Main Research

1) In overweight or obese individuals, treatment with Cagrilintide was found to significantly reduce overall body weight.

2) Cagrilintide was found to lower body weight through activation of amylin receptors 1 and 3.

 

Selected Data
1) This study performed by the research team of Lau et al evaluated the efficacy, safety, and optimal dosing of Cagrilintide, a long-acting amylin analogue, in adults with obesity or overweight associated with comorbidities. The study included a 26-week treatment period including up to six weeks of dose escalation, followed by a 6-week post-treatment follow-up, extending to week 32. Participants were male and female adults aged ≥18 years who were of non-childbearing potential and met the BMI inclusion criteria of either ≥30.0 kg/m², or ≥27.0 kg/m² with hypertension or dyslipidemia. Individuals with diabetes characterized by HbA1c ≥6.5%, or a history of surgical or device-based obesity treatment, were excluded. All participants provided written informed consent before enrollment [1].
Randomization was conducted using an interactive web response system, assigning participants in a 6:1 ratio to one of several treatment arms: once-weekly subcutaneous Cagrilintide administered in doses of 0.3, 0.6, 1.2, 2.4, or 4.5 mg, once-daily liraglutide 3.0 mg, or a volume-matched placebo. The study maintained blinding for active versus placebo treatment; however, differences in injection frequency, dose escalation, and device design meant that investigators were not blinded to which active treatment participants received [1].
Participants self-administered subcutaneous injections of the assigned treatment for 26 weeks. Cagrilintide was initiated at 0.3 mg for the 0.3 mg group, or 0.6 mg for all higher-dose groups and escalated every two weeks until reaching the final dose. Liraglutide, the active comparator, was initiated at 0.6 mg daily and titrated weekly up to 3.0 mg. Matching placebos were administered with identical pen-injectors. Participants were trained to self-inject and received periodic retraining during the trial.
All participants were counseled on lifestyle modification, including a daily 500-kcal calorie deficit and at least 150 minutes of physical activity per week. Body weight was measured at screening, randomization, and at regular intervals throughout the study (weeks 2, 4, 6, 8, 10, 14, 18, 22, 26, and 32). The trial also included comprehensive efficacy and safety assessments at each visit.
The primary endpoint was the percentage change in body weight from baseline to week 26. Secondary endpoints included the proportion of participants achieving ≥5% and ≥10% body weight reduction, absolute weight change in kg, change in waist circumference, lipid parameters including total cholesterol, HDL, LDL, VLDL, triglycerides, and glycaemic variables such as HbA1c, fasting glucose, insulin, HOMA-IR, and β-cell function. Safety outcomes encompassed treatment-emergent and serious adverse events, the presence of anti-cagrilintide antibodies, and changes in blood pressure, pulse rate, high-sensitivity C-reactive protein, plasma renin activity, and aldosterone levels. Exploratory endpoints included achieving ≥15% and ≥20% weight loss, and patient-reported outcomes assessed using the SF-36 v2.0 and the Three-Factor Eating Questionnaire (TFEQ-R18 v2). However, analysis of ≥20% weight loss was not performed for the 0.3 mg and placebo groups because no participants in those arms achieved that degree of reduction [1].
Statistical analysis was rigorously designed to assess treatment efficacy and account for missing or incomplete data. Based on power calculations, approximately 100 participants per active treatment group were required to provide >99% power to detect a significant difference between the optimal Cagrilintide dose and pooled placebo, and 98% power for comparisons with liraglutide 3.0 mg. Superiority testing followed a hierarchical order, beginning with the highest Cagrilintide dose versus placebo, using a two-sided 5% significance threshold. Comparisons with liraglutide were exploratory and not adjusted for multiplicity.
Two estimands were employed: the trial product estimand, which evaluated treatment effects assuming perfect adherence to the assigned regimen, and the treatment policy estimand, which included all randomized participants regardless of adherence. Missing data for the trial product estimand were handled through multiple imputation using the Markov Chain Monte Carlo method, assuming that non-adherent participants would have responded similarly to adherent participants within the same treatment arm. For the treatment policy estimate, missing data were imputed using outcomes from participants who discontinued treatment but completed the week 26 visit [1].
Continuous outcomes were analyzed using ANCOVA, with randomized treatment as a factor and baseline body weight as a covariate, while categorical data were analyzed with binary logistic regression. Sensitivity analyses included a mixed-effects model for repeated measures and exclusion of post-baseline data from non-adherent participants to confirm robustness. Additionally, a post-hoc compiler average causal effect analysis was performed to estimate the influence of treatment adherence on outcomes. Safety analyses included all participants who received at least one dose of the assigned intervention, with results summarized descriptively [1].
Overall, this trial was designed to precisely determine the dose-response relationship, efficacy, and safety of Cagrilintide compared with placebo and liraglutide, while employing advanced statistical methods to ensure reliable interpretation of treatment effects under both ideal and real-world adherence conditions.
