7 Indications for GLP-1s Beyond Weight Loss

Friday’s approval of Eli Lilly’s weight loss Zepbound (tirzepatide) to treat moderate to severe obstructive sleep apnea in adults with obesity solidified an expansionist precedent first set by Lilly’s main GLP-1 competitor, Novo Nordisk. In March, the FDA greenlit Novo’s Wegovy (semaglutide) for lowering cardiovascular risk in overweight or obese individuals.

GLP-1 receptor agonists can lower glucose levels in the blood, while also slowing down the movement of food through—and its clearance from—the gastrointestinal tract, in turn suppressing appetite. These effects have won GLP-1s FDA approvals for the treatment of type 2 diabetes (T2D) and obesity—while also making the drug class one of the most lucrative investment opportunities for biopharma companies.

A November 2024 report from Coherent Market Insights forecasts that the GLP-1 market will reach nearly $56 billion by 2031, while GlobalData’s June 2024 projection was nearly twice that—$111 billion by 2033, despite insurance and supply headwinds.

In recent months, an increasing number of studies have called attention to the potential of GLP-1 treatments in other conditions. While these are still just preliminary findings, they set the class up for expansion into more indications, further increasing its market potential.

“The GLP-1 receptor agonists may have wider pharmacological effects because these analogs have modified peptide structure profiles compared to endogenous peptides,” Chun-Su Yuan, a professor of Anesthesia and Critical Care at the University of Chicago, told BioSpace in an email. He explained that these structural changes could give the peptide therapies novel functionalities.

These additional effects could also be due to GLP-1 analogs’ higher plasma concentrations and prolonged persistence in the body over natural GLP-1 receptor–activating molecules, according to Yuan.

Here, BioSpace looks at seven indications ripe for GLP-1 expansion.

Afflicting more than 1 billion people worldwide, obstructive sleep apnea (OSA) is one of the most common breathing-related sleep disorders, though most cases are either undiagnosed or untreated.

Patients with the condition suffer from blocked airways that interfere with or outright prevent proper breathing. These blockages can manifest as excessive snoring or lead to dangerous drops in blood oxygen, which trigger a key reflex in the brain that wakes patients up so they can breathe.

Notably, there is a strong link between OSA and obesity or overweight. According to the Cleveland Clinic, excess body weight is a risk factor for OSA because it increases the volume of tissue that can press down on the windpipe during sleep. A 2017 review article published in the journal Sleep Medicine and Disorders noted that there is a “linear correlation between obesity and OSA.”

This link is what Eli Lilly has successfully leveraged to expand its blockbuster weight-loss therapy Zepbound (tirzepatide) into OSA. The pharma released detailed results in June 2023 from its Phase III SURMOUNT-OSA program, demonstrating that Zepbound could significantly reduce disease severity in obese patients with moderate-to-severe OSA.

Novo is seeking to expand the therapeutic reach of GLP-1 receptor agonists by looking at conditions closely related to the drug class’s approved indications.

In this case, the Danish pharma has positioned semaglutide—marketed as Ozempic for type 2 diabetes and Wegovy for chronic weight management—as a treatment for chronic kidney disease in patients with T2D. The FDA is currently reviewing Novo’s application for an expansion and is set to release a verdict in January 2025, the company announced in June. Earlier this month, Novo announced that the European Medicines Agency would allow it to add risk reduction for events related to kidney disease to Ozempic’s label.

In patients with diabetes, high levels of sugar in the blood can over time damage the blood vessels that supply the nephrons in the kidneys. If left unchecked, this can lead to the progressive loss of kidney function or to abnormalities in the kidneys’ structure, both of which often show no signs until they’ve reached an advanced stage. High blood pressure, a common comorbidity of diabetes, can have a similar effect.

According to the National Kidney Foundation, diabetes is the top cause of kidney failure and is responsible for more than 40% of new cases of the condition.

In the Phase III FLOW trial, Novo demonstrated that T2D patients taking semaglutide were 24% less likely to develop the study’s primary composite outcome of kidney failure onset, reduced kidney function and kidney-related or cardiovascular death. Death from any cause was 20% lower in semaglutide-treated patients.

