Cardioprotective potential of glucagon-like peptide-1 receptor agonist – a new frontier

In recent years, there has been a significant shift in the treatment of type 2 diabetes. Earlier, the focus was primarily on glycemic control; now, the approach is shifting toward improving overall cardiometabolic health. Efforts are being made to develop a comprehensive and holistic treatment strategy, and the use of molecules like glucagon-like peptide-1 (GLP-1) is paving the way toward such integrated solutions. These agents now represent a paradigm shift in the prevention and management of cardiovascular diseases, standing at the crossroads of endocrinology and cardiology.

The mechanism of action of GLP-1 analogs is to increase insulin secretion, reduce glucagon release, slow gastric emptying, and also promote satiety. Due to these combined actions, they have shown beneficial outcomes in the management of type 2 diabete s. In recent years, several clinical trials have drawn researchers’ attention by highlighting the cardioprotective effects of GLP-1, as seen in studies such as LEADER, SUSTAIN-6, REWIND, EXSCEL, and AMPLITUDE-O.^[1] In these studies, drugs such as liraglutide, semaglutide, dulaglutide, and efpeglenatide significantly reduced major adverse cardiovascular events (MACE), including cardiovascular death and stroke. In patients with impaired renal function (eGFR [estimated glomerular filtration rate] <60 mL/min/1.73 m²), liraglutide showed a notably greater reduction in cardiovascular risk and mortality compared to those with normal kidney function.^[2] Similarly, SUSTAIN-6 demonstrated a 26% reduction in stroke and major adverse cardiovascular events with semaglutide. These effects were consistent across patient populations and were validated by meta-analyses and real-world data, confirming a 12–14% relative reduction in MACE.^[3]

The cardioprotective mechanisms of GLP-1 RAs are multifaceted and rooted in both systemic and molecular pathways. These agents activate GLP-1 receptors (GLP1R) present in pancreatic, cardiac, and vascular tissues, initiating signaling cascades involving G-proteins (Gs, Gi/o, Gq, and G11). This receptor activation leads to the engagement of cardioprotective kinases, including protein kinase A (PKA), protein kinase C (PKC), Protein kinase B (Akt), AMP-activated protein kinase (AMPK), phosphoinositide 3-kinase (PI3K), extracellular signal-regulated kinases 1 and 2 (ERK1/2), mechanistic target of rapamycin/mammalian target of rapamycin (mTOR), glycogen synthase kinase 3 Beta (GSK-3β). These kinases promote increased nitric oxide production through endothelial nitric oxide synthase (eNOS) activation and cytoprotective effects through heme oxygenase-1 induction. In addition, transcription factors such as nuclear factor erythroid 2–related factor 2 (Nrf2), signal transducer and activator of transcription 3(STAT3), forkhead box O3 (FoxO3) enhance antioxidant responses and reduce apoptosis.^[4]

GLP-1 RAs also mitigate regulated cell death pathways such as apoptosis, necroptosis, pyroptosis, and ferroptosis, preserving cardiomyocyte viability. These agents improve cardiac function by enhancing left ventricular ejection fraction and reducing fibrosis, hypertrophy, oxidative stress, and apoptosis. Mechanistically, they activate survival pathways such as Akt and SIRT1, inhibit deleterious mediators such as glycogen synthase kinase 3 Beta (GSK-3β), matrix metalloproteinases (MMPs), fibroblast growth factor-2 (FGF-2), nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), and reduce inflammatory cytokines (IL-6 [interleukin], TNF-α [tumor necrosis factor]) and oxidative stress markers (NOX1/2 [NADPH oxidase 1 and 2], ROS [reactive oxygen species]). They also promote autophagy and mitophagy, contributing to better myocardial remodeling outcomes. The beneficial effects are mostly abolished when GLP1R is blocked, confirming receptor-dependent mechanisms. They inhibit apoptosis by activating the PI3K/Akt signaling pathway, enhancing anti-apoptotic proteins such as Bcl-2, and suppressing caspase activity. GLP-1 RAs also reduce necroptosis by downregulating key mediators such as RIPK1, RIPK3, and MLKL, while attenuating pyroptosis through suppression of the NLRP3 inflammasome and caspase-1, thereby limiting inflammatory damage. Chronic administration of GLP-1 RAs suppresses key inflammatory mediators, such as IL-β (Interleukin-1 beta), TNF-α (Tumor necrosis factor alpha), IL-6 (Interleukin-6), and MCP-1 (Monocyte chemoattractant protein-1), while reducing ROS and improving mitochondrial function.^[5]

Comparative studies have established GLP-1 RAs as superior to DPP-4 (dipeptidyl peptidase 4) inhibitors in reducing major adverse cardiovascular events (MACE), while offering complementary benefits to sodium-glucose cotransporter-2 (SGLT2) inhibitors. While SGLT2 inhibitors excel in managing heart failure with reduced ejection fraction and chronic kidney disease, GLP-1 RAs are more effective in atherosclerotic cardiovascular disease (ASCVD) prevention. Combination therapy of GLP-1 RAs with SGLT2 inhibitors has shown synergistic effects in reducing mortality and hospitalizations in patients with heart failure.^[6]

In the STEP 1 trial, participants with overweight or obesity who received once-weekly semaglutide 2.4 mg, along with lifestyle intervention, experienced a significant and sustained reduction in body weight over 68 weeks compared to those who received a placebo.^[7]

Despite their benefits, GLP-1 receptor agonists (GLP-1 RAs) have limitations. Gastrointestinal side effects such as nausea, vomiting, and diarrhea are common but typically transient and dose-dependent. Rare but serious adverse events include pancreatitis and cholelithiasis. Hypoglycemia is rare unless GLP-1 RAs are used in combination with insulin or sulfonylureas. Renal safety profiles are generally neutral to mildly protective. Formulation advances, such as the development of oral semaglutide using SNAC technology, have improved patient adherence; however, high costs and injection-related hesitancy remain barriers to the widespread adoption of this treatment.^[8]

Recognizing their impact, international guidelines from the American Diabetes Association, American Heart Association, European Association for the Study of Diabetes, American College of Cardiology, and European Society of Cardiology now recommend GLP-1(glucagon-like peptide-1) and receptor agonists (Ras) for patients with T2DM (type 2 diabetes) and established ASCVD or multiple cardiovascular risk factors. They are often positioned as second-line therapy after metformin, particularly when cardiovascular protection is a therapeutic goal. These recommendations emphasize the importance of shifting from a glucose-centric model to a comprehensive, risk-based approach.

From a public health perspective, GLP-1 RAs significantly reduce cardiovascular morbidity and mortality, improving patient survival and quality of life. Although cost remains a challenge, health-economic analyses support their cost-effectiveness, particularly in high-risk populations, as measured by favorable quality-adjusted life years and incremental cost-effectiveness ratios. Nonetheless, access disparities persist, especially in low- and middle-income countries.

As we continue to uncover new therapeutic avenues, the development of dual and triple agonists (such as tirzepatide) and the application of GLP-1 RAs in non-diabetic populations highlight the expanding potential of this drug class. Future research will further define optimal patient selection, dosing strategies, and combination therapies.

In conclusion, GLP1R agonists embody a revolutionary advancement in cardiovascular and metabolic medicine. Their ability to integrate molecular, hemodynamic, and systemic mechanisms into a cohesive cardioprotective strategy makes them uniquely suited for addressing the dual burden of diabetes and cardiovascular disease. As we move toward a mechanism-guided, patient-centered therapeutic paradigm, GLP-1 RAs are poised to play a central role in shaping the future of cardiometabolic care.