Glucagon-like peptide 1 (GLP-1) receptor agonists are transforming the treatment landscape for type 2 diabetes ( T2D) and obesity, in addition to their cardiovascular benefits. These drugs also show promise in managing inflammatory and neurodegenerative diseases, offering a comprehensive approach for patients with multiple comorbidities.
This multifaceted pharmacological class mimics the action of endogenous GLP-1 and has demonstrated benefits far beyond glycemic control and weight loss. Therefore, it is essential for healthcare professionals to stay updated on the latest evidence.
Mechanism of Action
GLP-1, an incretin hormone secreted by intestinal L cells in response to food intake, enhances glucose-dependent insulin secretion, suppresses glucagon release, and delays gastric emptying, thereby aiding postprandial glucose control. It also acts on the brain to promote satiety and reduce caloric intake. GLP-1 analogs mimic these actions by activating GLP-1 receptors in the pancreas, brain, and gastrointestinal tract.
Glycemic Control
The GLP-1 hormone plays a vital role in the regulation of blood sugar levels. Drugs that mimic its action enhance insulin secretion in a glucose-dependent manner and have been shown to effectively lower glycosylated hemoglobin (A1c) levels in patients with T2D.
Studies indicate that GLP-1 agonists can reduce A1c levels by 1%-1.5%, depending on the specific drug and patient population. This reduction is comparable with or even greater than that achieved with basal insulin, providing better glycemic control with a lower risk for hypoglycemia.
Moreover, these medications reduce glucagon secretion during hyperglycemia, decreasing hepatic glucose production and further supporting glycemic control. This advancement has revolutionized T2D treatment.
Weight Loss
Beyond glycemic benefits, GLP-1 analogs such as semaglutide have demonstrated exceptional weight loss outcomes, with clinical trials reporting up to 15% body weight reduction.
These drugs act through multiple mechanisms. “At the brain level, these drugs modulate the hypothalamic appetite centers, promoting satiety and significantly reducing calorie intake,” Sharona Azriel, MD, PhD, an endocrinologist at the Hospital Universitario Infanta Sofía in Madrid, Spain, and secretary of the Spanish Society for the Study of Obesity, told El Médico Interactivo, a Medscape Network platform.
This regulation also extends to reward circuits, decreasing the need to seek pleasure from food. As a result, patients treated with these drugs reduce their food and water intake.
Another noteworthy aspect, she added, is the altered perception of food palatability, “Although the exact mechanism is not yet fully understood, it has been suggested that GLP-1 analogs could modify preferences for certain types of foods, also contributing to a healthier diet.”
Gastric Emptying
At the gastrointestinal level, these drugs slow gastric emptying, resulting in a greater sense of postprandial satiety or fullness. Consequently, the rate at which glucose enters the bloodstream after a meal is reduced, improving postprandial glucose spikes and satiety, which also supports weight loss.
These drugs may also help preserve beta cell function, protecting them against stress and apoptosis. “This is important for patients with T2D, as progressive beta-cell dysfunction is a key factor in the disease’s development,” she highlighted.
These mechanisms explain why GLP-1 analogs have emerged as an effective therapeutic option approved for treating both T2D and obesity.
Cardiovascular Protection
Studies such as SUSTAIN-6, SELECT, and LEADER reveal that GLP-1 analogs such as semaglutide and liraglutide reduce major cardiovascular events. These benefits are independent of weight loss. A 2023 study found that semaglutide (2.4 mg) significantly reduced major cardiovascular events, such as heart attack and stroke, in patients with obesity and cardiovascular disease but without diabetes. Its obesity formulation also provides benefits for heart disease prevention and related conditions, including hypertension and sleep apnea.
“This is particularly interesting because one might think that this benefit could be secondary to weight loss as it reduces the risk of associated complications. However, in this case, various sub-studies have shown that the benefit is independent of whether patients lost more or less than 5% of their weight,” emphasized Azriel.
Anti-Inflammatory Effects
Although the exact mechanism for this reduction in cardiovascular risk has not been established, “these benefits appear to be related to the anti-inflammatory properties of these drugs, which also promote vasodilation and reduce arterial stiffness and oxidative stress. These drugs have a clear antiatherosclerotic effect and a positive impact on postprandial lipid metabolism, helping to reduce the burden of triglycerides and other fats in circulation after food intake,” Azriel explained. This is particularly relevant in patients with dyslipidemia, which is a key factor in the progression of cardiovascular diseases.
In patients with heart failure with preserved ejection fraction, these drugs enhance exercise tolerance and quality of life, as reflected by improved scores on the Quality of Life Scale and fewer hospitalizations for cardiac decompensation.
