Cagrilintide–Semaglutide Combination for Obesity and Fat Loss: Benefits and Risks
Obesity is a major health challenge, and new treatments are emerging that combine semaglutide (a GLP-1 receptor agonist) with cagrilintide (a long-acting amylin analog). Semaglutide (sold as Wegovy/Ozempic) mimics the gut hormone GLP-1, which stimulates insulin, suppresses glucagon, slows stomach emptying and reduces appetite. Cagrilintide mimics amylin, a hormone co‑secreted with insulin, that promotes satiety and also delays gastric emptying. Together, these drugs act on complementary pathways in the brainstem and gut to curb hunger and improve metabolic balancethe-innovation.orgpmc.ncbi.nlm.nih.gov. The idea is that dual therapy (“CagriSema”) produces more weight loss than either drug alonediabetes.orgthe-innovation.org.
How Each Drug Works
- Semaglutide (GLP-1 agonist): By activating GLP-1 receptors, semaglutide increases insulin release (when glucose is high), suppresses glucagon, slows digestion, and signals fullness to the brainthe-innovation.org. This leads to lower blood sugar and reduced food intake. Long-acting GLP-1 drugs are already approved for diabetes and weight loss.
- Cagrilintide (Amylin analog): Cagrilintide activates amylin and calcitonin receptors in the hindbrain, mimicking the effects of amylinthe-innovation.orgpmc.ncbi.nlm.nih.gov. It enhances satiety (feeling of fullness), cuts cravings, and delays gastric emptying, often reducing snacking and overeatingthe-innovation.org. Importantly, animal studies show cagrilintide causes most weight loss from fat while preserving muscle (lean mass)pmc.ncbi.nlm.nih.gov, an effect thought to improve body composition.
- Synergy: By combining semaglutide’s incretin effects with cagrilintide’s amylin signaling, the two drugs target appetite and metabolism from different anglesthe-innovation.org. In theory and in practice, this leads to additive or synergistic weight loss. In trials, the combination drove far greater weight loss than either drug alonediabetes.orgthe-innovation.org.
Clinical Trial Results (Weight and Fat Loss)
Two large phase 3 trials (REDEFINE 1 and 2) have tested this once-weekly combo (called “CagriSema”) for up to 68 weeks:
- REDEFINE 1 (overweight/obese, no diabetes): Patients without diabetes lost on average 20.4% of their body weight on CagriSema after 68 weeks, compared to only 3.0% for placebopubmed.ncbi.nlm.nih.gov. In the same trial, semaglutide alone caused ~14.9% loss and cagrilintide alone ~11.5%diabetes.org. When compliance was high, mean loss with the combo was even 22.7%, with over 40% of patients losing ≥25% of their weightdiabetes.org. These reductions dwarf the ~3–5% losses seen in typical diet/exercise programs and approach the results of bariatric surgerypubmed.ncbi.nlm.nih.govthe-innovation.org. (Most of this loss was body fat – animal studies suggest the combo preferentially melts fat stores while sparing musclepmc.ncbi.nlm.nih.gov.)
- REDEFINE 2 (overweight/obese with type 2 diabetes): Adults with obesity and diabetes also saw big benefits. Those on CagriSema lost 13.7% of body weight on average, versus 3.4% with placebopubmed.ncbi.nlm.nih.gov. In addition, nearly 74% of the combination group achieved a blood sugar (HbA1c) ≤6.5% by week 68 (vs 15.9% on placebo)pubmed.ncbi.nlm.nih.gov. This shows the dual therapy sharply improved glucose control along with weight.
Key trial findings (68 weeks):
- Weight loss: ~20% on combo vs ~15% on semaglutide alone vs ~3% on placebodiabetes.orgpubmed.ncbi.nlm.nih.gov.
- Fat reduction: Most lost weight was fat (body composition analyses showed large drops in fat mass)pmc.ncbi.nlm.nih.gov.
- Glycemic control: In REDEFINE 2, 73.5% reached HbA1c ≤6.5%pubmed.ncbi.nlm.nih.gov, and many prediabetic patients reverted to normal blood sugar levelsthe-innovation.org.
- Other markers: Patients on CagriSema had bigger drops in waist circumference and visceral fat (noted in trial data) and substantial improvements in cholesterol and inflammation (see below).
Taken together, the combination outperformed each drug alone and far exceeded the weight-loss seen with semaglutide monotherapydiabetes.orgthe-innovation.org. In practical terms, losing ~15–20% of body weight in a year is unprecedented outside of surgery, and most of that was body fat.
Metabolic and Cardiovascular Benefits
Beyond weight, the CagriSema trials showed broad metabolic improvements. As patients lost weight, many also saw better blood pressure, blood sugar, lipids, and inflammation markers:
- Blood sugar (HbA1c): CagriSema lowered HbA1c dramatically. In the diabetes trial, the combination group’s mean HbA1c fell so that 73.5% of patients were at or below 6.5%pubmed.ncbi.nlm.nih.gov. In the non-diabetic trial, many prediabetic patients returned to normal glucose levelsthe-innovation.org. These changes are clinically meaningful for reducing diabetes risk.
