Beyond GLP‐1: Dual/Triple Agonists Set to Transform Obesity Treatment

What happened

New clinical data and conference results show the obesity/ metabolic field moving beyond single‐hormone GLP‐1 drugs toward dual- and triple‐agonist therapies and alternative modalities. On 6 Nov 2025 Novo Nordisk’s dual agonist CagriSema (cagrilintide + semaglutide) reported Phase III REDEFINE 1 results with a systolic blood pressure drop of 10.9 mmHg (vs 8.8 mmHg for semaglutide and 2.1 mmHg for placebo) and a 68.9% reduction in hs‐CRP (vs 55.4% and 16%). ObesityWeek 2025 data (Redefine‐5) showed mean weight loss of 18.4% for CagriSema vs 11.9% for semaglutide, and higher rates of ≥5% and ≥20% weight loss. Separately, Eli Lilly’s oral GLP‐1 orforglipron achieved ~11% mean weight loss at 72 weeks, and early developers (e.g., Syntis Bio’s SYNT‐101 bypass‐mimetic) plan human safety/PK data in 2026.

Why this matters

Market & clinical shift — therapies that target multiple pathways are proving benefits beyond weight loss. These results suggest next‐generation drugs can:

• Improve cardiovascular and inflammatory markers (blood pressure, hs‐CRP) as well as weight, widening clinical value beyond kilogram reduction.
• Offer new formats (oral pills, bypass‐mimetic capsules) that may expand patient uptake for those who avoid injectables.
• Force differentiation: incumbents (Novo, Lilly) and startups must show multi‐parameter benefits (cardio outcomes, lean‐mass preservation, tolerability) to win regulators and payers.

Key trade‐offs noted in the data and analysis include efficacy versus tolerability (some oral or alternative agents show lower weight loss than top injectables), formulation and manufacturing complexity for multi‐agonist peptides, and rising regulatory expectations for cardiovascular/inflammatory endpoints — all of which affect pricing, access, and time to market. Novo Nordisk may file for CagriSema approval in early 2026 (Q1 2026 cited), a potential industry inflection point.

Sources

• Reuters coverage of CagriSema results (6 Nov 2025): Novo Nordisk’s experimental obesity drug CagriSema shows blood‐pressure benefits
• PR Newswire ObesityWeek 2025 summary: ObesityWeek 2025 breakthrough results
• BioPharmaDive on Lilly’s orforglipron: Lilly GLP‐1 orforglipron FDA submission reporting
• BioBuzz on novel modalities including Syntis Bio: Five companies defining the next billion‐dollar frontier in weight loss

• Systolic blood pressure reduction with CagriSema (REDEFINE 1) — 10.9 mmHg, over 68 weeks it outperformed semaglutide (8.8 mmHg) and placebo (2.1 mmHg), signaling cardiovascular risk reduction beyond weight loss.
• hs-CRP reduction with CagriSema (REDEFINE 1) — 68.9%, over 68 weeks it exceeded semaglutide (55.4%) and placebo (16%), indicating stronger anti-inflammatory and cardiometabolic benefit.
• Mean weight loss with CagriSema (Redefine-5) — 18.4%, in 331 participants (Japan/Taiwan) it surpassed semaglutide’s 11.9%, demonstrating superior efficacy in body-weight reduction.
• Patients achieving ≥20% weight loss on CagriSema (Redefine-5) — 39.4%, more deep responders than semaglutide (18.6%), enabling greater clinically meaningful weight loss.
• Mean weight loss with orforglipron — 11%, after 72 weeks at high dose in people with obesity and diabetes it beat placebo, and its oral format may improve uptake and adherence.

• Regulatory bar & timeline risk: Despite promising surrogates (CagriSema cut systolic BP by 10.9 mmHg and hs-CRP by 68.9% over 68 weeks), agencies now expect cardiovascular outcome data and long‐term safety beyond weight loss, which can delay approvals to ≥2026 and require larger, costlier trials. Sponsors that pre-build trials around multi-parameter endpoints and real‐world evidence can justify premium pricing and faster reimbursement; Novo, Lilly, and data‐savvy startups stand to benefit.

• Cost & access pressure: As efficacy and novelty rise, payers may resist high prices, especially when oral options like orforglipron show ~11% weight loss—below some injectables—complicating value narratives and coverage decisions. Outcome-based contracts and patient-friendly formats (oral daily pill, less frequent injections) can widen access and adherence, benefiting payers, employers, and companies with robust health‐economic dossiers.

• Known unknown: durability and payer behavior: Unresolved questions on long‐term cardiovascular outcomes, lean mass preservation, and whether multi‐system benefits translate into favorable formulary decisions will determine market size and pricing power (with key Phase 3/long‐term data and filings targeted around 2026). Early movers that generate convincing durability and outcomes data (including inflammation and BP) can secure preferential coverage and create defensible market leadership.

Supporters say the pivot beyond GLP-1 monotherapy is overdue: in REDEFINE 1, CagriSema lowered systolic blood pressure by 10.9 mmHg and cut the inflammation marker hs-CRP by 68.9% over 68 weeks, and at ObesityWeek it beat semaglutide on weight loss with comparable safety through week 68. They see early 2026 filings as a validation moment and point to daily-pill options like orforglipron and even bypass-mimetic capsules as widening the tent. Skeptics counter that the field is trading clean efficacy narratives for messy realities: orforglipron’s ~11% weight loss lags injectables, multi-agonists are harder to make and deliver (especially orally), and regulators now want cardiovascular outcomes and long-term safety, not just lighter patients. Add pricing pressure and payer pushback, and momentum can stall. Provocation: What if “weight loss” is the least interesting thing about these drugs—and the wrong yardstick to pick winners?

The counterintuitive takeaway is that the next competitive edge isn’t the biggest number on the scale but the densest bundle of health outcomes patients feel and payers can price: blood pressure, inflammation, metabolic markers, tolerability, and format. That favors dual and multi-agonists that show multidimensional gains, while creating room for an oral with modest efficacy or a surgery-mimicking capsule to win on experience, access, and logistics. Watch the near-term inflection points the article flags: a potential CagriSema approval window in early 2026, orforglipron’s post–Phase 3 path, and new Phase 3 or long-term cardiovascular readouts that will decide reimbursement. Investors, clinicians, and designers should tilt trials and products toward these broader endpoints—and be ready for manufacturing and regulatory drag. The headline is weight, but the plot is risk reduction; watch the blood pressure and hs-CRP curves, not just the scales.