Cagrilintide

Coadministered Cagrilintide and Semaglutide in Adults with Overweight or Obesity.

Semaglutide at a dose of 2.4 mg has established weight-loss and cardiovascular benefits, and cagrilintide at a dose of 2.4 mg has shown promising results in early-phase trials; the efficacy of the combination (known as CagriSema) on weight loss in persons with either overweight and coexisting conditions or obesity is unknown. In a phase 3a, 68-week, multicenter, double-blind, placebo-controlled and active-controlled trial, we enrolled adults without diabetes 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 a BMI of 27 or higher with at least one obesity-related complication. Participants were randomly assigned in a ratio of 21:3:3:7 to receive the combination of semaglutide at a dose of 2.4 mg and cagrilintide at a dose of 2.4 mg, semaglutide alone at a dose of 2.4 mg, cagrilintide alone at a dose of 2.4 mg, or placebo, plus lifestyle interventions for all groups. The coprimary end points were the relative change in body weight and a reduction of 5% or more in body weight from baseline to week 68 with cagrilintide-semaglutide as compared with placebo. Body-weight reductions of 20% or more, 25% or more, and 30% or more were assessed as confirmatory secondary end points. Effect estimates were assessed with the treatment-policy estimand (consistent with the intention-to-treat principle). Safety was assessed. A total of 3417 participants underwent randomization, with 2108 assigned to receive cagrilintide-semaglutide, 302 to receive semaglutide, 302 to receive cagrilintide, and 705 to receive placebo. The estimated mean percent change in body weight from baseline to week 68 was -20.4% with cagrilintide-semaglutide as compared with -3.0% with placebo (estimated difference, -17.3 percentage points; 95% confidence interval, -18.1 to -16.6; P<0.001). Participants receiving cagrilintide-semaglutide were more likely than those receiving placebo to reach weight-loss targets of 5% or more, 20% or more, 25% or more, and 30% or more (P<0.001 for all comparisons). Gastrointestinal adverse events (affecting 79.6%&#xa0;in the cagrilintide-semaglutide group and 39.9% in the placebo group), including nausea, vomiting, diarrhea, constipation, or abdominal pain, were mainly transient and mild-to-moderate in severity. Cagrilintide-semaglutide provided significant and clinically relevant body-weight reductions in adults with overweight or obesity, as compared with placebo. (Funded by Novo Nordisk; REDEFINE 1 ClinicalTrials.gov number, NCT05567796.).

Cagrilintide-Semaglutide in Adults with Overweight or Obesity and Type 2 Diabetes.

Cagrilintide and semaglutide have each been shown to induce weight loss as monotherapies. Data are needed on the coadministration of cagrilintide and semaglutide (called CagriSema) for weight management in adults with type 2 diabetes, including those in a subgroup who are undergoing continuous glucose monitoring. In this phase 3a, double-blind, randomized, placebo-controlled trial conducted in 12 countries, we assigned adults with a body-mass index of 27 or more, a glycated hemoglobin level of 7 to 10%, and type 2 diabetes in a 3:1 ratio to receive once-weekly cagrilintide-semaglutide (2.4 mg each) or placebo, along with lifestyle intervention, for 68 weeks. The two primary end points were the percent change in body weight and the percentage of patients with a weight reduction of at least 5%. Additional end points were changes in glycemic measures and safety assessments. Effect estimates were calculated with the use of the treatment-policy estimand (consistent with the intention-to-treat principle). A total of 1206 patients underwent randomization to either the cagrilintide-semaglutide group (904 patients) or the placebo group (302 patients). The estimated mean change in body weight from baseline to week 68 was -13.7% in the cagrilintide-semaglutide group and -3.4% in the placebo group (estimated difference, -10.4 percentage points; 95% confidence interval, -11.2 to -9.5; P<0.001). More patients in the cagrilintide-semaglutide group than in the placebo group had a weight reduction of 5% or more (P<0.001); the same was true of reductions of at least 10%, 15%, and 20% (P<0.001 for the last comparison). The percentage of patients who had a glycated hemoglobin level of 6.5% or less was 73.5% in the cagrilintide-semaglutide group and 15.9% in the placebo group. Gastrointestinal adverse events were reported by 72.5% of the patients in the cagrilintide-semaglutide group and 34.4% in the placebo group, most of which were transient and mild or moderate in severity. Once-weekly cagrilintide-semaglutide (at a dose of 2.4 mg each) resulted in a significantly lower body weight than placebo in adults with obesity and type 2 diabetes. (Funded by Novo Nordisk; REDEFINE 2 ClinicalTrials.gov number, NCT05394519.).

Comparative effectiveness of GLP-1 receptor agonists on glycaemic control, body weight, and lipid profile for type 2 diabetes: systematic review and network meta-analysis.

To evaluate the comparative efficacy and safety of glucagon-like peptide-1 receptor agonists (GLP-1RAs) on glycaemic control, body weight, and lipid profile in adults with type 2 diabetes. Systematic review and network meta-analysis. PubMed, Web of Science, Cochrane Central Register of Controlled Trials (CENTRAL), and Embase from database inception to 19 August 2023. Eligible randomised controlled trials enrolled adults with type 2 diabetes who received GLP-1RA treatments and compared effects with placebo or any GLP-1RA drug, with a follow-up duration of at least 12 weeks. Trials with a crossover design, non-inferiority studies comparing GLP-1RA and other drug classes without a placebo group, using withdrawn drugs, and non-English studies were deemed ineligible. 76 eligible trials involving 15 GLP-1RA drugs and 39&#x2009;246 participants were included in this network meta-analysis; all subsequent estimates refer to the comparison with placebo. All 15 GLP-1RAs effectively lowered haemoglobin A1c and fasting plasma glucose concentrations. Tirzepatide induced the largest reduction of haemoglobin A1c concentrations (mean difference -2.10% (95% confidence interval -2.47% to -1.74%), surface under the cumulative ranking curve 94.2%; high confidence of evidence), and fasting plasma glucose concentrations (-3.12 mmol/L (-3.59 to -2.66), 97.2%; high confidence), and proved the most effective GLP-1RA drug for glycaemic control. Furthermore, GLP-1RAs were shown to have strong benefits to weight management for patients with type 2 diabetes. CagriSema (semaglutide with cagrilintide) resulted in the highest weight loss (mean difference -14.03 kg (95% confidence interval -17.05 to -11.00); high confidence of evidence), followed by tirzepatide (-8.47 kg (-9.68 to -7.26); high confidence). Semaglutide was effective in lowering the concentration of low density lipoprotein (-0.16 mmol/L (-0.30 to -0.02)) and total cholesterol (-0.48 mmol/L (-0.84 to -0.11)). Moreover, this study also raises awareness of gastrointestinal adverse events induced by GLP-1RAs, and concerns about safety are especially warranted for high dose administration. GLP-1RAs are efficacious in treating adults with type 2 diabetes. Compared with the placebo, tirzepatide was the most effective GLP-1RA drug for glycaemic control by reducing haemoglobin A1c and fasting plasma glucose concentrations. GLP-1RAs also significantly improved weight management for type 2 diabetes, with CagriSema performing the best for weight loss. The results prompt safety concerns for GLP-1RAs, especially with high dose administration, regarding gastrointestinal adverse events. PROSPERO CRD42022342845.

Efficacy and safety of co-administered once-weekly cagrilintide 2&#xb7;4 mg with once-weekly semaglutide 2&#xb7;4 mg in type 2 diabetes: a multicentre, randomised, double-blind, active-controlled, phase 2 trial.

