Experts Uncertain of GLP-1s’ Long-Term Clinical Benefits

Glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) receptor agonists have expanded indications at an unprecedented pace, showing benefits for diabetes, obesity, cardiovascular health, and more. However, with these significant benefits only being observed in short-term timeframes, researchers have expressed significant uncertainty regarding the long-term benefits of GLP-1s and GIPs.¹

“Although multiple randomized controlled trials have confirmed the short-term efficacy and safety of GLP-1 receptor agonists, the long-term outcomes, particularly regarding sustained weight loss, weight regain, and safety profiles, remain areas of active investigation,” wrote the authors of a study published in Cureus.² “Understanding how well these agents maintain weight loss over time and how tolerable they remain during extended use is vital for clinical decision-making and guideline development.”

Pharmacology expert Robert Roskoski Jr. describes how the clinical success of GLP-1 and GIP receptor agonists has fundamentally shifted the management of metabolic disorders, though many clinical hurdles remain. To bypass the rapid enzymatic degradation of native peptides in the bloodstream, molecular engineering strategies have been utilized to dramatically prolong their circulating half-lives and enable weekly dosing.¹

READ MORE: Study Links GLP-1s to Lower Fragility Fractures in Adults With Diabetes

Pharmacists play a central role in guiding patients through these complex regimens, particularly since gastrointestinal distress, including nausea and vomiting, represents a universal class adverse effect of all GLP-1 receptor agonists. Mitigating these highly common adverse effects requires sequential, weekly dose escalations to build patient tolerance.

This clinical management is further complicated by high rates of discontinuation, often driven by the high monthly costs ranging from $1000 to $1600 in the US, which represents a severe financial toxicity for many patients. Yet, obesity is a chronic, relapsing disorder that demands ongoing, long-term pharmacological management rather than short-term interventions.^1,2

When therapy is stopped, the benefits quickly reverse; in a notable 120-week trial, patients who withdrew from semaglutide regained approximately two-thirds of their lost weight within a year, demonstrating that sustained outcomes depend on continued, possibly lifelong treatment.²

The Risks Associated with GLP-1s

Pharmacists must also remain vigilant about potential risks spanning multiple organ systems.³

In a massive study of over 2 million veterans with diabetes, researchers identified modest but notable secondary benefits, including a 10% to 20% reduced risk of neurocognitive disorders like Alzheimer and dementia, as well as decreases in suicidal ideation and substance addiction.

Crucially, however, the study confirmed serious risks, demanding that pharmacists counsel patients on signs of pancreatitis and monitor renal function, as kidney conditions can progress silently without symptoms until advanced stages.³

Furthermore, the long-term clinical utility of GLP-1 receptor agonists compared directly with other active medications remains highly uncertain. A comprehensive systematic review of 45 randomized trials lasting 52 weeks or longer showed that, although GLP-1 receptor agonists successfully reduce cardiovascular risk factors, stroke, renal events, and all-cause mortality when compared with a placebo, active comparisons are inconclusive.⁴

There is currently no randomized trial evidence over a year proving that these drugs offer superior microvascular or macrovascular protection compared with active alternatives like sulfonylureas, insulin, or DPP-4 inhibitors. Consequently, pharmacists must recognize that side-effect profiles, financial toxicity, and patient preference must remain central to shared clinical decision-making when selecting therapies.

A Continued Lack of Long-Term Benefits

This advice is especially pertinent as the commercial market balloons, with national expenditures in the US in 2025 reaching $62.8 billion for tirzepatide and $59.1 billion for semaglutide. More than 200 clinical trials are currently underway to explore further indications, ranging from liver disease to neurodegenerative disorders, and new oral formulations like the nonpeptide small molecule orforglipron emerge.^1,5

Although these oral alternatives are hypothesized to bypass needle aversion and improve adherence, pharmacists must caution that comparative, real-world data regarding their long-term clinical persistence and safety are still lacking.¹

“Owing to the recent approvals of tirzepatide and orforglipron, we lack data on their extended benefits and sequalae,” concluded Roskoski Jr. “We want to see whether these current beneficial short-term pharmacological efficacies can be converted into long-term health benefits that decrease the worldwide burden of diabetes, obesity, and obesity-related diseases.”

READ MORE: Diabetes Resource Center

REFERENCES

1. Roskoski R. The role of GLP-1 and GIP receptor agonists in the treatment of diabetes and obesity. Pharmacol Res. August 6, 2026:108365. doi:10.1016/j.phrs.2026.108365

2. Shah MY, Mohammad A, Bashir Ahmed Samejo R, et al. Weight loss that lasts: reviewing the long-term impact of GLP-1 receptor agonists. Cureus. 2025 Jul 19;17(7):e88334. doi: 10.7759/cureus.88334

3. Sauerwein K. Study identifies benefits, risks linked to popular weight-loss drugs. Washington University Medicine. January 20, 2025. Accessed August 6, 2026. https://medicine.washu.edu/news/study-identifies-benefits-risks-linked-to-popular-weight-loss-drugs/

4. Alexander JT, Staab EM, Wan W, et al. The longer-term benefits and harms of glucagon-like peptide-1 receptor agonists: a systematic review and meta-analysis. J Gen Intern Med. 2022 Feb;37(2):415-438. doi: 10.1007/s11606-021-07105-9

5. Exploring how the GLP-1 function may provide benefits beyond weight loss and diabetes. American Chemical Society. October 4, 2024. Accessed August 6, 2026. https://www.cas.org/resources/cas-insights/glp1-function