Semaglutide: a key medication for managing cardiovascular-kidney-metabolic syndrome

ABSTRACT

Recent trials underscore the cardiovascular (CV), renal, and metabolic benefits of semaglutide in individuals with and without type 2 diabetes (T2D). In T2D, semaglutide enhances glycemic control, reduces major adverse CV events (MACE), and slows chronic kidney disease (CKD) progression. The SUSTAIN-6 trial demonstrated a 26% MACE reduction (HR 0.74; 95% CI: 0.58–0.95; p = 0.02) in high CV-risk patients with T2D using semaglutide (0.5 or 1.0 mg weekly). Similarly, the FLOW trial showed a 24% reduction in major kidney disease events (HR 0.76; 95% CI: 0.66–0.88; p = 0.002) with weekly 1.0 mg semaglutide in individuals with T2D with CKD. Beyond T2D, the SELECT trial highlighted semaglutide’s efficacy in reducing MACE by 20% (HR 0.80; 95% CI: 0.72–0.90; p < 0.001) and slowing kidney function loss in overweight or obese individuals with preexisting CV disease using 2.4 mg weekly. Additionally, semaglutide alleviates heart failure symptoms and reduces hospitalizations in obese individuals regardless of T2D status. These findings underscore semaglutide’s role in improving kidney, CV, and survival outcomes among high-risk patients. This review highlights the cardio-kidney-metabolic benefits of semaglutide in individuals with and without T2D to inform cardiologists about its potential to enhance patient care.

Plain Language Summary

Semaglutide, a medication in the glucagon-like peptide-1 receptor agonist (GLP-1 RA) class, offers significant health benefits across cardiovascular (CV), kidney, and metabolic conditions, collectively known as cardiovascular-kidney-metabolic (CKM) syndrome. CKM syndrome encompasses interconnected issues such as obesity, type 2 diabetes (T2D), CV disease (CVD), and chronic kidney disease (CKD). These conditions are commonly seen together, increasing the risk of heart and kidney problems.

Semaglutide has proven effective for weight loss, improved blood sugar control, and CV protection. Clinical trials have shown it reduces major heart events like heart attacks and strokes in individuals with and without diabetes. It also slows CKD progression and lowers hospitalization rates for heart failure, particularly in patients with obesity. Emerging evidence suggests semaglutide might have additional benefits, such as reducing inflammation, improving liver health, and lowering risks associated with atrial fibrillation and osteoarthritis.

Semaglutide’s real-world use supports clinical trial findings, demonstrating safety and effectiveness across diverse patient groups. Its safety profile is generally favorable, though gastrointestinal side effects can occur.

By addressing multiple interconnected conditions, semaglutide is poised to transform care for patients at high risk of heart, kidney, and metabolic complications. Further research is exploring new dosing methods, combinations with other medications, and expanded use in non-diabetic populations to maximize its benefits

1. Introduction

The interconnectedness of obesity, type 2 diabetes mellitus (T2D), cardiovascular disease (CVD), and chronic kidney disease (CKD) reflects a rising epidemic in industrialized nations [1]. While these diseases are traditionally managed as distinct conditions, there is increasing recognition that they are closely linked through shared biological and social risk factors. Reflecting this understanding, the American Heart Association (AHA) now collectively defines these interrelated conditions as cardiovascular-kidney-metabolic (CKM) syndrome. The AHA has also recently introduced a novel staging construct based on risk factors and established disease to facilitate better clinical outcomes through targeted interventions and collaborative care to improve CKM health [2].

New data highlights the widespread prevalence of CKM syndrome. A study by Aggarwal et al., using the new AHA classification system and data from the National Health and Nutrition Examination Survey (NHANES) from 2011 to March 2020, assessed the presence and evolution of CKM syndrome among 10,762 adults (≥20 years of age) in the United States (US) [3]. Their findings revealed that nearly 90% of adults met the criteria for CKM syndrome stage 1 or higher, and 15% had advanced stage disease (stages 3 and 4). In another contemporary study, Ostrominski et al. investigated the impact of overlapping conditions. They reported that the risk of experiencing primary CV events increases proportionately to the overlap of CKM conditions [4]. Individuals with all three CKM conditions had the highest risk, with an adjusted hazard ratio (HR) of 2.16 compared to those with heart failure (HF) alone.

The prevalence of CKM syndrome and its association with poor CV and kidney outcomes underscores the need for effective preventive strategies. The combination of CVD, CKD, and metabolic dysfunction, such as T2D and obesity, creates a unique set of management challenges. Addressing these overlapping conditions through comprehensive strategies is critical to improving clinical outcomes and reducing the burden of CKM syndrome.

Recent clinical trials have demonstrated the potential for long-acting glucagon-like peptide-1 (GLP-1) receptor agonists (RAs), particularly semaglutide, to address this challenge. Beyond its well-documented effects on glycemic control, including reduced risk of progression to diabetes, and weight loss in individuals with and without T2D [5–8], semaglutide has been shown to reduce major adverse CV events (MACE) in adults with and without T2D [9–13]. Semaglutide’s benefits in kidney disease are also promising [13]; however, no definitive trial has yet established its efficacy in patients with CKD without diabetes. Collectively, semaglutide’s ability to target adverse CV and metabolic pathways makes it a promising therapeutic option for managing patients with CKM syndrome.

This review aims to summarize the metabolic, CV, and kidney benefits of semaglutide in people with and without T2D, highlighting its potential role in improving clinical outcomes for patients affected by CKM syndrome. The findings discussed here give cardiologists and other healthcare providers key insights into how semaglutide could be integrated into managing this multifaceted syndrome.