2) This extensive experimental protocol designed by researchers Carvos et al describes a series of animal studies investigating the pharmacological and neurobiological effects of Cagrilintide, a long-acting amylin analogue, in wild-type (WT) and receptor activity-modifying protein (RAMP) knockout mice. The studies were conducted using various mouse models to elucidate the role of RAMP1 and RAMP3 in mediating cagrilintide’s central and metabolic actions [2].
The experiments employed RAMP1 knockout (KO), RAMP3 KO, and RAMP1/3 double KO mice on a 129S2/SvEv genetic background. Single KOs were maintained through heterozygous breeding, while double KOs were bred homozygously and WT mice were age-matched controls. All animals were housed under controlled temperature and a 12-hour light–dark cycle, with ad libitum access to food and water.
Study 1 assessed the acute effects of Cagrilintide in 32 twelve-week-old male WT mice fed a standard chow diet of 3.14 kcal/g. Mice were housed individually in automated food-monitoring cages and acclimated for two weeks before testing. The study aimed to determine short-term changes in feeding behavior following subcutaneous injections of vehicle or Cagrilintide at 3, 30, or 300 nmol/kg [2].
Study 2 examined the subchronic effects of Cagrilintide in diet-induced obese WT mice. Thirty-two male mice were started on a 60% high-fat diet of 5.24 kcal/g at three weeks of age for 19 weeks, followed by a 45% HFD of 4.73 kcal/g for six additional weeks. The animals were group-housed until one week before treatment initiation, after which they were given daily subcutaneous injections of vehicle or Cagrilintide at doses of 0.3, 3, or 30 nmol/kg for 21 days. Body weight and food intake were recorded daily, and animals were euthanized 24 hours after the final dose for biochemical and tissue analyses [2].
Study 3 compared subchronic Cagrilintide treatment in WT and RAMP1/3 double KO mice under HFD conditions. Twenty-four WT and twenty-four RAMP1/3 KO male mice were fed a 60% HFD for 18 weeks followed by a 45% HFD for six weeks. At 25 weeks of age, mice were divided into groups receiving daily subcutaneous injections of vehicle, 150 nmol/kg/day salmon calcitonin, or 3 nmol/kg/day Cagrilintide for three weeks. Animals were pre-acclimated with vehicle injections for three days to reduce injection stress. At sacrifice, blood and brain tissues were collected for metabolic, body composition, and transcriptomic analyses.
Body composition was determined post-mortem using EchoMRI, which measured lean and fat mass as percentages of total body weight. Plasma glucose was measured with a glucometer, and insulin and leptin concentrations were analyzed via the U-PLEX Custom Metabolic Group 1 mouse assay [2].
To investigate the neural mechanisms of Cagrilintide, next-generation sequencing (NGS) was performed on three key hypothalamic and brainstem regions: the area postrema/nucleus tractus solitarius (AP/NTS), lateral parabrachial nucleus (LPBN), and ventromedial hypothalamus (VMH). Brain punches were obtained using a cryostat, and RNA was extracted using the Promega RNA extraction kit. RNA integrity was confirmed using a Nanodrop spectrophotometer and electrophoresis. Samples with RNA integrity numbers (RIN) > 8 and concentrations ≥ 30 µg/µL were sequenced using the Illumina NovaSeq platform, generating 20–25 million single-end reads per sample [2].
Data processing utilized the SUSHI pipeline for alignment, read counting, and quality control. Transcript abundance was quantified with Kallisto, and differentially expressed genes (DEGs) were identified using DESeq2. Further integrative analysis applied weighted gene co-expression network analysis (WGCNA) to identify co-regulated gene modules within each brain region. Correlations between gene modules and experimental conditions (genotype or treatment) were tested using the limma R package, with multiple testing corrections via the Benjamini–Hochberg method. Additional enrichment analyses were conducted for cell-type markers (via Fisher’s exact test) and Gene Ontology (GO) terms using the clusterProfiler R package.
Study 4 evaluated neuronal activation in response to acute treatment with Cagrilintide or sCT in WT, RAMP1 KO, RAMP3 KO, and RAMP1/3 KO mice. In Cohort 1, 25 WT and 25 RAMP1/3 KO male mice aged 12–20 weeks old were injected intraperitoneally after a 12-hour fast with vehicle, sCT at doses of 3 or 150 nmol/kg, or Cagrilintide at a dose of3 nmol/kg. In Cohort 2, 18 mice per genotype received a vehicle or 3 nmol/kg Cagrilintide. Ninety minutes post-injection, animals were anesthetized and perfused for c-Fos immunostaining, a marker of neuronal activation [2].
Brains were fixed, cryoprotected, and sectioned for immunofluorescent labeling using anti-Fos antibodies and fluorescent secondary antibodies. Nuclei were counterstained with DAPI and mounted for imaging. High-resolution images of AP, NTS, and LPBN regions were captured using a Zeiss Axio Scan.Z1 microscope. Quantification was conducted in QuPath software, with cell detection algorithms identifying DAPI-positive nuclei co-expressing c-Fos. Analyses were blinded to treatment conditions.
Overall, these studies integrated behavioral, metabolic, molecular, and neuroanatomical approaches to characterize cagrilintide’s effects and receptor interactions in mice. The combination of genetic models, controlled diets, detailed pharmacological dosing, and multi-level analyses provided a comprehensive framework for understanding the mechanisms underlying cagrilintide’s central regulation of energy balance [2].

