Abstract

Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) have emerged as a pivotal class of medications in the management of type 2 diabetes mellitus (T2DM). Originally developed to improve glycemic control, these agents now demonstrate significant benefits beyond glucose lowering, including weight reduction, cardiovascular protection, and renal benefits. Recent evidence from large-scale cardiovascular outcome trials (CVOTs) such as LEADER, SUSTAIN-6, and REWIND has positioned GLP-1 RAs as first-line therapy in patients with T2DM and established atherosclerotic cardiovascular disease (ASCVD) or high cardiovascular risk. Clinical guidelines from the American Diabetes Association (ADA) and European Association for the Study of Diabetes (EASD) now endorse GLP-1 RAs not only for glycemic efficacy but also for their role in reducing major adverse cardiovascular events (MACE). This review highlights the evolving role of GLP-1 RAs, emphasizing their expanding utility in comprehensive cardiometabolic care.

Introduction:_

Type 2 diabetes mellitus (T2DM) is a progressive metabolic disorder characterized by insulin resistance and relative insulin deficiency. It affects over 500 million individuals worldwide and is a leading contributor to cardiovascular morbidity and mortality. Traditionally, management of T2DM has focused on achieving glycemic control to prevent microvascular complications. However, macrovascular outcomes such as myocardial infarction and stroke remain the predominant causes of death in this population.

In recent years, glucagon-like peptide-1 receptor agonists (GLP-1 RAs) have emerged as a transformative class of antidiabetic agents. Initially introduced for their ability to enhance insulin secretion and suppress glucagon release in a glucose-dependent manner, GLP-1 RAs have demonstrated pleiotropic effects, including significant weight loss, improvement in blood pressure, and anti-inflammatory properties.

Crucially, landmark cardiovascular outcome trials (CVOTs) such as LEADER (liraglutide), SUSTAIN-6 (semaglutide), and REWIND (dulaglutide) have confirmed that selected GLP-1 RAs confer substantial cardiovascular and renal protection in patients with T2DM, independent of glycemic control. These findings have redefined therapeutic goals and prompted updates in clinical guidelines, positioning GLP-1 RAs as foundational therapy in individuals with T2DM and cardiovascular risk.

Pathophysiology:

Type 2 diabetes mellitus (T2DM) is characterized by a complex interplay of insulin resistance, β-cell dysfunction, and increased hepatic glucose production. One important hormonal defect involves impaired incretin function—particularly the reduction in glucagon-like peptide-1 (GLP-1) activity.

GLP-1 is an incretin hormone secreted by the L-cells of the distal ileum and colon in response to nutrient ingestion. It enhances glucose-dependent insulin secretion, inhibits glucagon secretion, slows gastric emptying, and promotes satiety, thereby reducing postprandial glucose excursions. In individuals with T2DM, endogenous GLP-1 secretion is reduced, and its activity is rapidly diminished due to enzymatic degradation by dipeptidyl peptidase-4 (DPP-4).

GLP-1 receptor agonists (GLP-1 RAs) are synthetic analogs of the endogenous hormone that resist degradation by DPP-4, resulting in prolonged biological activity. By activating GLP-1 receptors on pancreatic β-cells, they enhance insulin secretion only when glucose levels are elevated, thus reducing the risk of hypoglycemia. Additionally, they suppress inappropriate glucagon secretion, delay gastric emptying, and promote weight loss through central appetite regulation. These combined effects make GLP-1 RAs uniquely beneficial in addressing both hyperglycemia and associated cardiometabolic risks in T2DM.

Emerging evidence also suggests that GLP-1 RAs exert anti-inflammatory and anti-atherosclerotic effects, which may underlie their observed cardiovascular and renal benefits in large outcome trials.

Clinical Benefits:

GLP-1 receptor agonists (GLP-1 RAs) offer multiple clinical benefits that extend beyond glycemic control, making them a valuable therapeutic option in the management of type 2 diabetes mellitus (T2DM).

