GLP-1 Receptor Agonists as Treatments for Type 2 Diabetes

Author: Ashley Aguillard
Editor: Michaela Price

This article will cover a well-known class of drugs for type 2 diabetes (T2D), GLP-1 receptor agonists. Multiple drugs within this class have been approved for T2D management since the mid-2000s. Here, we review the pathophysiology and treatment of T2D, the many mechanisms of action of the GLP-1 receptor agonists, and their efficacy as T2D and obesity treatments.

Type 2 Diabetes Prevalence and Etiology 

T2D is a common metabolic disorder characterized by major dysregulations in glucose homeostasis. In 2020, it was estimated that nearly 462 million people worldwide suffer from the disorder.1  It also continues to be one of the most common comorbidities of obesity with nearly half of new T2D cases being reported in patients with obesity.2 T2D can cause serious complications, including neuropathy, retinopathy, nephropathy (kidney damage), and cardiovascular disease. If left untreated, these complications can progress to blindness and may necessitate limb amputations.3 

Systemic glucose levels are tightly regulated by hormone signaling. Under normal physiological conditions, the fed state leads to increased circulating glucose, which stimulates the secretion of insulin from pancreatic β-cells. Insulin binds to receptors on insulin-sensitive tissues to trigger the uptake of glucose into the cell. In the fasted state, when glucose levels drop, glucagon is secreted by pancreatic ɑ-cells to trigger the release of stored glucose from the liver to maintain normal blood glucose levels. During T2D development, chronic overnutrition interferes with insulin signaling leading to decreases in insulin sensitivity. Initially, the body compensates for this by enhancing insulin secretion leading to abnormally high concentrations of insulin in the blood, a condition called hyperinsulinemia. If interventions are not started, the increased demand for insulin can overload pancreatic β-cells leading to pancreatic β-cell failure, decreased insulin secretion, and uncontrolled glycemia (Figure 1).4,5 

Figure 1: Schematic depicting the physiological response to high glucose levels after feeding: (Left) In healthy patients , 1) The pancreas senses elevated blood glucose and secretes insulin from pancreatic beta cells. 2) Insulin binds to receptors. 3) Insulin binding stimulates the translocation of glucose transporters. 4) Glucose is taken into the cell. (Right) In T2D patients, 1) insulin secretion is impaired and 2) cells do not respond to insulin binding. 3) The impaired response to insulin leads to less glucose transporters and 4) lower glucose uptake. Figure adapted from a BioRender template.

Current Treatment Options for T2D

Oftentimes, the first form of treatment for patients with T2D is lifestyle intervention. Patients are usually advised to decrease sugar consumption, lower their intake of processed foods, and add more fruits, vegetables, and legumes to their diet.5,6 Increasing physical activity is also recommended as it has been shown to improve glycemic control.5,6 Along with lifestyle changes, oral medications, such as metformin, may be prescribed. Metformin is a safe and highly effective drug treatment for T2D and is the most commonly prescribed drug to treat the disorder.6 Although metformin is usually an effective treatment for regulating glucose levels, many patients with T2D have an elevated risk of cardiac events that does not improve in response to metformin.6 Alternatively, some patients may be prescribed sulfonylureas or thiazolidiniones to improve insulin secretion, but both of these treatment options are associated with an elevated risk of heart failure making them unsuitable for use in patients with cardiovascular disease.6,7 Sulfonylurea treatment is also associated with hypoglycemia.7 If these treatments do not improve glycemia or if patients stop producing insulin, doctors may prescribe insulin in combination with other drugs to be injected directly by patients.6 

GLP-1 Agonists and the Mechanism of Action

Glucagon-like peptide 1 (GLP-1) is a gut-derived hormone that plays an integral role in initiating the physiological response to feeding.8 L cells in the gastrointestinal tract sense the presence of nutrients in the gut lumen during feeding and secrete GLP-1 to act on multiple tissues, including the pancreas, intestines, and brain.9,10 GLP-1 receptor agonists (GLP-1RAs) are a class of drugs designed to mimic endogenous GLP-1 and bind to its receptors to promote glucose homeostasis in patients with T2D.11 Importantly, structural modifications to GLP-1RAs can prolong their half-life to 5-7 days compared to the 1-5 minute long half-life of endogenous GLP-1.11-13 GLP-1 receptors are expressed in multiple tissues, therefore, GLP-1RAs have multiple mechanisms of action (Figure 2). 