Combining the GLP-1 receptor agonist semaglutide with the long-acting amylin analogue cagrilintide has weight-loss benefits; the impact on glycated haemoglobin (HbA1c) is unknown. This trial assessed the efficacy and safety of co-administered semaglutide with cagrilintide (CagriSema) in participants with type 2 diabetes. This 32-week, multicentre, double-blind, phase 2 trial was conducted across 17 sites in the USA. Adults with type 2 diabetes and a BMI of 27 kg/m2 or higher on metformin with or without an SGLT2 inhibitor were randomly assigned (1:1:1) to once-weekly subcutaneous CagriSema, semaglutide, or cagrilintide (all escalated to 2&#xb7;4 mg). Randomisation was done centrally using an interactive web response system and was stratified according to use of SGLT2 inhibitor treatment (yes vs no). The trial participants, investigators, and trial sponsor staff were masked to treatment assignment throughout the trial. The primary endpoint was change from baseline in HbA1c; secondary endpoints were bodyweight, fasting plasma glucose, continuous glucose monitoring (CGM) parameters, and safety. Efficacy analyses were performed in all participants who had undergone randomisation, and safety analyses in all participants who had undergone randomisation and received at least one dose of the trial medication. This trial is registered on ClinicalTrials.gov (NCT04982575) and is complete. Between Aug 2 and Oct 18, 2021, 92 participants were randomly assigned to CagriSema (n=31), semaglutide (n=31), or cagrilintide (n=30). 59 (64%) participants were male; the mean age of participants was 58 years (SD 9). The mean change in HbA1c from baseline to week 32 (CagriSema: -2&#xb7;2 percentage points [SE 0&#xb7;15]; semaglutide: -1&#xb7;8 percentage points [0&#xb7;16]; cagrilintide: -0&#xb7;9 percentage points [0&#xb7;15]) was greater with CagriSema versus cagrilintide (estimated treatment difference -1&#xb7;3 percentage points [95% CI -1&#xb7;7 to -0&#xb7;8]; p<0&#xb7;0001), but not versus semaglutide (-0&#xb7;4 percentage points [-0&#xb7;8 to 0&#xb7;0]; p=0&#xb7;075). The mean change in bodyweight from baseline to week 32 (CagriSema: -15&#xb7;6% [SE 1&#xb7;26]; semaglutide: -5&#xb7;1% [1&#xb7;26]; cagrilintide: -8&#xb7;1% [1&#xb7;23]) was greater with CagriSema versus both semaglutide (p<0&#xb7;0001) and cagrilintide (p<0&#xb7;0001). The mean change in fasting plasma glucose from baseline to week 32 (CagriSema: -3&#xb7;3 mmol/L [SE 0&#xb7;3]; semaglutide: -2&#xb7;5 mmol/L [0&#xb7;4]; cagrilintide: -1&#xb7;7 mmol/L [0&#xb7;3]) was greater with CagriSema versus cagrilintide (p=0&#xb7;0010) but not versus semaglutide (p=0&#xb7;10). Time in range (3&#xb7;9-10&#xb7;0 mmol/L) was 45&#xb7;9%, 32&#xb7;6%, and 56&#xb7;9% at baseline and 88&#xb7;9%, 76&#xb7;2%, and 71&#xb7;7% at week 32 with CagriSema, semaglutide, and cagrilintide, respectively. Adverse events were reported by 21 (68%) participants in the CagriSema group, 22 (71%) in the semaglutide group, and 24 (80%) in the cagrilintide group. Mild or moderate gastrointestinal adverse events were most common; no level 2 or 3 hypoglycaemia was reported. No fatal adverse events were reported. In people with type 2 diabetes, treatment with CagriSema resulted in clinically relevant improvements in glycaemic control (including CGM parameters). The mean change in HbA1c with CagriSema was greater versus cagrilintide, but not versus semaglutide. Treatment with CagriSema resulted in significantly greater weight loss versus semaglutide and cagrilintide and was well tolerated. These data support further investigation of CagriSema in this population in longer and larger phase 3 studies. Novo Nordisk.

Once-weekly cagrilintide for weight management in people with overweight and obesity: a multicentre, randomised, double-blind, placebo-controlled and active-controlled, dose-finding phase 2 trial.

Natural amylin is a pancreatic hormone that induces satiety. Cagrilintide is a long-acting amylin analogue under investigation for weight management. We assessed the dose-response relationship of cagrilintide regarding the effects on bodyweight, safety, and tolerability. We conducted a multicentre, randomised, double-blind, placebo-controlled and active-controlled, dose-finding phase 2 trial at 57 sites including hospitals, specialist clinics, and primary care centres in ten countries (Canada, Denmark, Finland, Ireland, Japan, Poland, Serbia, South Africa, the UK, and the USA). Eligible participants were adults aged at least 18 years without diabetes, with a body-mass index of at least 30 kg/m2 or at least 27 kg/m2 with hypertension or dyslipidaemia. Participants were randomly assigned (6:1) to subcutaneous self-injections of once-weekly cagrilintide (0&#xb7;3, 0&#xb7;6, 1&#xb7;2, 2&#xb7;4, or 4&#xb7;5 mg), once-daily liraglutide 3&#xb7;0 mg, or volume-matched placebo (for six placebo groups). The trial had a 26-week treatment period, including a dose-escalation period of up to 6 weeks, and a 6-week follow-up period without treatment. Participants and investigators were masked to the assigned study treatment with respect to active versus pooled placebo treatment, but not to different active treatments. The primary endpoint was the percentage change in bodyweight from baseline to week 26, assessed in all randomly assigned participants according to the trial product estimand (assuming all participants were adherent to treatment) and to the treatment policy estimand (regardless of adherence to treatment). Safety was assessed in all participants who received at least one dose of randomised treatment. This trial is registered with ClinicalTrials.gov, NCT03856047, and is closed to new participants. Between March 1 and Aug 19, 2019, we randomly assigned 706 participants to cagrilintide 0&#xb7;3-4&#xb7;5 mg (100-102 per dose group), 99 to liraglutide 3&#xb7;0 mg, and 101 to placebo. Permanent treatment discontinuation (n=73 [10%]) occurred similarly across treatment groups, mostly due to adverse events (n=30 [4%]). In total, 29 participants (4%) withdrew from the trial. According to the trial product estimand, mean percentage weight reductions from baseline were greater with all doses of cagrilintide (0&#xb7;3-4&#xb7;5 mg, 6&#xb7;0%-10&#xb7;8% [6&#xb7;4-11&#xb7;5 kg]) versus placebo (3&#xb7;0% [3&#xb7;3 kg]; estimated treatment difference range 3&#xb7;0%-7&#xb7;8%; p<0&#xb7;001). Weight reductions were also greater with cagrilintide 4&#xb7;5 mg versus liraglutide 3&#xb7;0 mg (10&#xb7;8% [11&#xb7;5 kg] vs 9&#xb7;0% [9&#xb7;6 kg]; estimated treatment difference 1&#xb7;8%, p=0&#xb7;03). Similar weight loss reductions were observed with the treatment policy estimand. The most frequent adverse events were gastrointestinal disorders (eg, nausea, constipation, and diarrhoea) and administration-site reactions. More participants receiving cagrilintide 0&#xb7;3-4&#xb7;5 mg had gastrointestinal adverse events compared with placebo (41%-63% vs 32%), primarily nausea (20%-47% vs 18%). Treatment with cagrilintide in people with overweight and obesity led to significant reductions in bodyweight and was well tolerated. The findings support the development of molecules with novel mechanisms of action for weight management. Novo Nordisk A/S.

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.

Drugs for Treating Obesity.

Older medications approved for chronic weight management (orlistat, naltrexone/bupropion, liraglutide 3&#xa0;mg and, in the USA, phentermine/topiramate) have not been widely adopted by health care providers. Those medications produce only modest additional weight loss when used to augment lifestyle intervention. However, semaglutide 2.4&#xa0;mg weekly has recently emerged and produces much more weight loss - on average 15% weight loss at 1 year. Semaglutide's enhanced efficacy and that its class (GLP-1 receptor analogs) is well-known may result in more clinicians adopting pharmacotherapy. Furthermore, the first dedicated cardiovascular outcome trial powered for superiority testing an anti-obesity medication (SELECT) is underway with semaglutide 2.4&#xa0;mg. A positive outcome will further promote the concept that weight management should be a primary target for cardiometabolic disease control. In phase 3, tirzepatide and cagrilintide/semaglutide combination are showing promise for even greater weight loss efficacy. Another recently approved medication takes a personalized medicine approach; setmelanotide is approved as a therapy for those with some of the ultra-rare genetic diseases characterized by severe, early onset obesity. This chapter reviews the currently available and anticipated medications for chronic weight management as well as those approved for the genetic and syndromic obesities.

Efficacy and Safety of Cagrilintide Alone and in Combination with Semaglutide (Cagrisema) as Anti-Obesity Medications: A Systematic Review and Meta-Analysis.

