Beyond Blood Sugar: A Scoping Review of GLP-1 Receptor Agonists in Cardiovascular Care

Abstract

Glucagon-like peptide 1 receptor agonists (GLP-1 RAs) have emerged as a transformative class of therapies initially developed for glycemic control in type 2 diabetes mellitus. Now, they are also getting recognized for their broader cardiometabolic effects. In this review, we discuss the mechanism of action of GLP-1 RAs, focusing on their proposed cardiometabolic impact and the key clinical trials that have demonstrated improvement in cardiovascular outcomes. GLP-1 RAs have demonstrated benefits in coronary artery disease, heart failure, blood pressure, and atrial fibrillation irrespective of type 2 diabetes mellitus status, with new possible applications in peripheral arterial disease. Findings thus far have been translated into recommendations in clinical guidelines by the American College of Cardiology, American Heart Association, European Society of Cardiology, and American Diabetes Association. As GLP-1 RAs become more prevalent in treating diabetes and patients with cardiovascular disease (CVD) or risk factors for CVD, clinicians will ultimately manage the practical aspects of patient selection, dosing, special considerations, and side effects of these medications. Ongoing and future clinical trials are expected to further define the cardiovascular role of GLP-1 RAs, expand their therapeutic indications, and solidify their place in the evolving landscape of cardiovascular care.

Key Summary Points

Glucagon-like peptide 1 receptor agonists (GLP-1 RAs) are a transformative class of therapies developed to improve glycemic control in type 2 diabetes mellitus, with growing evidence of their beneficial cardiometabolic effects in patients without diabetes.

There are several proposed drivers for cardiovascular disease (CVD). GLP-1 RAs may act through a multitude of cardiometabolic mechanisms that reduce metabolic stressors, improve vascular and cardiac function, aid angiogenesis, and reduce atherosclerosis development.

GLP-1 RAs reduce major adverse cardiovascular events. More so, these agents show significant impacts on reducing blood pressure and may help improve symptoms in heart failure with preserved ejection fraction.

Guidelines recommend the use of GLP-1 RAs in patients with diabetes and CVD, particularly in patients with diagnosed clinical atherosclerotic cardiovascular disease.

GLP-1 RAs are available in both injectable and oral formulations, and selecting the appropriate patients based on their current disease states and risk factors is essential to optimize outcomes. Equally important is ongoing monitoring to assess therapeutic effectiveness and manage common side effects.

Introduction

Glucagon-like peptide 1 receptor agonists (GLP-1 RAs) are transformative therapies initially developed for glycemic control in type 2 diabetes mellitus (T2DM). GLP-1 is an incretin hormone that enhances glucose-dependent insulin secretion, suppresses glucagon release, and slows gastric emptying, improving glycemic control and promoting weight loss. Landmark trials have established GLP-1 RAs’ efficacy in reducing major adverse cardiovascular events (MACE) in patients with T2DM and atherosclerotic cardiovascular disease (ASCVD). This review seeks to highlight emerging evidence that suggests a growing benefit of GLP-1 RAs irrespective of T2DM status in coronary artery disease (CAD), heart failure (HF), atrial fibrillation (AF), and blood pressure. Furthermore, the benefits of GLP-1 RA now extend to patients with peripheral artery disease (PAD) and T2DM. Finally, this review describes the practical considerations of incorporating GLP-1 RAs into contemporary cardiovascular care.

Methods

We searched PubMed for studies published before March 2025. Search items included medication-related items—“GLP-1 receptor agonist”, “GLP-1RA,” “dual-agonist,” and “glucagon-like peptide-1” along with cardiovascular outcome-related items “major adverse cardiovascular event,” “myocardial infarction,” “coronary artery disease,” “peripheral arterial disease,” “heart failure,” “hypertension,” and “atrial fibrillation.” Studies were meticulously screened and included if they reported cardiovascular outcomes related to MACE, myocardial infarction (MI), CAD, PAD, HF, hypertension (HTN), or AF.

This article is based on previously conducted studies and does not contain any new studies with human participants or animals performed by any of the authors.

Effects of GLP-1 on Cardiovascular Disease

GLP-1 is secreted by gut endocrine cells in response to nutrient intake, promoting insulin secretion and suppressing glucagon release. GLP-1 RAs mimic this effect by enhancing glucose-dependent insulin secretion, inhibiting glucagon, delaying gastric emptying, and reducing appetite mechanisms that can improve glycemic control and support weight loss [1].

