Oral GLP-1 Efficacy Confirmed, But GI Toxicity and CV Data Void Threaten Global Ambitions

Hengrui and Kailera's Oral GLP-1 Achieves Phase 3 Endpoints in China

Hengrui Pharma and Kailera Therapeutics announced positive late-stage results for their investigational oral GLP-1 receptor agonist, HRS-7535/KAI-7535, in China. The Phase 3 HARBOR-1 trial for obesity or overweight adults demonstrated mean weight loss of 8% and 9.8% from baseline at week 44 for 120 mg and 180 mg doses, respectively, significantly outperforming the 2.4% reduction in the placebo arm. Concurrently, the Phase 3 OUTSTAND-2 study for type 2 diabetes achieved non-inferiority to dapagliflozin, showing a 1.68% HbA1c reduction with the highest HRS-7535 dose. These results pave the way for regulatory submissions in China for both indications. However, high rates of gastrointestinal adverse events, including ~70% nausea and ~68.6% vomiting, were observed in HARBOR-1, posing a challenge for Kailera's ongoing U.S. trial.

• Significant Weight Loss Efficacy in Obesity Trial: The HARBOR-1 Phase 3 trial, involving adults with obesity or overweight, successfully met its primary endpoint. Patients treated with HRS-7535 achieved a mean weight loss of 8% at 120 mg and 9.8% at 180 mg from baseline by week 44. This compares favorably to a 2.4% reduction in the placebo group, demonstrating a statistically significant and clinically meaningful weight reduction, positioning the drug as a competitive oral option in the obesity landscape.
• Positive Outcomes in Type 2 Diabetes Study: The OUTSTAND-2 Phase 3 trial for type 2 diabetes patients also met its main goal, demonstrating non-inferiority to dapagliflozin (Farxiga). The highest dose of HRS-7535 (90 mg) led to a 1.68% reduction in HbA1c from baseline at 32 weeks, surpassing dapagliflozin's 1.28% reduction. The study also reported improvements in body weight, systolic blood pressure, lipid profiles, and urinary albumin-to-creatinine ratio, indicating broad metabolic benefits.
• Gastrointestinal Safety Profile and Future Optimization: While efficacious, the HARBOR-1 trial reported high rates of gastrointestinal treatment-emergent adverse events (TEAEs), with approximately 70% of patients experiencing nausea and up to 68.6% experiencing vomiting. These rates were higher than in previous studies, leading to analyst concerns. Kailera Therapeutics is actively addressing these safety signals in an ongoing global Phase 2 trial, exploring a wider dose range, lower starting doses, and more gradual titration to optimize the drug's overall clinical profile for diverse patient populations.

Hengrui/Kailera's Oral GLP-1 Achieves Key Endpoints in China

Two pivotal recent trials illustrate the evolving oral GLP-1 landscape in obesity pharmacotherapy. The OASIS-4 trial (2025) evaluated oral semaglutide 25 mg in 307 adults over 64 weeks, demonstrating a mean body weight reduction of 13.6%, with 63% of participants achieving ≥10% weight loss alongside favourable metabolic changes. Gastrointestinal adverse events were consistent with the GLP-1 receptor agonist class, with mild dysesthesia additionally reported. The ATTAIN-1 trial (2025) assessed orforglipron, an oral non-peptide GLP-1 receptor agonist, in 3,127 adults with obesity over 72 weeks. Mean weight loss reached 11.2%, with 54.6% of participants achieving ≥10% reduction and meaningful improvements in cardiometabolic parameters. Safety was similarly characterised by GLP-1-class gastrointestinal effects, with five mild cases of pancreatitis observed.

In the injectable dual agonist space, a 2026 randomised trial of mazdutide 9 mg — a dual glucagon and GLP-1 receptor agonist — in Chinese adults with BMI ≥30 kg/m² without diabetes reported a mean percentage weight change of −12.78% at week 24, versus +1.80% with placebo (treatment difference −14.58%; 95% CI −18.00 to −11.16; p < 0.0001). Weight reduction of ≥5% was achieved by 81.7% of mazdutide-treated participants, accompanied by greater improvements in cardiometabolic risk factors relative to placebo. The most commonly reported adverse events were nausea (50.0% vs. 0% placebo), diarrhoea (38.3% vs. 10.0%), and vomiting (36.7% vs. 10.0%), predominantly mild to moderate in severity — a tolerability profile consistent with the mechanistic class.

A 2025 Cochrane systematic review of tirzepatide — the approved dual GIP/GLP-1 receptor agonist administered once weekly at doses of 5 mg to 15 mg — synthesised evidence from 8 studies (6,317 participants) at medium-term follow-up (12–18 months), reporting a mean percentage weight reduction of −16.03% (95% CI −18.91 to −13.14; moderate-certainty evidence) and a risk ratio of 3.60 (95% CI 2.44 to 5.30) for achieving ≥5% weight loss. At long-term follow-up (3.5 years; 1 study, 1,032 participants), mean weight reduction was −15.66% (95% CI −19.14 to −12.18). From a safety perspective, non-serious adverse events were elevated at medium term (RR 1.33; 95% CI 1.03 to 1.71; low-certainty evidence), while effects on serious adverse events remained uncertain (RR 0.99; very low-certainty evidence). MACE and mortality showed little to no difference versus comparator at both timepoints, though evidence certainty was moderate to low.

