NCT05813925) and is complete. FINDINGS: Between April 3, 2023, and Sept 15, 2023, we screened 355 individuals; 331 were randomly assigned to cagrilintide-semaglutide (n=164) or semaglutide (n=167). 226 (68%) participants were male and 105 (32%) were female; 80 (24%) had type 2 diabetes. 17 (10%) participants discontinued cagrilintide-semaglutide and ten (6%) discontinued semaglutide. The estimated mean change in bodyweight from baseline to week 68 was -18·4% (SE 0·7) in the cagrilintide-semaglutide group versus -11·9% (0·7) in the semaglutide group (estimated treatment difference [ETD] -6·5 percentage points [95% CI -8·4 to -4·6]; p<0·0001). Adverse events were reported by 143 (87%) of 164 participants in the cagrilintide-semaglutide group and 141 (84%) of 167 in the semaglutide group, the most common of which were gastrointestinal disorders (87 [53%] of 164 participants in the cagrilintide-semaglutide group vs 85 [51%] of 167 in the semaglutide group). One death was reported in the semaglutide 2·4 mg group, which was not judged to be treatment related by the investigator. INTERPRETATION: These findings support the efficacy and safety of cagrilintide-semaglutide for weight management in individuals from east Asia with overweight or obesity, with or without type 2 diabetes. FUNDING: Novo Nordisk. TRANSLATIONS: For the Japanese and Mandarin translations of the abstract see Supplementary Materials section.
Obesity pharmacotherapy reimagined: The era of multi-receptor agonists and next-generation metabolic modulators, perspectives and controversies.
Lempesis IG, Dalamaga M — 2026
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.
Mishra NK — 2026
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.
New Drugs on the Block: Dietary Management and Nutritional Considerations During the Use of Anti-Obesity Medication.
Pardali EC, Gkouskou KK, Cholevas C, Poulimeneas D, Tsiroukidou K, et al. — 2026
Incretin-based pharmacotherapy has rapidly transformed obesity management. However, despite its efficacy, gastrointestinal (GI) adverse events (AEs) are common and represent a major driver of treatment discontinuation. Symptoms such as nausea, vomiting, acid reflux, diarrhea, and constipation, not only impair the quality of life, but also compromise adherence, thereby limiting the real-world effectiveness of these agents. Targeted nutritional strategies may play a pivotal role in mitigating these symptoms and supporting sustained treatment. However, most clinical trials have relied on generalized lifestyle advice combined with hypocaloric dietary prescriptions, with limited integration of structured, mechanism-based nutritional counseling tailored to the physiological actions of glucagon-like peptide-1 receptor agonists (GLP-1 RAs) and dual glucose-dependent insulinotropic polypeptide (GIP)/GLP-1 RAs. Consequently, practical guidance for clinicians and dietitians remains fragmented. The present review synthesizes the available evidence on GI AEs associated with incretin-based therapies and examines whether structured, targeted nutritional management can meaningfully reduce symptom burden. We also outline key monitoring strategies and focus on important clinical aspects for physicians and dietitians, aiming to optimize patient outcomes. In addition, we provide detailed information on the spectrum of GI AEs to guide effective management and limit intolerance. By bridging pharmacology with applied clinical nutrition, we aim to provide a pragmatic framework for improving tolerability, sustaining adherence, and translating trial efficacy into durable real-world effectiveness.
Mitochondrial Adaptations in Skeletal Muscle Following Incretin-Based Therapies: In Vitro.
Old V, Davies M, Denniff M, Choudhary P, Eastley N, et al. — 2026
BACKGROUND: Incretin-based therapies such as glucagon-like peptide-1 receptor agonists (GLP-1Ras), dual GLP-1/GIP agonists and amylin analogues have demonstrated significant weight loss benefits. However, their impact on skeletal muscle mitochondrial function, particularly under metabolic stress, remains unclear. This study aimed to investigate the effects of semaglutide (GLP-1RA), tirzepatide (dual GLP-1/GIP agonist) and cagrilintide (amylin analogue) on mitochondrial function in C2C12 skeletal muscle myotubes under both healthy and lipotoxic (palmitic acid-treated) conditions. METHODS: Differentiated C2C12 myotubes were treated with doses of each drug for 48 h and 5 days. Mitochondrial respiration was assessed using the Seahorse XFp analyser, mitochondrial DNA (mtDNA) copy number and oxidative phosphorylation (OXPHOS) complex protein expression were measured by qPCR and western blotting. Key findings were repeated in primary human skeletal muscle cells. RESULTS: Palmitic acid (PA) significantly impaired mitochondrial function, reducing basal oxygen consumption rate (OCR) by 22% (p = 0.0056) and ATP production by 25% (p = 0.0022). In healthy myotubes, semaglutide and cagrilintide transiently reduced basal respiration (↓21%-28%, p < 0.05) and ATP production (↓24%-31%, p < 0.01) at 48 h, along with reductions in Complexes I, III and IV protein expression, all of which resolved by 5 days. Tirzepatide significantly increased maximal respiration (↑20%-25%, p < 0.005) and spare respiratory capacity (↑22%-30%, p < 0.005) after 5 days. In PA-treated myotubes, semaglutide and cagrilintide acutely worsened mitochondrial impairment (↓ATP production by ~20%-25%, p < 0.01), but these effects resolved by Day 5. Tirzepatide initially suppressed mitochondrial function (↓ATP production, p = 0.0087) but reversed these effects by Day 5, significantly improving ATP production (↑27%-30%, p < 0.005), basal respiration (↑20%, p = 0.0152), and coupling efficiency. mtDNA content remained unchanged across all conditions. Similar responses were noted in human myotubes, with a transient reduction in respiration for semaglutide and cagrilintide (↓30%-62%, p < 0.05) at 48 h and a significant improvement in maximal respiration for tirzepatide at 5 days (↑42%-52%, p = 0.0022). CONCLUSION: Incretin-based therapies exert distinct, time and dose-dependent effects on skeletal muscle mitochondrial function. Tirzepatide promoted sustained improvements in mitochondrial respiration under both healthy and lipotoxic conditions, indicating potential benefits for maintaining skeletal muscle bioenergetic function. These findings underscore the need for further mechanistic studies and suggest that tirzepatide may have the potential to support skeletal muscle health in metabolic disease.