sulin from β-cells following meals [1-3]. This hormone exerts several actions that result in amelioration of glycemic control including slowing of gastric emptying and suppression of postprandial glucagon release [1-3]. In addition, amylin may lower body weight by decreasing appetite and increasing satiety [1-3]. Pre-clinical data suggests that amylin may affect hedonic aspects in eating control and reduce the rewarding value of food via receptors in the central nervous system such as the caudal hindbrain area postrema and the hypothalamic arcuate [2]. Moreover, while obesity is characterized by resistance to leptin, amylin may improve body responsiveness to leptin [3]. The first available amylin agonist was pramlintide, which is already approved for treatment of type 1 and type 2 diabetes in conjunction with insulin [4]. Yet, pramlintide has a short half-life (20-45 min) and therefore must be injected subcutaneously 3 times daily before meals [4]. Furthermore, pramlintide causes only modest mean weight loss of 1.6 kg and HbA1c reduction of 0.34% compared with placebo [4]. Cagrilintide is a long acting acylated agonist of amylin receptor [1]. The half-life of cagrilintide is 159-195 hours (approximately 6.6 to 8.1 days) making it suitable for once weekly subcutaneous administration [5]. Semaglutide is a GLP-1R agonist approved for treatment of type 2 diabetes (in doses of 0.5-2.0 mg once weekly) and obesity (2.4 mg once weekly) [6,7]. The anti-diabetic actions of semaglutide include stimulation of insulin secretion, inhibition of glucagon secretion after meals and delay of gastric emptying [6,7]. Its anti-obesity effects are related to decrease appetite and induction of early satiety through receptors in the central nervous system [6,7]. Despite some overlap in actions exists between cagrilintide and semaglutide, the combination of the 2 agonists was investigated to enhance their efficacy. Fortunately, the half-life of semaglutide is close to that of cagrilintide, 145-165 hours (6.0 to 6.8 days) [6,7]. Thus, it was possible to formulate a cagrilintide/semaglutide combination, called CagriSema, to be injected subcutaneously through a dual-chamber, single-dose, single-use pen device [8,9]. The main purpose of this review is to provide an appraisal of CagriSema regarding its efficacy and safety for treatment of obesity with and without type 2 diabetes.

REDEFINE is a phase 3 clinical program formed of 4 trials (REDEFINE 1 through 4) to evaluate efficacy and safety of CagriSema in different settings [2]. The recently published REDEFINE 1 and 2 Studies were randomized, double-blind, placebo-controlled, phase 3a multinational trials of 68-week duration [8,9]. In the 2 studies, the coprimary endpoints were the percent change in body weight from baseline to week 68 and percentage of subjects with a weight reduction of at least 5% as compared with placebo [8,9]. The REDEFINE 1 included 4 groups of subjects without diabetes with body mass index (BMI) of ≥30 kg/m2 or BMI ≥27 kg/m2 plus one or more obesity-related complication [8]. Subjects were randomized to CagriSema (n=2108), semaglutide (n=302), cagrilintide (n=302) and placebo (n=705) [8]. Meanwhile, the REDEFINE 2 study included only patients with type 2 diabetes randomized to CagriSema (n=904) or placebo (n=302) (table 1) [9]. Subjects’ demographics and characteristics were different in the 2 trials (table 1). All participants received counseling on diet (500 Kcal deficit per day) and moderate-intensity physical activity of 150 minutes per week. CagriSema was administered as fixed-dose combination of cagrilintide and semaglutide by means of a dual-chamber pen at a starting dose of 0.25 mg once-weekly of each drug, titrated every 4 weeks (to 0.5 mg, 1.0 mg, and 1.7 mg of each drug) to attain the maintenance dose of 2.4 mg of each drug after 16 weeks.