- Lipid profile: Participants had greater drops in LDL cholesterol and triglycerides than those on placebo. A Novo Nordisk report noted significant reductions in LDL and non-HDL cholesterol with CagriSema (driven by the larger fat loss)sciencehub.novonordisk.com. (In general, weight loss – especially fat loss – tends to improve lipids.) The Innovation review also confirmed that cholesterol and an inflammation marker called C-reactive protein (hs-CRP) fell markedly with treatmentthe-innovation.org. Lower hs-CRP suggests reduced cardiovascular risk.
- Blood pressure: On average, systolic blood pressure fell more in the combo group than placebo (consistent with weight loss). One analysis reported significant reductions in both systolic and diastolic pressure in CagriSema patients.
- Inflammation: CagriSema treatment dramatically cut hs-CRP (by ~60-70%), far more than placebosciencehub.novonordisk.com. This anti-inflammatory effect likely comes from rapid fat loss and improved metabolic health.
All together, these changes mean CagriSema may substantially lower heart and metabolic risk. GLP-1 agonists like semaglutide are already known to reduce major cardiovascular events in diabetics, so the combo may confer similar or greater benefit. (A dedicated CV outcomes trial, REDEFINE 3, is planned to test heart-attack and stroke outcomes on this combination.)
Side Effects and Safety
The most common side effects of CagriSema mirror those of GLP-1 and amylin drugs: gastrointestinal symptoms and nausea. In the trials:
- Gastrointestinal effects: Roughly 70–80% of patients on the combo reported some GI side effects (vs ~30–40% on placebo)pubmed.ncbi.nlm.nih.govpubmed.ncbi.nlm.nih.gov. These included nausea, vomiting, diarrhea, constipation or stomach discomfort. Importantly, these symptoms were generally mild to moderate and most patients acclimated over timepubmed.ncbi.nlm.nih.govpubmed.ncbi.nlm.nih.gov. Fewer than 10% of patients stopped therapy because of GI intolerance.
- Other common effects: Injection‐site reactions (redness, itching) can occur. Some patients may experience headache, fatigue or dizziness. Because semaglutide slows gastric emptying, low blood sugar can happen if other diabetes drugs (like insulin) are used simultaneously. However, without insulin or sulfonylureas, hypoglycemia is uncommon on GLP-1 therapies.
- Serious but rare risks: GLP-1 agonists carry warnings about pancreatitis (pancreas inflammation) and gallbladder problems. Though rare, these events have been reported in some patients on semaglutide. There is also a theoretical concern for thyroid C-cell tumors (seen in rodents with other GLP-1 drugs), so people with a history of certain thyroid cancers are advised not to use GLP-1 analogs. Cagrilintide alone has not shown new safety signals in humans, but it will carry similar precautions.
- Overall safety profile: Across trials, the combination’s safety was “consistent with the GLP-1 agonist class”diabetes.orgthe-innovation.org. Notably, discontinuation rates were low (around 6–8%) despite the potent weight lossthe-innovation.org. In short, most patients find the side effects tolerable compared to the benefit of rapid weight loss.
Regulatory Status and Outlook
As of 2025, CagriSema is still investigational. Novo Nordisk has completed its pivotal trials and plans to seek approval soon. The company reports it will file for FDA approval in the first quarter of 2026novonordisk.comreuters.com (slightly later than initially expected). No official regulatory decisions have been made yet. If approved, this would be the first FDA-approved combination of an amylin analog and GLP-1 agonist for obesity.
Meanwhile, semaglutide alone is already FDA-approved for chronic weight management (as Wegovy) and is widely prescribed. Cagrilintide by itself is not yet marketed; all current data come from trials or combination studies. Physicians will need to weigh the dramatic weight loss benefits against the cost and side-effect profile if this combo reaches patients. Ongoing studies (including longer-term safety and cardiovascular trials) are expected before widespread use.
Conclusion
In summary, combining semaglutide and cagrilintide produces unprecedented weight loss in adults with obesity – on the order of 15–22% of body weight over 68 weeksdiabetes.orgpubmed.ncbi.nlm.nih.gov – much greater than either drug alone. This translates into substantial fat loss and often reversal of diabetes. The combination also improves key metabolic risk factors (blood sugar, lipids, blood pressure)the-innovation.orgpubmed.ncbi.nlm.nih.gov. The main downside is typical GLP-1/amylin side effects (nausea, gastrointestinal upset), which are common but usually manageablepubmed.ncbi.nlm.nih.govpubmed.ncbi.nlm.nih.gov. CagriSema represents a promising next-generation therapy for obesity, but it remains experimental until regulatory approval. Patients and doctors should stay informed of the ongoing trial results and approvals through 2025–2026.
Sources: Recent phase 3 trial reports and analysespubmed.ncbi.nlm.nih.govpubmed.ncbi.nlm.nih.govdiabetes.orgthe-innovation.orgpmc.ncbi.nlm.nih.gov, company and news releasesreuters.comnovonordisk.com.
https://www.the-innovation.org/article/doi/10.59717/j.xinn-med.2025.100150