No meta-analysis has analysed role of cagrilintide as weight-loss medication in obese individuals. Electronic databases were searched for RCTs involving obese individuals receiving cagrilintide or cagrilintide-2.4 mg with semaglutide-2.4 mg combination (Cagrisema) compared to placebo/active comparator. Primary outcomes were changes in body weight; secondary outcomes were alterations in glycemia, lipids, and adverse events. From 678 articles, data from 3 RCTs involving 430 individuals were analysed. At 20-32 weeks, patients receiving Cagrisema weekly had significantly greater percentage [mean difference (MD)-9.07% (95%CI: -11.91, -6.23); P < 0.00001;I 2 = 96%] and absolute [MD-9.11 kg (95%CI: -12.84, -5.39); P < 0.00001; I 2 = 98%] weight-loss, compared to semaglutide 2.4 mg weekly. At 26-32 weeks, cagrilintide 2.4 mg had a similar percentage [MD - 1.83% (95%CI: -4.08, -0.42); P = 0.11; I 2 = 98%] and absolute [MD - 1.88 kg (95%CI: -4.23,0.47); P = 0.12; I 2 = 98%] weight-loss, compared to semaglutide/liraglutide. Treatment-emergent and serious adverse events were comparable between groups. Gastrointestinal adverse events and vomiting were significantly higher with Cagrisema compared to semaglutide. Vomiting was significantly lower with cagrilintide compared to semaglutide/liraglutide. Cagrisema outperforms semaglutide regarding weight loss. Cagrilintide shows comparable weight loss to semaglutide/liraglutide with significantly lower vomiting.

Amylin analogs for the treatment of obesity without diabetes: present and future.

Obesity is a pandemic, linked with increased morbidity including diabetes mellitus (DM) and certain cancer types. Amylin is a major regulatory hormone for satiation and food intake perception in humans. Amylin analogs (pramlintide and cagrilintide) are emerging as promising anti-obesity agents in non-DM subjects. Pramlintide, the first amylin analog, initially used for the treatment of both type 1 and type 2 DM, has demonstrated weight-lowering action. Clinical trials confirmed a weight loss exceeding 3% in the study period without major untoward effects, which was maintained beyond the follow-up period. Recently, cagrilintide, a long-lasting synthetic amylin analog has been introduced. Cagrilintide has achieved adequate weight loss, reaching even more than 10% of the total weight in early clinical trials. However, adverse gastrointestinal effects, particularly nausea, were more frequent compared with pramlintide. Clinical trials have also confirmed the effectiveness of cagrilintide in comparison with glucagon-like peptide 1 receptor agonists. Amylin analogs will certainly enrich the growing therapeutic armamentarium aimed at tackling obesity. The most exciting future research venue could be the development of their combinations with other weight-lowering drugs, especially dual and triple incretin-based co-agonists, thus potentially providing massive weight-loss effects.

Development of Cagrilintide, a Long-Acting Amylin Analogue.

A hallmark of the pancreatic hormone amylin is its high propensity toward the formation of amyloid fibrils, which makes it a challenging drug design effort. The amylin analogue pramlintide is commercially available for diabetes treatment as an adjunct to insulin therapy but requires three daily injections due to its short half-life. We report here the development of the stable, lipidated long-acting amylin analogue cagrilintide (23) and some of the structure-activity efforts that led to the selection of this analogue for clinical development with obesity as an indication. Cagrilintide is currently in clinical trial and has induced significant weight loss when dosed alone or in combination with the GLP-1 analogue semaglutide.

Cagrilintide: A Long-Acting Amylin Analog for the Treatment of Obesity.

Despite the worldwide epidemic of obesity, there remain few approved pharmacological treatment options to bridge the gap between lifestyle therapy and bariatric surgery. Cagrilintide is an amylin-analog, now being developed in combination with the GLP-1 agonist semaglutide to achieve sustained weight loss in persons with overweight and obesity. Amylin, released with insulin from beta cells in the pancreas, induces its satiating effect via both the homoeostatic and hedonic regions of the brain. Semaglutide, a GLP-1 receptor agonist, reduces appetite via GLP-1 receptors in the hypothalamus and increases the production of insulin, and reduces glucagon secretion, delaying gastric emptying. These separate, but related mechanisms of action of an amylin-analog and a GLP-1 receptor agonist appear to have an additive effect on appetite reduction. Given the heterogeneity and complex pathogenesis of obesity, combination therapy with multiple pathophysiological targets is a logical approach to increasing weight loss response with pharmacotherapy. Cagrilintide alone, as well as cagrilintide in combination with semaglutide have shown promising weight loss in clinical trials that supports the further development of this therapy for sustained weight management.

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.

Amylin, Another Important Neuroendocrine Hormone for the Treatment of Diabesity.

Diabetes mellitus is a devastating chronic metabolic disease. Since the majority of type 2 diabetes mellitus patients are overweight or obese, a novel term-diabesity-has emerged. The gut-brain axis plays a critical function in maintaining glucose and energy homeostasis and involves a variety of peptides. Amylin is a neuroendocrine anorexigenic polypeptide hormone, which is co-secreted with insulin from &#x3b2;-cells of the pancreas in response to food consumption. Aside from its effect on glucose homeostasis, amylin inhibits homeostatic and hedonic feeding, induces satiety, and decreases body weight. In this narrative review, we summarized the current evidence and ongoing studies on the mechanism of action, clinical pharmacology, and applications of amylin and its analogs, pramlintide and cagrilintide, in the field of diabetology, endocrinology, and metabolism disorders, such as obesity.

AM833 Is a Novel Agonist of Calcitonin Family G Protein-Coupled Receptors: Pharmacological Comparison with Six Selective and Nonselective Agonists.

Obesity and associated comorbidities are a major health burden, and novel therapeutics to help treat obesity are urgently needed. There is increasing evidence that targeting the amylin receptors (AMYRs), heterodimers of the calcitonin G protein-coupled receptor (CTR) and receptor activity-modifying proteins, improves weight control and has the potential to act additively with other treatments such as glucagon-like peptide-1 receptor agonists. Recent data indicate that AMYR agonists, which can also independently activate the CTR, may have improved efficacy for treating obesity, even though selective activation of CTRs is not efficacious. AM833 (cagrilintide) is a novel lipidated amylin analog that is undergoing clinical trials as a nonselective AMYR and CTR agonist. In the current study, we have investigated the pharmacology of AM833 across 25 endpoints and compared this peptide with AMYR selective and nonselective lipidated analogs (AM1213 and AM1784), and the clinically used peptide agonists pramlintide (AMYR selective) and salmon CT (nonselective). We also profiled human CT and rat amylin as prototypical selective agonists of CTR and AMYRs, respectively. Our results demonstrate that AM833 has a unique pharmacological profile across diverse measures of receptor binding, activation, and regulation. SIGNIFICANCE STATEMENT: AM833 is a novel nonselective agonist of calcitonin family receptors that has demonstrated efficacy for the treatment of obesity in phase 2 clinical trials. This study demonstrates that AM833 has a unique pharmacological profile across diverse measures of receptor binding, activation, and regulation when compared with other selective and nonselective calcitonin receptor and amylin receptor agonists. The present data provide mechanistic insight into the actions of AM833.

Cagrilintide lowers bodyweight through brain amylin receptors 1 and 3.

Amylin (AmyR) and calcitonin (CTR) receptor co-agonists are currently in Phase II/III clinical trials for obesity treatment. Amylin binds to a heterodimeric receptor composed of CTR and the receptor activity modifying proteins 1, 2 or 3 (RAMP1-3). We investigated the role of amylin 1 and 3 (AMY1R, AMY3R) receptors in modulating the pharmacological effects of the dual amylin-calcitonin receptor agonists, cagrilintide and salmon calcitonin (sCT), in RAMP1/3 knockout (KO) mice. Male wild-type (WT) and KO littermate mice were fed high-fat diet for 23 weeks prior to the 3-week treatment period with vehicle, 150 nmol/kg sCT or 3 nmol/kg cagrilintide (subcutaneously, SID). Body weight loss was observed in WT cagrilintide-treated mice (-3.4 &#xb1; 0.51 g, P < 0.005; n = 8/group), whereas sCT rather increased it (0.60 &#xb1; 0.38 g, P < 0.01; n = 8/group). The absence of RAMP1 and RAMP3 impeded cagrilintide's potency but improved sCT's efficacy on weight loss. Cagrilintide and sCT both decreased food intake during the first few days of treatment in WT mice only (Day 1: vehicle 2.7 &#xb1; 0.2 g; cagrilintide 1.2 &#xb1; 0.1 g, P < 0.0001; sCT 1.5 &#xb1; 0.2 g, P < 0.0021; n = 7-8/group). Both peptides activated cFos signal in neurons of the dorsal vagal complex (DVC) and lateral parabrachial nucleus (LPBN) of WT mice while AP cFos signal was decreased in cagrilintide-treated RAMP1/3 KO mice by 57% compared to WT cagrilintide-injected mice (P < 0.001, n = 5-6/group). Differential gene expression was analysed in the DVC, LPBN and mediobasal hypothalamic area of WT and RAMP1/3 KO mice. After 3 weeks of treatment, neither sCT nor cagrilintide significantly altered gene expression in the DVC or LPBN in WT mice. However, mRNA bulk sequencing points to a role of RAMP1/3 in synaptic function and receptor trafficking. Altogether, these results demonstrate the dependency of cagrilintide on AMY1R and AMY3R to lower body weight. This work was supported by an investigator led Novo Nordisk Consortium grant, Swiss National Foundation and the University of Zurich.