The onset of cardiovascular disease (CVD) is proposed to be mediated by a multitude of drivers, like metabolic stressors, cardiac and vascular dysfunction, impaired angiogenesis, and the development of atherosclerosis [2]. In relation to these broad drivers for CVD, GLP-1 can mitigate metabolic stressors by curbing excess nutrient intake through the promotion of satiety, weight loss, and reducing hyperglycemia and lipid levels [3–5]. These agents can promote vascular function by vasodilation and improve endothelial function by enhancing nitric oxide production [3, 6, 7]. GLP-1 acts to inhibit cardiac remodeling and cardiomyocyte apoptosis pathways, which can help repair cardiac dysfunction [8, 9]. Furthermore, GLP-1 has been shown to downregulate inflammatory and oxidative stress pathways that are linked to atherosclerosis development [9–11]. GLP-1 has shown the ability to promote angiogenesis by increasing vessel formation and perfusion [12, 13]. A brief mechanistic summary of potential pathways targeted by GLP-1s in relation to CVD is provided in Fig. 1 [2–13]. Together, these metabolic and vascular effects of GLP-1 serve to form the basis for the therapeutic potential of GLP-1 RAs in cardiovascular conditions.

Fig. 1.

A summary of glucagon-like peptide 1 (GLP-1) impacts and mechanisms of action on cardiovascular disease drivers. GLP-1 glucagon-like peptide 1, CVD cardiovascular disease, cAMP cyclic adenosine monophosphate, PKA protein kinase A, CREB CAMP response element-binding protein, AKT protein kinase B, ERK extracellular signal-regulated kinase, ANG II angiotensin II, IL-1 interleukin-1, IL-6 interleukin-6, TNF tumor necrosis factor, LDL-C low-density lipoprotein cholesterol, CD36 cluster of differentiation 36, eNOS endothelial nitric oxide synthase, NO nitric oxide, VEGF vascular endothelial growth factor, cGMP cyclic guanosine monophosphate, PKG protein kinase G. References [2–13]

Cardiovascular Outcomes

This section reviews current evidence regarding GLP-1 RA’s effects on MACE, PAD, CAD, HF, blood pressure, and AF, with detailed findings of trials and meta-analyses discussed in Tables 1 and 2

Table 1.

Populations of interest and duration of follow-up for major glucagon-like peptide 1 receptor agonists (GLP-1 RA) randomized control trials and meta-analyses

Study	Year	Population	Follow-up (months)	Primary outcome(s)
AMPLITUDE-O	2021	T2DM, with CVD or CKD, and one CV risk factor	21.6	MACE
ELIXA	2015	T2DM with recent acute coronary syndrome	25	MACE
EXSCEL	2017	T2DM with or without prior CVD	38.4	MACE
Harmony Outcomes	2018	T2DM and CVD	18	MACE
LEADER	2016	T2DM with CVD or CV risk factor	45.6	MACE
PIONEER 6	2019	CVD or CKD, or a CV risk factor	15.9	MACE
REWIND	2019	T2DM with CV event or CV risk factor	64.8	MACE
SELECT	2023	BMI ≥ 27 and CVD, without T2DM	39.8	MACE
SOUL	2025	T2DM with CVD with or without CKD	49.5	MACE
SUSTAIN-6	2016	T2DM with CVD or CKD or HF or CV risk factor	25.2	MACE
Zhao et al. (MA)	2023	HF	3–45.6	MACE
STRIDE	2025	T2DM and PAD with intermittent claudication and ABI ≤ 0.90 or TBI ≤ 0.70	12	Maximum walking distance ratio
FIGHT	2016	HFrEF and recent hospitalization	6	Global rank score of time to death, time to rehospitalization for HF, and change in NTpro-BNP
Huixing et al. (MA)	2023	Patients with type 2 diabetes with or without CVD, or CVD alone	0.07–64.8	HF hospitalization, cardiac function, structure measures
Lepore et al.	2016	HFrEF with NYHA 2 or 3	3	Changes in EF %, 6-min walk test, glucose use, and oxygen consumption
LIVE	2017	HF with EF ≤ 45% in NYHA 1–3	6	Change in EF %
STEP-HFpEF	2023	HF with EF ≥ 45% with BMI ≥ 30	12	Change in KCCQ-CSS and % change in body weight
DURATION-1	2008	T2DM	7.5	Change in HbA1c %
SURMOUNT-1	2022	BMI > 30 or ≥ 27 with at least one weight-related complication, without T2DM	16.5	% Change in body weight and weight reduction ≥ 5% from baseline
Saglietto et al. (MA)	2024	High CV risk	68	Risk of incident atrial fibrillation

CKD chronic kidney disease, CV cardiovascular, CVD cardiovascular disease, HFrEF heart failure with reduced ejection fraction, EF ejection fraction, KCCQ-CSS Kansas City Cardiomyopathy Questionnaire Clinical Summary Score, ABI ankle-brachial index, TBI toe-brachial index, BMI body mass index, NYHA New York Heart Association functional classification, NT-proBNP N-terminal pro-B-type natriuretic peptide, MA meta-analysis, MACE major adverse cardiovascular events, T2DM type 2 diabetes mellitus

Table 2.

Summary of key cardiovascular outcomes from GLP-1 RA studies

Study	GLP-1 RA agent	Outcome of interesta	Observed difference (95% CI)
Major adverse cardiac events
AMPLITUDE-O	Efpeglenatide	MACE (HR)	0.73 (0.58–0.92)⇞
EXSCEL	Exenatide	MACE (HR)	0.91 (0.83–1.00)
Harmony Outcomes	Albiglutide	MACE (HR)	0.78 (0.68–0.90)⇞
LEADER	Liraglutide	MACE (HR)	0.87 (0.78–0.97)⇞
PIONEER 6	Semaglutide	MACE (HR)	0.79 (0.57–1.11)
REWIND	Dulaglutide	MACE (HR)	0.88 (0.79–0.99)⇞
SOUL	Semaglutide	MACE (HR)	0.86 (0.75–0.99)⇞
SUSTAIN-6	Semaglutide	MACE (HR)	0.74 (0.58–0.95)⇞
Coronary and peripheral artery disease
AMPLITUDE-O	Efpeglenatide	MI (HR)	0.75 (0.54–1.05)
ELIXA	Lixisenatide	MI (HR)	1.03 (0.87–1.22)
EXSCEL	Exenatide	MI (HR)	0.97(0.85–1.10)
Harmony Outcomes	Albiglutide	MI (HR)	0.75 (0.61–0.90)⇞
LEADER	Liraglutide	MI (HR)	0.86 (0.73–1.00)
SELECT	Semaglutide	MI (HR)	0.72 (0.61–0.85)⇞
SOUL	Semaglutide	MI (HR)	0.73 (0.61–0.88)⇞
SUSTAIN-6	Semaglutide	MI (HR)	0.74 (0.51–1.08)
STRIDE	Semaglutide	Max walking distance (treatment ratio)	1.13 (1.06–1.21)
Heart failure
EXSCEL	Exenatide	Hospitalization for HF (HR)	0.94 (0.78–1.13)
FIGHT	Liraglutide	Hospitalization for HF (HR)	1.30 (0.89–1.88)
SELECT	Semaglutide	Hospitalization or urgent care visit for HF (HR)	0.79 (0.60–1.03)
STEP-HFpEF	Semaglutide	Hospitalization or urgent care visit for HF (HR)	0.08 (0.00–0.42)⇞
SUSTAIN-6	Semaglutide	Hospitalization for HF (HR)	1.11 (0.77–1.61)
Huixing et al.	Lixisenatide, liraglutide, semaglutide, exenatide, albiglutide, dulaglutide, efpeglenatide	Hospitalization for HF (HR)	1.07 (0.91–1.25)
Zhao et al.	Liraglutide, abliglutide, exenatide, semaglutide, lixisenatide	Hospitalization for HF (HR)	1.04 (0.89–1.22)
Lepore et al.	Albiglutide	LVEF (mean difference EF%)	− 2.0% (CI unavailable)
LIVE	Liraglutide	LVEF (mean difference EF%)	− 0.8% (− 2.1 to 0.5%)
Blood pressure
DURATION-1	Exenatide	Reduction in SBP	Once weekly: − 4.7 (− 6.9 to − 2.6)⇞
ELIXA	Lixisenatide	Reduction in SBP	− 0.8 (− 1.3 to − 0.3)⇞
EXSCEL	Exenatide	Reduction in SBP	− 1.57 (− 1.92 to − 1.21)⇞
Harmony Outcomes	Albiglutide	Reduction in SBP	− 0.65 (− 1.27 to − 0.03)⇞
LEADER	Liraglutide	Reduction in SBP	− 1.2 (− 1.9 to − 0.5)⇞
PIONEER 6	Semaglutide	Reduction in SBP	− 2.6 (− 3.7 to − 1.5)⇞
SURMOUNT-1	Tirzepatide (dual agonist)	Reduction in SBP	− 6.2 (− 7.7 to − 4.8)⇞
SUSTAIN-6	Semaglutide	Reduction in SBP	1.0 mg dose: − 2.59 (− 4.09 to − 1.08)⇞
Atrial fibrillation
Saglietto et al.	Semaglutide	Risk of AF episodes (RR)	0.58 (0.40–0.85)⇞

GLP-1 RA glucagon-like peptide 1 receptor agonists, CI confidence interval, MACE major adverse cardiovascular event, MI myocardial infarction, SBP systolic blood pressure in mmHg, HR hazard ratio, RR relative risk, HF heart failure, LVEF left-ventricular ejection fraction

^aPrimary or secondary outcome of interest as reported by the study

^⇞Statistically significant confidence interval

Major Adverse Cardiac Events Among Patients with T2DM

Strong evidence supports using GLP-1 RAs to reduce MACE among patients with T2DM and established CVD. The LEADER trial showed a significant reduction in MACE and cardiovascular mortality with liraglutide [14]. Subsequent trials, including SUSTAIN-6, Harmony Outcomes, and AMPLITUDE-O, reported similar MACE reductions but without a mortality benefit [15–17].

In a broader T2DM population, the REWIND trial demonstrated a significant reduction in MACE, primarily driven by fewer nonfatal strokes [18]. This trial was important because a significant clinical benefit was seen in a lower-risk patient population irrespective of baseline cardiovascular risk. However, nearly 25% discontinued dulaglutide by the end of the study. Similarly, the EXSCEL trial failed to show MACE superiority with exenatide, possibly due to high premature discontinuation rates [19].

The question of tolerability and adherence ultimately led to investigating oral forms of GLP-1 RAs. The PIONEER-6 trial evaluated the effects of oral semaglutide in patients. While it found no significant reduction in MACE, it was one of the initial trials that helped expand the safety and tolerability information regarding oral GLP-1 RAs [20]. In contrast, the SOUL trial, which enrolled a higher-risk population, showed a significant reduction in MACE with oral semaglutide [21].

Coronary and Peripheral Artery Disease

GLP-1 RAs have shown mixed results in the management of CAD, particularly regarding MI outcomes. The LEADER and SOUL trials significantly reduced both fatal and non-fatal MI with liraglutide and semaglutide, respectively [14, 21]. Harmony Outcomes and SELECT trials only significantly reduced non-fatal MI using abliglutide and semaglutide, respectively [16, 22]. While all four of these trials did enroll patients with established ASCVD, the SELECT trial showed benefit for patients with no history of T2DM. In contrast, trials such as ELIXA, SUSTAIN-6, AMPLITUDE-O, and EXSCEL, which included broader T2DM populations without established CVD, did not show similar MI reductions [15, 17, 19, 23]. These findings suggest that GLP-1 RAs may be more effective in reducing MI risk, primarily among patients with known ASCVD. While data on GLP-1 RAs use in acute MI are limited, preliminary studies suggest potential benefits, including smaller infarct size, attenuated CK-MB elevation, and improved subclinical left ventricular function [24].

Approximately 22–42% of patients with CAD also suffer from PAD. These patients are at greater risk of adverse cardiovascular events compared to those with CAD alone [25]. The STRIDE trial evaluated semaglutide in patients with T2DM and PAD, finding a 13% improvement in maximum walking distance and a significant increase in ankle-brachial index, indicating improved perfusion. Although quality of life scores did not significantly change, the trial highlights clinically significant changes in functional mobility and shows direct vascular benefits from GLP-1 RAs [26].

