Beyond diabetes and obesity: Can GLP-1 therapies also transform chronic disease treatment?

Glucagon-like peptide-1 (GLP-1) receptor agonists like semaglutide and tirzepatide have cemented their status as two of the most successful drugs in recent memory. Recent projections have estimated that the drug class could fetch $44 billion by 2030 and $71 billion by 2032.

But GLP-1 sales could potentially reach greater heights as these therapies move beyond their established territories of diabetes and obesity and start tackling major conditions like chronic liver and kidney disease, Alzheimer’s disease, and heart failure.

Promising clinical trial results highlight the potential of GLP-1s in an array of disease, including chronic kidney disease, nonalcoholic steatohepatitis (NASH), various forms of heart failure and potentially even Alzheimer’s.

There are, however, hurdles, such as a relatively high rate of gastrointestinal (GI) side effects, which affect somewhere around 40–70% of patients.  But the promise of GLP-1 therapies across a range of complex conditions is considerable as the table below reflects: 

Condition	Potential Benefit of GLP-1 Receptor Agonists	Current Status of Research
Chronic kidney disease	Improved kidney outcomes	Phase 3 trial underway
Alzheimer’s disease	Slower progression of disease	Phase 3 trials ongoing, including the EVOKE study. Other studies investigating the impact of semaglutide on amyloid and tau and the impact of the drug on the immune system of Alzheimer’s patients.
Heart failure with preserved ejection fraction	Improved symptoms, physical limitations, and exercise function	Phase 3 trial completed
Obstructive sleep apnea	Reduced risk of apnea	Phase 3 trial ongoing focused on tirzepatide
MASH/NASH	NASH resolution, potentially fibrosis improvement	Promising early data, with trials and analysis ongoing
Cardiovascular Diseases	Reduction in risk factors and improvement in cardiovascular health	Evidence from various clinical trials indicating beneficial effects
Parkinson’s disease	Possible delay in onset and progression of Parkinson’s	Exenatide, a GLP-1 agonist, has shown potential in improving Parkinson’s disease in models.
Cancer	Potential role in cancer prevention and management	Preliminary positive findings with ongoing studies
Skeletal Muscle Wasting	Protection against muscle wasting, particularly in aging populations	Clinical trials showing protective effects

 

Addressing the growing burden of liver disease

Liver disease throughout much of the world is reaching epidemic proportions with non-alcoholic fatty liver disease (NAFLD) affecting approximately 38% of the global population, according to a 2023 estimate in the Journal of Hepatology. NASH, a more severe form of NAFLD, affects between 4% in Western Europe and East Asia to over 7% in South America. This progressive form of NAFLD, where inflammation and liver cell damage occur, has recently been renamed metabolic associated steatohepatitis (MASH) to better capture its connection to underlying metabolic issues such as obesity and diabetes.

“The actions of GLP-1 and GIP suggest tirzepatide could offer benefits for MASH/NASH,” said Khang Hoang, cardiovascular and metabolic and infectious diseases analyst at Citeline. Eli Lilly’s dual GLP-1 and GIP receptor agonist tirzepatide recently demonstrated promising results in a phase 2 NASH trial, significantly improving NASH symptoms compared to semaglutide. The findings were “early but promising,” Hoang said, referring to key endpoints related to NASH resolution without worsening liver fibrosis and/or improving liver fibrosis without worsening of NASH. “Although cross trial comparisons should be made with caution, tirzepatide’s efficacy for NASH resolution are among the best reported so far,” Hoang noted.

Analysts continue to await more details on the impact on liver fibrosis as liver fibrosis is a strong predictor of outcomes for NASH patients. While Novo Nordisk’s GLP-1 receptor agonist semaglutide effectively improved NASH symptoms, it did not demonstrate improvement in liver fibrosis. “There are more advanced drug candidates for NASH that have demonstrated benefits for both key endpoints, including some orally administered agents, such as Madrigal Pharmaceuticals’ resmetirom,” Hoang added. “A lack of fibrosis benefit may not hold back approval in the United States, as benefits in either key endpoint is currently the threshold, but European regulators need to see improvements for both.”

