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Incretins as Multi–Disease State Treatments

July 22, 2025

What would life be like if one medicine could reduce your weight, improve your cognition, clear your skin, help you sleep better, and even protect your heart—all at the same time? It seems that this goal may not be as far-fetched as previously imagined. A novel class of incretin-based therapies consisting of glucagon-like peptide-1 (GLP-1) receptor agonists (RAs) and dual (GLP1/glucose-dependent insulinotropic polypeptide [GIP]) RAs acts by lowering blood sugar and inducing weight loss. However, research has begun to discover applications for these therapies beyond cardiometabolic health due to their systemic antiinflammatory properties. This next article in our series aims to provide an overview of incretins, examine the effects they exert on the body, and discuss their potential in the treatment of conditions associated with chronic inflammation. 

GLP-1 and GIP are incretin hormones.1 GIP was the first incretin hormone to be discovered in 1971 and is secreted from the upper gastrointestinal tract.1-3 GIP receptors are found in the central nervous system (eg, pituitary gland, cerebral cortex, hippocampus, olfactory bulb), adrenal cortex, heart, adipose tissue, and bone.4 GLP‑1 was identified in 1983 and is released from the small and large intestines.2,5-7 GLP-1 receptors are present throughout the body, including the skin, central nervous system (eg, hypothalamus, brainstem, amygdala, hippocampus, cerebellum, spinal cord), vagus nerve, gastrointestinal system, pancreas, kidneys, and lungs.5 This wide distribution of incretin hormone receptors may indicate important whole-body functions of these compounds.5

GLP-1 and GIP are responsible for triggering the incretin effect. This phenomenon refers to increased stimulation of insulin secretion by the pancreas after oral glucose ingestion compared to intravenous glucose infusion. Oral glucose leads to the release of GLP-1 and GIP by intestinal cells into the bloodstream, thus augmenting insulin secretion by the pancreas and lowering blood glucose.1,6

Despite normal secretion of GLP-1 and GIP, the incretin effect is reduced or absent in people with type 2 diabetes, with the insulin-stimulating effect of GIP being more impaired when compared to GLP-1.6 This involvement of incretin hormones in people with type 2 diabetes contributed to the development of GLP-1 and GLP-1/GIP RAs, which mimic the naturally occurring incretin hormones.8-10 The ability of GLP-1 and GLP-1/GIP RAs to lower glucose as well as reduce weight led to their initial approvals for use in patients with type 2 diabetes and obesity.11 It is worth noting that the induction of weight loss by incretin-based therapies is also dependent on additional mechanisms, such as decreasing gastric emptying, lowering food intake, and improving satiety (Figure).8,12

Figure. Direct and Indirect Effects of GLP-1 and GIP Receptor Agonism in the Human Body2,4,5,12

In addition to their beneficial actions in diabetes and obesity, new research suggests that incretin-based therapies may reduce inflammation in the heart, liver, kidneys, and brain.10 While these effects have been associated with indirect mechanisms such as glucose control and weight loss, scientists have also observed that some of the anti-inflammatory effects begin before a significant reduction in adiposity is achieved.10,13 GLP-1 RAs have been found to impact inflammation by directly interacting with their receptors on immune cells. They also decrease the inflammatory response by modulating several processes, including cytokine generation, immune cell infiltration into tissues, oxidative stress, glucotoxicity, and lipotoxicity.9,13 These newly identified properties of GLP-1 RAs have opened the possibility of their use in several chronic conditions that have been linked to inflammation, like cardiovascular disease, psoriasis, and Alzheimer’s disease.10,11,13 Such effects of GIP RAs and dual agonists are still under investigation.14

Atherosclerosis is a chronic disease characterized by both the formation of lipid deposits on the arterial walls and inflammation.5,15,16 GLP-1 RAs reported to improve atherosclerosis by shifting macrophage function and changing inflammatory pathways.5 Moreover, GLP-1 RAs have demonstrated cardioprotective properties that are independent of weight loss by reducing the content of systemic inflammation markers.5,10,14

Psoriasis, an autoimmune inflammatory skin condition, was shown to resolve in patients with obesity who underwent bariatric surgery, thus linking this disorder to increased adiposity.11,17 However, this autoimmune disease also improved after treatment with a GLP‑1 RA, even before glycemic control or weight loss was achieved.11 Moreover, systemic inflammation in psoriasis was shown to be reduced by direct interaction of GLP-1 RAs with inflammatory signaling pathways and immune cells.11

Alzheimer’s disease is a neurodegenerative disorder that is characterized by the formation of amyloid β plaques, development of tau protein tangles, and neuroinflammation.18-20 GLP‑1 receptors are present in the brain, and preclinical studies indicated that even though only small amounts of GLP-1 RAs crossed the blood-brain barrier, they exerted significant anti‑inflammatory effects.10 The results from various studies indicated that incretin-based therapies such as exenatide, liraglutide, and semaglutide were able to improve clinical outcomes through decreasing neuroinflammation, increasing neuroprotection, and enhancing cognition.21

Several incretin-based therapies, including liraglutide, dulaglutide, semaglutide, and tirzepatide, are currently approved for patients with type 2 diabetes (Table).10,11

Table. US Food and Drug Administration (FDA) Approvals of GLP-1 and GLP‑1/GIP RAs11,22-34

However, these labels are being expanded to include additional indications for patients with a spectrum of other cardiometabolic conditions, such as obesity, cardiovascular disease, chronic kidney disease, and obstructive sleep apnea. Semaglutide has been approved for reducing the risk of major adverse cardiovascular events in patients with obesity and heart disease, as well as for preventing the progression of kidney disease in individuals with type 2 diabetes and chronic kidney disease.35,36 The dual GLP-1/GIP RA tirzepatide is the first pharmacotherapy to be approved for the treatment of moderate-to-severe obstructive sleep apnea in adults with obesity.37

Future research is needed to investigate the role of GIP in inflammatory disorders and evaluate additional types of combination RAs in patients with chronic conditions associated with inflammation.14,38,39 Several therapies currently in clinical development target glucagon receptors in addition to incretin receptors due to the effects of glucagon on reducing food intake and increasing energy expenditure. Amylin is another molecular target being investigated in clinical trials for obesity owing to its role in regulating satiety.39-43

Since inflammation appears to play a role in cardiometabolic, immunologic, and neurodegenerative diseases, targeting it as a mechanism of disease could aid in managing multiple disorders with just a single drug. As we learn more about the anti‑inflammatory properties of incretin-based therapies, it becomes likely that they could be effective across a wide spectrum of diseases. With more late-stage clinical trial results forthcoming for this class of drugs, we will soon learn whether the promise of incretin-based therapies is justified.

References

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