In REDEFINE 1 trial, mean percent change in body weight from baseline to week 68 was significantly higher with Cagrisema versus other groups being -20.4%, -14.9%, -11.5% and -3.0% with CagriSema, semaglutide, cagrinlitide, and placebo, respectively (P<0.001) [8]. The placebo-adjusted difference in percent weight loss between Cagrisema and placebo groups was -17.3% (95% CI, -18.1 to -16.6; P<0.001) [8]. 91.9% of participants randomized to CagriSema lost ≥5% of weight compared with 31.5% randomized to placebo, difference 60.4% (95% CI; 56.4 to 64.5; P<0.001) (table 1) [8]. As shown in table 1, proportions of subjects losing ≥20% and ≥30% were also significantly higher with CagriSema versus placebo. In REDEFINE 2 trial including overweight/obese patients with type 2 diabetes, weight loss at week 68 was -13.7% and -3.4% with Cagrisema and placebo, respectively with a significant difference of -10.4% (95% CI, -11.2 to -9.5; P< 0.001) (table 1) [9]. More patients randomized to CagriSema lost ≥5% of weight compared with placebo, 83.6% and 30.8%, respectively; difference 52.8% (95% CI, 46.7 to 58.9; P<0.001) [9]. In addition, weight reduction of ≥20% and ≥30% was more frequent with Cagrisema versus placebo (table 1).

Table 1: Comparison of Effects of Cagrisema on Body Weight in DEFINE 1 And REDEFINE 2 Trials.

[9]. It should be emphasized that the magnitude of weight loss induced by CagriSema was much higher in the REDEFINE 1 trial than in the REDEFINE 2 trial due to several reasons. First, patients with diabetes had generally decreased response to anti-obesity strategies in terms of weight reduction, in part due to the use of anti-diabetic agents causing weight gain such as SU and thiazolidinediones [10]. The latter 2 classes of drugs were used by approximately 30% of patients in the REDEFINE 2 study [9]. Second, the proportions of women were greater in REDEFINE 1 than REDEFINE 2 studies, 67.6% and 47.2%, respectively [table 1]. For unclear reasons, it has been shown that weight loss induced by GLP-1 agonists in more pronounced in women compared to men [11]. Third, the higher proportions of Asian subjects in REDEFINE 2 (28.7% vs 18.5% in REDEFINE 1) might have attenuated weight loss efficacy of semaglutide (table 1). Regarding the time course of weight loss associated with CagriSema, in the REDEFINE 1 Study, weight loss continued to progress up to the end of follow-up [8]. Meanwhile, in the REDEFINE 2 Study, maximum weight loss was reached at 52 weeks followed by a plateau, again a finding that emphasized the difficulty of inducing weight loss in patients with type 2 diabetes [9].

Effect of Cagrisema on Body Composition

In the REDIFINE 1 trial, 7% of individuals (252 of 3417) underwent a whole-body dual-energy X-ray absorptiometry (DXA) scan to evaluate changes in body composition. At 68 weeks, DXA results showed that 67% of weight loss with CagriSema was from fat mass, whereas the remaining 33% was from lean soft-tissue mass [8].

While patients with diabetes were excluded from the REDEFINE 1 Study, 32.1% of participants had pre-diabetes (HbA1c ≥5.7% to <6.5%) [9]. In the latter subgroup, normoglycemia was attained in 88% with CagriSema versus 32% with placebo [9]. In the REDEFINE 2 trial, mean baseline HbA1c levels were 8.0% and mean duration of diabetes was 8.5 years [9]. At week 68, HbA1c reduction was -1.8 and -0.4 percentage points with CagriSema and placebo, respectively with an estimated difference of -1.4 percentage points (95% CI, -1.6 to -1.2; P < 0.001). Maximum reduction in HbA1c occurred at 36 weeks followed by a plateau until week 68 [9]. Among the 199 patients (16.5% of the study population) using continuous glucose monitoring (CGM), percentage of time spent in glycemic target range of 70-180 mg/dl increased from 43.6% at baseline to 86.8% at week 68 in the CagriSema group. In the placebo group, the corresponding levels were 41.3% and 50.2% [9].

Effects of Cagrisema on Cardiometabolic Risk Factors and Physical Function

Use of CagriSema was associated with amelioration of several cardiovascular (CV) risk factors. In patients with diabetes, the placebo-adjusted reduction in systolic blood pressure (SBP) was -4.1 mmHg (95% CI, -7.8 to -5.6; P< P<0.001) [9]. In obese subjects without diabetes, the corresponding value was -6.7 mmHg (95% CI, -6.0 to -2.1; P<0.001) [8]. Compared with placebo, CagriSema resulted in significant reductions of low-density lipoprotein cholesterol (LDL-C) by -26.3%, triglycerides by -26.7%, and an increase in high-density lipoprotein cholesterol (HDL-C) by 10.0% after 68 weeks [9]. In addition, CagriSema led to significant reductions in fasting insulin levels, and the inflammatory marker C-reactive protein (CRP) [8,9]. Furthermore, physical function scores improved significantly with CagriSema versus placebo, particularly in the subgroup of patients with poor physical function at baseline [8,9]. The above changes were mainly attributed to CagriSema-induced weight loss, but direct effects of the drug on these outcomes could not be excluded.

Safety of Cagrisema

Overall, CagriSema was fairly tolerated, in part because the protocol of the REDEFINE Studies allowed using submaximal doses according to subjects’ tolerance [8,9]. Thus, in the REDEFINE 1 and 2 trials, 57.4-61.9% of patients (versus 70.6-80.5% in the placebo groups) were taking the highest dose of CagriSema (2.4 mg/2.4mg) at the end of the studies [8,9]. In the REDEFINE 1 trial, proportions of subjects who discontinued CagriSema due to adverse effects were 5.9% as compared with 3.5% with placebo, 3.6% with semaglutide and 2.6% with cagrinlitide [8]. In the REDEFINE 2 Study including older subjects with type 2 diabetes, discontinuation rates were much higher with CagriSema; 8.4% versus 3.0% with placebo [9]. GI adverse effects were the most common safety events associated with the use of CagriSema occurring in 72-80% vs 34-54% with placebo [8,9]. This increased in GI events was likely attributed to the semaglutide component of CagriSema. This conclusion was based on the finding of low frequency of GI adverse effects with carginlitide (2.6%) compared with CagriSema (5.9%), semaglutide (3.6%), and placebo (3.5%) [8]. On the contrary, injection-site reactions seemed to be more related to the cagrilintide component. Thus, these skin events occurred in 12.2%, 16.9%, 2.6% and 3.0% in the CagriSema, cagrilintide, semaglutide, and placebo, respectively [8]. Interestingly, decreased appetite was assessed among the adverse effects and was reported by 16.3% (versus 6.5% with placebo) in the REDEFINE 1 trial and by 13.9% (versus 5.3% with placebo) in the REDEFINE 2 trial [8,9]. Apart from hypoglycemia (see below), other adverse effects of CagriSema were uncommon, e.g. pancreatitis occurred in 0.2-0.3% of patients randomized to CagriSema versus none with placebo [8,9].

Hypoglycemia

In the REDEFINE 1 study that excluded diabetes, no hypoglycemia was reported in relation to cagriSema, semaglutide or cagrinlitide [8]. On the contrary, in the diabetes trial (REDEFINE 2), all levels of hypoglycemia occurred more commonly with CagriSema compared with placebo. Thus, level 1 (also called “alert”, blood glucose 54-69 mg/dl) hypoglycemia was recorded in 11.9% and 7.9% in the CagriSema and placebo group, respectively [9]. Level 2 hypoglycemia (clinically significant, blood glucose <54 mg/dl) occurred in 6.0% and 3.3%, in the CagriSema and placebo groups, respectively [9]. Level 3 hypoglycemia (severe, causing cognitive impairment) was reported in 2 patients (0.2%) in the CagriSema group versus none in the placebo group [9]. Of note, the concomitant use of SUs increased the risk of hypoglycemia. In fact, the 2 patients who experienced severe hypoglycemia were taking a SU [9].

Advantages of Cagrisema

The drug combination Cagrisema offers several advantages. First, it is highly effective in inducing substantial weight loss in obese subjects with and without diabetes. Second, it is also a potent anti-diabetic agent leading to a clinically significant HbA1c reduction of 1.4% compared with placebo. Third, its easy once-weekly administration is certainly a factor that would enhance compliance. Fourth, the tolerance of CagriSema is generally acceptable, with allowance of using submaximal doses in cases of emergence of adverse effects.

