Lilly’s daily GLP-1 pill beats Novo’s oral semaglutide in diabetes trial, but side effects drive more dropouts

Over the past three years, drugs like Ozempic and Wegovy have turned weekly injections into household names and fueled a global debate about weight, willpower and access to care. Now the same biology that powered those shots is moving into a simple daily pill — and a new study suggests one experimental tablet may outmuscle the first oral drug in this class, if patients can tolerate it.

Head-to-head Phase 3 results

Eli Lilly and Co. said its once‑daily oral drug orforglipron helped adults with type 2 diabetes lose more weight and achieve better blood sugar control than Novo Nordisk’s oral semaglutide, sold as Rybelsus, in a large Phase 3 trial. The study, called ACHIEVE‑3, followed 1,698 people for 52 weeks.

The results sharpen the next phase of the booming GLP‑1 drug market: a shift from refrigerated injections, often handled in specialty care, to mass‑market pills that could be prescribed in a typical primary care visit.

In ACHIEVE‑3, adults with type 2 diabetes that was not adequately controlled on metformin were randomly assigned to one of four once‑daily regimens: a lower or higher dose of orforglipron, or one of two label‑recommended doses of oral semaglutide.

Blood sugar control

After 52 weeks, people taking the higher dose of orforglipron cut their average A1c — a measure of blood sugar over about three months — by 2.2 percentage points, compared with a 1.4‑point drop on the 14‑milligram dose of oral semaglutide, according to Lilly. At the lower doses, orforglipron reduced A1c by 1.9 points versus 1.1 on 7 milligrams of semaglutide.

Lilly also reported that 37.1% of participants taking 36 milligrams of orforglipron reached near‑normal blood sugar levels, defined as an A1c below 5.7%, compared with 12.5% on the highest dose of semaglutide.

Weight loss

Weight loss told a similar story. Patients on 36 milligrams of orforglipron lost an average of 19.7 pounds, or about 9.2% of their body weight, over one year. Those on 14 milligrams of oral semaglutide lost 11 pounds, or 5.3% of body weight. At lower doses, orforglipron led to a 6.7% loss versus 3.7% for the lower‑dose semaglutide arm.

Lilly said that at the highest doses, orforglipron delivered about 74% greater relative weight loss than oral semaglutide.

A tolerability trade-off

The gains came with a trade‑off. Like other GLP‑1 drugs, orforglipron frequently caused gastrointestinal side effects, including nausea, vomiting, diarrhea and indigestion. Those events were generally mild to moderate but led more patients to quit.

About 8.7% of people on 12 milligrams of orforglipron and 9.7% on 36 milligrams stopped treatment because of side effects, roughly double the 4.5% and 4.9% discontinuation rates seen with the 7‑ and 14‑milligram oral semaglutide doses, Lilly reported.

The trial was open‑label, meaning patients and investigators knew which drug was being taken, though primary outcomes were based on laboratory measurements.

Why an easier pill matters

Orforglipron is a small‑molecule drug that activates the GLP‑1 receptor, the same target used by injectable semaglutide and Lilly’s dual‑agonist tirzepatide. It is taken once daily and, unlike Rybelsus, does not require fasting or special timing around meals.

Rybelsus must be taken on an empty stomach first thing in the morning with no more than 4 ounces of water. Patients are told to wait at least 30 minutes before eating, drinking anything else or taking other oral medicines. Clinicians and patients have described those instructions as a barrier to consistent use, especially for people juggling multiple prescriptions or irregular schedules.

By contrast, Lilly says orforglipron can be taken at any time of day, with or without food or water. The company has called it a “convenient once‑daily pill” that “could be readily manufactured and launched at scale.”

What other studies show

The ACHIEVE‑3 findings are part of a broader development program that Lilly hopes will support global regulatory submissions for both diabetes and obesity.