2. The cardiovascular-kidney-metabolic axis

The pathophysiology of CKM syndrome involves a complex interplay of hemodynamic and neurohormonal mechanisms, including sympathetic overactivity, renin-angiotensin-aldosterone system (RAAS) activation, oxidative stress, and chemical mediators (e.g., nitric oxide, prostaglandins, endothelins) [14,15]. In diabetes, high blood sugar triggers excess glucose influx into cells, increasing mitochondrial superoxide production and oxidative stress, believed to initiate diabetes-related organ damage [14,16]. Elevated reactive oxygen species (ROS) activate polyol and hexosamine pathways, enhancing oxidative stress. Protein kinase C (PKC) activation and advanced glycation end-products (AGEs) exacerbate tissue damage by cross-linking matrix proteins, increasing stiffness in the heart, blood vessels, and kidneys [14,16–18]. AGEs contribute to complications like cardiomyopathy, diabetic kidney disease (DKD), and atherosclerosis. Preclinical studies show that receptor for advanced glycation end products (RAGE) deletion reduces inflammation, and RAGE knockout mice are protected against nephropathy [19,20]. AGEs and ROS also drive endothelial dysfunction, a key factor in diabetic vascular complications [14,17,18].

Hyperglycemia locally activates RAAS in the myocardium and kidneys, worsening vasoconstriction and fibrosis [21]. Other contributors to CV and CKD in T2D include endoplasmic reticulum (ER) stress and chronic inflammation [14,17]. ROS regulate essential functions like cell growth and platelet adhesion but, when dysregulated, create a proinflammatory environment, disrupting insulin signaling and endothelial function [22–24].

These pathways, shared by prediabetes and obesity, highlight the need for strategies targeting these mechanisms to prevent CV and kidney complications in metabolic disorders [16,25,26].

There is ongoing debate about whether the liver should be formally integrated into the CKM axis, given the well-established links between metabolic-associated steatotic liver disease (MASLD) and increased risk of CVD, CKD, and HF. MASLD is a recently adopted nomenclature that shifts the focus away from the older term NAFLD, emphasizing the metabolic underpinnings of liver fat accumulation rather than its association with alcohol exclusion [27]. A recent proposal by Theodorakis et al. introduces the Cardiovascular-Renal-Hepatic-Metabolic (CRHM) syndrome, a broadened framework that recognizes MASLD as a key driver of multiorgan dysfunction [28]. This model emphasizes shared pathophysiological mechanisms such as systemic inflammation and insulin resistance and supports a unified approach to staging and treating cardiometabolic diseases in clinical practice.

2.1. Recent advances in managing the cardiovascular-kidney-metabolic axis

In a Scientific Statement, the AHA recently introduced a novel staging construct to enhance multidisciplinary approaches for the prevention, risk stratification, and management of CKM syndrome [2]. The stages range from 0 (no risk factors) to 4 (established CVD), reflecting the complexity of managing patients with overlapping risk factors and disease states (Table 1). Within the AHA’s summary, GLP-1 RAs are positioned as important therapeutic options, recognized for improving glycemic control and offering CV benefits, making them particularly relevant for patients with T2D and concurrent heart or kidney issues. Indeed, GLP-1 RAs, directly and indirectly, target more of the key physiological pathways known to contribute to the pathophysiology of T2D than currently available treatment options, including insulin, metformin and dipeptidyl peptidase-4 inhibitors (DPP-4is) [29]. Figure 1 summarizes the effects of GLP-1 on multiple target organs. The heart and kidney protective effects of sodium-glucose cotransporter-2 (SGLT2) inhibitors are also now recognized [33,34], and reviewed elsewhere [35,36].

Table 1.

Definitions of CKM health stages and recommended approaches/treatments*.

CKM health stages	Definition	Summary of recommended approaches and treatments
Stage 0: No CKM health risk factors	Individuals without overweight/obesity, metabolic risk factors (hypertension, hypertriglyceridemia, MetS, diabetes), CKD, or subclinical/clinical CVD	Focus on preventative strategies. Maintain optimal CV health through healthy lifestyle practices.
Stage 1: Excess and/or dysfunctional adiposity	Individuals with overweight/obesity, abdominal obesity, or dysfunctional adipose tissue, without the presence of other metabolic risk factors or CKD BMI ≥25 kg/m2 (or ≥23 kg/m2 if Asian ancestry) Waist circumference ≥ 88/102 cm in women/men (or if Asian ancestry, ≥80/90 cm in women/men) and/or Fasting blood glucose ≥ 100–124 mg/dL or HbA1c between 5.7% and 6.4%†	Prevent the development of metabolic risk factors. Encourage heart-healthy diet and physical activity. Support weight loss through patient-centered approaches, lifestyle modification, obesity pharmacotherapies, and bariatric surgery if needed.
Stage 2: Metabolic risk factors and CKD	Individuals with metabolic risk factors (hypertriglyceridemia (≥135 mg/dL), hypertension, MetS‡, diabetes) or CKD	Prevent CVD. Control BP, manage hypertriglyceridemia, and address MetS. Use cardioprotective antihyperglycemic therapies (e.g., SGLT2 inhibitors, GLP-1 RAs) for diabetes management. Optimize kidney function with ACE inhibitors/ARBs and other relevant therapies.
Stage 3: Subclinical CVD in CKM	Subclinical ASCVD or subclinical HF among individuals with excess/dysfunctional adiposity, other metabolic risk factors, or CKD Subclinical ASCVD to be principally diagnosed by coronary artery calcification (subclinical atherosclerosis by coronary catheterization/CT angiography also meets criteria) Subclinical HF diagnosed by elevated cardiac biomarkers (NT-proBNP ≥125 pg/mL, high sensitivity troponin T ≥ 14 ng/L for women and ≥ 22 ng/L for men, high-sensitivity troponin I ≥ 10 ng/L for women and ≥ 12 ng/L for men) or by echo parameters, with combination indicating highest HF risk. Risk equivalents of subclinical CVD Very high-risk CKD (G4 or G5 CKD or very high risk per KDIGO classification) High predicted 10-y CVD risk	Intensify lifestyle changes and preventive therapies. Use cardiac biomarkers and imaging to identify subclinical HF and ASCVD. Consider additional preventive therapies for those with very high-risk CKD or high predicted CVD risk.
Stage 4: Clinical CVD in CKM	Clinical CVD (coronary heart disease, heart failure, stroke, peripheral artery disease, AFib) among individuals with excess/dysfunctional adiposity, other metabolic risk factors, or CKD Stage 4a: no kidney failure Stage 4b: kidney failure present	Manage patients with CVD and overlapping CKM risk factors. Implement GDMT for HF and ASCVD. Address obesity, MetS components, and diabetes with appropriate lifestyle and pharmacological interventions. Optimize management of CKD and CVD, including SGLT2 inhibitors and other relevant therapies.