1. Glycemic Control

GLP-1 RAs significantly reduce both fasting and postprandial plasma glucose levels by enhancing glucose-dependent insulin secretion and suppressing inappropriate glucagon release. Clinical trials have demonstrated reductions in HbA1c ranging from 0.8% to 1.6%, depending on the agent and dose.

2. Weight Loss

GLP-1 RAs promote satiety by acting on hypothalamic centers and delaying gastric emptying. Most agents are associated with clinically meaningful weight loss, particularly semaglutide and liraglutide, which have also been approved for obesity management.

3. Cardiovascular Protection

Several GLP-1 RAs have demonstrated a reduction in major adverse cardiovascular events (MACE) in patients with established atherosclerotic cardiovascular disease (ASCVD) or multiple risk factors. For example:

Liraglutide (LEADER trial): 13% relative risk reduction in MACE.

Semaglutide (SUSTAIN-6): 26% relative risk reduction in MACE.

Dulaglutide (REWIND): Benefit observed even in patients without prior ASCVD.

4. Renal Benefits

GLP-1 RAs have shown renal protective effects, including a reduction in the progression of albuminuria and preservation of estimated glomerular filtration rate (eGFR). These effects are thought to be mediated through both hemodynamic and anti-inflammatory mechanisms.

5. Low Risk of Hypoglycemia

Due to their glucose-dependent mechanism of action, GLP-1 RAs carry a low risk of hypoglycemia when not combined with insulin or sulfonylureas.

6. Potential Benefits in NAFLD/NASH

Emerging evidence suggests GLP-1 RAs may improve liver enzymes and reduce hepatic steatosis, making them promising in patients with non-alcoholic fatty liver disease (NAFLD).

Guideline Recommendations and Clinical Usage:

The role of GLP-1 receptor agonists (GLP-1 RAs) in the management of type 2 diabetes mellitus (T2DM) has evolved significantly, with major guidelines now recommending their use not only for glycemic control but also for cardiovascular and renal risk reduction.

1. ADA–EASD 2023 Consensus Guidelines:

In patients with T2DM and established atherosclerotic cardiovascular disease (ASCVD), GLP-1 RAs with proven cardiovascular benefit (e.g., liraglutide, semaglutide, dulaglutide) are recommended independently of baseline HbA1c or metformin use.

For individuals with T2DM and high ASCVD risk, GLP-1 RAs may be considered early in the treatment pathway.

In patients with chronic kidney disease (CKD) and a need to reduce the risk of progression or cardiovascular events, GLP-1 RAs are suggested if SGLT2 inhibitors are not tolerated or contraindicated.

GLP-1 RAs are preferred in patients with obesity, as they promote meaningful weight loss and improve cardiometabolic profiles.

2. NICE (UK) Guidelines:

Recommends GLP-1 RAs in patients who have a BMI ≥35 kg/m² or have obesity-related comorbidities, particularly if other therapies have failed or are not tolerated.

3. WHO Guidelines:

Endorses the use of GLP-1 RAs in resource-available settings for individuals at high cardiovascular risk, particularly where SGLT2 inhibitors are not feasible or insufficient.

Usage Considerations:

Dosing: Varies by agent; most are administered subcutaneously, ranging from once daily (liraglutide) to once weekly (dulaglutide, semaglutide).

Initiation: Start at the lowest dose and titrate gradually to minimize gastrointestinal side effects.

Combination therapy: Can be used with metformin, SGLT2 inhibitors, basal insulin, or other agents depending on individual patient needs.

Contraindications: Personal or family history of medullary thyroid carcinoma or multiple endocrine neoplasia syndrome type 2 (MEN2); caution in pancreatitis.

Recent Advances in GLP-1 Receptor Agonist Therapy

Recent developments in GLP-1 receptor agonist (GLP-1 RA) therapy have expanded their clinical applications, improved patient adherence, and introduced novel treatment options beyond glycemic control.

1. Once-Weekly and Oral Formulations

Once-weekly GLP-1 RAs such as semaglutide and dulaglutide have significantly improved patient convenience and compliance without compromising efficacy.