 

Discussion
1) The research team of Lau et al evaluated the efficacy and safety of the amylin analogue Cagrilintide for weight management. Ultimately, 706 participants met the eligibility criteria and were randomly assigned to one of several treatment arms: once-weekly subcutaneous injections of Cagrilintide at doses of 0.3, 0.6, 1.2, 2.4, or 4.5 mg, once-daily liraglutide 3.0 mg, or a volume-matched placebo. All randomized participants received at least one dose of the study drug and were included in both the full and safety analysis populations [1].
In the primary analysis using the “trial product estimand,” which evaluated participants who adhered to treatment, bodyweight decreased progressively in all active treatment groups over the 26-week period, without clear evidence of reaching a plateau. Mean weight reductions from baseline at week 26 were dose-dependent for Cagrilintide. The group receiving a 0.3 mg dose experienced a 6.0% weight loss, with 0.6 mg there was a 6.8% weight loss, with 1.2 mg there was a 9.1% weight loss, with 2.4 mg there was a 9.7% weight loss, and weigh 4.5 mg there was a 10.8% weight loss, compared with 3.0% weight loss for pooled placebo. These reductions represented estimated treatment differences ranging from 3.0% to 7.8% weight loss versus placebo, all of which were statistically significant. Furthermore, participants receiving Cagrilintide 4.5 mg achieved greater weight loss than those on liraglutide 3.0 mg demonstrated by a 10.8% vs. 9.0% weight loss, with an estimated treatment difference of −1.8% [1].
When all participants were analyzed regardless of treatment adherence, weight reduction trends were consistent with those from the primary analysis, confirming robustness of the findings. Absolute weight losses in kilograms mirrored the percentage changes. Sensitivity analyses also supported the primary results. Overall compliance scores were high, ranging from 0.95 to 0.97 across Cagrilintide dose groups, and a post-hoc compiler average causal effect analysis yielded similar results, reinforcing that adherence strongly correlated with weight loss outcomes.
After treatment cessation at week 26, some weight regain was observed by the week 32 follow-up visit. In the Cagrilintide groups, observed mean weight losses ranged from 5.0% to 9.8% at week 32, slightly less than the 6.1% to 10.8% observed at week 26. Participants in the liraglutide group demonstrated a similar pattern, with mean weight loss decreasing from 8.5% at week 26 to 7.2% at week 32, indicating partial weight gain after discontinuation [1].
Categorical analyses of weight loss outcomes showed that higher proportions of participants in the Cagrilintide groups achieved at least 5%, 10%, and 15% weight reductions compared to placebo, with results generally comparable to liraglutide. Waist circumference reductions were also dose-dependent for Cagrilintide, notably at 1.2–4.5 mg, exceeding those in the placebo group and approximating the reductions seen with liraglutide 3.0 mg.

Figure 1: Changes in percentage of weight lost across all experimental treatment groups.
Regarding metabolic parameters, Cagrilintide treatment did not produce significant changes in HbA1c or fasting plasma glucose from baseline to week 26, while liraglutide 3.0 mg significantly improved both measures, consistent with its known glucose-lowering effects. Across all groups, fasting insulin levels decreased, suggesting improved insulin sensitivity. Notably, reductions in triglycerides and very-low-density lipoprotein (VLDL) cholesterol were greater with Cagrilintide 2.4 mg and 4.5 mg compared to placebo and were similar to those achieved with liraglutide. Other lipid parameters, including total, LDL, and HDL cholesterol, remained relatively unchanged across all treatment arms [1].
Patient-reported outcomes also reflected positive changes. Scores on the Three-Factor Eating Questionnaire (TFEQ-R18) improved in all treatment groups, with Cagrilintide producing greater improvements than placebo in specific domains: cognitive restraint, notably at 1.2 mg and 4.5 mg, emotional eating notably at 0.3 mg and 2.4 mg, and uncontrolled eating notably at 1.2–4.5 mg. These behavioral improvements were comparable to those seen with liraglutide. Meanwhile, changes in quality-of-life scores measured by the Short Form-36 (SF-36) physical and mental components were small and not clinically significant across groups [1].
Overall, the trial demonstrated that once-weekly Cagrilintide induced clinically meaningful, dose-dependent weight loss in adults with overweight or obesity, with efficacy comparable or superior to liraglutide 3.0 mg. The drug was well tolerated, with high adherence and consistent improvements in weight-related and behavioral outcomes.

2) This series of experiments completed by researchers Carvos et al systematically investigated the pharmacological effects, receptor dependence, and central mechanisms underlying cagrilintide’s anorectic and weight-lowering properties in mice. The studies began with the determination of the optimal dosing for Cagrilintide in both chow-fed and high-fat diet (HFD)-fed wild-type (WT) mice, followed by analyses of its receptor dependence using receptor activity-modifying protein (RAMP) knockout (KO) models, and mechanistic studies involving neuronal activation and gene expression profiling [2].
In the initial dose-finding studies, three concentrations of Cagrilintide ranging from 3, 30, and 300 nmol/kg, were tested in chow-fed WT mice. All doses markedly suppressed food intake compared to vehicle controls, with the 30 and 300 nmol/kg doses producing the strongest anorectic effects, reducing 24-hour food intake by 51% and 57%, respectively. These reductions were accompanied by significant body weight loss, confirming a robust pharmacodynamic response. Subsequent subchronic dosing in HFD-fed mice revealed that Cagrilintide doses of 3 and 30 nmol/kg produced significant decreases in food intake during the first three days of treatment, but this effect waned over time. However, body weight remained significantly lower in these groups throughout the 21-day study, suggesting that cagrilintide’s weight-lowering action extends beyond acute appetite suppression. Given the comparable efficacy of the 3 and 30 nmol/kg doses, the lower dose was chosen for further studies [2].

Figure 2: Changes in A) daily food intake, B) weekly food intake, C) daily body weight, and D) overall change in body weight.
To determine whether these effects depend on RAMP-containing amylin receptor subtypes (AMY1R and AMY3R), experiments were conducted in HFD-fed WT and RAMP1/3 double knockout (KO) mice. During a three-week treatment period, both Cagrilintide and salmon calcitonin (sCT), another amylin receptor agonist, produced an acute reduction in food intake in WT mice on day 1 by −53% and −42%, respectively, but not in RAMP1/3 KO mice. Despite the absence of a prolonged anorectic effect, Cagrilintide produced a sustained and significant reduction in body weight in WT mice by −3.4 g after 21 days, while no such effect was observed in KO animals. This finding strongly supports the necessity of RAMP1 and RAMP3 for mediating cagrilintide-induced weight loss through AMY1R and AMY3R signaling [2].
Analysis of body composition further demonstrated that Cagrilintide specifically reduced fat mass while preserving lean mass in WT mice. Although these changes did not reach statistical significance, they were accompanied by a twofold decrease in plasma leptin levels, consistent with fat mass reduction. In contrast, RAMP1/3 KO mice exhibited disrupted metabolic responses: Cagrilintide treatment increased relative fat mass and decreased lean mass, along with elevated leptin and insulin levels. These results indicate that cagrilintide’s metabolic effects are receptor-dependent and that functional AMY1R/AMY3R signaling is essential for proper nutrient partitioning and energy balance regulation.
Neuronal activation mapping using cFos immunostaining in the area postrema (AP), nucleus tractus solitarius (NTS), and lateral parabrachial nucleus (LPBN) provided mechanistic insight. In WT mice, both Cagrilintide and sCT significantly increased cFos expression in these hindbrain nuclei compared to vehicles, indicating activation of satiety-related pathways. However, Cagrilintide failed to induce significant cFos activation in RAMP1/3 KO mice, whereas sCT retained its ability to do so, likely via residual AMY2R signaling. Notably, Cagrilintide activated fewer neurons overall than sCT, particularly in the AP by −75% and LPBN by −36%, suggesting differences in their receptor selectivity and downstream signaling dynamics [2].
A second cohort of mice including WT, RAMP1 KO, RAMP3 KO, and RAMP1/3 KO genotypes confirmed that both RAMP1 and RAMP3 are individually essential for a full cagrilintide-induced neuronal activation response. In all KO genotypes, cFos induction in the AP and NTS was markedly blunted compared to WT mice, establishing that both AMY1R and AMY3R are necessary for transmitting cagrilintide’s central effects.
Finally, transcriptomic analyses were performed on key metabolic brain regions including the dorsal vagal complex (DVC), LPBN, and mediobasal hypothalamus (MBH), after 21 days of treatment. Bulk RNA sequencing revealed that gene expression changes were most pronounced in the MBH, where RAMP1/3 KO mice treated with sCT showed extensive differential expression of over 1,700 genes, while WT mice exhibited comparatively minor transcriptional shifts. Weighted gene co-expression network analysis (WGCNA) identified genotype-driven, rather than treatment-driven, gene modules, highlighting distinct transcriptional architectures between WT and KO animals. Modules correlated with the KO genotype were enriched for neuronal and synaptic genes involved in vesicle-mediated transport, neurotransmitter secretion, and GTPase activity, suggesting that RAMP deletion disrupts synaptic signaling networks critical for metabolic regulation [2].
Overall, these findings demonstrate that Cagrilintide exerts potent, RAMP-dependent effects on food intake, body weight, and neuronal activation. Its mechanism involves specific engagement of AMY1R and AMY3R in hindbrain and hypothalamic circuits that regulate energy homeostasis, leading to preferential fat mass reduction and altered hypothalamic gene expression profiles [2].