Heart Failure

Current evidence overall does not support the routine use of GLP-1 RAs to improve cardiac function or reduce HF hospitalizations. Large outcome trials like SUSTAIN-6 [15] and EXSCEL [19] reported no significant reductions in HF-related hospitalizations. These findings were further explored in the FIGHT trial, which found no reduction in rehospitalizations with liraglutide in patients recently hospitalized for HF [27]. Similarly, when abliglutide was used in patients with known HFrEF, no improvement was noted in LVEF (left ventricular ejection fraction) [28]. The LIVE trial in patients with heart failure with reduced ejection fraction (HFrEF) showed no improvement in left ventricular (LV) systolic function. It notably reported increased serious cardiac events—including ventricular tachycardia, worsening HF, and aggravating ischemic heart disease—in the liraglutide group [29]. These adverse findings may relate to the increased heart rate observed in the liraglutide arm—a known effect of liraglutide [29]. Increased heart rates have been linked to poor outcomes in HF and may help explain the findings from the LIVE trial [29–31]. More recently, the SELECT trial evaluated overweight patients with CVD but without T2DM. It showed no significant reduction in HF hospitalizations or urgent care visits when using semaglutide [22].

These results are echoed through meta-analyses. A meta-analysis of randomized controlled trials (RCTs) including patients with HF found no improvement in hospitalization rates or echocardiographic parameters such as LVEF or LV end-systolic or diastolic volume. However, a modest increase in 6-min walk distance (6MWD) was noted, suggesting a role in exercise capacity [32]. Another, larger meta-analysis reported no reduction in HF hospitalizations but did observe improvements in tissue Doppler measurements and diastolic function, suggesting possible benefits in diastolic HF [33].

The STEP-HFpEF trial reflected similar outcomes; semaglutide improved body weight, quality of life, and 6MWD in obese patients with heart failure with reduced ejection fraction (HFpEF) and T2DM, likely mediated through weight loss [34]. Additionally, there was a significant reduction in HF-related events with semaglutide. While STEP-HFpEF was underpowered to truly detect outcome differences, the difference observed supports the need for larger, outcomes-driven trials in obese patients with HFpEF.

Blood Pressure

GLP-1 RAs modestly reduce blood pressure, with more potent effects observed in patients with established hypertension. The degree of systolic blood pressure (SBP) reduction varies across studies. The DURATION-1 trial reported a 4.7 mmHg reduction with weekly 2 mg exenatide [35], while more modest decreases (0.65–2.6 mmHg) were observed in other trials [14, 16, 19, 20, 23]. This effect is partly attributed to weight loss, a known mechanism for lowering blood pressure, so it is not surprising that this is part of the mechanism for GLP-1 RAs blood pressure reduction [36, 37]. However, a pooled analysis of liraglutide trials demonstrated that blood pressure lowering occurs within two weeks of treatment initiation, suggesting other effects on vasculature beyond weight loss [36]. Additionally, a dose–response relationship has also been noted with specific agents; in SUSTAIN-6, 1 mg of semaglutide lowered SBP more than the 0.5 mg dose [15].

Tirzepatide, a dual GLP-1/glucose-dependent insulinotropic polypeptide receptor agonist, is noteworthy for its robust response and is mechanistically distinct from the GLP-1 RAs discussed so far. In overweight or obese patients with no history of T2DM, tirzepatide achieved a significant approximately 6 mmHg SBP reduction in the SURMOUNT-1 trial [38]. This is likely due to greater weight loss seen in this trial, approximately 21% with 15 mg dosing, far exceeding the 1–4% weight loss observed in GLP-1 RA trials [14, 16, 19, 20, 23].

While there are notable effects on blood pressure lowering with GLP-1 RAs, limitations of the above trials include only measuring blood pressure variations primarily as secondary endpoints. Limited RCTs have been published thus far on patient populations with hypertension specifically, with blood pressure variations being measured as a primary endpoint and tracked long-term.

Atrial Fibrillation

AF was not a primary outcome in major GLP-1 RA cardiovascular outcomes trials, and its role in AF remains under investigation. Given the potential for GLP-1 RA to affect heart rates [30], a meta-analysis of 43 RCTs using GLP-1 RAs showed no increased risk of AF with GLP-1 RAs [39]. Furthermore, a separate meta-analysis of 10 RCTs using different formulations of semaglutide suggested a potential reduction in AF incidence independent of T2DM status [40]. Proposed mechanisms include indirect effects via weight loss and reduced inflammation, though no direct electrophysiological action on atrial tissue has been established. Although there is limited current RCT data, a nested case–control study revealed a significant decrease in new-onset AF 1 year after HF hospitalization for patients with HFpEF [41]. Overall, more studies are needed to elucidate the role of GLP-1 RA in AF.