Oral semaglutide, the first and only oral GLP-1 RA, offers an alternative to injectable formulations, expanding accessibility for patients who prefer non-injectable options. The PIONEER trials demonstrated its efficacy in reducing HbA1c and weight with a favorable safety profile.

2. GLP-1/GIP Dual Agonists (Incretin Co-Agonists)

Tirzepatide, a dual GIP/GLP-1 receptor agonist, has shown superior glucose-lowering and weight loss effects compared to existing GLP-1 RAs in the SURPASS trials.

It represents a new class of incretin-based therapies with enhanced metabolic benefits and is already approved for T2DM in multiple countries.

3. Role in Obesity and NAFLD/NASH

GLP-1 RAs, particularly semaglutide (2.4 mg), are now approved for obesity management in patients without diabetes (e.g., STEP trials).

Several trials are investigating the role of GLP-1 RAs in non-alcoholic steatohepatitis (NASH), where they show promise in reducing hepatic fat content and liver inflammation.

4. Cardiovascular Outcome Research Beyond Diabetes

Ongoing studies (e.g., SELECT trial) are evaluating the cardiovascular benefits of GLP-1 RAs in non-diabetic populations with obesity, aiming to position them as cardiometabolic drugs beyond diabetes care.

5. Emerging GLP-1 Agonists and Combinations

Research is underway on GLP-1/Glucagon dual agonists and triple agonists (GLP-1/GIP/Glucagon) targeting multiple metabolic pathways for improved efficacy in obesity, T2DM, and cardiovascular outcomes.

Conclusion:

GLP-1 receptor agonists (GLP-1 RAs) have revolutionized the therapeutic landscape of type 2 diabetes mellitus (T2DM) by offering a multifaceted approach that extends well beyond glycemic control. Their ability to lower blood glucose, reduce body weight, and deliver significant cardiovascular and renal benefits has redefined treatment goals and strategies for patients with T2DM, particularly those with high cardiometabolic risk.

Major guidelines from the ADA, EASD, and other international bodies now recommend GLP-1 RAs as a preferred option in patients with established cardiovascular disease, chronic kidney disease, or obesity. Recent advances, including the development of oral formulations, dual and triple incretin co-agonists, and expanding indications in non-diabetic populations, suggest that GLP-1 RAs may soon serve as cornerstone therapies for a broad spectrum of metabolic disorders.

As ongoing clinical trials continue to explore their potential in obesity, NASH, and cardiovascular prevention, GLP-1 RAs are poised to play an increasingly central role in integrated cardiometabolic care.

References:_

1.Gerstein HC, et al. Dulaglutide and cardiovascular outcomes in type 2 diabetes (REWIND). Lancet. 2019;394(10193):121-130.

2. Davies MJ, et al. Management of hyperglycemia in type 2 diabetes, 2023 consensus report by the ADA and the EASD. Diabetes Care. 2023;46(1):1-20.

3.Marso SP et al. Liraglutide and Cardiovascular Outcomes in Type 2 Diabetes. N Engl J Med. 2016;375(4):311-322.

4.Drucker DJ. Mechanisms of Action and Therapeutic Application of Glucagon-like Peptide-1. Cell Metab. 2018;27(4):740-756.

5.Frias JP, et al. Efficacy and safety of once-weekly semaglutide vs placebo in patients with NAFLD. Lancet Gastroenterol Hepatol. 2021;6(9):710-721.

6. National Institute for Health and Care Excellence (NICE). Type 2 diabetes in adults: management. NICE guideline [NG28], 2022.

7. American Diabetes Association. Standards of Medical Care in Diabetes-2024. Diabetes Care. 2024;47(Suppl 1):S125-S143.

8.Rubino DM, et al. Effect of Continued Weekly Subcutaneous Semaglutide vs Placebo on Weight Loss Maintenance in Adults With Overweight or Obesity. JAMA. 2021;325(14):1414-1425.

9.Nauck MA, et al. Oral Semaglutide in Type 2 Diabetes (PIONEER Program). Diabetes Obes Metab. 2020;22(9):1605-1615.