From Weight Loss to Heart Health: New Era in Obesity Therapeutics

What happened

On 6 Nov 2025, Novo Nordisk reported Phase III REDEFINE 1 data for CagriSema (cagrilintide + semaglutide) showing benefits beyond weight loss: over 68 weeks CagriSema lowered systolic blood pressure by 10.9 mm Hg (versus 8.8 mm Hg for semaglutide alone and 2.1 mm Hg for placebo) and cut high‐sensitivity C‐reactive protein by 68.9% (vs 55.4% and 16%). Novo plans a regulatory filing in early 2026. Separately, retatrutide (LY‐3437943), a GLP‐1/GIP/glucagon “triple agonist,” has shown mean weight loss of 24.2% at the highest dose over 48 weeks and is in Phase 3. Oral semaglutide data (~15% weight loss over 64 weeks) and an FDA submission are also in play.

Why this matters

Policy shift & market impact: Regulators and payers are moving the bar from pure percentage weight loss to broader hard and multi‐metric outcomes (cardiovascular events, inflammatory markers). Novo’s REDEFINE program now includes REDEFINE 3 — a cardiovascular outcomes trial (CVOT) testing effects on heart attacks and strokes — signaling that approval and reimbursement may depend on demonstrating reduced clinical events, not just pounds lost.

• Scale: Obesity drugs that reduce blood pressure, inflammation and fat mass could change cardiovascular risk at population scale.
• Competition: Retatrutide’s large weight losses may become a new benchmark; oral semaglutide could widen access if approved.
• Risks: Efficacy varies by subgroup (people with type 2 diabetes in REDEFINE‐2 saw 15.7% weight loss vs ~22–24% in nondiabetic arms), GI side effects and dropout rates limit tolerance, and investor expectations have already shifted with mixed readouts.

Bottom line: The field is evolving from single‐metric weight outcomes to multidimensional, long‐term health benefits — a change that will affect clinical use, regulatory trials, payer demands and valuations.

Sources

• Reuters — Novo Nordisk’s REDEFINE 1 CagriSema results (6 Nov 2025): https://www.reuters.com/business/healthcare-pharmaceuticals/novo-nordisks-experimental-obesity-drug-cagrisema-shows-blood-pressure-benefits-2025-11-06/
• CNBC — REDEFINE‐2 and investor reaction: https://www.cnbc.com/2025/03/24/novo-nordisks-next-gen-obesity-drug-cagrisema-trial-results-disappoint-investors.html
• Wikipedia — Retatrutide (LY‐3437943): https://en.wikipedia.org/wiki/Retatrutide
• Wikipedia — Cagrilintide/semaglutide page: https://en.wikipedia.org/wiki/Cagrilintide/semaglutide
• BioPharmaDive — Oral semaglutide FDA submission and data: https://www.biopharmadive.com/news/novo-oral-semaglutide-fda-approval-application-obesity/745882/

• Systolic blood pressure (CagriSema) — -10.9 mm Hg (68 weeks; vs semaglutide -8.8 mm Hg, vs placebo -2.1 mm Hg; Phase III REDEFINE 1, obese/overweight adults)
• High-sensitivity C-reactive protein (CagriSema) — -68.9% (68 weeks; vs semaglutide -55.4%, vs placebo -16%; Phase III REDEFINE 1, obese/overweight adults)
• Weight loss (CagriSema, type 2 diabetes cohort) — 15.7% reduction (68 weeks; vs non-diabetic trial arms ~22–24%; REDEFINE-2)
• Weight loss (Retatrutide, highest dose, no diabetes) — 24.2% mean reduction (48 weeks; change from baseline; overweight/obese adults)
• Weight loss (oral semaglutide, no diabetes) — ~15% reduction (64 weeks; change from baseline; obese/overweight adults)

• Bold Regulatory bar shifts to cardiovascular outcomes: why it matters: Regulators and payers are prioritizing CVOTs and multi-metric benefits, raising approval and reimbursement thresholds; CagriSema shows BP (-10.9 mm Hg) and CRP (-68.9%) gains but may still face CVOT-driven timing and cost pressures (est.). Opportunity: Developers that demonstrate hard-outcome risk reduction can secure differentiated labels and payer preference; Novo and peers can leverage REDEFINE 1 and accelerate REDEFINE 3 design/communications.

• Bold Population efficacy variability and expectation volatility: why it matters: Weight loss varies by cohort (15.7% in T2D vs ~22–24% in non-diabetic arms), risking restrictive labeling, segmented reimbursement, and clinician hesitancy; investor selloffs after REDEFINE-2 show valuation sensitivity to these gaps. Opportunity: Stratified trial programs, indication-specific pricing, and clearer expectation-setting can de-risk access and stabilize valuations; payers and developers benefit from precision positioning.

• Bold Known unknown: CVOT results, oral approval, and real-world retention: why it matters: Pending readouts (REDEFINE 3 in 2026; Retatrutide Phase 3 late 2025/early 2026; FDA decision on oral semaglutide by YE 2025) and GI-related dropout/tolerability will determine uptake, adherence, and total addressable market (est.). Opportunity: Proactive adherence support, dose-titration protocols, and expanding oral options can convert tolerability and access risks into share gains; clinicians and patients benefit from tailored regimens.

Supporters of the new playbook say REDEFINE 1 reframes success: CagriSema cut systolic blood pressure by 10.9 mm Hg and slashed high-sensitivity CRP by 68.9% over 68 weeks—signals of cardiovascular risk modification that regulators and payers increasingly prize. Skeptics counter that the scale still rules the market: CagriSema’s 15.7% weight loss in type 2 diabetes underwhelmed investors, safety and GI tolerability drive dropouts, and variability between diabetic and nondiabetic cohorts complicates labeling and reimbursement. Retatrutide’s 24.2% weight loss looms as the rival benchmark, while CagriSema isn’t approved and must clear a CVOT before the narrative holds. Maybe percent weight loss is the wrong North Star—and the market is still sailing by it. The article’s uncertainties are plain: pending CVOT readouts, real-world retention, and uneven efficacy across populations.

Here’s the twist: the drug that wins may not be the one that melts the most pounds, but the one that most convincingly prevents cardiovascular events—and CRP and blood pressure are the breadcrumbs leading there. If payers and regulators consolidate around hard outcomes, REDEFINE 3 becomes the kingmaker, retatrutide’s allure will be measured against event reduction, and an oral semaglutide decision could broaden access while raising the bar on durability and safety. Watch three dials: CVOT results, retention in the wild, and performance in underserved subgroups. In this race, the decisive number may be heart attacks averted, not percentage points on a scale.