CagriSema Superiority Claim Meets Payer Walls as Oral GLP-1s Fund Growth

Novo Nordisk Raises Full-Year Outlook on Strong GLP-1 Sales and Pipeline Progress

Novo Nordisk has raised its full-year outlook for adjusted sales and operating profit for 2026, following a strong third quarter. Q3 2026 saw adjusted sales increase by 4% at constant exchange rates (CER) and adjusted operating profit rise by 27% at CER to DKK 31,720 million, primarily driven by robust GLP-1 product volume growth, especially in obesity. Key commercial successes include the Wegovy® pill, which generated DKK 5,394 million in Q3 sales across eight launched markets, and the Ozempic® pill, showing encouraging early US uptake. The company also reported significant pipeline progress, with CagriSema demonstrating 21% weight loss in the REDEFINE 9 obesity trial and superior weight loss compared to tirzepatide in the REIMAGINE 5 trial for type 2 diabetes and obesity. Additionally, Frehemgo® (denecimig) received a positive CHMP opinion, with EU launches anticipated around year-end.

• Novo Nordisk delivered a stronger-than-expected third quarter in 2026, leading to an improved full-year outlook for adjusted sales and operating profit. The company's adjusted operating profit surged by 27% at constant exchange rates (CER) to DKK 31,720 million, while adjusted sales grew 4% at CER. This positive financial trajectory is largely attributed to the sustained momentum and volume growth of its GLP-1 product portfolio, particularly within the obesity segment, across both US and International operations.
• The Wegovy® pill demonstrated significant commercial success, generating DKK 5,394 million in sales during Q3 2026 after launches in the US, UAE, UK, Germany, and four additional countries. It maintains a leading position in the US branded obesity market with over 50% share in new patient starts. Furthermore, the Ozempic® pill, launched in the US in May, showed encouraging early uptake, with weekly new-to-brand prescriptions approximately doubling compared to pre-launch levels of the Rybelsus® brand.
• Novo Nordisk's pipeline saw notable progress with CagriSema (1.0/1.0 mg). In the REDEFINE 9 phase 3 trial for obesity, it achieved an encouraging 21% weight loss at week 68. For adults with type 2 diabetes and obesity, the REIMAGINE 5 trial showed CagriSema delivered superior weight loss of 12.4% compared to 9.1% for tirzepatide 5 mg, alongside non-inferior HbA1c reduction at week 60, underscoring its potential in complex metabolic conditions.
• The company achieved a significant regulatory milestone with Frehemgo® (denecimig), which received a positive CHMP opinion on September 17 for blood and endocrine disorders, with initial European launches planned around the year-end. In the US, the regulatory review for denecimig is ongoing, with a potential launch projected for the first half of 2027. Additionally, the phase 3 AMAZE 9 trial for oral zenagamtide in obesity was initiated in September, further strengthening the late-stage pipeline.

CagriSema's Comparative Efficacy in Obesity and Type 2 Diabetes

The phase 3a, 68-week REDEFINE 1 trial randomised adults without diabetes with BMI ≥ 30 kg/m, or ≥ 27 kg/m with ≥ 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. The proportion of participants achieving both BMI < 27 kg/m and WHtR < 0.53 targets at week 68 was 30.3%, 19.1%, 9.0%, and 3.3% in participants who received CagriSema, semaglutide, cagrilintide, or placebo respectively. Both BMI and WHtR performed similarly as indicators for all four cardiometabolic outcomes: normoglycemia (glycated haemoglobin < 5.7% and fasting plasma glucose < 5.6 mmol/L); blood pressure (< 130/80 mmHg); triglycerides (< 1.7 mmol/L); lipids (high-density lipoprotein cholesterol ≥ 1.3 mmol/L [female] or ≥ 1.0 mmol/L [male]). At more stringent cut-off values, anthropometric targets were better measures than percentage weight loss.