GLP-1 therapies may help manage CKD

Chronic kidney disease, or CKD, is a silent but growing crisis. Currently, therapeutic options are limited to symptom management in cases of severe kidney failure, with only transplantation offering a definitive treatment option.

Tim Blackstock, Cardiovascular and Metabolic & Infectious Diseases Therapy Area Director at Citeline, highlights the role of metabolic disease in CDK, referring to diabetes as “a leading cause.” “Better glycemic control and weight loss are associated with slower reduction in kidney function,” he said. “We have some treatments that can slow CKD progression but more and better are needed.”

Enter GLP-1 receptor agonists. Recent research suggests GLP-1 drugs like semaglutide or tirzepatide might also protect the kidneys. “Studies of outcomes trial data have shown that GLP-1 receptor agonists also have benefits in kidney outcomes possibly due to blood pressure lowering, weight loss, improved glucose control, and more detailed investigations suggest these agents can increase natriuresis and diuresis, decrease oxidative stress and inflammation, and have beneficial glomerular hemodynamic effects,” Blackstock said.

Novo Nordisk recently halted the phase 3 FLOW trial investigating semaglutide for CKD early after semaglutide met pre-specified criteria for efficacy, a move usually indicative of overwhelmingly positive results. The company plans to release results from the study in the first half of 2024.

Can GLP-1 receptor agonists help with Alzheimer’s symptoms?

Diabetes and Alzheimer’s disease appear to be more entwined than previously suspected. One study found that 81% of Alzheimer’s patients struggled with either full-blown diabetes or its precursor — impaired fasting glucose. (35% had type 2 diabetes and 46% had impaired fasting glucose.) This intersection, affecting roughly millions globally, suggests that these two major health challenges might share common disease mechanisms, such as insulin resistance. “Type 2 diabetes mellitus (T2DM) is a risk factor for Alzheimer’s disease,” Blackstock said. The silver lining in the overlap perhaps is that the shared pathology, including insulin resistance, could pave the way for new ways to fight back.

The need for new treatment options is urgent given the surging prevalence of both conditions. Diabetes alone could impact 1.3 billion people by 2050, as the Washington Post noted. That rising tide has grave implications for Alzheimer’s Disease, whose numbers could triple by the same year to potentially 153 million cases, a projection published in The Lancet. Harnessing GLP-1 drugs to tackle Alzheimer’s could potentially help stem the tide. “Slowed progression of AD has been demonstrated with antidiabetic agents in experimental models,” Blackstock said. GLP-1 receptor agonists specifically, “have been shown to reduce the risk of neurological complications of diabetes,” Blackstock said. The therapies have been linked to reduced neuroinflammation, less oxidative stress, and less amyloid-beta deposition in Alzheimer’s models.

Novo Nordisk’s EVOKE and EVOKE Plus trials are investigating semaglutide for Alzheimer’s disease.

GLP-1 agonists show promise for HFpEF symptom relief

Obesity exacerbates the treatment of heart failure with preserved ejection fraction (HFpEF). “There is evidence that obese patients with HFpEF have worse symptoms, greater impairment of function, and worse quality of life than those without obesity,” Blackstock said.

The potential of GLP-1 receptor agonists to benefit heart health is an area of growing interest given their potential to improve heart failure symptoms and reduce the risk of heart attack and stroke. Some of the clearest data to date for HFpEF comes from the STEP-HFpEF trials, which were highlighted in NEJM.  Data from the phase 3 STEP-HFpEF trial of semaglutide “demonstrated benefits for symptoms, physical limitations, and exercise function that were tied to the degree of weight loss,” Blackstock said. Semaglutide recipients also saw improvements in “markers of inflammation and haemodynamics.

Could GLP-1 drugs also help address sleep apnea?

Affecting roughly 39 million U.S. adults, obstructive sleep apnea (OSA) significantly impacts quality of life, with obesity exacerbating the condition. Extra weight can increase pressure on the airways, leading to their collapse during sleep. “Obesity is a major risk factor for OSA, so weight loss agents could be beneficial,” Blackstock noted. A pivotal phase 3 trial of tirzepatide is currently underway, styding whether tirzepatide can address core OSA symptoms. If successful, managing sleep apnea could be an additional benefit offered by GLP-1 therapies, further expanding their potential for patients across a  spectrum of serious health conditions.