Guidelines

Multiple professional societies, including the ACC, ESC, and ADA, have updated their clinical guideline recommendations to incorporate GLP-1 RAs as a therapy component for patients with T2DM and ASCVD. Below, we summarize the most recent guideline updates highlighting the evolving role of GLP-1 RAs in cardiometabolic care in Table 3.

Table 3.

ACC/AHA, ESC and ADA summary of guidelines recommendations for GLP-1 RA use

ACC American College of Cardiology, AHA American Heart Association, ESC European Society of Cardiology, ADA American Diabetes Association, GLP-1 RA glucagon-like peptide 1 receptor agonists, T2DM type 2 diabetes mellitus, ASCVD atherosclerotic cardiovascular disease, CV cardiovascular, CVD cardiovascular disease, MACE major adverse cardiovascular event, SGLT2i sodium-glucose co-transporter 2 inhibitors, BMI body mass index, MI myocardial infarction, HFpEF heart failure with preserved ejection fraction

^aACC/AHA and ESC utilize class of recommendation (1, 2a, 2b, 3) which highlights the overall benefit of a treatment compared to its risks. Class 1 = Recommendation is indicated/useful/effective/beneficial; Class 2a = Recommendation can be useful/effective/beneficial; Class 2b = Recommendations' usefulness/effectiveness is unknown/unclear/uncertain or not well established; Class 3 = Recommendation is not indicated/useful/effective/beneficial; No class assigned = more evidence is needed to ascertain a recommendation. The ADA uses a grading system (A, B, C, E) to show evidence level that supports each recommendation. Grade A = Clear evidence from well-conducted, generalizable randomized controlled trials that are adequately powered; Grade B = Supportive evidence from well-conducted cohort studies; Grade C = Supportive evidence from poorly controlled or uncontrolled studies; Grade E = Expert consensus or clinical experience

ACC/AHA

In 2019, the ACC and AHA published “Guidelines on Primary Prevention of Cardiovascular Disease”, suggesting that GLP-1 RA may help reduce CVD risk in patients with T2DM who require glucose-lowering medications despite lifestyle changes and use of metformin (Class 2a, Level of Evidence (LoE) B-R) [42].

After review of additional data, the 2023 ACC/AHA Guidelines for the Management of Patients with Chronic Coronary Disease published a strong (Class 1, LoE A) recommendation for the use of GLP-1 RA with proven cardiovascular benefits in patients with diabetes and chronic coronary disease to reduce the risk of MACE. This was followed by an assessment of the cost-effectiveness of using GLP-1 RAs. The recommendations suggest that the use of GLP-1 RAs is projected to be of high value in comparison to other classes of diabetes medications. However, this was supported by moderate-quality evidence and based on analyses of all patients with T2DM, rather than those with chronic coronary disease [43].

In February of 2025, ACC/AHA released guidelines on the Management of Patients with Acute Coronary Syndromes. Further evaluation of GLP-1 RA needs to be performed before determining its efficacy in reducing MACE after acute coronary syndrome [44].

ACC guidelines published in 2024 for lower extremity arterial disease management do not discuss GLP-1 RA as part of management, likely due to the recency of the STRIDE trial findings [45]. ACC guidelines for atrial fibrillation published in 2023 also do not mention GLP-1 RA as part of their recommendations, likely due to the limited data currently available [46].

ESC

The ESC guidelines recommend the use of GLP-1 RAs in overweight or obese patients with T2DM to promote weight reduction (Class IIa, LoE B). Additionally, GLP-1 RAs with established CV benefits—specifically liraglutide, subcutaneous semaglutide, dulaglutide, and efpeglenatide—are recommended for patients with T2DM and ASCVD to reduce CV events, regardless of baseline or target HbA1c levels or concurrent glucose-lowering therapy (Class I, LoE A). Furthermore, semaglutide should be considered for overweight (BMI > 27 kg/m²) or obese patients with chronic coronary syndrome who do not have diabetes to lower the risk of CV mortality, MI, or stroke (Class IIa, LoE B) [47, 48].

In 2024, the ESC guidelines for elevated blood pressure and hypertension classified GLP-1 RA as therapies that have shown blood pressure-lowering properties but are awaiting further supportive evidence from cardiovascular outcomes trials prior to guideline endorsement and routine use in hypertension [49]. In the 2024 guidelines published by the ESC for PAD management, the authors do not mention GLP-1 RAs as part of management, likely due to limited data at the time [50]. Similarly 2024 guidelines published by ESC for atrial fibrillation management do not mention GLP-1 RAs as part of management [51].

ADA

In 2022, the “Standards of Medical Care in Diabetes” published by the ADA recommended the concurrent use of GLP-1 RAs in patients with ASCVD and T2DM, independent of HbA1c and metformin use [52]. This was the first instance of ADA guidelines outlining the use of GLP-1 receptor agonists in patients with T2DM with ASCVD or risk factors for ASCVD. In the “Pharmacologic Approaches to Glycemic Treatment: Standards of Care in Diabetes” published in 2024, it was recommended to start GLP-1 RA ± sodium-glucose co-transporter 2 inhibitors (SGLT2i) in patients with T2DM and ASCVD, while also commenting upon noted benefit in specifically HFpEF as well [53]. The 2025 “Standards of Medical Care in Diabetes” ADA guidelines designate using GLP-1 RA with or without SGLT2i in patients with T2DM and ASCVD in preventing MACE [54]. All recommendations by the ADA regarding GLP-1 RAs have been assigned an A rating, which is the association’s highest rating of evidence.

Practical Considerations

Identifying patients who can benefit from GLP-1 RAs remains in the hands of the clinician. On the basis of current guidelines, GLP-1 RAs should be considered in patients with T2DM and CVD or CV risk factors. Since GLP-1 RAs are primarily glucose-lowering medications, the benefits of selecting these agents should be weighed against the benefits of alternative diabetes control options. For example, SGLT2i should be prioritized in patients with HF or CKD, while GLP-1 RAs may be more favorable in patients with higher ASCVD risk or obesity.

Initiation of therapy typically involves a low starting dose to reduce gastrointestinal side effects, followed by gradual titration based on clinical response and tolerability. Dosing regimens vary between short-acting and long-acting formulations. Long-acting agents are generally preferred owing to their once-weekly dosing, which improves patient adherence and convenience. Finally, agent selection is influenced by insurance formulary and cost. Table 4 lists the agents currently available in the USA and their dosing strategies [19, 38, 55–58].

Table 4.

Dosing regimen for GLP-1 RA available in the USA

Medication	Starting dose	Dose titration	Titration frequency
Dulaglutide [55]	0.75 mg subcutaneous (SC) once weekly	Titrate to 1.5 mg as tolerated	Typically after ≥ 4 weeks
Exenatide [19, 56]	Immediate release (IR): 5 mcg SC twice daily before meals	IR: increase to 10 mcg SC twice daily ER: N/A	Every 4 weeks
	Extended-release (ER): 2 mg once weekly
Liraglutide [57]	0.6 mg SC daily	Increase to 1.2 mg, then to 1.8 mg	Increase by 0.6 mg weekly as tolerated
Semaglutide (SC) [55]	0.25 mg SC weekly for 4 weeks	Increase to 0.5 mg, then to 1 mg	Every 4 weeks
Semaglutide (oral) [58]	R1 formulation: 3 mg daily R2 formulation: 1.5 mg daily	R1: increase to 7 mg, then to 14 mg daily R2: Increase to 4 mg, then to 9 mg	Every 4 weeks
Tirzepatide [38]	2.5 mg SC weekly for 4 weeks	Increase to 5 mg, then by 2.5 mg increments until 15 mg	Every 4 weeks

GLP-1 RA glucagon-like peptide 1 receptor agonists

In patients with CKD, liraglutide, semaglutide, and dulaglutide do not require dose adjustment in mild to moderate renal impairment. Caution is advised in severe CKD (eGFR < 30 mL/min/1.73 m²) given limited current data in this specific patient population [59].

The most common side effects are gastrointestinal, including nausea, vomiting, diarrhea, and constipation. These are generally transient and are mitigated by starting a low dose and titrating slowly. Other potential side effects include injection site reactions, pancreatitis, gallbladder disease such as cholelithiasis, and a theoretical increased risk for thyroid C-cell tumors, although human data have not corroborated this risk. Currently, the use of GLP-1 RAs in individuals with a personal or family history of medullary thyroid carcinoma (MTC) or multiple endocrine neoplasia syndrome type 2 (MEN2) is contraindicated. The US Food and Drug Administration (FDA) does not otherwise recommend routine thyroid monitoring [60].