 

Disclaimer

**LAB USE ONLY**
*This information is for educational purposes only and does not constitute medical advice. THE PRODUCTS DESCRIBED HEREIN ARE FOR RESEARCH USE ONLY. All clinical research must be conducted with oversight from the appropriate Institutional Review Board (IRB). All preclinical research must be conducted with oversight from the appropriate Institutional Animal Care and Use Committee (IACUC) following the guidelines of the Animal Welfare Act (AWA).

 

Citations

[1] Lau DCW, Erichsen L, Francisco AM, et al. 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. Lancet. 2021;398(10317):2160-2172. doi:10.1016/S0140-6736(21)01751-7

[2] Carvas AO, Leuthardt A, Kulka P, et al. Cagrilintide lowers bodyweight through brain amylin receptors 1 and 3. EBioMedicine. 2025;118:105836. doi:10.1016/j.ebiom.2025.105836

What is Cagrilintide

Cagrilintide is a long-acting amylin analogue that is currently being assessed for its potential to manage obesity. Amylin is a pancreatic beta-cell hormone that is typically secreted in combination with insulin in order to manage nutrient intake. The compound has been found to operate in the postrema and nucleus of the hindbrain solitary tract in order to both induce satiety and regulate appetite by acting on receptors found in the laterodorsal tegmental nucleus, ventral tegmental area, and the hypothalamus [1].

It is important to mention that obesity is a significant risk factor related to several leading causes of death in the United States including: heart disease, cancer, type 2 diabetes, and hypertension, all of which decrease quality of life and life expectancy. That being said, current research has been focused on the ability of the peptide to reduce body weight as well as the identifying the optimal dose-response relationship between treatment with cagrilintide and overall body weight [1].

 

Main Research Findings

1) Administration of cagrilintide to overweight and obese patients was a well tolerated treatment that led to a significant reduction in body weight.

2) Administration of a combination of cagrilintide and semaglutide resulted in significant weight loss, as well as reductions in HbA1c levels in type 2 diabetic participants.

 

Selected Data

1) The research team of Lau et al conducted a randomized, double-blind, placebo-controlled, and active controlled trial in order to assess the dose-response relationship between bodyweight and once-weekly administration of cagrilintide. The experimental trail included a 26-week treatment period, a dose-escalation period of up to 6 weeks, and a 6-week follow-up period after the end of treatment. Inclusion criteria consisted of male and female participants without child bearing ability either due to menopause, documented hysterectomy, bilateral salpingectomy, bilateral oophorectomy, or bilateral tubal ligation, as well as age of at least 18 years, a body mass index of 30, or a body mass index of 27 with the presence of hypertension or dyslipidemia [1].

All study participants were randomly assigned to an experimental treatment group that received subcutaneous injection of cagrilintide, once-weekly, in doses of either 0.3, 0.6, 1.2, 2.4, or 4.5 mg, as well as a one-daily 3.0 mg dose of liraglutide, and a volume matched placebo for control purposes. In addition to education on proper treatment administration, the participants of the study also received dietary and physical activity counseling aimed towards achieving 150 minutes of physical activity per week and a 500 calorie deficit per day. Body weight of the test subjects was measured when the patients were screened, when they were randomly assigned to treatment groups, and at weeks 2, 4, 6, 8, 10, 14, 18, 22, 26, and 32 [1].

The primary outcome measurements of the study included change in body weight from baseline to week 26. Secondary outcome measurements included reduction in body weight from baseline by at least 5% or 10% by week 26, changes in waist circumference, total cholesterol, HDL, LDL, VLDL, and triglycerides, and levels of different glycemic variables including HbA1C, fasting plasma glucose, fasting insulin, insulin resistance, and the functioning of beta-cells. Throughout the 0-32 week treatment period, adverse outcomes and the occurrence of anti-cagrillintide antibodies were assessed in addition to any changes in systolic and diastolic blood pressure, pulse rate, plasma high-sensitivity C-reactive protein, aldosterone, and the activity of renin.