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.

Structural and dynamic features of cagrilintide binding to calcitonin and amylin receptors.

Obesity is a major and increasingly prevalent chronic metabolic disease with numerous comorbidities. While recent incretin-based therapies have provided pharmaceutical inroads into treatment of obesity, there remains an ongoing need for additional medicines with distinct modes of action as independent or complementary therapeutics. Among the most promising candidates, supported by phase 1 and 2 clinical trials, is cagrilintide, a long-acting amylin and calcitonin receptor agonist. As such, understanding how cagrilintide functionally engages target receptors is critical for future development of this target class. Here, we determine structures of cagrilintide bound to Gs-coupled, active, amylin receptors (AMY1R, AMY2R, AMY3R) and calcitonin receptor (CTR) and compare cagrilintide interactions and the dynamics of receptor complexes with previously reported structures of receptors bound to rat amylin, salmon calcitonin or recently developed amylin-based peptides. These data reveal that cagrilintide has an amylin-like binding mode but, compared to other peptides, induces distinct conformational dynamics at calcitonin-family receptors that could contribute to its clinical efficacy.

Eloralintide (LY3841136), a novel amylin receptor agonist for the treatment of obesity: From discovery to clinical proof of concept.

Eloralintide (LY3841136), a novel amylin analog, was evaluated in translational studies to characterize its therapeutic potential for treating obesity. In vitro assays were performed in cell lines selectively expressing rat or human amylin 1 receptor (AMY1R), amylin 3 receptor (AMY3R), or calcitonin receptor (CTR). In vivo studies were conducted in rats and monkeys. A phase 1, randomized, placebo-controlled, participant/investigator-blinded trial evaluated the safety and tolerability of single-ascending eloralintide doses (0.04-12 mg) in healthy participants (NCT05295940). In vitro, eloralintide preferentially activated human AMY1R (12-fold > CTR, 11-fold > AMY3R), while in rats, both AMY1R and AMY3R were activated more potently than CTR. Eloralintide induced significantly less conditioned taste avoidance in lean rats than cagrilintide, a non-selective amylin receptor agonist (p < 0.05). Eloralintide dose dependently reduced food intake and lowered body weight, primarily through fat mass loss, in diet-induced obese rats. Eloralintide demonstrated favorable pharmacokinetics in both rats and monkeys. In the phase 1 trial, 48 healthy participants had a mean body mass index of 27.5 kg/m2. Nine participants in the eloralintide cohorts reported 16 adverse events, with most being mild (n = 15/16). Two participants reported 4 gastrointestinal events, including one moderate vomiting event. The pharmacokinetic profile of eloralintide supports once-weekly dosing. In eloralintide cohorts receiving single doses of 4 or 12 mg, week-4 mean percent change from baseline in body weight was -2.5% (p < 0.01) and -4.4% (p < 0.001), respectively, vs placebo (+0.6%). Once-weekly dosing with eloralintide, an AMY1R-selective agonist, may offer a promising new therapeutic with favorable gastrointestinal tolerability for the treatment of obesity.

CagriSema Reduces Blood Pressure in Adults With Overweight or Obesity: REDEFINE 1.

Fixed-dose combination of semaglutide/cagrilintide (CagriSema 2.4 mg/2.4 mg) has demonstrated significant and clinically relevant body weight reductions in adults with overweight or obesity compared with placebo. The phase 3a, 68-week REDEFINE 1 trial randomized adults without diabetes with body mass index &#x2265;30 kg/m2, or &#x2265;27 kg/m2 with &#x2265;1 obesity-related complication, to once-weekly CagriSema 2.4 mg/2.4 mg, semaglutide 2.4 mg, cagrilintide 2.4 mg, or placebo, plus lifestyle intervention. Secondary and post hoc analyses evaluated the antihypertensive effect from REDEFINE 1, focusing on CagriSema and placebo groups, by subgroup/category, including baseline body mass index, the presence of hypertension or resistant hypertension at baseline, and concomitant changes in the use of antihypertensive medications. Overall, 3417 participants underwent randomization; CagriSema: n=2108, semaglutide: n=302, cagrilintide: n=302, and placebo: n=705. Changes from baseline to week 68 in blood pressure (BP) were greater with CagriSema versus placebo (systolic BP: -10.9 versus -2.8 mm&#x2009;Hg; diastolic BP: -5.4 versus -1.7 mm&#x2009;Hg, respectively). The proportion of participants reaching BP targets at week 68 was 63.0% and 32.0% for CagriSema and placebo, respectively. The proportion of participants with resistant hypertension at baseline (n=167) that reached BP targets at week 68 was 42.0% and 29.3% for CagriSema and placebo, respectively (odds ratio, 1.7 [95% CI, 0.7-4.4]). Among participants who used antihypertensive medication during the study, 39.6% in the CagriSema group decreased or stopped treatment from week 0 to week 68 versus 18.8% with placebo. CagriSema presents clinically relevant reductions in BP across a wide range of participant subgroups, including those with resistant hypertension. URL: https://www.clinicaltrials.gov; Unique identifier: NCT05567796.

Safety, tolerability, pharmacokinetics, and pharmacodynamics of concomitant administration of multiple doses of cagrilintide with semaglutide 2&#xb7;4 mg for weight management: a randomised, controlled, phase 1b trial.

