Oral Wegovy Scales as CagriSema Chases Tirzepatide and Payers Balk

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

Novo Nordisk has raised its full-year 2026 financial outlook for adjusted sales and operating profit, driven by robust performance in its GLP-1 product portfolio, particularly in obesity. The company reported a 27% increase in Q3 2026 adjusted operating profit at Constant Exchange Rates (CER) to DKK 31,720 million, with adjusted sales growing 4% at CER. Key commercial successes include Wegovy® pill sales of DKK 5,394 million and strong early uptake of the Ozempic® pill in the US. The pipeline also advanced with positive results for CagriSema in obesity and type 2 diabetes, and a positive CHMP opinion for Frehemgo® (denecimig).

• Novo Nordisk significantly improved its full-year 2026 financial guidance, now projecting adjusted sales and operating profit growth of -2% to +2% at CER. This upgrade follows a strong third quarter, where adjusted operating profit surged 27% at CER to DKK 31,720 million, and adjusted sales increased 4% at CER, primarily fueled by the company's GLP-1 product portfolio.
• The company's obesity portfolio, spearheaded by the Wegovy® pill, was a major contributor to Q3 2026 sales, reaching DKK 5,394 million. Wegovy® maintains its leadership in the US branded obesity market with over 50% share in new patient starts. Additionally, the Ozempic® pill, launched in the US in May, demonstrated encouraging early momentum, with weekly new-to-brand prescriptions approximately doubling compared to pre-launch levels of Rybelsus®.
• Novo Nordisk reported promising pipeline progress, including CagriSema (1.0/1.0 mg) achieving a 21% weight loss at week 68 in the REDEFINE 9 trial for obesity. In the REIMAGINE 5 trial for type 2 diabetes and obesity, CagriSema showed superior weight loss (12.4%) compared to tirzepatide 5 mg (9.1%) while maintaining non-inferior HbA1c reduction. Furthermore, Frehemgo® (denecimig) received a positive CHMP opinion in Europe, with a US launch anticipated in the first half of 2027.

CagriSema's Promising Efficacy in Obesity and Type 2 Diabetes

Recent Phase 3 studies in overweight or obesity evaluated incretin-based therapies as adjunct therapy to lifestyle modifications. The primary efficacy focus was change in body weight and body mass index, with gastrointestinal events representing the most consistently reported safety concern.

• The Semaglutide Treatment Effect in People with obesity (STEP) program evaluated subcutaneous semaglutide as 2.4 mg once weekly among 5000 randomized participants who were overweight or had obesity. A change in body weight from baseline to end of study was the primary outcome, with dose-dependent reduction in body weight from baseline compared to placebo and higher percentages of participants with 5%-10% weight reduction from baseline. Gastrointestinal adverse events were the most common safety concerns.

• The SURMOUNT-3 phase 3 trial randomized adults with body mass index ≥30 or ≥27 kg/m and at least one obesity-related complication to tirzepatide maximum tolerated dose (10 or 15 mg) or placebo once weekly for 72 weeks (n = 579). Additional mean per cent weight change from randomization to week 72 was -18.4% (standard error (s.e.) 0.7) with tirzepatide and 2.5% (s.e. 1.0) with placebo, with 87.5% (s.e. 2.2) with tirzepatide and 16.5% (s.e. 3.0) with placebo achieving additional weight reduction ≥5%. The most common adverse events with tirzepatide were gastrointestinal, with most being mild to moderate in severity.

• STEP TEENS enrolled adolescents (12 to <18 years of age) with obesity or with overweight and at least one weight-related coexisting condition to receive once-weekly subcutaneous semaglutide (at a dose of 2.4 mg) or placebo for 68 weeks, plus lifestyle intervention. The mean change in BMI from baseline to week 68 was -16.1% with semaglutide and 0.6% with placebo (estimated difference, -16.7 percentage points; 95% confidence interval [CI], -20.3 to -13.2; P<0.001), with weight loss of 5% or more in 95 of 131 participants (73%) in the semaglutide group and 11 of 62 participants (18%) in the placebo group. The incidence of gastrointestinal adverse events was greater with semaglutide than with placebo (62% vs. 42%), with cholelithiasis in five participants (4%) in the semaglutide group and serious adverse events in 15 of 133 participants (11%) in the semaglutide group and in 6 of 67 participants (9%) in the placebo group.

Novo Nordisk's Role in the Evolving GLP-1 Obesity Landscape

Incretin-based pharmacotherapies have transformed obesity management over the past five years, shifting expectations from modest weight reduction to levels that begin to narrow the gap with metabolic surgery in selected populations. Approved long-term agents, orlistat, phentermine/topiramate, naltrexone/bupropion, liraglutide, semaglutide, and tirzepatide, differ in mechanism, weight-loss magnitude, and safety considerations. Agents like liraglutide, semaglutide, and tirzepatide 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) have demonstrated remarkable efficacy in promoting weight loss and improving metabolic outcomes. These agents demonstrate unprecedented efficacy, achieving 15-25% mean weight loss in clinical trials, with semaglutide and tirzepatide redefining expectations for pharmacological weight loss.

The field has rapidly expanded beyond glucagon-like peptide-1 receptor agonist (GLP-1RA) monotherapy toward multimodal strategies including dual and triple incretin- or glucagon-based agonists, long-acting amylin analogues, oral agents, and combination approaches targeting complementary satiety and metabolic pathways. Next-generation drugs, such as oral glucagon-like peptide 1 receptor agonists (e.g., orforglipron) and multireceptor agonists (e.g., retatrutide), show even greater efficacy in early studies, while GLP-1/GIP/glucagon (retatrutide) triple receptor agonists can achieve more than 20% weight loss in obesity. Recent human trial data illustrate this momentum: VCT220, a once-daily oral nonpeptide GLP-1RA, produced mean body weight decreases of -5.75% (80 mg) to -9.73% (160 mg-FT) versus -1.61% with placebo at week 16 (all p < 0.001), with the proportion achieving ≥5% weight loss ranging from 55.4% (80 mg) to 90.3% (160 mg-ST) versus 13.1% with placebo. In the REDEFINE 5 phase 3a trial in Japan and Taiwan, once-weekly subcutaneous injections of fixed-dose combination cagrilintide 2·4 mg and semaglutide 2·4 mg versus semaglutide 2·4 mg for 68 weeks produced estimated mean change of -18·4% (SE 0·7) versus -11·9% (0·7) (estimated treatment difference [ETD] -6·5 percentage points [95% CI -8·4 to -4·6]; p<0·0001).

Published data increasingly link these weight effects to broader cardiometabolic benefits alongside persistent durability and tolerability challenges. Across large cardiovascular-outcome trials, GLP-1RAs consistently reduce major adverse cardiovascular events (MACE), all-cause mortality, and heart-failure hospitalizations in individuals with T2D, and in populations with overweight or obesity without diabetes, semaglutide, as shown in the SELECT trial, has demonstrated significant cardiovascular risk reduction, partly independent of weight loss. Reviews report reducing major adverse cardiovascular events by 20% and T2D incidence by 72%, with common safety concerns including gastrointestinal effects, gallbladder events, pancreatitis risk, thyroid C-cell tumor warnings, and teratogenicity. Durability remains a central limitation, with 85% of patients discontinue within the second year of real-world use, post-cessation weight regain averaging 5.6 kg within one year, and a 2-year real-world cohort showing average TWL% of 9.22% (standard deviation 9.73%) for patients who stayed on GLP1RA for 2 years, while patients who stopped treatment experienced similar weight loss to those who never started treatment.

Exploring Novel Targets: Oral Zenagamtide in Obesity

Amylin receptor signaling has re-emerged as a distinct therapeutic axis from incretin-based therapies. Amylin is a pancreatic β-cell hormone co-secreted with insulin that contributes to postprandial glucose regulation, slows gastric emptying, suppresses glucagon secretion, and promotes satiation through actions in the central nervous system via amylin receptor subtypes 1-3, namely the calcitonin receptor (CTR) and the receptor activity-modifying proteins (RAMPs) 1, 2 or 3. Long-acting engineering through lipidation and reversible albumin binding has enabled agents including cagrilintide, eloralintide, petrelintide and NN1213, alongside pramlintide, KBP-series DACRAs, ZP8396 and amycretin, ranging from more selective amylin receptor agonists to dual amylin/calcitonin receptor agonists. In RAMP1/3 knockout mice fed high-fat diet for 23 weeks, body weight loss was observed in wild-type cagrilintide-treated mice (-3.4 ± 0.51 g, P < 0.005), whereas the absence of RAMP1 and RAMP3 impeded cagrilintide's potency, and AP cFos signal was decreased in cagrilintide-treated RAMP1/3 KO mice by 57% compared to wild-type cagrilintide-injected mice, demonstrating dependency of cagrilintide on AMYR1 and AMYR3 to lower body weight.

Multi-agonist gut-brain peptides represent a second advancing frontier, progressing from exendin-4 to dual GLP-1/glucagon receptor agonists (first discovered in 2009), dual GLP-1/GIP receptor agonists (first described in 2013), and triple GLP-1/GIP/glucagon receptor agonists (initially designed in 2015). The GLP-1/GIP receptor co-agonist tirzepatide was approved by the U.S. Food and Drug Administration (FDA) for the treatment of T2DM and facilitated weight loss of up to 22.5% in non-diabetic individuals living with obesity, while retatrutide, a triple-agonist of GLP-1, GIP, and glucagon receptor, and orforglipron, a GLP-1 receptor partial agonist, are reported effective in weight loss and improving metabolic parameters. Mechanistic work with cotadutide, a dual receptor agonist of GLP-1R/GCGR, showed enhanced POMC and CART neuropeptides and depressed NPY and AgRP neuropeptides in obese mice, with Lepr, Calcr, Mc4r, Glp1r and Gcgr higher in HFC compared to HF, supporting modulation of energy balance through the gut-brain axis.

Precision approaches targeting monogenic pathways and body-composition quality are expanding alongside these peptides. Monogenic variants (e.g., LEP, LEPR, MC4R, POMC, PCSK1) explain rare, early-onset phenotypes, with heterozygous variants in LEP, LEPR, POMC, and PCSK1 found in 6.7% (n = 100) and homozygous variants in 1.7% (n = 26) of 1486 probands with severe obesity, and approval of melanocortin-4 receptor (MC4R) agonists such as setmelanotide for hyperphagia and obesity in POMC, PCSK1, and LEPR deficiencies and Bardet-Biedl syndrome (BBS). For preservation of lean body mass during GLP-1 RA-induced weight loss, activin II receptor inhibition with bimagrumab demonstrated preservation and increases in LBM with FM reduction in preclinical and phase 2 studies, with similar effects observed for trevogrumab, garetosmab, apitegromab, SRK-439, and enobosarm. Broader discovery from large-scale GWAS has implicated over 127 candidate genes and 253 QTLs, with FTO and MC4R as major loci, while epigenetic mechanisms, dietary composition, physical activity, and microbial diversity recalibrate obesity trajectories within precision nutrigenomics frameworks.