In order to assess the superiority of each cagrilintide dose in comparison to the placebo and the dose of liraglutide, the researchers ranked each treatment in hierarchical order. From there, the trial product estimand and the treatment policy estimand were used to assess the efficacy of the treatment in all randomly assigned participants. The trial product estimand assumed participants adhere to their assigned treatment during the trial. Data from treatment-adherent participants was collected and included in the analyses for the trial product product estimand [1].

Continuous data collected from the participants over the 26 week treatment period was assessed using an ANCOVA model, using randomized treatment as a factor and baseline bodyweight as a covariate. Additional analysis was performed in order to estimate the effects of cagrilintide in patients regardless of their adherence to the treatment where body weight of all patients was included and any missing data was filled in through the multiple imputation method. Finally, descriptive statistics were used to analyze safety endpoints of the randomized treatments in all participants that were exposed to at least one dose [1].

2) In addition to testing various doses of cagrilintide, the peptide was also tested in combination with semaglutide, a GLP-1 receptor agonist, in order to assess the impact treatment has on HbA1c levels in participants diagnosed with type 2 diabetes mellitus. The research team of Frias et al designed a 32-week, randomized, double-blind, parallel-group, active control trial that included adults with a diagnosis of type 2 diabetes and a body mass index of 27 and HbA1C levels ranging from 7.5% to 10% despite a daily dose of metformin. After a 2 week screening period all eligible participants were randomly assigned to treatment groups receiving either a subcutaneous injection of 2.4 mg of semaglutide, 2.4 mg of cagrilintide, a combination of cagrilintide and semaglutide, a semaglutide placebo, or a cagrilintide placebo [2].

All participants received a treatment dosage once a week for 32 weeks; the doses were escalated every 4 weeks starting from 0.25 mg to 0.5 mg, 1.0 mg, and 1.7 mg until a dose of 2.4 mg was met and maintained for the remaining 16 weeks. This maintenance period was followed by a 5-week follow up period. Following the guidelines for studies involving participants with a type 2 diabetes diagnosis, there was no adjunct nutrition or physical activity plans provided to the subjects. Alternatively, they were provided with a Dexcom G6 device for the purpose of continuous glucose monitoring [2]. The device was worn starting 10 days before baseline measurements were obtained throughout the course of the 32-week period. Rescue medication was available for patients whose fasting plasma glucose exceeded the predefined limits of 15.0 mmol/L from week 8, 13.3 mmol/L from week 9 to week 20, and 11.1 mmol/L from week 21 to week 32.

The primary goal of this study was to determine the effects of a combined treatment of cagrilintide and semaglutide versus treatment with semaglutide alone. The scondary goal of the study was to compare the effects of combined treatment of cagrilintide and semaglutide versus treatment with cagrilintide alone and how the effected HbA1c levels and various parameters of glycemic control and bodyweight as well as the safety and tolerability of the treatment. The primary outcome measure being assessed was the change in HbA1c from baseline to the end of treatment at week 32, while seconday outcome measures were related to endpoints of continuous glucose monitoring included time in range and time aboe range [2]. Other biomarkers measured by the research team including blood pressure, heart rate, hypoglycemic episodes, fasting glucagon, fasting serum insulin, high-sensitivity C-reactive protin, leptin, and a general lipid panal.

In terms of statistical analysis, various efficacy analyses were performed in all participants that went through the randomization process while safety analysis were used to assess all participants that underwent randomization and were also exposed to one experimental treatment dosage. Statistical analysis of the experimental findings included a trial product estimate that evaluated the treatment effect in the participants based on data that was collected through the 32 week treatment period. A mixed model for repeated measurements was used to input any missing data from test subjects that discontinued treatment or required a dose of rescue medication. On the other hand, the treatment policity estimand was used to evaluate the treatment effect for all randomized participants regardless of whether the trial was discontinued early or rescue medicien was used [2].

 

Discussion

1) At the end of the trial it was recorded that 100-102 participants received an active dose of cagrilintide, 99 participants were administered a 3.0 mg dose of liraglutide and 101 participants were given volume-matched placebo. Primary analysis using trial product estimand found that bodyweight was significantly decreased in the active treatment groups. It was important to note that reduction in body weight did not appear to reach a plateau at the end of the treatment and all significant reduction in weight from baseline was seen in all groups administered cagrilintide, in comparison to the placebo group. The results reported a 6.0%, 6.8%, 9.1%, 9.7%, and 10.8% decrease in body weight for the groups receiving cagrilintide in doses of 0.3 mg, 0.6 mg, 1.2 mg, 2.4 mg, and 4.5 mg, respectively [1].