*Adapted from Ndumele CE, et al. Circulation. 2023;148:1636–1664 [2].

^†Individuals with gestational diabetes should receive intensified screening for impaired glucose tolerance after pregnancy.

^‡MetS is defined by the presence of ≥ 3 of the following: (1) waist circumference ≥88 cm for women and ≥102 cm for men (if Asian ancestry, ≥80 cm for women and ≥90 cm for men), (2) high-density cholesterol <40 mg/dL for men and <50 mg/dL for women; (3) triglycerides ≥150 mg/dL; (4) elevated blood pressure (systolic blood pressure ≥130 mmHg and/or diastolic blood pressure ≥80 mmHg and/or use of antihypertensive medications); and (5) fasting blood glucose ≥100 mg/dL.

ACE, angiotensin-converting-enzyme inhibitors; ARB, angiotensin II receptor blockers; AFib, atrial fibrillation; ASCVD, atherosclerotic cardiovascular disease; BMI, body mass index; BP, blood pressure; CKD, chronic kidney disease; CKM, cardiovascular-kidney-metabolic; CT, computed tomography; CVD, cardiovascular disease; GDMT, guideline-directed medical therapy; GLP-1 RA, glucagon-like peptide 1 receptor agonist; HbA1c, hemoglobin A1c; HF, heart failure; KDIGO, Kidney Disease Improving Global Outcomes; MetS, metabolic syndrome; NT-proBNP, N-terminal pro-B-type natriuretic peptide; SGLT2, sodium-glucose cotransporter-2 inhibitor.

Figure 1.

Summary of the effect of glucagon-like peptide 1 on target organs. GLP-1, glucagon-like peptide-1. Created using data from [30–32].

In CKM Stage 1, GLP-1 RAs may be recommended for patients with metabolic dysfunction to improve weight management and glycemic control [2]. As patients progress to Stage 2 and beyond, the CV protective effects of GLP-1 RAs become increasingly significant, especially for those with established CVD [2]. The AHA’s recommendations for GLP-1 RAs are consistent with other international guidelines. The American College of Cardiology (ACC) [37], the European Society of Cardiology (ESC) [38], the American Stroke Association (ASA) [39] and the American Diabetes Association (ADA) [40] recommend GLP-1 RAs for use in treatment regimens aimed at reducing atherosclerotic CVD (ASCVD) in high-risk patients. Furthermore, the Kidney Disease: Improving Global Outcomes (KDIGO) Clinical Practice Guideline for the Evaluation and Management of CKD promotes GLP-1 RAs above other glucose-lowering medications because of their favorable CV profile [41]. It should be recognized that these guidelines were published before the results of a specific trial evaluating the effects of semaglutide on the progression of kidney function loss were released [42]. By aligning with these global perspectives, the AHA’s Scientific Statement underscores the importance of GLP-1 RAs as a cornerstone in managing CKM syndrome.

3. Semaglutide

Semaglutide was designed as a potent, long-acting GLP-1 RA for once-weekly subcutaneous administration, improving convenience and adherence compared to daily dosing [43]. Semaglutide retains 94% similarity to natural GLP-1 but incorporates structural modifications for stability against the DPP-4 enzyme. Enhanced albumin binding and fatty acid attachment extend its half-life, enabling once-daily dosing [44]. It is currently available in three formulations: a once-weekly subcutaneous injection for T2D in doses of 0.25 mg, 0.5 mg, 1.0 mg, and 2.0 mg [45–48]; a once-daily oral tablet for T2D in doses of 3 mg, 7 mg, and 14 mg [49–51]; and a once-weekly subcutaneous injection for weight loss, with dose options of 0.25 mg, 0.5 mg, 1.0 mg, 1.7 mg, and 2.4 mg [52–55]. Regulatory indications vary; however, in the US and European Union (EU), it is approved as an addition to diet and exercise to improve glycemic control in adults with T2D [45,46]. For weight management, it is indicated alongside a reduced-calorie diet and increased physical activity for adults with a body mass index (BMI) of 30 kg/m² or more, or between 27 and 30 kg/m² if at least one weight-related comorbidity is present [52,53]. Semaglutide is also approved for adolescents aged 12 and older whose BMI is at or above the 95th percentile for their age and gender, with a weight threshold of 60 kg [52,53]. In the US, once-weekly semaglutide is also approved to reduce MACE in adults with T2D and established CVD [45].