Retatrutide, a glucose-dependent insulinotropic polypeptide, glucagon-like peptide-1, and glucagon receptor agonist, achieved up to 24.2% mean weight loss after 48 weeks in individuals with obesity and 16.9% in those with T2D after 36 weeks. In the T2D study, HbA1c improved by 2.2%, with 82% of participants reaching HbA1c ≤ 6.5%. In a frequentist network meta-analysis of fourteen randomised controlled trials, retatrutide demonstrated the greatest weight reduction versus placebo (MD -13.44 kg; 95% CI [-18.38, -8.51]), followed by survodutide (MD -10.74 kg; 95% CI [-15.68, -5.80]) and mazdutide (MD -6.47 kg; 95% CI [-10.71, -2.24]). In a phase 3, double-blind trial in adults with a BMI of 30 or higher, or 27 or higher with at least one obesity-related complication (excluding diabetes), mean change in body weight from baseline at week 76 was -12.2% (95% confidence interval [CI], -13.6 to -10.8) in the 3.6-mg survodutide group, -13.0% (95% CI, -14.4 to -11.6) in the 6.0-mg group, and -5.4% (95% CI, -6.9 to -4.0) in the placebo group; 72.6%, 71.9% and 46.3% of the participants, respectively, had weight reduction of at least 5% (P<0.001 for all comparisons with placebo).

Tirzepatide, the first dual GLP-1/glucose-dependent insulinotropic polypeptide (GIP) RA approved for both conditions, has shown dose-dependent weight loss of tirzepatide 15-18.5% compared with semaglutide 2.4 mg/wk. -14.9% to -15.2%, liraglutide -8.8-11%, dulaglutide -1.3-2.0%, and dual GIP/GLP-1 therapy up to 21.5%. In a Bayesian network meta-analysis of seven RCTs with more than 12,300 patients with BMI ≥ 30 kg/m, or BMI ≥ 27 kg/m with comorbidities, weekly tirzepatide 10 and 15 mg resulted in more weight loss than weekly semaglutide 2.4 mg, daily semaglutide 0.4 mg, or liraglutide 3 mg. Tirzepatide and weekly semaglutide demonstrated comparable results but with significantly higher odds of achieving ≥5%-20% weight loss compared with liraglutide, with GLP-1RAs triggering more gastrointestinal adverse events than placebo, with no in-between difference.

Initiating Phase 3 for Oral Zenagamtide in Obesity

GLP-1-based and related pharmacotherapies for obesity have been evaluated in Phase III randomized trials, systematic reviews, and meta-analyses alongside lifestyle, surgical, and behavioral interventions. Key trials vary in population, comparator, duration, and primary definitions, spanning percent weight change, categorical weight-loss thresholds, and cardiometabolic measures.

• Systematic review per PRISMA 2020 guidelines analyzed GLP-1-based anti-obesity pharmacotherapies across five databases, including 15 studies of semaglutide, liraglutide, tirzepatide, dulaglutide, and dual GIP/GLP-1 receptor agonists, with variables of weight loss, glycemic control, cardiometabolic efficacy, gastro-intestinal tolerability, and serious adverse events.

• Dose-dependent tirzepatide meta-analysis pooled four RCTs (n = 3,553 participants) comparing tirzepatide (5-15 mg or maximum tolerated dose (MTD)) to placebo over minimum 52 weeks, with primary outcome percent change in body weight and secondary outcomes of BMI, waist circumference, HbA1c, SBP, SF-36v2 and IWQOL-Lite-CT scores, categorical weight-loss thresholds, and adverse events, plus dose-response meta-regression.

• Randomized Phase III non-inferiority study of synthetic semaglutide injection (Test semaglutide) versus Wegovy (Reference semaglutide) enrolled 270 patients with BMI ≥ 30 kg/m or ≥ 27 kg/m with hypertension, dyslipidemia or type 2 diabetes mellitus across 21 centers in India, randomized 2:1 with dose escalation from 0.25 to 2.4 mg once weekly, with primary endpoint percentage change in bodyweight from baseline to Week 24.

• Long-term tirzepatide systematic review synthesized 26 publications representing 11 independent parent studies comprising eight Phase III randomised controlled trials, one long-term extension study, two real-world observational cohort studies, and 15 prespecified secondary analyses, with narrative synthesis per SWiM guidelines.

• Randomized comparison of laparoscopic adjustable gastric band (LAGB) (n = 18) versus 1-year diabetes and weight management (DWM) program (n = 22) in 40 patients with type 2 diabetes examined resolution of hyperglycemia (A1C <6.5% and fasting glucose <126 mg/dL) at 3 years, with reductions in A1C, weight, HDL-cholesterol, triglycerides, LDL-cholesterol, and blood pressure.

