ISTANBUL — The once-daily oral GLP-1 receptor agonist orforglipron (Foundayo, Eli Lilly) produced clinically meaningful weight loss in adults aged 65 and older, whether or not they had type 2 diabetes (T2D). Its safety profile also closely mirrored the one seen in younger patients, according to a post hoc analysis of the phase 3 ATTAIN clinical trial program. 

The findings may help address longstanding uncertainty and a lack of robust evidence around the use of GLP-1 receptor agonists in older adults. This group is often underrepresented in obesity trials and considered more vulnerable to reduction in lean muscle mass, potentially precipitating frailty, sarcopenia, falls, fractures, and renal complications. They also have a high prevalence of obesity and cardiometabolic disease. 

“This data provides the information clinicians needed to feel confident prescribing orforglipron to older individuals who often have many other medications and health concerns,” lead author, Deborah Horn, DO, MPH, director of the Center for Obesity Medicine and Metabolic Performance at McGovern Medical School at UTHealth Houston, told Medscape News Europe. 

Asked whether the trial findings could be extended to routine clinical practice, she said that, “primary care providers and specialists [can] feel confident that the results in our older patients are similar to our broader practice population in weight loss, diabetes improvement, and safety.” 

Horn presented the findings here at the 33^rd European Congress on Obesity (ECO) 2026.

ATTAIN Trial Analysis Focused on Older Adults 

The new analysis evaluated efficacy and safety outcomes among participants who were at least 65 years old and enrolled in the multinational phase 3 ATTAIN-1 and ATTAIN-2 trials. ATTAIN-1 included adults with obesity or overweight without diabetes (BMI at least 30.0, or BMI at least 27.0 and at least one weight-related comorbidity ). ATTAIN-2 enrolled adults with obesity or overweight and pre-existing T2D (BMI of at least 27, diagnosed with T2D [A1c ≥ 7% to ≤ 10%]).

Across both studies, 616 participants were 65 years or older, including 196 participants in ATTAIN-1 and 420 in ATTAIN-2.

Of these, 613 received study treatment (6 mg orforglipron, n = 118; 12 mg, n = 135; 36 mg, n = 146; placebo, n = 214), in addition to a healthy diet and physical activity. In this sub-group analysis, efficacy outcomes were analyzed separately for each trial while safety data were pooled. The primary endpoint was percent change in body weight from baseline to week 72.

Meaningful Benefits Across Both Trials 

Most participants had at least one obesity-related comorbidity. Hypertension was particularly common, affecting 79.1% of older adults in ATTAIN-1 and 86.2% in ATTAIN-2.

At week 72, older adults without diabetes in ATTAIN-1 lost a mean of 7.9%, 11.3%, and 13.0% of body weight with orforglipron 6 mg, 12 mg, and 36 mg, respectively, compared with 1.6% with placebo. 

Among older adults with T2D in ATTAIN-2, mean weight losses were 7.5%, 8.3%, and 12.2% across the three increasing dose groups, respectively, vs 2.3% with placebo. All comparisons with placebo were statistically significant.

The analysis also showed improvements in A1c among participants with T2D. A1c levels fell by 1.5%-1.7% across orforglipron doses, compared with just 0.1% with placebo. 

Compared with placebo, orforglipron also improved BMI, waist circumference, triglycerides, non-high-density lipoprotein cholesterol, and health-related quality of life measures, regardless of whether participants had diabetes. 

Notably, the magnitude of weight loss observed in adults aged 65 and older was broadly similar to that seen in the overall ATTAIN trial populations.

Safety in Older Adults 

Questions around safety in older adults remain central to clinical discussions surrounding obesity pharmacotherapy. In participants 65 and older, treatment discontinuations due to adverse events were higher with orforglipron than placebo, occurring in 5.2%, 17%, and 13.7% of those taking increasing doses, respectively, vs 5.5% on placebo. Treatment discontinuations due to adverse events in participants younger than 65 were 5.6%, 7.5%, and 9.9%, respectively, vs 3.1% on placebo. Gastrointestinal adverse events were the most common side effects and included nausea, constipation, diarrhea, vomiting, and dyspepsia. Most were mild to moderate in severity.

Adverse events possibly related to lean muscle mass loss occurred in 6.0%-6.8% of adults aged 65 and older receiving orforglipron compared with 4.3% receiving placebo. These events in participants younger than 65 were 2.7%-3.6% vs 3.1% in placebo. Overall comparison of groups showed the findings did not reach statistical significance. 