A recent study by Shi et al. highlights semaglutide’s potential to improve population health [56]. Using NHANES data (2015–2020), they estimate 136.8 million US adults meet eligibility for semaglutide across its three indications: weight management, T2D, and secondary prevention of CVD. This figure surpasses the 82 million adults eligible for statins, the most widely prescribed medications in the US [57].

3.1. Metabolic benefits of semaglutide

Comprehensive phase III clinical trial programs have demonstrated the significant metabolic benefits of semaglutide in individuals with overweight or obesity, both with and without T2D. The Semaglutide Treatment Effect in People with Obesity (STEP) program evaluated the efficacy and safety of once-weekly subcutaneous semaglutide (2.4 mg). In STEP trials 1, 3, 4, and 8, participants without T2D achieved mean weight losses ranging from 14.9% to 17.4% from baseline to week 68 [8,58–60]. Moreover, 69% to 79% of these individuals experienced a ≥ 10% weight reduction, and 51% to 64% achieved ≥ 15% weight loss, substantially outperforming placebo groups, which only saw 12% to 27% and 5% to 13% of participants achieving these levels of weight loss, respectively. In STEP-5, mean weight loss with semaglutide was 15.2% over 104 weeks, compared to just 2.6% with placebo (p < 0.0001) [61]. For participants with T2D in STEP-2, the mean weight loss reached 9.6% over 68 weeks, again showing superior efficacy compared to placebo (3.4%; p < 0.0001) [6].

Additional data from the STEP-10 trial demonstrated a notable reduction in body weight and reversion to normoglycemia among individuals with obesity and prediabetes [62]. The benefits of semaglutide were also observed in adolescents, as shown in the STEP TEENS trial, where significant weight loss was achieved in obese or overweight adolescents aged 12 to 18 [63]. Furthermore, post hoc analyses of the STEP trials highlighted semaglutide’s positive impact on cardiometabolic risk factors, such as blood pressure and lipids, as well as improvements in physical function and overall quality of life [64,65]. Recently, the Oral Semaglutide Treatment Effect in People with Obesity (OASIS 1) trial reported that a daily dose of semaglutide 50 mg resulted in a significantly greater and clinically meaningful reduction in body weight compared to placebo [66].

Semaglutide has been approved for the treatment of individuals with T2D based on data from two phase III clinical trial programs, SUSTAIN and PIONEER. The SUSTAIN (Semaglutide Unabated Sustainability in Treatment of Type 2 Diabetes) trials evaluated the efficacy and safety of once-weekly subcutaneous semaglutide (0.5 or 1.0 mg), demonstrating its superiority over placebo and several active comparators, including DPP-4is, SGLT2is, insulin, and other GLP-1 RAs [7,11,67–72]. In the SUSTAIN 1, 2, 4, and 5 trials, participants receiving once-weekly semaglutide 0.5 mg achieved reductions in glycated hemoglobin (HbA1c) ranging from −1.20% to −1.45%, while those randomized to once-weekly semaglutide 1.0 mg experienced HbA1c reductions between −1.50% and −1.80% [7,68,69,71].

Similarly, the PIONEER (Peptide Innovation for Early Diabetes Treatment) program focused on the oral formulation of semaglutide (at doses of 3, 7 and 14 mg OD), which also outperformed placebo and active comparators, such as a DPP-4i and SGLT2i, in terms of glycemic control [5,9,73–80]. In the PIONEER 1, 3, 8, and 9 trials, participants receiving oral semaglutide 3, 7, and 14 mg once-daily achieved reductions in HbA1c ranging from −0.6% to −1.1%, −0.9 to −1.2%, and −1.3% to −1.7%, respectively [5,77,79,80]. Oral semaglutide also provided superior weight loss compared to placebo and other active treatments, including liraglutide, another GLP-1 RA.

3.2. Semaglutide and major adverse cardiovascular events

3.2.1. MACE

Both subcutaneous and oral formulations of semaglutide have been shown to reduce MACE – a composite endpoint including death from CV causes, non-fatal myocardial infarction (MI), and non-fatal stroke – in various high-risk patient populations (Table 2). The SUSTAIN-6 trial was the first pivotal CV outcomes trial for subcutaneous once-weekly semaglutide (0.5 or 1.0 mg) in T2D patients ≥50 years of age with established CVD, chronic HF, or CKD, or in patients aged ≥ 60 with additional CV risk factors [11]. Over a 2.1-year follow-up, semaglutide demonstrated non-inferiority to placebo but also, although not prespecified in the trials statistical plan, a significant 26% reduction in MACE compared to placebo, with a number needed to treat (NNT) of 45 to prevent one primary CV event. Semaglutide was also associated with significant and sustained reductions in HbA1c levels, body weight and a reduction in systolic blood pressure. SUSTAIN-6 marked a major milestone in understanding semaglutide’s cardioprotective potential and was the first trial to show that a GLP-1 RA can reduce MACE in patients with T2D and established CVD.

Table 2.

Key cardiovascular outcomes reported in semaglutide trials.