Cagrilintide, a long-acting amylin analogue, and semaglutide 2&#xb7;4 mg, a glucagon-like peptide-1 analogue, are both being investigated as options for weight management. We aimed to determine the safety, tolerability, pharmacokinetics, and pharmacodynamics of this drug combination. In this randomised, placebo-controlled, multiple-ascending dose, phase 1b trial, individuals aged 18-55 years with a body-mass index 27&#xb7;0-39&#xb7;9 kg/m2 and who were otherwise healthy were recruited from a single centre in the USA. The trial included six sequential overlapping cohorts, and in each cohort eligible participants were randomly assigned (3:1) to once-weekly subcutaneous cagrilintide (0&#xb7;16, 0&#xb7;30, 0&#xb7;60, 1&#xb7;2, 2&#xb7;4, or 4&#xb7;5 mg) or matched placebo, in combination with once-weekly subcutaneous semaglutide 2&#xb7;4 mg, without lifestyle interventions. In each cohort, the doses of cagrilintide and semaglutide were co-escalated in 4-week intervals to the desired dose over 16 weeks, participants were treated at the target dose for 4 weeks, and then followed up for 5 weeks. Participants, investigators, and the sponsor were masked to treatment assignment. The primary endpoint was number of treatment-emergent adverse events from baseline to end of follow-up. Secondary pharmacokinetic endpoints assessed from day of last dose (week 19) to end of treatment (week 20) were area under the plasma concentration-time curve from 0 to 168 h (AUC0-168 h) and maximum concentration [Cmax] of cagrilintide and semaglutide; exploratory pharmacokinetic endpoints were half-life, time to Cmax [tmax], plasma clearance, and volume of distribution of cagrilintide and semaglutide; and exploratory pharmacodynamic endpoints were changes in bodyweight, glycaemic parameters, and hormones. Safety, pharmacokinetic, and pharmacodynamic endpoints were assessed in all participants who were exposed to at least one dose of study drug. This study is registered with ClinicalTrials.gov, NCT03600480, and is now complete. Between July 25, 2018, and Dec 17, 2019, 285 individuals were screened and 96 were randomly assigned to cagrilintide (0&#xb7;16-2&#xb7;4 mg group n=12; 4&#xb7;5 mg group n=11) or placebo (n=24), in combination with semaglutide 2&#xb7;4 mg, of whom 95 were exposed to treatment (one patient in 0&#xb7;60 mg cagrilintide group was not exposed) and included in the safety and full analysis datasets. The mean age was 40&#xb7;6 years (SD 9&#xb7;2), 56 (59%) of 95 participants were men and 51 (54%) were Black or African American. Of 566 adverse events reported in 92 participants (69 [97%] of 71 participants assigned to 0&#xb7;16-4&#xb7;5 mg cagrilintide and 23 [96%] of 24 assigned to placebo), 207 (37%) were gastrointestinal disorders. Most adverse events were mild to moderate in severity and the proportion of participants with one or more adverse event was similar across treatment groups. Exposure was proportional to cagrilintide dose and did not affect semaglutide exposure or elimination. AUC0-168 h ranged from 926 nmol&#x2009;&#xd7;&#x2009;h/L to 24&#x2009;271 nmol&#x2009;&#xd7;&#x2009;h/L, and Cmax ranged from 6&#xb7;14 nmol/L to 170 nmol/L with cagrilintide 0&#xb7;16-4&#xb7;5 mg. AUC0-168 h ranged from 12&#x2009;757 nmol&#x2009;&#xd7;&#x2009;h/L to 15&#x2009;305 nmol&#x2009;&#xd7;&#x2009;h/L, and Cmax ranged from 96&#xb7;4 nmol/L to 120 nmol/L with semaglutide 2&#xb7;4 mg. Cagrilintide 0&#xb7;16-4&#xb7;5 mg had a half-life of 159-195 h, with a median tmax of 24-72 h. Semaglutide 2&#xb7;4 mg had a half-life of 145-165 h, with a median tmax of 12-24 h. Plasma clearance and volume of distribution for both cagrilintide and semaglutide were similar across treatment groups. At week 20, mean percentage bodyweight reductions were greater with cagrilintide 1&#xb7;2 and 2&#xb7;4 mg than with placebo (15&#xb7;7% [SE 1&#xb7;6] for cagrilintide 1&#xb7;2 mg and 17&#xb7;1% [1&#xb7;5] for cagrilintide 2&#xb7;4 mg vs 9&#xb7;8% [1&#xb7;2] for pooled placebo cohorts 1-5; estimated treatment difference of -6&#xb7;0% [95% CI -9&#xb7;9 to -2&#xb7;0] for cagrilintide 1&#xb7;2 mg and -7&#xb7;4% [-11&#xb7;2 to -3&#xb7;5] for cagrilintide 2&#xb7;4 mg vs pooled placebo), and with cagrilintide 4&#xb7;5 mg than with matched placebo (15&#xb7;4% [1&#xb7;3] vs 8&#xb7;0% [2&#xb7;2]; estimated treatment difference -7&#xb7;4% [-12&#xb7;8 to -2&#xb7;1]), all in combination with semaglutide 2&#xb7;4 mg. Glycaemic parameters improved in all treatment groups, independently of cagrilintide dose. Changes in hormones were similar across treatment groups. Concomitant treatment with cagrilintide and semaglutide 2&#xb7;4 mg was well tolerated with an acceptable safety profile. Future larger and longer trials are needed to fully assess the efficacy and safety of this treatment combination. Novo Nordisk A/S.

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.

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).

Comparative Effectiveness of Semaglutide, Liraglutide, Orlistat, and Phentermine for Weight Loss in Obese Individuals: A Systematic Review.

Obesity, a multifaceted and chronic condition characterized by excessive fat accumulation, poses significant risks to overall health and is associated with various metabolic and cardiovascular complications. This literature review evaluates and compares the effectiveness of four pharmacological agents semaglutide, liraglutide, orlistat, phentermine, and emerging agents like&#xa0;setmelanotide, amycretin, retatrutide, cagrilintide, and cotadutide in managing weight loss among obese. A detailed analysis was conducted on their mechanisms of action, dosing regimens, efficacy in weight loss, safety profiles, and their impact on obesity-related comorbidities. Although all agents presented distinct benefits, side effects such as gastrointestinal discomfort with orlistat and GLP-1 receptor agonists, and potential dependency with phentermine, necessitate tailored treatment approaches.&#xa0;This review highlights the importance of integrating pharmacotherapy with lifestyle interventions to achieve sustainable weight management and identifies areas for future research to optimize therapeutic outcomes for individuals with obesity.

Amylin as a Future Obesity Treatment.

Obesity is defined as abnormal or excessive fat accumulation that contributes to detrimental health impacts. One-third of the population suffers from obesity, and it is important to consider obesity as a chronic disease requiring chronic treatment. Amylin is co-secreted with insulin from &#x3b2; pancreatic cells upon nutrient delivery to the small intestine as a satiety signal, acts upon sub-cortical homeostatic and hedonic brain regions, slows gastric emptying, and suppresses post-prandial glucagon responses to meals. Therefore, new pharmacological amylin analogues can be used as potential anti-obesity medications in individuals who are overweight or obese. In this narrative review, we analyse the efficacy, potency, and safety of amylin analogues. The synthetic amylin analogue pramlintide is an approved treatment for diabetes mellitus which promotes better glycaemic control and small but significant weight loss. AM833 (cagrilintide), an investigational novel long-acting acylated amylin analogue, acts as a non-selective amylin receptor. This calcitonin G protein-coupled receptor agonist can serve as an attractive novel treatment for obesity, resulting in reduction of food intake and significant weight loss in a dose-dependent manner.

A Cross-Species Atlas of the Dorsal Vagal Complex Reveals Neural Mediators of Cagrilintide's Effects on Energy Balance.

Amylin analogs, including potential anti-obesity therapies like cagrilintide, act on neurons in the brainstem dorsal vagal complex (DVC) that express calcitonin receptors (CALCR). These receptors, often combined with receptor activity-modifying proteins (RAMPs), mediate the suppression of food intake and body weight. To understand the molecular and neural mechanisms of cagrilintide action, we used single-nucleus RNA sequencing to define 89 cell populations across the rat, mouse, and non-human primate caudal brainstem. We then integrated spatial profiling to reveal neuron distribution in the rat DVC. Furthermore, we compared the acute and long-term transcriptional responses to cagrilintide across DVC neurons of rats, which exhibit strong cagrilintide responsiveness, and mice, which respond poorly to cagrilintide over the long term. We found that cagrilintide promoted long-term transcriptional changes, including increased prolactin releasing hormone (Prlh) expression, in the nucleus of the solitary tract (NTS) Calcr/Prlh cells in rats, but not in mice, suggesting the importance of NTS Calcr/Prlh cells for sustained weight loss. Indeed, activating rat area postrema Calcr cells briefly reduced food intake but failed to decrease food intake or body weight over the long term. Overall, these results not only provide a cross-species and spatial atlas of DVC cell populations but also define the molecular and neural mediators of acute and long-term cagrilintide action.

Oral glucagon-like peptide-1 receptor agonists and combinations of entero-pancreatic hormones as treatments for adults with type 2 diabetes: where are we now?

Glucagon-like peptide-1 (GLP-1) receptor agonists (RAs) have changed the landscape of type 2 diabetes (T2D) management due to their cardio-renal benefits, their glucose-lowering efficacy and weight loss (WL) maintenance. However, the response to GLP-1 RA monotherapy is heterogeneous. Additionally, the majority of GLP-1 RAs are injectable treatments. Oral GLP-1 RAs and injectable combinations of GLP-1 with other entero-pancreatic hormones (glucose-dependent insulinotropic polypeptide (GIP), glucagon and amylin) are under development for T2D and obesity management. Herein, we review the data on (i) oral GLP-1 RAs (oral semaglutide 25/50&#x2009;mg and orforglipron) and (ii) dual/triple agonists (tirzepatide, cagrilintide 2.4&#x2009;mg/semaglutide 2.4&#x2009;mg, survodutide, mazdutide, retatrutide) that have recently completed phase 3 trials for T2D or are currently in phase 3 clinical trials. Tirzepatide is the first approved dual agonist (GLP-1/GIP) for T2D and obesity management. We are in a new era in T2D management where entero-pancreatic hormone-based treatments can result in&#x2009;&#x2265;15% WL and euglycemia for many people with T2D. Multiple molecules with different mechanisms of action are under development for T2D, obesity and other metabolic complications. Data on their cardio-renal benefits, long-term efficacy and safety as well as their cost-effectiveness will better inform their position in treatment algorithms.