Far behind Novo in this indication, Lilly is developing its next-generation obesity candidate retatrutide to improve cardiovascular and kidney outcomes in obese patients—though the pharma does not explicitly state that the drug is being tested for CKD. Aside from GLP-1, retatrutide also targets and activates the GIP and glucagon receptors.

Recent studies have suggested that using GLP-1 receptor agonists could have liver health benefits.

In June 2024, for instance, Lilly published detailed results from its Phase II SYNERGY-NASH study, demonstrating that tirzepatide could potentially improve fibrosis—liver scarring—in patients with metabolic dysfunction-associated steatohepatitis (MASH). At 52 weeks, the study found that up to 73% of patients treated with tirzepatide achieved the absence of MASH without the worsening of fibrosis. Additionally, up to 59% of tirzepatide-treated participants saw at least a one-stage improvement in fibrosis without MASH worsening.

At the time, Lilly in a press announcement cautioned that SYNERGY-NASH was not powered to definitively prove that tirzepatide can significantly improve fibrosis. Still, the pharma aims to push tirzepatide into MASH.

The company is once again chasing Novo, however, which last month unveiled detailed findings from the Phase III ESSENCE study in MASH. The trial showed that nearly 63% of patients treated with semaglutide saw hepatitis resolution without fibrosis worsening over 72 weeks of follow-up; 37% of patients on semaglutide showed fibrosis improvements without deterioration of steatohepatitis. Meanwhile, almost 33% of treated patients showed both steatohepatitis resolution and fibrosis improvement.

According to the Cleveland Clinic, steatotic liver diseases are caused by the presence of excess fat in the liver. As such, being overweight or obese aggravates the risk of these liver conditions, as does having type 2 diabetes.

Aside from Novo and Lilly, Boehringer Ingelheim is developing survodutide, a dual glucagon/GLP-1 receptor agonist, for MASH. A Phase II readout in February showed that 83% of patients saw biopsy-proven improvement in MASH without worsening of fibrosis at 48 weeks, versus 18.2% in placebo comparators. The pharma in October kicked off two Phase III MASH trials of survodutide. Meanwhile, Hanmi Pharmaceuticals is advancing its triple agonist efocipegtrutide. Designed to target and activate the GLP-1, GIP and glucagon receptors, efocipegtrutide is intended to have better efficacy against MASH and fibrosis versus other single-target agents. The candidate is currently in Phase IIb development.

Last month, a real-world study linked Novo’s semaglutide with a 40% to 70% drop in the risk of Alzheimer’s disease in patients with type 2 diabetes, versus treatment with insulin.

A few months earlier, in July 2024, a Phase IIb study found that Novo’s older GLP-1 therapy liraglutide—marketed as Saxenda for obesity and Victoza for type 2 diabetes—could slow cognitive decline in patients with mild Alzheimer’s disease. The trial was not sufficiently powered to assess the cognitive effects of liraglutide, though its results showed that treated patients deteriorated 18% slower than placebo comparators over a year of follow-up.

The link between obesity and cognition is less clear, though not entirely absent. According to the Alzheimer’s Society, obesity from 35 to 65 years of age can raise the risk of dementia by up to 30%. Obesity is tied to higher blood pressure, depression, social isolation, low levels of physical activity and a greater likelihood of diabetes—all of which are known risk factors of dementia, according to the organization.

There appear to be direct molecular links, too. In a January 2024 study published in the Journal of Translational Medicine, researchers elucidated the role of Lilly’s tirzepatide in activating a signaling pathway involved in neuronal growth and its protective effects against hyperglycemia- and insulin resistance-mediated neuronal damage.

Novo is running the Phase III EVOKE and EVOKE Plus trials to test semaglutide in patients with early Alzheimer’s disease. Both studies have primary completion dates in September 2025.

Fellow Denmark-based company Kariya Pharmaceuticals is also targeting neurodegeneration with KP405, a first-in-class dual agonist of the GLP-1 and GIP receptors. The biotech is testing KP405 in Phase I as a treatment to slow the progression of Parkinson’s disease.

Another disease primed for GLP-1 expansion is type 1 diabetes.

Unlike T2D, type 1 diabetes is an autoimmune disease marked by the impaired production of insulin due to immune cells attacking the islet cells in the pancreas. The exact cause of type 1 diabetes is still unknown, though potential factors include viral infections, genetic predisposition and exposure to certain foods or chemicals.

Still, both types of diabetes share core characteristics, particularly the harmful accumulation of sugar in the blood and the risk of damage to organs.

Because GLP-1s work by inducing insulin secretion in response to blood glucose, it stands to reason that these drugs could also be effective for type 1 diabetes. An October 2024 study in the Journal of the American Medical Association found that from 2010 to 2023, the proportion of type 1 diabetes patients being treated with GLP-1 receptor agonists grew from 0.3% to 6.6%—indicating that even without the FDA’s approval, physicians and prescribers appear to see the value of the drug class in this indication.

Some data support this idea. In 2022, for instance, a retrospective study showed that in the real-world setting, after a year of treatment with GLP-1 receptor agonists, patients with type 1 diabetes needed a significantly lower dose of insulin. Meanwhile, a 2019 review concluded that GLP-1 therapies could serve as an “important add-on therapy option” for type 1 diabetes patients.

In July 2024, a large study published in JAMA Network Open looked at the health benefits of GLP-1 therapies further downstream from obesity.

Researchers from the Case Western Reserve University School of Medicine and the MetroHealth System in Ohio zeroed in on obesity-associated cancers (OAC)—a list of 13 malignancies whose risks are aggravated and prognoses are worsened by the presence of excess fat tissue.

Using electronic health records of 113 million patients in the U.S., of whom more than 1.6 million had T2D and were treated with GLP-1 receptor agonists, insulins or metformin, the Ohio team found that GLP-1 receptor agonists were associated with significantly lower risk of several OACs versus insulin, but not metformin.

For example, patients on GLP-1 treatment were 65% and 63% less likely to develop gallbladder cancer and meningioma, respectively, than patients on insulin. GLP-1s also slashed the risk of pancreatic cancer by 59%, hepatocellular carcinoma by 53% and ovarian cancer by 48%.

In all, GLP-1 receptor agonists were correlated with reduced risks for 10 of the 13 OACs investigated in the study.

Versus metformin, however, the risk of kidney cancer was more than 50% higher in patients on GLP-1 treatment.

Arguably the most unexpected off-target benefit of GLP-1 receptor agonists on this list is their potential protective effects in addictive disorders.

There have been relatively few studies in this area, and the vast majority have been correlative, falling short of establishing a causal link between GLP-1 use and a lower risk of substance abuse. In July 2024, for instance, an emulation trial used electronic health record data from nearly 223,000 patients and found that, compared with insulin, semaglutide was associated with a 32% drop in the risk of tobacco use disorder.

A few months later, in September 2024, a retrospective cohort study linked Novo’s GLP-1 analog to a lower risk of opioid overdose. Compared with insulin and metformin, semaglutide was tied to a 58% and 54% reduction in opioid overdose, respectively. Semaglutide’s advantage was strongest against thiazolidinediones and DPP-4 inhibitors, in which it cut the risk of opioid overdose by 68% and 63%, respectively.

Neurologically, obesity and addiction could potentially share dysregulated dopaminergic pathways, in turn compromising sensitivity to rewards, self-control and stress reactivity. Whether GLP-1 receptor agonists might act on the dopamine cascade or suppress addictive impulses via other pathways has yet to be determined.

While Lilly has not officially announced any trials, CEO David Ricks recently said at an event that the company would begin large studies of its obesity drugs in alcohol and drug abuse next year, according to Endpoints News.

So far, though, universities and federal agencies are leading the charge in this space. The National Institute on Alcohol Abuse and Alcoholism, for instance, is working with the University of North Carolina at Chapel Hill on a Phase II trial testing semaglutide in people with alcohol use disorder.

Meanwhile, at Pennsylvania State University, addiction researcher Patricia Grigson is running a study of Novo’s Victoza (liraglutide) for people with opioid use disorder.

People who are addicted have a “real physiological need for the drug,” Grigson told BioSpace in August 2023. GLP-1 therapies, in turn, could help “reduce that heavy physiological need.”