Finally, patients on GLP-1 RAs undergoing elective surgical procedures may need the therapy held before surgery [61]. Factors that increase the patient’s risk for delayed gastric emptying, including higher doses, escalation phases, and dosing frequency, may be considered in determining continuation versus holding before surgery. Holding duration will vary based on frequency of administration, with day of surgery for daily formulations and a week prior for weekly formulations being the current recommendation.

Regular follow-up is essential to assess therapeutic response, monitor glycemic and cardiovascular outcomes, and manage adverse effects. Close clinical monitoring ensures the optimization of both efficacy and safety.

Ongoing Trials

Current research continues to expand the understanding of GLP-1 RAs and their benefits in CVD, HF, and AF.

The PREvention of CardIovascular and DiabEtic kidNey Disease in Type 2 Diabetes trial is a multicenter study evaluating GLP-1 RAs versus SGLT2i for both primary and secondary prevention of ASCVD in patients with T2DM [62].

Multiple trials are investigating the effects of GLP-1 RAs on HF. The Mechanisms of Semaglutide Therapy in Heart Failure Patients trial will assess the impact of semaglutide on biomarkers, echocardiographic parameters, and functional outcomes in patients with HF [63]. Similarly, the Cardiac and Metabolic Effects of Semaglutide in Heart Failure With Preserved Ejection Fraction study focuses on obese patients with HFpEF to evaluate improvements in cardiac structure, exercise tolerance, and metabolic health [64].

The Semaglutide for Metabolic Intervention and Adipose Loss to Treat Atrial Fibrillation trial represents a novel approach by examining whether semaglutide-induced weight loss can reduce AF burden and arrhythmia recurrence in obese patients with AF [65].

Beyond T2DM, the Multifactorial Intervention to Reduce Cardiovascular Disease in Type 1 Diabetes trial is assessing whether GLP-1 RAs can meaningfully reduce MACE, HF hospitalizations, and other cardiovascular endpoints in patients with type 1 diabetes, a population generally underrepresented in cardiovascular prevention studies [66].

Together, these studies will further define the cardiometabolic, renal, and rhythm-related benefits of GLP-1 RAs, potentially expanding their use beyond glycemic control.

Conclusions

GLP-1 RAs have emerged as novel agents in managing CVD, extending their utility beyond glycemic control in T2DM. The impact of their molecular mechanisms has been evidenced by landmark trials, which have repeatedly demonstrated that certain GLP-1 RAs—including liraglutide, semaglutide, and dulaglutide—are particularly efficacious in reducing MACE, especially in patients with established ASCVD. Among these agents, semaglutide and liraglutide have consistently shown the strongest cardiovascular benefit, with semaglutide showing additional promise in patients with obesity and HFpEF. Although the benefits of GLP-1 RAs in HF (particularly HFrEF) and CAD remain less definitive, emerging data suggest potential roles in improving PAD and blood pressures, reducing symptoms in HF, and possibly lowering the risk of AF. Ultimately, care must be utilized in selecting patients with appropriate medical history, and regular monitoring of side effects is paramount. As the wealth of research continues to evolve, ongoing and future trials will help refine the role of GLP-1 RAs in a broader range of conditions and chart new therapies for the next generation of cardiovascular care.

Author Contributions

Neil Gupta, Zaid Zayyad, and Adhir R. Shroff contributed to the review conception and design. Literature review and data analysis were performed by Neil Gupta, Zaid Zayyad, Rohan Bhattaram, David Tiu, Jennifer Dau, Stephanie Dwyer Kalzuna, and Vidur Guburxani. All authors contributed to drafting the manuscript and commented on previous versions of the manuscript. All authors read and approved the final manuscript.

Funding

No funding or sponsorship was received for this study or the publication of this article.

Data Availability

Data sharing is not applicable to this article as no datasets were generated or analyzed during the current study.

Declarations

Conflict of Interest

Neil Gupta, Zaid Zayyad, Rohan Bhattaram, David Tiu, Jennifer Dau, Stephanie Dwyer Kalzuna, Vidur Gurbuxani, and Adhir R. Shroff declare that they have no competing interests.

Ethical Approval

This article is based on previously conducted studies and does not contain any new studies with human participants or animals performed by any of the authors.