In comparison to treatment with 3.0 mg of liraglutide, the treatment group administered a 4.5 mg dose of cagrilintide experienced a greater reduction in weight loss by 1.8%. Regardless of treatment adherence, the data gathered from all participants of the study indicated a similar decrease in weight from baseline levels. It is important to note that following the cessation of treatment at week 26 and again at the end of the weaning treatment administration there was a slight increase in weight in both the cagrilintide and the liraglutide groups. However, overall body weight was still reduced by 5.0% to 9.8% at the end of week 32 in the groups administered cagrilintide and by 7.2% at the end of week 32 in the group administered liraglutide [1].

Figure 1: Changes in body weight from baseline to the end of treatment at week 26 associated with the trial product estimand, in the randomly assigned treatment groups administered either 0.3 mg of cagrilintide, 0.6 mg of cagrilintide, 1.2 mg of cagrilintide, 2.5 mg of cagrilintide, 4.5 mg of cagrilintide, 3.0 mg of liraglutide, or a placebo. Also included is the number of participants in each experimental group.

Figure 2: Changes in body weight from baseline to the end of treatment at week 26 associated with the treatment policy estimand, in the randomly assigned treatment groups administered either 0.3 mg of cagrilintide, 0.6 mg of cagrilintide, 1.2 mg of cagrilintide, 2.5 mg of cagrilintide, 4.5 mg of cagrilintide, 3.0 mg of liraglutide, or a placebo. Also included is the number of participants in each experimental group.

When evaluating the changes in the secondary outcome measures, there was a dose-dependent decrease in waist circumference elicited by treatment with the peptide. The findings related to waist circumference related to a categorical weight loss of at least 5%, 10%, or 15% by week 26 of treatment administration. Additionally, there were no apparent changes in the concentration of fasting glucose of HbA1c across all treatment groups. Also observed in all treatment groups was a decrease from baseline in fasting insulin concentrations. Reduction of triglyceride levels and very-low-density cholesterol were greatest with the 2.4 and 4.5 mg doses of cagrilintide, while changes from baseline of the other lipid and cholesterol levels were relatively similar across treatment groups [1].

Figure 2: Categorical weight loss of either 5%, 10%, or 15% in the randomly assigned treatment groups administered either 0.3 mg of cagrilintide, 0.6 mg of cagrilintide, 1.2 mg of cagrilintide, 2.5 mg of cagrilintide, 4.5 mg of cagrilintide, 3.0 mg of liraglutide, or a placebo.

In terms of safety and tolerability of the compound, there were fewer adverse events per 100 patients across all experimental groups administered cagrilintide. This was in comparison to the subjects administered liraglutide and a placebo compound, as well. When looking at the percentage of participants that dropped out of the trial due to adverse effects, 2-6% of patients in the cagrilintide group discontinued treatment early while 7% of the participants receiving liraglutide discontinued treatment early, These findings were in comparison to only 3% of test subjects from the placebo group that discontinued treatment due to adverse events [1].

It is important to note that adverse events that occurred in the cagrilintide groups were not dependent on dosage and there were no fatal events that occurred across all groups. Additionally, while the most common side effect was mild to moderate gastrointestinal upset, there were fewer events per 100 patients across all of the cagrilintide treatment groups in comparison to the subjects receiving 3.0 mg of liraglutide [1]. Permanent discontinuation of treatment only occurred in one participant receiving 1.2 mg of cagrilintide, one participant receiving 2.4 mg of cagrilintide, and one participant that developed a case of pancreatitis after administration of liraglutide.

The findings of this study allowed the research team of Lau et al to conclude that treatment with cagrilintide in doses ranging from 0.3-4.5 mg resulted in significant dose-dependent weight loss. Treatment took place over the course of 26 weeks and was most successful in combination with adjunct lifestyle interventions related to nutrition and physical activity [1].

2) A total of 162 participants were screened and assigned to a treatment group; in terms of treatment completion, 27 participants were administered a combined treatment of cagrilintide and semaglutide, 28 participants were administered semaglutide, and 30 were administered cagrilintide. In terms of completion of the entire trial, 29 participants were treated with a combined treatment of cagrilintide and semaglutide and treatment with semaglutide by itslef while 30 participants were treated with cagrilintide. 13% of the participants treated with the combined compound ended up discontinuing the trial, while 10% of the participants treated with semaglutide discontinued, however, none of the participants treated with cagrilintide discontinued their treatment plan indicating that cagrilintide was the most well tolerated by the study participants [2].

Baseline measurements obtained from the participants determined that 64% of the participants were male, while the mean age was 58 years old, average diabetes duration was approximaely 9 years, the mean HbA1c was recorded at 8.4%, as well as an average body weight of 105.7 kg. When assessing changes in HbA1c, there was a significant reduction in these levels seen after 32 weeks of treatment in comparison to baseline levels in the experimental groups receiving a combined treatment. The combined treatment reduced HbA1c to a greater degree considering it decreased by 2.2% with the combination of semaglutide and cagrilinide, 1.8% with semaglutide alone, and 0.9% with cagrilintide [2].