Navigating the Safety Profile of HRS-7535: GI Events in Focus

Across both its Phase 1 (healthy participants) and Phase 2 (type 2 diabetes inadequately controlled with metformin) trials, HRS-7535 has demonstrated a safety and tolerability profile broadly consistent with the established GLP-1 receptor agonist (GLP-1 RA) class. The high completion rate in the Phase 2 trial — 177 of 194 randomized patients (91.2%) completing 16 weeks of treatment — further underscores its overall tolerability.

• Gastrointestinal adverse events predominate across both studies: In the Phase 1 trial (SAD, food effect, and MAD parts), nausea and vomiting were the most frequently reported adverse events (AEs). In the Phase 2 trial, AEs occurred in 71.8%–84.6% of HRS-7535-treated patients versus 71.8% of placebo-treated patients, with events characterized as predominantly mild to moderate in severity and gastrointestinal in nature.

• Hypoglycemia risk appears low and confined to Grade 1 events: In the Phase 2 trial, Level 1 hypoglycemia was recorded in 9 HRS-7535-treated patients; no Level 2 or Level 3 hypoglycemic events were observed, suggesting a limited risk of clinically significant hypoglycemia in a metformin-combination setting.

• No pancreatic or hepatic safety signals were identified: The Phase 2 trial recorded no cases of pancreatitis and no elevations of alanine aminotransferase (ALT) or aspartate aminotransferase (AST) exceeding 3× the upper limit of normal, indicating an absence of concerning pancreatic or hepatotoxic findings to date.

• Phase 1 pharmacokinetics support a once-daily oral regimen: Beyond tolerability, the Phase 1 trial confirmed that HRS-7535's pharmacokinetic profile is suitable for once-daily dosing, with the MAD cohort receiving HRS-7535 120 mg (via a 30/60/90/120 mg titration scheme) over 28 days without emergent safety concerns.

HRS-7535 in the Oral GLP-1 Landscape: US Market Challenges

The investigational pharmacotherapy landscape for obesity has undergone a marked transformation, with GLP-1 receptor agonists, dual and triple incretin agonists, and amylin-based combination therapies demonstrating unprecedented efficacy in clinical trials. Recent data indicate that some agents induce 15–25% body weight reduction, approaching outcomes historically exclusive to surgical intervention. Oral semaglutide 25 mg, approved for obesity treatment based on the OASIS programme, is particularly notable: in patients with overweight/obesity without type 2 diabetes (T2D), it achieved weight reductions of 16.3% and 14.7% for the trial product and treatment policy estimands, respectively. In those with concomitant T2D, reductions of 9.4% and 7.8% were observed. Critically, 82.2% of participants treated with oral semaglutide 25 mg achieved systemic exposure levels within the same range as those receiving once-weekly subcutaneous semaglutide 2.4 mg in STEP 1, with overall efficacy profiles considered comparable between the two formulations. Earlier-generation anti-obesity medications — including phentermine/topiramate, liraglutide, naltrexone/bupropion, and orlistat — achieved more modest placebo-subtracted weight reductions ranging from 2.9% to 6.8% across meta-analyses of ≥12-month trials, underscoring the step-change in efficacy represented by newer incretin-based agents.

Against this evolving pharmacotherapy benchmark, bariatric surgery has historically been considered the most effective intervention for severe obesity. Cost-effectiveness analyses with long time horizons for patients with BMI >35 kg/m² found that four of fifteen adapted studies classified bariatric surgery as cost-saving (dominant) versus conventional treatment, with the remainder demonstrating ICERs below CHF 50,000 per QALY gained. For patients with BMI <35 kg/m², two studies similarly returned ICERs below 50,000 per QALY, and gastric bypass demonstrated superiority over gastric banding, albeit at higher cost. However, the emergence of pharmacotherapies achieving 15–25% weight loss now challenges the established criteria for surgical candidacy, and a stepwise pharmacotherapy-first approach may be justified, particularly in patients with BMI in the 30–40 kg/m² range. A large retrospective analysis of 261,408 adults with BMI ≥35 further highlighted that clinical obesity — defined by the presence of at least one obesity-related condition — was associated with significantly higher odds of post-treatment complications within 90 days compared to pre-clinical obesity, for both anti-obesity medications (aOR 1.10, p<0.001) and bariatric surgery (aOR 1.39, p<0.001), reinforcing the importance of patient stratification in treatment selection.

Non-pharmacological and device-based interventions occupy a distinct niche, generally demonstrating more modest and anatomically localised effects. Among non-invasive modalities, radiofrequency produced a pooled mean abdominal circumference reduction of 2.7 cm (95% CI: 2.3–3.1), while lipolysis achieved a pooled reduction in fat layer thickness of 78% (95% CI: 73–83%), and liposuction yielded a pooled weight loss of 3.01 kg (95% CI: 2.3–3.6). Notably, cost analyses revealed no significant differences between non-invasive and invasive interventions, with non-invasive approaches appearing to offer superior clinical efficacy in body shape metrics at comparable or lower cost. Behavioural interventions such as alternate-day fasting and 16/8 time-restricted fasting demonstrated statistically significant reductions in body weight, BMI, waist circumference, blood glucose, and triglycerides versus control in overweight/obese adults with prediabetes, with alternate-day fasting producing greater reductions in body weight and BMI than the 16/8 protocol. Taken together, the published evidence positions next-generation oral and injectable incretin-based therapies as the most clinically transformative investigational and recently approved options relative to established standards of care, with non-pharmacological approaches retaining utility in defined patient subgroups.