In the pancreas, GLP-1RAs are well known to promote insulin secretion.4 Receptor binding activates adenylate cyclase causing intracellular accumulation of cyclic adenosine monophosphate (cAMP), which activates protein kinase A (PKA) and triggers insulin secretion.14 At the same time, GLP-1RAs can also inhibit glucagon secretion from pancreatic ɑ-cells.15 GLP-1RAs also improve β-cell proliferation and inhibit β-cell apoptosis to promote cellular survival by preventing oxidative stress and lipotoxicity.14,16 

In the brain, GLP-1RAs bind to receptors in the hypothalamus to promote satiety and reduce food intake.10,17 GLP-1 receptor stimulation in the arcuate nucleus also improves glycemic control independent of feeding behavior.18 Exendin-4, a GLP-1 analogue, also elicits protection against neuroinflammation, which is linked to a decrease in stroke risk.19 This effect likely contributes to the decreased risk of stroke in T2D patients receiving treatment with certain GLP-1RAs.19,20 

In the gastrointestinal tract, GLP-1RAs can activate the autonomic nervous system that regulates gastrointestinal motility to slow the movement of food from the stomach to the intestines, a process called gastric emptying.4,21 There is also evidence to suggest GLP-1RAs can reduce motility in the small intestine.21 These effects can lower nutrient absorption and prevent overnutrition directly related to T2D development and weight gain. While the specific mechanism causing the effects on the gastrointestinal tract are not fully elucidated, studies suggest GLP-1 and its analogues likely exert effects on the vagus nerve and inhibit cholinergic neurotransmission in the gastrointestinal system to prevent movement of the intestine.22,23 

In the liver, GLP-1RAs can also decrease hepatic gluconeogenesis and enhance glucose uptake, which can improve circulating glucose levels.24,25 Treatment can also reduce lipid storage to protect against the development of fatty liver disease by inhibiting fatty acid synthesis and promoting fatty acid oxidation.26,27

Figure 2: Schematic depicting the multiple mechanisms of action of GLP-1RAs on different organs, including the brain, pancreas, liver, and gastrointestinal (GI) tract. Figure made in BioRender.

Drug Efficacy and Side Effects in Clinical Trials

The first GLP-1RA that received FDA approval was put on the market in 2005 under the name exenatide. This drug is a synthetic version of the human GLP-1 analogue exendin-4, a hormone discovered in the saliva of Gila monsters.28,29 Although highly effective,30 patients must administer injections of exenatide multiple times a day leading to low patient compliance.31 

Over the past 20 years, new GLP-1RAs with extended half-lives have proven to be highly effective treatments for T2D and even weight loss. Though most GLP-1RAs are approved only for T2D, semaglutide and liraglutide are also approved for weight loss likely driven by GLP-1RA’s actions on satiety and gastric emptying.32 A meta-analysis of over 76 clinical trials that investigated the efficacy of 15 different types of GLP-1RAs revealed that all 15 of the drugs were highly effective at treating T2D. Patients consistently had improved glycemic levels and multiple drugs, such as tirzepatide alone or semaglutide in combination with cagrilinitide, were highly effective at promoting weight management.33 Similar findings were observed in a meta-analysis of 40 trials which concluded that GLP-1RAs were highly effective at lowering circulating glucose levels without causing hypoglycemia. Semaglutide and liraglutide alone are also more effective than metformin at lowering the risk of developing T2D in patients with prediabetes and pre-obesity.6 The use of GLP-1RAs is also associated with a lower risk of adverse cardiac events, such as myocardial infarction and stroke.20 This observation emphasizes their potential to promote systemic metabolic health beyond glucose homeostasis and makes GLP-1RAs a more suitable treatment option for T2D patients with a higher risk of cardiovascular disease compared to metformin. 

Unfortunately, many studies also reported concerns about adverse gastrointestinal events, likely related to GLP-1’s role in gastric emptying.33 Although decreases in gastric emptying via GLP-1RAs help prevent overnutrition by decreasing nutrient absorption, there is concern that patients could be at risk of nutrient deficiencies driven by malabsorption from delayed gastric emptying.34 This finding emphasizes the importance of nutrient-dense diets while taking these medications. Recent findings also revealed concerns with the loss of skeletal muscle mass when taking GLP-1RAs with some studies reporting up to 50% of weight loss being due to decreases in muscle mass.35,36 Although some studies report smaller reductions in muscle mass, many scientists argue that these findings should not be ignored due to the high metabolic rate of skeletal muscle which plays an important role in maintaining significant weight loss.36 Along these lines, maintaining weight loss is a common issue after halting GLP-1RA treatment, which raises concerns about the longevity of the treatment efficacy, especially considering the high financial cost to the patient.37,38 A recent preclinical study investigated a combination therapy with semaglutide and bimagrumab. Bimagrumab is a drug that promotes muscle hypertrophy. By combining the two drugs, researchers were hoping to preserve muscle mass during weight loss. The findings of this study revealed that the combination therapy was highly effective at preserving muscle mass in mice, though, whether these findings will translate to humans has yet to be determined.39 Although GLP-1RAs continue to be promising therapies for T2D, their long-term efficacy for weight loss after halting treatment should be further improved.  

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Figure 1: Created in BioRender. Aguillard, A. (2025) https://BioRender.com/8bj6eub

Figure 2: Created in BioRender. Aguillard, A. (2025) https://BioRender.com/3fd60ud

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