Joint and Skin Benefits
A study published in The New England Journal of Medicine found that semaglutide reduces knee osteoarthritis pain more effectively than a placebo. Similarly, animal studies have shown that liraglutide helps alleviate pain from this condition.
In addition to weight loss, which eases joint stress and improves mobility, GLP-1 analogs have anti-inflammatory and immunomodulatory effects that may reduce joint pain and inflammation.
“Similarly, patients with psoriasis treated with these drugs have shown improvement, suggesting a beneficial impact on chronic inflammatory diseases,” said Azriel. These findings reinforce the hypothesis that GLP-1 analogs may have a therapeutic role in various inflammation-based diseases, opening new avenues for research and clinical possibilities in the coming years.
Renal and Hepatic Benefits
These drugs may also have nephroprotective effects and the potential to treat metabolic liver diseases. GLP-1 analogs may slow the progression of chronic kidney disease, reduce albuminuria, a key marker of kidney damage, and increase diuresis and natriuresis, which contributes to less overload of the renal system in patients with T2D.
“While these effects have been observed in patients with T2D and obesity, specific studies in obese individuals without diabetes are still lacking, but the data suggest they may play a key role in the treatment of chronic kidney disease beyond glycemic control,” Azriel explained.
GLP-1 analogs are being studied for their hepatoprotective effects, reducing the progression of metabolic dysfunction–associated steatohepatitis, a condition characterized by liver inflammation and fibrosis in people with fatty liver disease associated with metabolic dysfunction.
Azriel noted that preclinical studies show patients treated with GLP-1 analogs or tirzepatide (a dual glucose-dependent insulinotropic polypeptide and GLP-1 analog) have less liver fibrosis progression, suggesting a hepatoprotective effect on the liver.
Neurodegenerative Potential
GLP-1 agonists show promise in neurology, as they reduce neuroinflammation, improve neuronal function, and minimize brain damage in diseases such as Alzheimer’s and Parkinson’s.
Currently, multiple phase 3 clinical trials are evaluating the effect of these drugs on neurodegenerative diseases. In Alzheimer’s, they reduce beta-amyloid plaques and enhance cognitive function. In Parkinson’s disease, they protect dopaminergic neurons, slow disease progression, and improve motor function.
Addiction and Psychiatric Disorders
GLP-1 analogs modulate the brain’s dopaminergic reward system, reducing cravings for addictive substances such as alcohol and drugs. Studies on semaglutide have revealed a lower incidence of alcohol abuse and relapse in individuals with alcohol dependence, likely due to its inhibition of positive reinforcement linked to alcohol consumption.
These effects on the dopaminergic system have also sparked interest in their potential for treating psychiatric disorders such as depression and mood disorders. Clinical trials are underway to determine whether modulating the reward system can improve depressive symptoms in patients with obesity and T2D.
Obstructive sleep apnea is a common condition in individuals with obesity and T2D and is associated with cognitive decline and cardiovascular risk.
A 2024 study found that tirzepatide significantly reduced the apnea-hypopnea index, lowered hypoxemic load, and improved sleep quality in patients with obstructive sleep apnea. These findings suggest that GLP-1 analogs may not only enhance metabolic health but also reduce the impact of intermittent hypoxia on the brain, which is a key factor in the development of neurodegenerative diseases.
Gastrointestinal Problems
Although GLP-1 analogs provide many benefits, they are associated with side effects, primarily gastrointestinal symptoms such as nausea (25%-50%), vomiting (10%-15%), diarrhea (8%-15%), and constipation. These symptoms are usually mild to moderate and tend to subside with time.
Azriel noted that these drugs are contraindicated in patients with a history of medullary thyroid carcinoma or multiple endocrine neoplasia syndrome type 2 due to the potential risk for tumor growth. They are also not recommended for patients with recurrent pancreatitis of unknown causes.
“However, in specific situations, such as pancreatitis secondary to cholelithiasis resolved by cholecystectomy, a history of pancreatitis does not represent an absolute contraindication,” she explained.
Less commonly, kidney issues and risk for eye damage have been observed, though further studies are needed to confirm any causal relationship.
Expert Guidance
The safe and effective use of these drugs requires an individualized risk-benefit assessment, as emphasized by Azriel. “It is crucial that these drugs are prescribed by professionals experienced in their management, avoiding indiscriminate use in nonspecialized settings, such as certain aesthetic clinics.”
These drugs “are highly effective with a favorable safety profile when used correctly.” While there are risks such as gallstone formation and potential pancreatic effects, “the benefits in diabetes control, weight loss, and cardiovascular risk reduction often far outweigh the drawbacks,” she added.
Azriel concluded that an integrated approach, including lifestyle modifications, medical supervision, and adjustment of other preexisting pharmacological treatments, is necessary to ensure the safety and efficacy of these drugs.
This story was translated from El Médico Interactivo using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication.