Zepbound outperforms Wegovy in SURMOUNT-5 trial: Eli Lilly’s weight-loss drug achieves 47% greater relative reduction

Why Is Eli Lilly’s SURMOUNT-5 Trial a Major Moment for Obesity Drug Innovation?

Eli Lilly and Company disclosed full results from the SURMOUNT-5 Phase 3b clinical trial on May 11, 2025, positioning its dual agonist therapy Zepbound (tirzepatide) as the most effective pharmaceutical intervention for chronic weight management to date. Published in The New England Journal of Medicine and presented at the European Congress on Obesity, the data compared Zepbound against Novo Nordisk’s GLP-1 agonist Wegovy (semaglutide). The findings arrive at a critical juncture, as the global obesity epidemic worsens and stakeholders demand more effective long-term treatments. The implications for clinical practice, pharmaceutical competition, and patient access are considerable.

How Did Zepbound Compare to Wegovy in the SURMOUNT-5 Study?

The 72-week open-label randomized trial revealed that Zepbound delivered significantly greater efficacy across both primary and secondary endpoints. Participants administered Zepbound experienced an average 20.2 percent reduction in body weight, substantially outpacing the 13.7 percent achieved by those on Wegovy. In real terms, this equated to 50.3 pounds lost with Zepbound compared to 33.1 pounds with Wegovy. The trial showed that Zepbound offered a 47 percent relative advantage over Wegovy in weight loss, setting a new benchmark for pharmacological obesity treatment.

What Clinical Outcomes Signal Zepbound’s Competitive Edge?

Zepbound showed superiority across all key secondary endpoints, including more aggressive weight-loss milestones. Over 81 percent of participants on Zepbound achieved at least a 10 percent weight reduction, while 64.6 percent reached 15 percent or more. In comparison, 60.5 percent and 40.1 percent of those on Wegovy met the same thresholds, respectively. At the higher end of weight-loss targets, 48.4 percent of Zepbound users lost at least 20 percent, and nearly a third achieved 25 percent reduction. These outcomes offer compelling clinical utility, particularly in the treatment of patients with severe obesity or those with comorbidities exacerbated by central adiposity. Waist circumference, another critical metric, decreased by 18.4 cm in the Zepbound group, versus 13.0 cm among Wegovy recipients, further emphasizing its metabolic advantages.

What Is Zepbound’s Mechanism and Regulatory Status?

Zepbound is based on tirzepatide, a novel dual agonist that activates both GIP (glucose-dependent insulinotropic polypeptide) and GLP-1 (glucagon-like peptide-1) receptors. These are natural incretin hormones that regulate appetite, insulin sensitivity, and energy expenditure. By targeting two receptors rather than one, tirzepatide delivers a synergistic effect that improves satiety, reduces calorie intake, and supports sustained weight loss. The U.S. Food and Drug Administration has approved tirzepatide as Zepbound for chronic weight management and as Mounjaro for glycemic control in type 2 diabetes. It is also approved to treat adults with moderate-to-severe obstructive sleep apnea and obesity. In markets outside the U.S., Mounjaro is being used under similar indications, although regulatory timelines vary by country.

How Was the SURMOUNT-5 Trial Structured?

The SURMOUNT-5 trial enrolled 751 adults with obesity or overweight status and at least one weight-related comorbidity, including cardiovascular disease, obstructive sleep apnea, hypertension, or dyslipidemia. Participants did not have diabetes and were randomized to receive either Zepbound or Wegovy in their maximum tolerated doses—10 mg or 15 mg for Zepbound and 1.7 mg or 2.4 mg for Wegovy. Approximately 89.3 percent of Zepbound participants received at least one 15 mg dose, and 92.8 percent of those on Wegovy received the 2.4 mg dose. Participants also underwent lifestyle counseling involving calorie-restricted diets and increased physical activity. The trial’s design reflected a pragmatic, real-world approach intended to assess outcomes beyond controlled environments.

What Are the Risks Associated With Zepbound?

Zepbound’s safety profile aligned with results from previous SURMOUNT trials. The most commonly reported adverse events were gastrointestinal in nature, such as nausea, diarrhea, and vomiting. These were generally mild or moderate in severity. Discontinuation rates due to side effects stood at 6.1 percent for Zepbound and 8.0 percent for Wegovy. Importantly, the trial was not powered to detect differences in tolerability between the two drugs. The most serious warnings tied to Zepbound involve thyroid tumors, particularly medullary thyroid carcinoma (MTC). As a result, the drug is contraindicated in individuals with a personal or family history of MTC or those with Multiple Endocrine Neoplasia syndrome type 2. Additional serious adverse events include pancreatitis, gallbladder complications, kidney issues due to dehydration, and allergic reactions. Patients undergoing surgery or anesthesia are advised to disclose Zepbound usage to reduce aspiration risks.

How Did Investors React to Eli Lilly’s Zepbound Data?

The release of SURMOUNT-5 results sparked renewed interest in Eli Lilly’s long-term pipeline. However, in the short term, Eli Lilly’s stock has experienced downside volatility. As of May 9, 2025, shares closed at $734.57, representing a sharp drop from its 52-week high of $972.53. The decline followed a Q1 2025 earnings report that revealed a 45 percent increase in revenue to $12.73 billion but missed consensus estimates for earnings per share, which came in at $3.34 versus $3.46 expected. This earnings miss, combined with concerns over high valuation multiples, has led to investor caution even in light of promising product performance. While the market punished the stock for near-term earnings gaps, the broader investment community continues to value Eli Lilly’s robust innovation pipeline, especially in obesity and diabetes care.

What Is the Buy-Sell-Hold Outlook for Eli Lilly Stock?

Sell-side analysts from Bank of America, Morgan Stanley, and J.P. Morgan have reiterated “Overweight” ratings, citing strong clinical efficacy of Zepbound and expected commercial scaling of its dual GLP-1/GIP therapy class. The buy case is strengthened by the long-term demand outlook for anti-obesity drugs, which some forecasts peg above $100 billion by 2030. The hold thesis is anchored in uncertainty around quarterly margin pressure and R&D investments, while the bear case focuses on valuation risks and increasing competition from Novo Nordisk and potential biosimilars in the pipeline. For investors with a long-term horizon, current share prices may represent an attractive entry point. On the other hand, shorter-term traders might continue to monitor technical weakness and earnings volatility before reentering.

What Are Institutional Flows and FII/DII Trends Telling Us?

Although Eli Lilly does not publicly report segmented FII or DII flows due to its U.S. listing, trends from 13F filings and ETF movements reveal a mixed sentiment among institutional investors. Several healthcare-focused mutual funds trimmed their exposure in the wake of Q1 earnings, citing valuation concerns. However, a significant number of long-only funds and healthcare ETFs either maintained or added to their positions, viewing the stock’s decline as a long-term accumulation opportunity. Notably, Eli Lilly remains a top holding in innovation-themed and ESG-linked portfolios, suggesting that structural investor belief in its fundamentals remains intact.

What Is the Broader Outlook for Obesity Drugs Like Zepbound and Wegovy?

The success of SURMOUNT-5 further solidifies Zepbound’s position in a rapidly expanding therapeutic class. With mounting evidence supporting dual agonist therapies and broader public health acceptance of obesity as a treatable chronic disease, analysts expect Zepbound to capture significant market share. Eli Lilly is currently progressing additional clinical trials focused on cardiovascular and renal outcomes that could extend Zepbound’s label and drive pricing leverage. In the meantime, global regulatory expansion, payer acceptance, and patient demand are expected to fuel rapid uptake, even as competition from Novo Nordisk’s portfolio remains strong.