The next generation of weight loss medications is producing unprecedented results. Eli Lilly's retatrutide (a triple agonist) just posted 28.7% weight loss in Phase 3—71 pounds on average. Novo Nordisk's amycretin hit 22% weight loss and is advancing to Phase 3 in 2026. And orforglipron, an oral pill with no food restrictions, achieved 12.4% weight loss and is awaiting FDA decision. These investigational drugs aren't yet approved, but they signal what's coming next.
Triple Agonist
Retatrutide
Eli Lilly
28.7%
Phase 3 (68 weeks)
GLP-1 + Amylin
Amycretin
Novo Nordisk
22%
Phase 2 (36 weeks)
Oral Pill
Orforglipron
Eli Lilly
12.4%
Phase 3 (72 weeks)
The current generation of GLP-1 medications—Wegovy, Zepbound, Ozempic, Mounjaro—has transformed obesity treatment. But for both Eli Lilly and Novo Nordisk, these blockbusters are just the beginning. Both companies are advancing next-generation candidates with the potential to push efficacy even higher or expand access through oral formulations.
Weight Loss: Up to 28.7% (71.2 lbs) on the highest dose (12 mg) among completers. Treatment-regimen analysis (all patients) showed 23.7% weight loss.
Pain Reduction: 75.8% reduction in knee osteoarthritis pain scores. More than 14% of patients on retatrutide were completely pain-free at study end vs. 4.2% on placebo.
Cardiovascular Markers: Reduced non-HDL cholesterol, triglycerides, hsCRP, and lowered systolic blood pressure by 14.0 mmHg.
These results exceeded analyst expectations. BMO Capital Markets' bull case was 25% weight loss; retatrutide beat that by nearly 4 percentage points.2
The Tolerability Question
The impressive efficacy came with notable discontinuation rates. In TRIUMPH-4, 18.2% of patients on the highest dose discontinued due to adverse events, compared to 4% on placebo. Common side effects were gastrointestinal: nausea (43.2%), diarrhea (33.1%), constipation (25.0%).3
Interestingly, discontinuation rates were highly correlated with baseline BMI. When restricted to patients with BMI ≥35 (excluding overweight and class 1 obesity), discontinuation rates dropped to 8.8-12.1%—suggesting the drug may be better tolerated by those who need it most. Some discontinuations were due to "perceived excessive weight loss."2
About 1 in 5 patients on the highest dose experienced dysesthesia (unusual skin sensations), though Lilly reported this was usually mild and rarely led to discontinuation.
What Makes It Different
The glucagon receptor agonism distinguishes retatrutide from current medications. While GLP-1 and GIP work primarily on appetite and glucose metabolism, glucagon directly stimulates energy expenditure and hepatic fat mobilization. The combination appears synergistic—early data suggested no weight loss plateau at 48 weeks, unlike with current GLP-1 medications.
Amycretin: Novo Nordisk's Answer
Facing intense competition from Lilly, Novo Nordisk is advancing amycretin—a different dual-target approach combining GLP-1 with amylin receptor agonism.
Phase 2 Results (January 2025)
In a Phase 1b/2a trial of 125 adults with overweight or obesity, subcutaneous amycretin achieved dose-dependent weight loss up to 22% at 36 weeks at the highest dose (20 mg weekly).4
| Dose |
Duration |
Weight Loss |
Placebo |
| 1.25 mg weekly |
20 weeks |
9.7% |
+1.9% |
| 5 mg weekly |
28 weeks |
16.2% |
+2.3% |
| 20 mg weekly |
36 weeks |
22.0% |
+2.0% |
Critically, no weight loss plateau was observed at the end of treatment, suggesting even greater efficacy might emerge with longer dosing periods.
Oral Amycretin
Novo is also developing an oral version. In a Phase 1 trial, oral amycretin achieved 13.1% weight loss after just 12 weeks of daily dosing (100 mg/day).5
Phase 2 in Type 2 Diabetes (November 2025)
Amycretin also showed strong results in its first type 2 diabetes trial. In 448 patients, subcutaneous amycretin achieved HbA1c reductions of up to 1.8% and weight loss of up to 14.5% at 36 weeks. Up to 89.1% of patients achieved HbA1c below 7%.6
Novo Nordisk's Strategy
Based on these results, Novo Nordisk received regulatory feedback to advance both subcutaneous and oral amycretin directly to Phase 3, skipping additional Phase 2 trials. Phase 3 for obesity is expected to begin Q1 2026, with potential approval forecast for Q4 2030 (US) and Q1 2031 (EU).
Orforglipron: The Oral Game-Changer
Perhaps the most practically significant next-gen candidate is orforglipron—not because of its efficacy numbers (which trail injectables), but because it's an oral pill that can be taken any time of day without food or water restrictions.
Why This Matters
Unlike oral semaglutide (Rybelsus), which must be taken on an empty stomach with minimal water and requires a 30-minute fast afterward, orforglipron is a small molecule (non-peptide) GLP-1 agonist that doesn't face the same bioavailability challenges. This could dramatically expand who can successfully use GLP-1 therapy.
Phase 3 Results: ATTAIN Program
ATTAIN-1 (August 2025): In 3,127 adults with obesity or overweight (without diabetes), orforglipron 36 mg daily achieved 12.4% weight loss (27.3 lbs) at 72 weeks.7
ATTAIN-2 (November 2025): In adults with obesity and type 2 diabetes, orforglipron 36 mg achieved 10.5% weight loss (22.9 lbs) at 72 weeks, plus HbA1c reduction of 1.3-1.8%.8
ATTAIN-MAINTAIN (December 2025): In a first-of-its-kind trial, patients who had lost weight on injectable Wegovy or Zepbound successfully maintained their weight loss after switching to oral orforglipron.9
Regulatory Status
Lilly has submitted a New Drug Application to the FDA for orforglipron for obesity treatment. The drug received a Commissioner's National Priority Voucher. If approved, it would be the first oral GLP-1 specifically indicated for weight management (Rybelsus is approved only for diabetes).
Head-to-Head Comparison
| Drug |
Mechanism |
Route |
Weight Loss |
Phase |
Est. Approval |
| Retatrutide |
GLP-1 + GIP + Glucagon |
Weekly injection |
28.7% (68 wks) |
Phase 3 |
2027 |
| Amycretin (SC) |
GLP-1 + Amylin |
Weekly injection |
22% (36 wks) |
Phase 2 → 3 |
2030 |
| Amycretin (oral) |
GLP-1 + Amylin |
Daily pill |
13.1% (12 wks) |
Phase 2 → 3 |
2030 |
| Orforglipron |
GLP-1 |
Daily pill (no restrictions) |
12.4% (72 wks) |
Phase 3 âś“ |
2026 |
| Zepbound (approved) |
GLP-1 + GIP |
Weekly injection |
~22% (72 wks) |
Approved |
— |
| Wegovy (approved) |
GLP-1 |
Weekly injection |
~15% (68 wks) |
Approved |
— |
Note: Cross-trial comparisons should be interpreted cautiously as populations, trial designs, and durations differ. These are efficacy estimand results (completers on treatment) where available.
What's Coming When
Expected Timeline
2026
Orforglipron FDA decision expected; Lilly targets year-end approval for obesity
2026
Retatrutide seven additional Phase 3 readouts expected throughout year
2026
Amycretin Phase 3 trials begin (Q1) for obesity and type 2 diabetes
2027
Retatrutide approval predicted (GlobalData forecast)
2028-29
Amycretin potential market entry based on Phase 3 timeline
2031
Retatrutide forecast $15.6B in sales (GlobalData projection)
What This Means for Patients
For patients currently using or considering GLP-1 medications, these developments signal several things.
More options are coming. Within a few years, patients and providers will have access to higher-efficacy options (retatrutide, amycretin) for those who need maximum weight loss, and more convenient oral options (orforglipron) for those who prefer pills over injections.
Current medications remain effective. Wegovy and Zepbound produce substantial, clinically meaningful weight loss. The next generation doesn't make current treatments obsolete—it expands the toolkit.
Tolerability may improve. As more targets are added, some patients may find certain combinations better suit their physiology. The diversity of mechanisms could help match patients to optimal treatments.
These drugs are not yet available. Retatrutide, amycretin, and orforglipron (for obesity) remain investigational. Anyone offering them outside clinical trials is operating illegally. Patients should be cautious of any provider claiming access to these medications.