Cagrilintide-semaglutide (CagriSema) versus semaglutide or cagrilintide in people with type 2 diabetes (REIMAGINE 2): a double-blind, randomised, controlled, phase 3 study.

The amylin receptor agonist cagrilintide and the GLP-1 receptor agonist semaglutide have complementary effects on glycaemic control and bodyweight. We aimed to investigate the efficacy and safety of a fixed-dose combination of cagrilintide and semaglutide (cagrilintide-semaglutide; known as CagriSema) versus semaglutide or cagrilintide for glycaemic control in people with type 2 diabetes and overweight or obesity. REIMAGINE 2 was a randomised, double-blind, placebo-controlled and active-controlled, parallel-group study conducted in 30 countries (trial sites included university hospitals, health-care centres, research centres, and other centres). Participants aged 18 years or older with inadequately controlled type 2 diabetes (HbA1c 7&#xb7;0-10&#xb7;5% [53-91 mmol/mol]) receiving metformin with or without an SGLT2 inhibitor, and a BMI of 25 kg/m2 or more, were randomly assigned (8:8:2:8:8:1:1) to receive once-weekly subcutaneous cagrilintide 2&#xb7;4 mg plus semaglutide 2&#xb7;4 mg (hereafter cagrilintide-semaglutide [2&#xb7;4 mg each]), semaglutide 2&#xb7;4 mg, cagrilintide 2&#xb7;4 mg, cagrilintide 1&#xb7;0 mg plus semaglutide 1&#xb7;0 mg (hereafter cagrilintide-semaglutide [1&#xb7;0 mg each]), semaglutide 1&#xb7;0 mg, or corresponding placebo for 68 weeks. Randomisation was done using a web-based system with blocked randomisation (block size 36) and stratification according to inclusion in the continuous glucose monitoring subgroup, HbA1c less than 8&#xb7;5% at screening (yes or no), and country of participation (Japan; yes or no). The study participants, investigators, and study sponsor staff were masked to treatment allocation within dose level throughout the study. The primary endpoint was change in HbA1c from baseline to week 68 with cagrilintide-semaglutide (2&#xb7;4 mg each) versus semaglutide 2&#xb7;4 mg in the full analysis set; safety was assessed in all participants who received at least one dose of study product. This study is registered with ClinicalTrials.gov (NCT06065540) and is complete. From Oct 10, 2023, to July 29, 2024, 3593 people were screened for eligibility, 2713 of whom were randomly assigned to cagrilintide-semaglutide (2&#xb7;4 mg each; n=603), semaglutide 2&#xb7;4 mg (n=605), cagrilintide 2&#xb7;4 mg (n=152), cagrilintide-semaglutide (1&#xb7;0 mg each; n=595), semaglutide 1&#xb7;0 mg (n=609), or placebo (pooled 2&#xb7;4 mg and 1&#xb7;0 mg; n=149). 1164 (42&#xb7;9%) of 2713 were female, 1549 (57&#xb7;1%) were male, and 2207 (81&#xb7;3%) were White. Of the randomly assigned participants, 2595 (95&#xb7;7%) completed the study and 2376 (87&#xb7;6%) were on treatment at week 68. Mean baseline HbA1c was 8&#xb7;2% (SD 0&#xb7;9). For the primary endpoint using the efficacy estimand, mean HbA1c change was significantly greater with cagrilintide-semaglutide (2&#xb7;4 mg each) versus semaglutide 2&#xb7;4 mg (-1&#xb7;91 percentage points [SE 0&#xb7;04] vs -1&#xb7;75 percentage points [0&#xb7;04]; estimated treatment difference -0&#xb7;16 percentage points [95% CI -0&#xb7;27 to -0&#xb7;05]; p=0&#xb7;0035). Adverse events were reported in 524 (86&#xb7;9%) of 603 participants in the cagrilintide-semaglutide (2&#xb7;4 mg each) group, 491 (81&#xb7;2%) of 605 in the semaglutide 2&#xb7;4 mg group, 125 (82&#xb7;2%) of 152 in the cagrilintide 2&#xb7;4 mg group, 485 (81&#xb7;6%) of 594 in the cagrilintide-semaglutide (1&#xb7;0 mg each) group, 477 (78&#xb7;5%) of 608 in the semaglutide 1&#xb7;0 mg group, and 105 (70&#xb7;5%) of 149 in the placebo group. The most common adverse events in the active treatment groups were gastrointestinal disorders. Cagrilintide-semaglutide (2&#xb7;4 mg each) was superior to semaglutide 2&#xb7;4 mg in reducing HbA1c in participants with type 2 diabetes receiving metformin with or without an SGLT2 inhibitor. The safety profile of cagrilintide-semaglutide was consistent with the GLP-1 receptor agonist class and previous safety data for cagrilintide. These findings support the added benefit of cagrilintide-semaglutide (2&#xb7;4 mg each) versus semaglutide 2&#xb7;4 mg for glycaemic control. Novo Nordisk.

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.

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&#xb7;4 mg and semaglutide 2&#xb7;4 mg versus semaglutide 2&#xb7;4 mg for weight management in an east Asian population. 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/m2 and at least two obesity-related complications, or with a BMI of at least 35 kg/m2 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&#xb7;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/m2, 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. 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&#xb7;4% (SE 0&#xb7;7) in the cagrilintide-semaglutide group versus -11&#xb7;9% (0&#xb7;7) in the semaglutide group (estimated treatment difference [ETD] -6&#xb7;5 percentage points [95% CI -8&#xb7;4 to -4&#xb7;6]; p<0&#xb7;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&#xb7;4 mg group, which was not judged to be treatment related by the investigator. 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. Novo Nordisk. For the Japanese and Mandarin translations of the abstract see Supplementary Materials section.

Creating the amylin story.

This paper is based on a presentation given at the Annual Meeting of the Society for the Study of Ingestive Behavior in July 2021 and provides a personal view on some of the milestones in the discovery of amylin as a constituent of pancreatic islet amyloid deposits, as a pancreatic beta-cell hormone, and on its role in physiology and pathophysiology. Only selected effects of amylin are discussed here because we recently published extensive reviews on the physiology and pathophysiology of amylin. Amylin was discovered as the main constituent of islet amyloid that is predominantly found in pancreatic islets in type 2 diabetics. These deposits, and in particular small oligomer aggregates of amylin seem to contribute to the progressive beta-cell damage seen in type 2 diabetics. Amylin is also a physiologically relevant circulating hormone with diverse metabolic functions, e.g. inhibition of eating, of pancreatic glucagon secretion and of gastric emptying. Knowledge of these types of functions and amylin's mechanisms of action lead to the development of amylin analogues that are now among the most promising anti-obesity targets in clinical testing. With this review, I want to give a short overview of 35 exciting years of amylin research.

CagriSema drives weight loss in rats by reducing energy intake and preserving energy expenditure.

CagriSema is a combination of amylin (cagrilintide) and glucagon-like peptide-1 (semaglutide) analogues being developed for weight management. Here, we show that CagriSema blunts metabolic adaptation in rats. Quantifying CagriSema's action on energy intake and expenditure in rats we observe 12% weight loss with a 39% reduction in food intake. By contrast, pair-feeding causes less-pronounced weight loss, while weight matching requires a 51% decrease in food intake. Therefore, approximately one-third of CagriSema's weight loss efficacy arises from an effect on energy expenditure, the blunting of metabolic adaptation, which contributes to the successful treatment of obesity.

Incretin-based therapies for the treatment of obesity-related diseases.

