Beyond Ozempic: The Race to Redefine Metabolic Medicine

Tyler Brown
Jun 10
3 min read

Updated: Jun 13

The success of GLP-1 receptor agonists like Ozempic (semaglutide) and Mounjaro (tirzepatide) has transformed obesity and diabetes care, generating over $100 billion in market value. These weekly injections typically reduce body weight by 15–20%, but they aren’t perfect - side effects include gastrointestinal discomfort and potential muscle loss, raising concerns about long-term frailty. As the GLP-1 era matures, biotech innovators are racing to find the next breakthrough: therapies that build on or surpass first-generation incretins.

1. Next-Gen Incretins: Dual & Triple Agonists

Retatrutide (Lilly): A GLP-1/GIP/glucagon “triple agonist” showing up to 24% weight loss over 48 weeks. Nearly all patients lost ≥15% body weight and no plateau was observed. Phase 3 studies are underway [1][2].
CagriSema (Novo Nordisk): A combo of semaglutide + cagrilintide (amylin analog) delivering 20–22.7% weight loss over 68 weeks—drastically exceeding semaglutide alone (~15%). Now in Phase 3 trials [3][4].
VK2735 (Viking Therapeutics): Dual GLP-1/GIP injection yielded 14.7% weight loss in early trials. The oral version achieved ~8% loss in 28-day dosing [5].

2. Oral GLP‑1 Pills

Orforglipron (Lilly): A daily oral GLP-1 analog achieving ~14.7% weight loss in Phase 2; now in Phase 3 [5].
Danuglipron (Pfizer): Achieved 8–13% weight loss in trials, but development was halted due to safety concerns [6][7].
Oral Semaglutide 50 mg (Novo Nordisk): In the OASIS-1 trial, a high-dose pill resulted in 15.1% weight lossover 68 weeks (17.4% among completers) with 89% of patients losing ≥5% [8][9].

Oral pills could spark a needle-free obesity revolution.

3. Beyond GLP‑1: Novel Mechanisms

Amylin Analogs: Cagrilintide and petrelintide improve satiety, reduce side effects, and preserve muscle.
FGF21 Mimetics: Agents like pegozafermin address metabolism and liver fat in obesity/NASH.
GDF15 Analogs: CinFina's CIN‑109 aims to suppress appetite with fewer side effects.
Mitochondrial Uncouplers: Rivus’s HU6 increases metabolic rate (~3,600–4,000 kcal/week), preserving lean mass while inducing fat loss.
Hypothalamic Targets: PYY analogs, MC4R agonists, and novel peptides aim to rewire hunger and fullness signals.

These innovations offer alternative or complementary strategies to GLP-1s.

4. Longevity & Healthspan Impacts

GLP-1s address inflammation, blood pressure, and cardiovascular risk, but muscle loss is a key drawback. Lilly is countering this with bimagrumab—a muscle-growth antibody—paired with semaglutide to preserve lean mass. Notably, GLP-1–driven weight loss has been linked to a 20% reduction in heart attacks and strokes in non-diabetic patients, expanding its role in preventive medicine.

5. Investment & Competitive Landscape

Big Pharma

Novo Nordisk: Q1 2025 revenue hit $11.9 B, with full-year growth guidance lowered to 13–21% due to compounding and Wegovy competition [10][11][12].
Eli Lilly: Q1 revenue was $12.7 B, driven by Mounjaro and Zepbound; confidence buoyed by retatrutide and orforglipron data [13][5].

Startups

Viking, Structure, Rivus, Zealand, CinRx, Rhythm, and others are advancing novel mechanisms and formats.
Pfizer’s withdrawal from danuglipron opened opportunity for others, prompting stock gains for Viking and Structure. Lilly’s strategic deals with Versanis and Juvena highlight a drive toward muscle-preserving regimens.

Bottom Line

The post-GLP‑1 era promises not a single hero drug but a suite of next-generation therapies that excel in fat loss, metabolic health, muscle preservation, and potentially longevity. Investors and founders in metabolic medicine should track:

Therapy Type	Fast-Mover Companies	Differentiation Factor
Triple agonists	Lilly (retatrutide)	Highest weight loss with cardiovascular impact
Oral GLP‑1 small molecules	Lilly (orforglipron), Structure, Novo	A needle-free, patient-friendly option
Muscle-sparing combos	Lilly + Versanis/Juvena	Prevent frailty during weight loss
Novel hormone analogs	Zealand, 89Bio, CinRx, Rivus	Different biology to avoid side effects

With a $150B+ market and aging linked to metabolic health, the next wave of therapies—be it injectable combinations, oral alternatives, or entirely new classes—offers vast opportunity. Success will depend on efficacy, safety, convenience, and longevity benefits.