Horn explained that trials consistently show that approximately one quarter of weight loss is muscle and three quarters is adipose or fatty tissue. “The most important approach clinicians can take is to advise all patients, and especially older patients, to increase their nutritional protein and their strength training. And then actually measure their body composition changes during treatment with GLP-1s to monitor for any elevated change in muscle.” 

In over-65s, rates of adjudication-confirmed major adverse cardiovascular events were 1.7%-3.7% with orforglipron and 2.3% with placebo. Renal events occurred in 0.7%-5.9% of treated patients older than 65 and 2.6% of placebo recipients.

The authors noted that these results were consistent with the higher baseline risk expected in older populations. Six deaths were reported across the analysis in the over 65s, with three in the orforglipron groups and three in the placebo group. None were considered related to treatment.

Oral Formulation May Suit Older People More 

The analysis may also draw attention because of the oral formulation itself. Although injectable GLP-1 therapies have dominated the obesity treatment landscape, some clinicians believe oral formulations could improve uptake among older adults reluctant to use injections or those managing multiple chronic illnesses and medications.

“It is easy to take, can be taken with other medications, with or without food, and at any time of day, and provides access with fewer barriers to all patients and especially individuals over 65 who are likely already on other medications. Still, experts caution that important questions remain unanswered regarding obesity pharmacotherapy in ageing populations.” 

They added that the analysis was post hoc and not specifically designed to evaluate frailty, physical function, or body composition. The study also may not fully reflect the frailer, multimorbid, older adults commonly encountered in routine clinical practice. 

Increasingly, geriatric obesity specialists argue that future trials should move beyond measuring weight loss alone and assess outcomes such as mobility, independence, strength, falls, and preservation of lean muscle mass.

Andreea Ciudin Mihai, MD, PhD, of the Endocrinology and Nutrition Department at Hospital Universitari Vall d'Hebron, Barcelona, Spain, told Medscape News Europe that the safety picture in older adults remains an open question. While falls and fractures occurred in both the placebo and active treatment arms — pointing to higher baseline frailty in this age group — she said the evidence on GLP-1 receptor agonist use in older patients is not yet conclusive.

“There is still limited data on people over 65 years and these results have to be interpreted with caution, because this was not the primary outcome. The trial did not prospectively measure these outcomes and was not designed nor powered for it. New studies specifically focused on this population, and specifically designed, are needed.” 

Ciudin Mihai added that although 2 years was long enough to detect many common adverse effects and some clinically meaningful functional decline, “it is probably not long enough to fully assess sarcopenia, frailty trajectory, fracture risk, disability, or loss of independence, especially if the trial did not prospectively measure those outcomes.” 

“We also know that BMI does not define health and obesity, and this is even more obvious in older people,” she asserted. “No doubt that not only for older adults, but in all clinical trials in obesity, we have to go beyond BMI and measure body composition — including both quantity and quality of the adipose tissue and muscle, and more importantly functionality, which is especially important and can have negative impacts on health in older people.” 

Orforglipron is part of a new generation of oral GLP-1 therapies approved by the US FDA in April 2026 for chronic weight management in adults with obesity or overweight and at least one weight-related condition. Unlike existing oral GLP-1 drugs such as Rybelsus (oral semaglutide for T2D, Novo Nordisk) and oral Wegovy (for obesity, Eli Lilly), orforglipron is a nonpeptide once-daily tablet that avoids the fasting restrictions required with earlier oral GLP-1 therapies.

The study was funded by Eli Lilly and Company. 

Horn reported receiving consulting fees or honoraria from Amgen, AstraZeneca, Boehringer Ingelheim, Eli Lilly, Kailera Therapeutics, Novo Nordisk, Roche, and Zealand Pharma; and institutional research support from Eli Lilly, KVK Tech, Novo Nordisk, and Weight Watchers. Several coauthors were employees and shareholders of Eli Lilly. Ciudin Mihai reported receiving speaking fees from AstraZeneca, Boehringer Ingelheim, Eli Lilly, Novo Nordisk, Sanofi, Menarini; research grants from Eli Lilly, Novo Nordisk, and Menarini; and is a member of the data monitoring committee of Boehringer Ingelheim.