Obesity-related disability-adjusted life years (DALYs) are expected to increase by approximately 40% from 2020 to 2030. DALYs and mortality related to obesity are the consequence of multiple comorbidities such as cardiovascular (i.e., heart failure) and metabolic diseases (i.e. type 2 diabetes [T2D], metabolic dysfunction-associated steatotic liver disease [MASLD]). Lifestyle interventions represent the foundation of obesity treatment, yet an escalation to pharmacological and/or surgical interventions is often needed. Liraglutide, semaglutide and tirzepatide are incretin-based therapies currently approved by FDA for the management of obesity, while triple GIPR/GCGR/GLP-1R agonist retatrutide (LY3437943), the cagrilintide/semaglutide (CagriSema) 2.4&#x2009;mg combination, high-dose oral semaglutide, and oral orforglipron are in advanced stages of development. Incretin-based therapies have been associated with a body weight (BW) reduction of &#x2265;5% in at least half of patients in most randomized controlled trials (RCT) and real-world studies (RWS). Semaglutide and tirzepatide have also displayed a mean 60-69% 10-years relative risk reduction of T2D development. In line with evidence accrued in patients with T2D, incretin-based therapies produced a favorable effect on traditional cardiovascular risk factors, such as lipids and blood pressure, and even reduced the risk of major cardiovascular events and heart failure-related events in individuals with obesity, as recently demonstrated for the first time in the SELECT trial with semaglutide 2.4&#x2009;mg once-weekly. Moreover, incretin-based therapies have also been proven beneficial on obesity-related comorbidities, such as knee osteoarthritis (KOA), obstructive sleep apnea (OSA) syndrome, and MASLD. Further research is needed to improve our understanding of their effects on obesity-related comorbidities and the underlying mechanism, whether involving direct effects on target tissues or mediated by improvement in BW, glucose levels and other CV risk factors.

Cagrilintide-semaglutide (CagriSema) as an add-on to basal insulin in adults with type 2 diabetes (REIMAGINE 3): a randomised, double-blind, placebo-controlled, multicentre, phase 3 study.

Basal insulin treatment for type 2 diabetes often results in inadequate glycaemic control and is associated with weight gain and increased risk of hypoglycaemia. We aimed to compare the efficacy and safety of a once per week combination of cagrilintide with semaglutide (CagriSema) versus placebo as an add-on to basal insulin in individuals with type 2 diabetes. This double-blind, parallel-group, randomised, controlled, phase 3a study (REIMAGINE 3) was done at 46 centres (university hospitals, health-care centres, research centres, and other clinical trial sites) in six countries (the USA, China, Japan, Serbia, Slovakia, and South Africa). Adults with type 2 diabetes (glycated haemoglobin [HbA1c] 7&#xb7;0-10&#xb7;5%) receiving stable once per day basal insulin with or without metformin were randomly assigned (2:2:1:1) to once per week subcutaneous cagrilintide 2&#xb7;4 mg plus semaglutide 2&#xb7;4 mg (hereafter cagrilintide-semaglutide [2&#xb7;4 mg each]) or cagrilintide 1&#xb7;0 mg plus semaglutide 1&#xb7;0 mg (hereafter cagrilintide-semaglutide [1&#xb7;0 mg each]) or dose-matched placebo (2&#xb7;4 mg plus 2&#xb7;4 mg or 1&#xb7;0 mg plus 1&#xb7;0 mg) for 40 weeks. Randomisation was stratified by HbA1c of less than 8&#xb7;5% at screening (yes or no) and country (Japan; yes or no). Participants, care providers, investigators, and outcome assessors were masked within each dose level to treatment allocation, with active treatments visually identical to placebo. The primary endpoint was mean HbA1c change (percentage points) from baseline to week 40 in all participants randomly assigned to treatment; secondary endpoints included change in bodyweight and safety, including hypoglycaemia. This trial was registered with ClinicalTrials.gov (NCT06323161) and is complete. Between March 26 and Nov 29, 2024, we screened 340 individuals and 274 were included and randomly assigned to cagrilintide-semaglutide (2&#xb7;4 mg each; n=90), cagrilintide-semaglutide (1&#xb7;0 mg each; n=93), or placebo (pooled; n=91). Mean baseline HbA1c was 8&#xb7;8% (SD 1&#xb7;0), 159 (58%) participants were male, and 115 (42%) were female. Mean HbA1c reductions were significantly greater with cagrilintide-semaglutide (2&#xb7;4 mg each -2&#xb7;33% [SE 0&#xb7;08] and 1&#xb7;0 mg each -2&#xb7;10% [0&#xb7;08]) versus placebo (-0&#xb7;66% [0&#xb7;11]) at week 40, using the efficacy estimand (estimated treatment difference for cagrilintide-semaglutide [2&#xb7;4 mg each] vs placebo -1&#xb7;68 percentage points [95% CI -1&#xb7;95 to -1&#xb7;41], p<0&#xb7;0001; for cagrilintide-semaglutide [1&#xb7;0 mg each] vs placebo -1&#xb7;44 percentage points [95% CI -1&#xb7;71 to -1&#xb7;17], p<0&#xb7;0001). Cagrilintide-semaglutide provided bodyweight reductions of 10-12%. Adverse events were reported by 72 (80%) of 90 participants receiving cagrilintide-semaglutide (2&#xb7;4 mg each), 66 (71%) of 93 receiving cagrilintide-semaglutide (1&#xb7;0 mg each), and 65 (71%) of 91 receiving placebo, and were mostly mild or moderate gastrointestinal disorders. No severe hypoglycaemia was reported. There was one death in the cagrilintide-semaglutide (1&#xb7;0 mg each) group not related to treatment (due to malignancy). Cagrilintide-semaglutide at doses of 2&#xb7;4 mg each and 1&#xb7;0 mg each met the primary endpoint, with statistically significant and clinically relevant HbA1c reductions versus placebo when added to basal insulin-treated type 2 diabetes. These reductions were accompanied by robust bodyweight reduction and no additional risk of hypoglycaemia. The safety profile was consistent with that of the GLP-1 receptor agonist class and previous safety data for cagrilintide. Findings support the use of cagrilintide-semaglutide as an add-on to once per day basal insulin to significantly improve glycaemic control. Novo Nordisk.

In adults with overweight or obesity, weekly subcutaneous cagrilintide-semaglutide increased weight loss at 68 wk.

GIM/FP/GP: [Formula: see text].

An update on peptide-based therapies for type 2 diabetes and obesity.

Long-acting analogues of the naturally occurring incretin, glucagon-like peptide-1 (GLP-1) and those modified to interact also with receptors for glucose-dependent insulinotropic polypeptide (GIP) have shown high glucose-lowering and weight-lowering efficacy when administered by once-weekly subcutaneous injection. These analogues herald an exciting new era in peptide-based therapy for type 2 diabetes (T2D) and obesity. Of note is the GLP-1R agonist semaglutide, available in oral and injectable formulations and in clinical trials combined with the long-acting amylin analogue, cagrilintide. Particularly high efficacy in both glucose- and weight lowering capacities has also been observed with the GLP-1R/GIP-R unimolecular dual agonist, tirzepatide. In addition, a number of long-acting unimolecular GLP-1R/GCGR dual agonist peptides and GLP-1R/GCGR/GIPR triagonist peptides have entered clinical trials. Other pharmacological approaches to chronic weight management include the human monoclonal antibody, bimagrumab which blocks activin type II receptors and is associated with growth of skeletal muscle, an antibody blocking activation of GIPR to which are conjugated GLP-1R peptide agonists (AMG-133), and the melanocortin-4 receptor agonist, setmelanotide for use in certain inherited obesity conditions. The high global demand for the GLP-1R agonists liraglutide and semaglutide as anti-obesity agents has led to shortage so that their use in T2D therapy is currently being prioritized.

Current and Emerging Parenteral and Peroral Medications for Weight Loss: A Narrative Review.

Obesity is a growing global health challenge, necessitating effective treatment options beyond lifestyle interventions. This narrative review explores established and emerging pharmacotherapies for weight management, including parenteral agents like Liraglutide, Semaglutide, Setmelanotide, and Tirzepatide, as well as peroral medications such as Phentermine, Phentermine/Topiramate, Bupropion/Naltrexone, Orlistat, and Metformin. Newer treatments like Cagrilintide and Bimagrumab show promise for enhancing weight loss outcomes. Parenteral GLP-1 receptor agonists demonstrate superior efficacy compared to traditional peroral medications, with gastrointestinal side effects being the most common. Artificial intelligence presents intriguing opportunities to enhance weight loss strategies; however, its integration into clinical practice remains investigational and requires rigorous clinical validation. While current anti-obesity medications deliver significant benefits, future research must determine the efficacy, safety, and cost-effectiveness of AI-driven approaches. This includes exploring how AI can complement combination therapies and tailor personalized interventions, thereby grounding its potential benefits in robust clinical evidence. Future directions will focus on integrating AI into clinical trials to refine and personalize obesity management strategies.

Approved and Emerging Hormone-Based Anti-Obesity Medications: A Review Article.