Limitations of Cagrisema

Although the magnitude of weight loss with CagriSema was greater than with cagrilintide or semaglutide monotherapy, results of the REDEFIBNE 1 Study showed that the effect of CagriSema on weight loss was less than additive [8]. Whether the antihyperglycemic efficacy of CagriSema was additive could not be inferred from the REDEFINE 2 Study because of lack of arms randomized to cagrilintide and semaglutide separately [9]. However, an earlier phase 2 trial of patients with type 2 diabetes has shown that HbA1c reduction after 32 weeks was -2.2%, -1.8%, and -0.9% with CagriSema, semaglutide and cagrilintide, respectively [12]. Thus, the anti-diabetic efficacy of CagriSema, like its anti-obesity efficacy, was less than additive. This finding was not surprising given the overlapping mechanisms of actions between cagrilintide and semaglutide [2]. The REDEFINE 1 and 2 Studies had many exclusion criteria that limited generalization of their results. For instance, patients treated with insulin were excluded. Therefore, risk of hypoglycemia with Cagrisema is unclear in insulin-treated patients. In addition, while patients with impaired kidney function with eGFR > 30 ml/min/1.73 m2 were able to participate in the REDEFINE study, approximately 95% of patients had an eGFR of ≥60 ml/min/1.73 m2 [9]. Other limitations included exclusion of patients with HbA1c levels > 10.0% [9]. Moreover, except for Asians, there was underrepresentation of other minority groups and limited inclusion of the elderly (above 70-year-old) (table 1) [8,9]. Finally, the long-term efficacy and safety of CagriSema are limited to 68 weeks of follow-up. Table 2 summarizes the advantages and limitations of CagriSema.

Who Are The Best Candidates For Cagrisema?

Based on the results of the REDEFINE 1 and 2 trials, the following patient categories can get the most benefit from CagriSema. First, obese subjects in general, particularly those with poor physical function and those with pre-diabetes. Indeed, in the latter group, 88% of subjects achieved normoglycemia with CagriSema. Second, obese patients with uncontrolled type 2 diabetes on oral agents who decline taking one or more insulin injections daily. In these patients, the once-weekly CagriSema represents a practical alternative to insulin.

CagriSema is a once-weekly drug formulation that combines the long-acting amylin analog cagrilintide and the GLP-1 R agonist semaglutide. Both drug constituents lower body weight and blood glucose levels by overlapping mechanisms. After 68 weeks of therapy, CagriSema caused mean placebo-adjusted weight loss of 17.3% in obese individuals without diabetes and 10.4% in obese patients with type 2 diabetes. In the latter subjects, CagriSema decreased HbA1c levels by 1.4% compared with placebo. In addition, Cagrisema significantly improved physical function, cardiometabolic factors, particularly SBP and dyslipidemia. The main limitation of CagriSema is the relatively high frequency of GI adverse events and lack of long-term data beyond 68 weeks.

Current Needs

Before approving CagriSema, its efficacy and safety should be evaluated in the elderly, patients with various degrees of chronic kidney disease, poorly controlled type 2 diabetes with HbA1c > 10.0%, and in conjunction with insulin. The effects of CagriSema on CV events and mortality should be studied. The ongoing REDEFINE 3 Study examines the effects of CagriSema on CV events in 7,000 adults with BMI ≥ 25 kg/m2 and established CV disease with and without type 2 diabetes followed for up 4.6 years (NCT05669755) [2]. The REDEFINE 4 Study will compare efficacy and safety of CagriSema with tirzepatide over 72 weeks in 800 subjects with obesity (NCT06131437) [2]. It will be interesting as well to compare CagriSema with the once-weekly IcoSema, the combination of the long-acting insulin icodec and semaglutide [13].

Conflict of Interest

The authors have no conflict of interest to declare.

Advantages and Limitations of Cagrisema

Advantages

High efficacy for weight loss and glycemic control

Easy administration once weekly

Amelioration of blood pressure, lipids, and C-reactive protein

Amelioration of physical function

In obese subjects with prediabetes, CagriSema is effective in achieving normoglycemia

Limitations

Reduced weight-loss efficacy in patients with type 2 diabetes.

Lack of efficacy and safety data beyond 68 weeks.

Not evaluated in conjunction with insulin therapy

Limited safety data in patients with chronic kidney disease and eGFR < 60 ml/min/1.73 m2

Limited inclusion of patients above 70 years

Poorly studied in Blacks and Hispanics

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