Eli Lilly's Oral GLP-1 Candidate Orforglipron Shows 12% Weight Loss in Pivotal Trial, Eyes Regulatory Filing

Eli Lilly’s experimental oral GLP-1 receptor agonist, orforglipron, has delivered up to 12.4% mean weight loss in a late-stage obesity trial, setting the stage for a regulatory submission by the end of 2025. While the results may not match the dramatic efficacy of injectable GLP-1 drugs, Lilly is positioning the once-daily pill as a more convenient, potentially lower-cost alternative in the rapidly expanding obesity market.

Attain-1: 3,100+ patients, three doses, clear dose-response

The phase 3 Attain-1 study enrolled 3,127 adults with obesity or overweight who had at least one weight-related comorbidity, such as hypertension or cardiovascular disease, but without diabetes. Participants were randomised to receive 6 mg, 12 mg, or 36 mg of orforglipron once daily, or placebo, for 72 weeks. All began at 1 mg/day, escalating every four weeks to their assigned maintenance dose.

At the highest 36 mg dose, participants achieved a mean 12.4% weight loss, equivalent to 27.3 pounds, compared with 0.9% (2.2 pounds) in the placebo arm. The 12 mg and 6 mg groups lost 9.3% (20.7 pounds) and 7.8% (17.6 pounds), respectively. Secondary endpoints reinforced the dose-response pattern: nearly 60% of high-dose patients lost ≥10% of body weight, and ~40% lost ≥15%.

Cardiometabolic signals and inflammation reduction

Lilly also highlighted pooled analysis data showing reductions in non-HDL cholesterol, triglycerides, and systolic blood pressure across all orforglipron arms. In a prespecified exploratory analysis, the highest dose reduced high-sensitivity C-reactive protein, a marker of systemic inflammation, by nearly 48%, suggesting potential cardiovascular risk benefits.

Safety profile in line with GLP-1 class, but some caveats

As with other GLP-1 agents, the most common adverse events were gastrointestinal (nausea, vomiting, diarrhoea). No liver safety signals emerged. Discontinuation due to adverse events ranged from 5.1% to 10.3% across doses, versus 2.6% for placebo, but total discontinuation rates were actually lower in active arms than in placebo. Notably, William Blair analysts flagged that GI side effects appeared to persist beyond the titration phase, unlike in some peptide-based GLP-1s.

Market context: convenience vs. efficacy gap

While Lilly executives touted the data as “as good as it gets” for a once-daily small-molecule GLP-1, the efficacy lags behind injectable rivals. Lilly’s own tirzepatide (Zepbound) has delivered >20% mean weight loss in non-diabetic patients, and Novo Nordisk’s investigational high-dose semaglutide (7.2 mg) has hit ~21% over a similar period.

For some patients, an oral therapy could be an attractive option, sidestepping injections and potentially lowering cost. In the UK, for instance, orforglipron could represent a simpler alternative for the NHS compared to injectable obesity medicines. But for those chasing maximal weight loss, injectables may retain the edge.

Competitive pressures and shifting obesity pipelines

Lilly’s data drop comes amid turbulence in the obesity R&D landscape. Novo Nordisk recently discontinued multiple obesity candidates, including a GLP-1/GIP co-agonist and a CB1 receptor blocker, following underwhelming results. Pfizer has similarly exited the GLP-1 race after setbacks in its own oral programs.

Yet, competition remains fierce. Viking Therapeutics and Structure Therapeutics, both developing oral metabolic agents, could see investor interest following Lilly’s slight miss against Wall Street efficacy forecasts.

Next steps

Lilly plans to present full Attain-1 data at the 2025 European Association for the Study of Diabetes (EASD) Annual Meeting and in a peer-reviewed journal. A second pivotal study, Attain-2, is ongoing, with results expected later this year. Together, the Attain trials form part of the broader seven-study Achieve program, which also includes trials in type 2 diabetes populations.

If approved, orforglipron could mark the first widely available oral GLP-1 therapy for obesity, a category still dominated by injectables, and reshape patient access strategies in a market projected to exceed $100 billion annually by the early 2030s.