Obesity is a heterogeneous, complex, and chronic disease that has a detrimental impact on disability-adjusted life years across the globe. Recent advancements in our understanding of gut-brain communication at the molecular level have driven the development of next-generation anti-obesity medications (AOMs). Glucagon-like peptide-1 receptor agonists (GLP1RAs) remain the front-runners in this rapidly evolving landscape of hormone-based AOMs. Two GLP1RAs, namely Liraglutide and Semaglutide, have been approved by the Food and Drug Administration (FDA) and European Medicine Agency (EMA) for use in clinical practice for weight loss. Three oral GLP1RAs, namely Semaglutide, Danuglipron, and Orforglipron, are undergoing advanced clinical trials in individuals with obesity. Amylin receptor agonist (AMYRA) Cagrilintide, when used alone or in combination with Semaglutide, has demonstrated substantial weight reduction in clinical trials. Tirzepatide, a dual agonist for the glucose-dependent insulinotropic polypeptide (GIP) and GLP-1 receptors, has been observed to be associated with a significant placebo-subtracted weight reduction of 17.8% in a 72-week randomized controlled trial. Novel approaches targeting glucagon signalling have also yielded promising preliminary results. Three long-acting GLP1R/glucagon receptor (GCGR) dual agonists, namely Survodutide, Mazdutide, and Pemvidutide, exhibited significant weight loss in clinical trials. Retatrutide, a GLP1R/GCGR/GIPR tri-agonist, has been associated with a placebo-subtracted weight reduction of -22.1% in a 48-week phase-II trial. As a note of caution, long-term data on such medications' safety and cardiovascular benefits is yet to be ascertained. Our review provides a comprehensive overview of the approved and emerging hormone-based AOMs, highlighting the diversity of options that might become available in the near future.

Mitochondrial Adaptations in Skeletal Muscle Following Incretin-Based Therapies: In&#xa0;Vitro.

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. Differentiated C2C12 myotubes were treated with doses of each drug for 48&#x2009;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. Palmitic acid (PA) significantly impaired mitochondrial function, reducing basal oxygen consumption rate (OCR) by 22% (p&#x2009;=&#x2009;0.0056) and ATP production by 25% (p&#x2009;=&#x2009;0.0022). In healthy myotubes, semaglutide and cagrilintide transiently reduced basal respiration (&#x2193;21%-28%, p&#x2009;<&#x2009;0.05) and ATP production (&#x2193;24%-31%, p&#x2009;<&#x2009;0.01) at 48&#x2009;h, along with reductions in Complexes I, III and IV protein expression, all of which resolved by 5&#x2009;days. Tirzepatide significantly increased maximal respiration (&#x2191;20%-25%, p&#x2009;<&#x2009;0.005) and spare respiratory capacity (&#x2191;22%-30%, p&#x2009;<&#x2009;0.005) after 5&#x2009;days. In PA-treated myotubes, semaglutide and cagrilintide acutely worsened mitochondrial impairment (&#x2193;ATP production by ~20%-25%, p&#x2009;<&#x2009;0.01), but these effects resolved by Day 5. Tirzepatide initially suppressed mitochondrial function (&#x2193;ATP production, p&#x2009;=&#x2009;0.0087) but reversed these effects by Day 5, significantly improving ATP production (&#x2191;27%-30%, p&#x2009;<&#x2009;0.005), basal respiration (&#x2191;20%, p&#x2009;=&#x2009;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 (&#x2193;30%-62%, p&#x2009;<&#x2009;0.05) at 48&#x2009;h and a significant improvement in maximal respiration for tirzepatide at 5&#x2009;days (&#x2191;42%-52%, p&#x2009;=&#x2009;0.0022). 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.

Renal or Hepatic Impairment Does Not Affect Pharmacokinetics, Safety, or Tolerability of Subcutaneous Cagrilintide.

Cagrilintide is a long-acting amylin agonist under development as monotherapy for weight management and as a fixed-dose combination with the glucagon-like peptide-1 receptor agonist semaglutide (CagriSema) for weight management and treatment of type 2 diabetes. Two studies were conducted to assess the effects of renal or hepatic impairment on pharmacokinetics, safety and tolerability following single doses of cagrilintide. In both studies, adult participants were categorised into four groups on the basis of renal or hepatic function (normal function and mild, moderate or severe impairment) and received a single dose of cagrilintide 0.6 or 0.9 mg, respectively. The primary endpoint was area under the cagrilintide plasma concentration curve from time zero extrapolated to infinity (AUC0-&#x221e;) from baseline (day 1) to day 36 (renal impairment study) or day 39 (hepatic impairment study). Other pharmacokinetic parameters included maximum observed cagrilintide plasma concentration (Cmax), time to Cmax (tmax) and safety. The renal impairment study included 33 participants (normal function, n = 14; mild impairment, n = 7; moderate impairment, n = 7; severe impairment, n = 5) and the hepatic impairment study included 32 participants (normal function, n = 14; mild impairment, n = 7; moderate impairment, n = 7; severe impairment, n = 4). In both studies, total cagrilintide exposure (AUC0-&#x221e;), Cmax and other pharmacokinetic parameters were similar across groups with no consistent patterns observed with renal or hepatic impairment. Compared with normal renal function, the estimated ratio of the mean AUC0-&#x221e; was 1.23 (90% confidence interval [CI], 0.91-1.66) in mild impairment, 1.18 (0.87-1.59) in moderate impairment and 1.21 (0.87-1.68) in severe impairment. Compared with normal hepatic function, the estimated ratio of the mean AUC0-&#x221e; was 0.99 (0.89-1.11) in mild impairment, 1.01 (0.91-1.12) in moderate impairment and 1.11 (0.96-1.30) in severe impairment. Overall, 21 and 16 treatment-emergent adverse events (TEAEs) were reported in 11 and 9 participants in the renal and hepatic studies, respectively. In both studies, no serious TEAEs, TEAEs leading to study withdrawal or deaths were reported. No increase in number of adverse events with increasing renal or hepatic impairment was observed, and no new safety or tolerability findings with cagrilintide were identified with renal or hepatic impairment. In these studies, within the limitations of small sample sizes, no clinically relevant differences in cagrilintide pharmacokinetics were observed in participants with renal or hepatic impairment compared with those with normal function, suggesting that dose adjustment is not warranted for these populations. Cagrilintide was well-tolerated and there were no unexpected safety issues. Studies are registered at ClinicalTrials.gov (NCT04209049 registered 23 December 2019 and NCT05564104 registered 3 October 2022).

Cagrilintide and CagriSema for weight reduction and metabolic risk modification in overweight or obesity: a systematic review and meta-analysis.

Obesity is a global health challenge associated with substantial cardiometabolic morbidity. Cagrilintide, a long-acting amylin analogue, alone or in combination with semaglutide (CagriSema), has emerged as a novel pharmacologic strategy for weight management. We conducted a systematic review and meta-analysis to evaluate the efficacy and safety of cagrilintide-based therapies in adults with overweight or obesity. A systematic review and meta-analysis of randomized controlled trials was conducted according to PRISMA 2020 and AMSTAR 2. Eligible studies enrolled adults with overweight or obesity randomized to cagrilintide or CagriSema versus placebo and reported at least one efficacy or safety outcome. The primary outcome was percent change in body weight. Secondary outcomes included absolute weight change, waist circumference, blood pressure, glycated hemoglobin (HbA1c), and safety outcomes. Random-effects meta-analyses were conducted, and risk of bias was assessed using the Cochrane RoB 2 tool. Four trials including 5,023 participants were pooled. Cagrilintide significantly reduced percent body weight versus placebo (mean difference&#x2009;-&#x2009;6.08%, 95% CI&#x2009;-&#x2009;8.02 to&#x2009;-&#x2009;4.14), as did CagriSema (-&#x2009;5.98%, 95% CI&#x2009;-&#x2009;10.64 to&#x2009;-&#x2009;1.32). Both interventions significantly reduced absolute body weight. CagriSema produced a significant reduction in waist circumference and HbA1c, whereas cagrilintide alone showed modest blood pressure improvements without significant glycemic effects. Overall adverse events were more frequent with active treatment, but discontinuation rates were comparable to placebo. Cagrilintide and CagriSema achieved clinically meaningful weight loss with favorable cardiometabolic effects and acceptable tolerability, supporting their role as emerging options in obesity pharmacotherapy. The online version contains supplementary material available at 10.1007/s40200-026-01942-3.

Cagrilintide-Semaglutide in Adults with Overweight or Obesity.