Figure 3: Reduction in HbA1c levels from baseline levels in treatment groups administered treatment with cagrilintide, semaglutide, or a combined treatment of both peptides.

Additionally, there was a significant reduction in body weight observed from baseline to week 32. The combination treatment of cagrilintide and semaglutide was more effective in decreasing body weight in comparison to treatment with cagrilintide and semaglutide alone. The group receiving the combined treatment experienced a 15.6% reduction in weight loss, while the groups receiving treatment with cagrilintide or semaglutide experienced an 8.1% and 5.1% reduction in body weight, respectively [2].

Figure 4: Reduction in body weight from baseline level in treatment groups administered treatment with cagrilintide, semaglutide, or a combined treatment of both peptides.

When looking at the time in range measured by continuous glucose measuring, results were found to be 88.9% with the combined treatment, 71.9% with cagrilintide treatment, and 76.2% with semaglutide treatment. On the other hand, when looking at the time above range measured by continuous glucose measuring, results were found to be 10.3% with the combined treatment, 28.1% with cagrilintide treatment, and 23.7% with semaglutide treatment [2]. Remarkable changes from baseline to week 32 were also seen in average glucose levels measured by continuous glucose measuring, as well as fasting plasma glucose. For both of these variables, the combined treatment of semaglutide and cagrilintide were shown to be more effective than either peptide treatment alone.

Figure 5: A) Time spent below range, time in range, time above high range, and time in tight range. B) Profiles of the 24 hours continuous glucose monitoring for each treatment group

In terms of secondary outcome measures and adverse events, the results of the study reported that all treatment groups experienced significant reductions in total cholesterol, triglycerides, LDL cholesterol, and VLDL cholesterol. As for adverse events, a similar percentage of participants across the treatment groups experienced the most common side effect of gastrointestinal upset [2]. Based on the overall findings of this study the research team was able to conclude that combined treatment with cagrilintide and semaglutide was able to significantly decrease body weight.

Disclaimer
**LAB USE ONLY**
*This information is for educational purposes only and does not constitute medical advice. THE PRODUCTS DESCRIBED HEREIN ARE FOR RESEARCH USE ONLY. All clinical research must be conducted with oversight from the appropriate Institutional Review Board (IRB). All preclinical research must be conducted with oversight from the appropriate Institutional Animal Care and Use Committee (IACUC) following the guidelines of the Animal Welfare Act (AWA).

 

Citations

[1] Lau DCW, Erichsen L, Francisco AM, Satylganova A, le Roux CW, McGowan B, Pedersen SD, Pietiläinen KH, Rubino D, Batterham RL. 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. Lancet. 2021 Dec 11;398(10317):2160-2172. doi: 10.1016/S0140-6736(21)01751-7. Epub 2021 Nov 16. PMID: 34798060.

[2] Frias JP, Deenadayalan S, Erichsen L, Knop FK, Lingvay I, Macura S, Mathieu C, Pedersen SD, Davies M. Efficacy and safety of co-administered once-weekly cagrilintide 2·4 mg with once-weekly semaglutide 2·4 mg in type 2 diabetes: a multicentre, randomised, double-blind, active-controlled, phase 2 trial. Lancet. 2023 Aug 26;402(10403):720-730. doi: 10.1016/S0140-6736(23)01163-7. Epub 2023 Jun 23. PMID: 37364590.

 

PEPTIDES PREFER THE COLD
Keep peptide vials refrigerated at all times to reduce peptide bond breakdown. DO NOT FREEZE. Most peptides, especially shorter ones, can be preserved for weeks if careful.
Always swab the top of the vial with an alcohol wipe, rubbing alcohol or 95% ethanol before use.
Before drawing solution from any dissolved peptide vial, fill the pin with air to the same measurement you will be filling with solution, ie. if you plan to take 0.1 ml, first fill the pin with 0.1ml of air, push the air into the vial, and then draw the peptide back up to the 0.1 ml marker. Doing so will maintain even pressure in the vial. Always remember to remove air bubbles from the pin by flicking it gently, pin side up, and pushing bubbles out. In addition, push out a tiny amount of solution to ensure there is no air left in the metal tip.

ONLY MIX WITH STERILE BACTERIOSTATIC WATER
The purity and sterility of bacteriostatic water are essential to prevent contamination and to preserve the shelf-life of dissolved peptides.
Push the pin through the rubber stopper at a slight angle, so that you inject the bacteriostatic water toward the inside wall of the vial, not directly onto the powder.
Lyophilized peptide should be stored at -20°C (freezer), and the reconstituted peptide solution at 4°C (refrigerated). Do not freeze once reconstituted.
NEVER SHAKE A VIAL TO MIX.

Air bubbles are unfavorable to the stability of proteins.

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