In a separate Phase 3 study known as ACHIEVE‑1, orforglipron was tested in 559 adults with type 2 diabetes managed with diet and exercise alone. Over 40 weeks, patients on higher doses of the drug lowered their A1c by up to 1.6 percentage points and lost about 7.9% of their body weight, or roughly 16 pounds, compared with minimal changes on placebo.

Two obesity‑focused trials, ATTAIN‑1 and ATTAIN‑2, extended that picture. ATTAIN‑2 enrolled more than 1,600 adults with obesity or overweight and type 2 diabetes. Patients on the highest, 36‑milligram dose of orforglipron lost an average of 10.5% of their body weight — about 22.9 pounds — over 72 weeks and saw A1c fall by roughly 1.8 points. ATTAIN‑1, in people with obesity but without diabetes, reported up to about 12% weight loss at similar time points, according to conference summaries.

Across these trials, the safety profile was dominated by gastrointestinal events, a feature common to GLP‑1 drugs. Lilly has not reported a liver safety signal with orforglipron, a point of interest after Pfizer halted development of a rival oral GLP‑1 compound due to elevated liver enzymes in some participants.

Safety, regulation and the limits of the data

Regulators will ultimately decide how to weigh the benefits and risks. GLP‑1 receptor agonists already carry warnings about thyroid C‑cell tumors in rodents, pancreatitis, gallbladder disease and, in some cases, retinal complications. While years of post‑marketing data have shaped how clinicians use injectable semaglutide, long‑term real‑world experience with high‑dose oral agents remains limited.

ACHIEVE‑3 participants were enrolled at sites in the United States, Argentina, China, Japan, Mexico and Puerto Rico. All had type 2 diabetes that remained above target despite metformin.

High commercial stakes—and access questions

GLP‑1 drugs have become one of the pharmaceutical industry’s most lucrative franchises. Novo Nordisk’s semaglutide products — Ozempic for diabetes, Wegovy for obesity, Rybelsus for oral diabetes treatment and a newly approved Wegovy pill for weight management — generated tens of billions of dollars in annual sales by 2025. Demand has repeatedly outstripped supply.

Lilly, based in Indianapolis, has emerged as Novo’s main rival through tirzepatide, marketed as Mounjaro for diabetes and Zepbound for obesity. Analysts see orforglipron, along with a separate experimental drug called retatrutide, as the company’s next wave of growth.

Some early reports have suggested Lilly could position orforglipron at a lower list price than injectable GLP‑1s, potentially in the range of a few hundred dollars a month through its LillyDirect prescribing service. Novo Nordisk has said it plans to cut list prices for Wegovy, Ozempic and Rybelsus starting in 2027 in response to pressure over affordability and competition.

Even with discounts, access remains uneven. Obesity and type 2 diabetes are more common in lower‑income communities and among Black, Hispanic and some Indigenous populations in the United States. Insurance coverage for weight‑loss medicines is patchy, and many employer plans require prior authorization or strict body mass index thresholds. A recent poll by KFF found about 12% of U.S. adults had used a GLP‑1 drug, but cost was a leading reason people stopped.

Globally, diabetes cases are projected to more than double to 1.3 billion by 2050, with many of the largest increases in low‑ and middle‑income countries. Pills that do not require refrigeration or injections could in theory be easier to distribute than biologic drugs, but only if pricing and supply allow broad use.

What comes next

For now, orforglipron remains an experimental medicine. Lilly has said it plans to file for approval in major markets in 2026 for type 2 diabetes and for obesity or overweight with weight‑related conditions, using data from the ACHIEVE and ATTAIN trials. The U.S. Food and Drug Administration has not publicly assigned a review deadline.

As regulators weigh those applications, clinicians and payers will be looking beyond the headline numbers. ACHIEVE‑3 suggests that a more potent, more flexible pill can deliver stronger improvements in blood sugar and weight than the current oral standard — at the cost of more patients dropping out because of side effects. How that balance plays out in everyday use, and who can afford to try the new drug at all, may determine how much the next phase of the GLP‑1 era is defined by pills rather than injections.