• Behavioral and supportive-care designs included a three-group randomized trial of goal-directed incentives versus outcome-based incentives versus resources-only in 668 adults with obesity with primary outcome proportion achieving 5% or greater weight loss at 6 months, and the EVOLUTION pragmatic randomized trial of in-person group-based intervention versus web-based intervention versus printed educational materials in 651 wait-listed patients with primary outcome proportion achieving 5% weight loss at 9 months.

Navigating the Dynamic Obesity Treatment Landscape

Over the past five years the pharmacologic landscape has shifted from first-generation agents to incretin-based therapies. Orlistat, bupropion/naltrexone, phentermine, phentermine-topiramate, liraglutide and semaglutide, combined with lifestyle changes, have proven to be effective in weight loss, with 6 FDA-approved medications for weight loss including 2 GLP1-receptor agonists liraglutide and semaglutide, 1 dual GLP-1 and gastric inhibitory peptide agonist tirzepatide, Contrave (naltrexone/bupropion), Qsymia (phentermine/Topamax), and Xenical (orlistat). Semaglutide was approved for obesity treatment in 2021 in the US and 2022 in Europe, supported by key clinical trials such as Satiety and Clinical Adipose Liraglutide Evidence (SCALE), Semaglutide Treatment Effect in People with Obesity (STEP) program trials, and Tirzepatide Once Weekly for the Treatment of Obesity (SURMOUNT-1), while first-generation anti-obesity drugs such as orlistat, phentermine/topiramate, and naltrexone/bupropion are poorly effective, whereas second-generation incretin receptor agonists, including liraglutide and semaglutide, and in particular the dual GLP-1/glucose-dependent insulinotropic polypeptide (GIP) co-agonist tirzepatide, substantially contribute to effective weight loss and blood pressure control. A systematic review and network meta-analysis of 56 clinical trials enrolling 60,307 patients found all obesity management medications showed a significantly greater percentage of total body weight loss versus placebo, more than 10% for semaglutide and tirzepatide, with tirzepatide consistently producing substantial, dose-dependent, and durable weight reduction, with mean weight loss approaching 21% after 72 weeks.

Cardiovascular outcomes data have redefined obesity pharmacotherapy from weight-centric to risk-modifying treatment. In SELECT, people with overweight or obesity and atherosclerotic cardiovascular disease without diabetes were randomized to weekly semaglutide 2.4 mg or placebo, and the primary end point of first major adverse cardiovascular event (cardiovascular mortality, nonfatal myocardial infarction, or stroke) was reduced by 20% with semaglutide versus placebo. Among 17,604 participants (mean age 61.6 years, 72.3% male), cardiovascular risk reduction with semaglutide versus placebo was not shown to be different across baseline HbA1c groups and was consistent across subgroups of HbA1c change, supporting use to lower major adverse cardiovascular events in patients with overweight/obesity and atherosclerotic cardiovascular disease but without type 2 diabetes. Complementary evidence shows semaglutide was effective in reducing major adverse cardiovascular events and reducing pain in knee osteoarthritis, tirzepatide was effective in remission of obstructive sleep apnea syndrome and metabolic dysfunction-associated steatohepatitis, and in patients with obesity and heart failure with preserved ejection fraction, tirzepatide lowered the occurrence of the composite endpoint of adverse heart failure events and cardiovascular death.

Trial efficacy has not fully translated to real-world persistence, driving interest in durability strategies and next-generation multi-agonists. Incretin-based therapies, including semaglutide and tirzepatide, produce substantial weight loss in trials but real-world effectiveness is relatively smaller because of non-initiation, incomplete dose escalation, gastrointestinal adverse effects, treatment interruptions, and financial or insurance barriers, with GLP-1 persistence of 46.3% at 180 days and 32.3% at 1 year, and 85% of patients discontinue within the second year of real-world use. Post-cessation weight regain averages 5.6 kg within one year, continued therapy maintained weight loss whereas treatment discontinuation resulted in progressive weight regain, and most participants reached a weight plateau by week 72 in SURMOUNT-1 and SURMOUNT-4. Retatrutide is the first triple agonist acting on GLP-1/GIP/glucagon receptors with published phase 2 data, achieving up to 24.2% mean weight loss after 48 weeks in individuals with obesity and 16.9% in those with type 2 diabetes after 36 weeks, with HbA1c improved by 2.2% and 82% reduction in hepatic steatosis, and a comprehensive phase 3 program is ongoing to evaluate efficacy, safety, and cardiovascular/renal outcomes.