Study(number enrolled)	Participants	Treatment	MACE* (HR, 95% CI)	CV death (HR, 95% CI)	Non-fatal MI (HR, 95% CI)	Non-fatal stroke (HR, 95% CI)	HF hospitalizations (HR, 95% CI)¶	Composite renal outcome (HR, 95% CI)	Ref.
SUSTAIN-6† (N = 3,297)	T2D ≥50 years with established CVD, HF (NYHA II/III) or CKD, or ≥60 years with CV risk factors only	SC semaglutide (0.5 mg or 1.0 mg QW) vs. placebo	0.74 (0.58–0.95)	0.98 (0.65–1.48)	0.74 (0.51–1.08)	0.61 (0.38–0.99)	1.11 (0.77–1.61)	0.64 (0.46–0.88)‡	[11]
PIONEER-6 (N = 3,183)	T2D ≥50 years with established CV or CKD, or ≥60 years with CV risk factors only	Oral semaglutide (14 mg OD) vs. placebo	0.79 (0.57–1.11)	0.49 (0.27–0.92)	1.18 (0.73–1.90)	0.74 (0.35–1.57)	0.86 (0.48–1.55)	Not reported	[9]
SELECT (N = 17,604)	≥45 years with established CVD and BMI ≥ 27 with no history of T2D	SC semaglutide (2.4 mg QW) vs. placebo	0.80 (0.72–0.90)	0.85 (0.71–1.01)	0.72 (0.61–0.85)§	0.93 (0.74–1.15)§	0.79 (0.60–1.03)§	0.78 (0.63–0.96)§ǁ	[10]
FLOWa (N = 3,533)	Adults with T2D and CKD	SC semaglutide (1.0 mg QW) vs. placebo	0.82 (0.68–0.98)	0.71 (0.56–0.89)	0.80 (0.55–1.15)	1.22 (0.84–1.77)	0.73 (0.58–0.92)	0.76 (0.66–0.88)	[13,42]
SOUL (N = 9,650)	T2D ≥50 years with established CV or CKD	Oral semaglutide (14 mg OD) vs. placebo	0.86 (0.77–0.96)	0.93 (0.80–1.09)	0.74 (0.61–0.89)	0.88 (0.70–1.11)	0.90b (0.79–1.03)	0.91 (0.80–1.05)	[12]

Comparisons across studies should be made cautiously due to differences in study design (e.g., patient populations included, background medications, outcomes measured).

*Three-point MACE (composite of CV death, MI or stroke).

^†SUSTAIN-6 was designed and powered as a non-inferiority trial. Testing for superiority for the primary CV outcome was not prespecified.

^‡New or worsening nephropathy includes persistent macroalbuminuria, persistent doubling of the serum creatinine level and a creatinine clearance of less than 45 ml per minute per 1.73 m² of body-surface area (according to the Modification of Diet in Renal Disease criteria), or the need for continuous renal-replacement therapy.

^§Because supportive secondary endpoints were not corrected for multiplicity, results are reported as point estimates and 95% CIs. The widths of the confidence intervals have not been adjusted for multiplicity and, therefore, should not be used to infer definitive treatment effects for supportive secondary endpoints.

^ǁThe nephropathy endpoint was a five-component composite of death from renal causes, initiation of long-term renal replacement therapy (dialysis or transplantation), onset of a persistent eGFR lower than 15 ml per minute per 1.73 m², persistent 50% reduction in eGFR relative to baseline, or onset of persistent macroalbuminuria (urinary albumin-to-creatine ratio, >300 mg per gram).

^¶HF composite endpoint (CV death or urgent hospitalization for HF).

^aMACE was a secondary outcome in the FLOW trial.

^bIn the SOUL trial, the HF events outcome was a three-point composite of death from CV causes, an urgent visit for HF, or hospitalization for HF.

BMI, body mass index; CI, confidence interval; CKD, chronic kidney disease; CVD, cardiovascular disease; eGFR, estimated glomerular filtration rate; HF, heart failure; HR, hazard ratio; MACE, major adverse cardiovascular event; MI, myocardial infarction; NYHA, New York Heart Association; SC, subcutaneous; T2D, type 2 diabetes; QD, once daily; QW, once weekly.

The PIONEER-6 trial, which evaluated oral semaglutide (14 mg daily) in a similar high-risk T2D population, confirmed the CV safety of the oral formulation [9]. Although the trial was not designed to demonstrate superiority, it confirmed non-inferiority, showing no increased CV risk with oral semaglutide compared to placebo (3.8% vs. 4.8%; HR 0.79; 95% CI: 0.57 to 1.11). The trial also noted favorable trends, particularly a reduction in CV death, which underscores the cardioprotective potential of semaglutide, even in oral form, as discussed later. Most recently, the SOUL (Semaglutide cardiOvascular oUtcomes) trial reported a statistically significant 14% reduction in MACE in patients with T2D and established CVD and/or CKD when treated with oral semaglutide (14 mg daily) compared to placebo [12]. This randomized controlled trial (RCT) involved 9,650 patients, of whom 26.9% received an SGLT2i as part of their standard care.

The SELECT trial focused on a different population, evaluating the effects of once-weekly subcutaneous semaglutide (2.4 mg) on MACE in patients with obesity but without T2D [10]. Enrolling over 17,600 patients with a BMI of ≥27 kg/m² and preexisting CVD, the SELECT trial demonstrated a significant 20% reduction in MACE over a mean follow-up of 39.8 months compared to placebo. This equates to a NNT of 67 to prevent one primary CV event. Semaglutide also improved multiple modifiable CV risk factors, including reductions in body weight, waist circumference, blood pressure, lipid levels, and high-sensitivity C-reactive protein (hsCRP). In a sub-analysis of SELECT, semaglutide significantly increased regression to normoglycemia (69.5% vs. 35.8% with semaglutide vs. placebo, respectively; p < 0.0001) and reduced progression to biochemical diabetes (HbA1c > 6.5%; 1.5% vs 6.9%; p < 0.0001) [81]. These changes in CV biomarkers suggest that semaglutide’s CV benefits are likely mediated through multiple interrelated pathways, including weight loss and improvements in metabolic and inflammatory markers [10].

The FLOW study primarily investigated semaglutide’s impact on kidney outcomes in T2D patients with CKD, yet it also observed CV benefits as secondary outcomes [13]. Compared to placebo, semaglutide reduced the incidence of MACE by 18% over a median follow-up of 3.4 years, with an NNT of 45 to prevent one MACE event.

3.2.2. Death from cardiovascular causes

Death from CV causes has been explored across multiple trials as part of the MACE composite endpoint. In the SUSTAIN-6 trial, no significant difference was observed between semaglutide and placebo groups, with rates of 2.7% and 2.8%, respectively (HR 0.98; 95% CI: 0.65 to 1.48; p = 0.92) [11]. However, the PIONEER-6 trial highlighted a significant reduction in death from CV causes with oral semaglutide (0.9%) compared to placebo (1.9%), yielding an HR of 0.49 (95% CI: 0.27 to 0.92) and a NNT of approximately 100 [9]. Similarly, the SELECT trial demonstrated a favorable (albeit not statistically significant) trend, with rates of 2.5% in the semaglutide group versus 3.0% in the placebo group (HR 0.85; 95% CI: 0.71 to 1.01; p = 0.07) [10]. Most notably, the FLOW trial reported a 29% risk reduction in death from CV causes in the semaglutide group (7.0%) versus placebo (9.6%), with an NNT of approximately 38, emphasizing semaglutide’s safety in patients with kidney comorbidities [13].

3.2.3. Non-fatal myocardial infarction

Semaglutide has demonstrated significant benefits in reducing ischemic heart disease events, particularly non-fatal MI, as evidenced by findings from the SELECT, SUSTAIN-6, and SOUL trials. In the SELECT trial, semaglutide was associated with a 28% reduction in the risk of non-fatal MI compared to placebo [10], while the SUSTAIN-6 and SOUL trials both reported a 26% risk reduction in the same endpoint [11,12]. These results align with a growing body of evidence to suggest a distinct differentiation between outcomes with GLP-1 RAs and SGLT2 inhibitors. Indeed, while both GLP-1 RAs and SGLT2 inhibitors have been shown to improve CV outcomes, the key difference appears to lie in their relative impact on individual components of the MACE endpoint. GLP-1 RAs appear to primarily reduce MACE, with an apparent focus on non-fatal MI and stroke [10,11,82,83]. In contrast, SGLT2 inhibitors primarily reduce HF hospitalizations and CV death [84–89].

3.2.4. Stroke events

Accumulating evidence suggests that GLP-1 RAs, including semaglutide, may offer protection against stroke beyond their effects on blood glucose levels in T2D [86,90,91]. In accordance, the AHA/ASA Primary Prevention Guidelines advocate for the use of these agents in patients with diabetes who have high CV risk or established CVD, particularly when HbA1c levels are ≥ 7%, to reduce the risk of stroke and other CV events [39].

In the SUSTAIN-6 trial, semaglutide significantly lowered the incidence of non-fatal stroke compared to placebo over a relatively short two-year follow-up period (1.6% vs. 2.7%, HR 0.61; 95% CI: 0.38–0.99; p = 0.04) [11]. This early benefit was further supported by a post hoc analysis of the combined SUSTAIN-6 and PIONEER 6 trials, which demonstrated a significant reduction in overall stroke incidence with semaglutide compared to placebo (0.8 vs. 1.1 events per 100 patient-years, HR 0.68; p = 0.048), largely attributed to a decrease in small-vessel occlusion (HR 0.51; p = 0.017) [92]. These benefits appeared consistent across subgroups, regardless of prior stroke history, except for patients with a history of atrial fibrillation (AF).

Recent real-world data further corroborate semaglutide’s stroke risk reduction in patients with T2D, including those with ASCVD. In a US claims-based analysis by Evans et al., adults with T2D initiating semaglutide (predominantly the subcutaneous formulation) had a significantly lower stroke risk compared to those starting a DPP4i, both in T2D-only cases (HR 0.63; 95% CI: 0.41–0.95; p = 0.029) and in those with concomitant ASCVD (HR 0.45; 95% CI: 0.24–0.86; p = 0.015) [93]. Of interest, and for currently unknown reasons, semaglutide failed to reduce the risk of stroke in people with T2D and CKD in the FLOW study [42]. Despite the above, overall findings highlight the potential of semaglutide to reduce stroke risk in high-risk T2D patients, suggesting a valuable role for GLP-1 RAs in CV risk management beyond glycemic control and weight reduction.

3.3. Semaglutide and heart failure

Semaglutide shows potential in reducing HF events and improving functional outcomes in patients with HF, especially in individuals with obesity, T2D, or high CV risk. In the SELECT and FLOW trials, 24.3% and 19·2% of participants, respectively, had a history of HF at enrollment, and sub-analyses from both trials examined the impact of weekly doses of semaglutide (2.4 mg and 1 mg, respectively) on HF outcomes in their respective cohorts (Table 3) [42,94]. In both trials, the effects of semaglutide were consistent regardless of HF history and subtype.

Table 3.

Outcomes for semaglutide versus placebo from the SELECT and FLOW trials according to the presence or absence of heart failure at baseline.

Study, enrollment criteria, treatment	Participant group, n	HF composite* (HR, 95% CI)	HF events alone (HR, 95% CI)	CV death alone (HR, 95% CI)	All-cause death (HR, 95% CI)	Ref.
SELECT HF sub-analysis, overweight or obesity, established CVD, without T2D, SC semaglutide (2.4 mg QW)	HF (n = 4,286)	0·79 (0·64–0·98)	Not reported	0·76 (0·59–0·97)	0·81 (0·66–1·00)	[94]
	No HF (n = 13,314)	0·85 (0·68–1·06)	Not reported	0·93 (0·72–1·21)	0·81 (0·67–0·97)
	HFpEF (n = 2,273)	0·75 (0·52–1·07)	0.59 (0.3–1.06)	0·87 (0·56–1·34)	0·83 (0·59–1·16)
	HFrEF (n = 1,347)	0·79 (0·58–1·08)	1.08 (0.68–1.72)	0·63 (0·43–0·91)	0·72 (0·53–0·99)
FLOW HF sub-analysis, T2D and CKD, SC semaglutide (1.0 mg QW)	HF (n = 678)	0.73 (0.54–0.98)	0.78 (0.55–1.10)	0.70 (0.46–1.05)	Not reported	[42]
	No HF (n = 2,855)	0.72 (0.58–0.89)	0.68 (0.50–0.91)	0.71 (0.53–0.93)	Not reported
	HFpEF (n = 325)	0.86 (0.56–1.34)	0.87 (0.52–1.46)	Not reported	Not reported
	HFrEF (n = 123)	0.88 (0.51–1.52)	0.89 (0.47–1.67)	Not reported	Not reported

Comparisons across studies should be made cautiously due to differences in study design (e.g., patient populations included, background medications, outcomes measured).

*HF composite endpoint varied by trial. In the SELECT trial, the composite endpoint comprised CV death, hospitalization, or urgent hospital visit for HF. In the FLOW trial, the composite endpoint consisted of new onset or worsening of HF leading to an unscheduled hospital admission or an urgent visit, with initiation of or intensified diuretic/vasoactive therapy.

CI, confidence interval; CV, cardiovascular; HF, heart failure; HFpEF, heart failure with preserved ejection fraction; HFrEF, heart failure with reduced ejection fraction; HR, hazard ratio; QW, once-weekly; SC, subcutaneous.

The STEP-HFpEF trial further demonstrated semaglutide’s benefits on functional symptoms and physical limitations in patients with obesity-related heart failure with preserved ejection fraction (HFpEF) [95]. Over a 52-week period, patients receiving once-weekly semaglutide (2.4 mg) showed significantly greater improvements in the Kansas City Cardiomyopathy Questionnaire Clinical Summary Score (KCCQ-CSS), which measures HF-related symptoms (estimated difference, 7.8 points; 95% CI: 4.8 to 10.9; p < 0.001) and achieved more substantial weight reduction compared to placebo (estimated difference, −10.7%; 95% CI: −11.9 to − 9.4; p < 0.001). Physical endurance, assessed by the 6-minute walk distance (6MWD), also improved significantly more in the semaglutide group compared to placebo (estimated difference, 20.3 m; 95% CI: 8.6 to 32.1; p < 0.001). Pooled data from the STEP-HFpEF and STEP-HFpEF DM trials (totaling 1,145 participants) corroborated these findings: semaglutide led to significant increases in KCCQ-CSS scores, body weight reduction and improvements in secondary endpoints, including the 6MWD and inflammation markers [96].

In secondary analyses from the STEP-HFpEF program, semaglutide led to significant reductions in NT-proBNP levels compared to placebo (estimated treatment ratio: 0.82; 95% CI: 0.74 to 0.91; p = 0.0002) [97], attenuated progression of left atrial remodeling (estimated mean difference [EMD] −6.13 mL; 95% CI: −9.85 to −2.41 mL; p = 0.0013) and right ventricular (RV) enlargement (EMD in RV end-diastolic area: −1.99 cm²; 95% CI: −3.60 to −0.38 cm²; p = 0.016) compared with placebo [98]. Furthermore, Verma et al. found a benefit of semaglutide in patients with and without AF at baseline in the SELECT trial but noted a greater benefit of semaglutide on KCCQ-CSS outcomes in individuals with AF [99].

In a pooled analysis of four trials (SELECT, FLOW, STEP-HFpEF, and STEP-HFpEF DM), involving 3,743 participants with HFpEF, semaglutide reduced the risk of the composite outcome of CV death or worsening HF events by 31% compared to placebo (HR 0.69; 95% CI: 0.53 to 0.89; p = 0.0045) [100]. Worsening HF events were also significantly reduced (2.8% vs. 4.7%; HR 0.59; 95% CI: 0.41 to 0.82; p = 0.0019), with a NNT of 97 to prevent one composite endpoint event and a NNT of 95 for one worsening HF event over one year.

Together, these findings support semaglutide as a promising treatment option for reducing HF events and enhancing physical function in HF patients, especially those with obesity – a population for whom limited treatment options exist. The broad efficacy observed across HF-related endpoints highlights semaglutide’s potential to address the multifaceted needs of patients with HF and high CV risk.

3.4. Kidney benefits of semaglutide

The growing body of evidence indicates that semaglutide may be effective in preventing and treating CKD in patients with overweight or obesity, with or without T2D. Multiple dedicated RCTs support this, as do post hoc analyses that have examined semaglutide’s impact on kidney function across various patient populations and baseline kidney health statuses.

The FLOW trial, which focused on patients with T2D and CKD, demonstrated that semaglutide 1.0 mg weekly significantly reduced the risk of major kidney disease events, including kidney failure and death from kidney-related or CV causes, by 24% compared to placebo (HR 0.76; 95% CI: 0.66 to 0.88; p = 0.0003) [13]. Kidney-specific outcomes were similarly reduced, with a slower decline in kidney function and a 40% reduction in urine albumin-to-creatinine ratio (UACR), highlighting semaglutide’s potential to slow the progression of kidney disease in this high-risk population. Apperloo et al. extended these findings to patients with CKD and obesity without T2D, in a trial that demonstrated a substantial reduction in UACR by 52.1% over 24 weeks with semaglutide 2.4 mg weekly, compared to a 7.4% increase in the placebo group [101]. To put these treatment benefits into context, a 2019 meta-analysis of trials showed that a 30% reduction in estimated UACR predicts a 27% lower hazard risk of the clinical endpoint of doubling of serum creatinine, incidence of an estimated glomerular filtration rate (eGFR) <15 mL/min/1.73 m² or end-stage kidney disease [102].

Similarly, in the SUSTAIN-6 trial, semaglutide significantly lowered the risk of nephropathy progression, with new or worsening nephropathy occurring in 3.8% of the semaglutide group versus 6.1% of the placebo group (HR 0.64; 95% CI: 0.46 to 0.88; p = 0.005), suggesting a broad benefit for kidney health in patients at high CV risk [11]. However, it should be noted that a reduction in progression to macroalbuminuria was the main driver for this outcome. In a post hoc analysis of the SUSTAIN 6/PIONEER 6 trials, Tuttle et al. investigated semaglutide’s effects on kidney outcomes across KDIGO (Kidney Disease Improving Global Outcomes) risk categories [103]. Semaglutide consistently reduced the risk of kidney disease events across all risk levels, with significant regression in UACR contributing to improvement in KDIGO risk classification. Additional analysis in participants with low baseline eGFR found that semaglutide significantly slowed the decline in eGFR. This suggests that the drug may offer kidney protection for those with more advanced kidney impairment.

Data from the SELECT trial further supports semaglutide’s benefit in kidney outcomes. Semaglutide 2.4 mg weekly lowered the incidence of a composite kidney endpoint (CV death, chronic kidney replacement therapy, or severe eGFR reduction) by 22% compared to placebo (HR 0.78; 95% CI: 0.63 to 0.96; p = 0.02) [104]. Moreover, semaglutide showed a significant benefit in preserving eGFR and reducing UACR over two years, with greater effects observed in patients with baseline eGFR <60 mL/min/1.73 m². Finally, post hoc analyses of the STEP trials further highlight semaglutide’s benefits for kidney health in people with obesity, with or without T2D. Across these studies, semaglutide doses of 1.0 and 2.4 mg weekly significantly reduced albuminuria, contrasting with UACR increases in the placebo group [105]. These reductions were clinically meaningful and provided evidence of semaglutide’s impact on CKD-related parameters over the longer term. Despite the above results, the benefits of semaglutide on retarding kidney function loss in people without diabetes remain to be definitively assessed [106].

3.5. Vascular effects of semaglutide

Semaglutide offers promising benefits for patients with peripheral arterial disease (PAD), leveraging its anti-inflammatory effects [107] and improvements in endothelial function [108] to support CV health. Recently, Novo Nordisk shared promising top-line results from the STRIDE trial, which assessed the efficacy of 1 mg once-weekly subcutaneous semaglutide in patients with symptomatic PAD and T2D [109]. Over 52 weeks, semaglutide demonstrated a significant 13% improvement in maximum walking distance compared to placebo, translating to a mean improvement of 40 meters and a median improvement of 26 meters. The trial included 792 participants, with a median age of 68 years and a median T2D duration of 12 years [110]. Most participants also had additional CV risk factors, including hypertension (87.9%) and coronary heart disease (42.7%). While these findings highlight semaglutide’s potential in addressing mobility challenges in this high-risk population, peer-reviewed publication of the STRIDE trial results is awaited to validate these outcomes.

3.5.1. Potential mechanisms

The vascular benefits of semaglutide appear to be partially mediated by its potent anti-inflammatory effects, which contribute to improved endothelial function and an enhanced antithrombotic profile. A recent systematic review and meta-analysis of 13 RCTs involving 26,131 participants reported a significant decrease in CRP levels with semaglutide compared to placebo (standardized mean difference [SMD] −0.56; 95% CI: −0.69 to − 0.43) and other glucose-lowering drugs (SMD −0.45; 95% CI: −0.68 to − 0.23) [111]. Notably, the anti-inflammatory effect of semaglutide was consistent across different treatment regimens (subcutaneous versus oral) and populations (with or without T2DM). These results align with a broader analysis of GLP-1RAs as a therapeutic class: a meta-analysis encompassing 52 RCTs by Ren et al., found that GLP-1RA treatment significantly reduced circulating levels of CRP, tumor necrosis factor-alpha (TNF-α), interleukin 6 (IL-6), IL-1β, and leptin, while increasing adiponectin – a hormone associated with anti-inflammatory and insulin-sensitizing properties [112].

While semaglutide-induced weight loss is considered a key mechanism driving reductions in inflammatory markers [113], data from the STEP-HFpEF program by Verma et al. suggest that the CRP reduction with semaglutide is independent of weight loss, highlighting additional anti-inflammatory pathways [114]. Further supporting this notion, García‑Vega and colleagues recently reported that semaglutide improved the antithrombotic profile of patients by modulating the endocrine activity of epicardial adipose tissue, altering neutrophil phenotype, and reducing endothelial adhesion [115].

Beyond its anti-inflammatory effects, semaglutide enhances vascular health by improving endothelial function, a crucial determinant of vascular reactivity and health. The Endothelium Dysfunction Assessment Study (ENDIS) study demonstrated that once-weekly semaglutide (1 mg) significantly improved flow-mediated dilation, a key marker of endothelial function, in 89 patients with type 1 diabetes [108]. Semaglutide also reduced peripheral resistance, suggesting a favorable effect on arterial stiffness, a parameter linked to CV outcomes. A recent pre-clinical study by Pan et al. reported that semaglutide protects endothelial progenitor cells (EPCs) from inflammation-induced injury by inhibiting miR-155 in macrophage exosomes, which promotes EPC viability and repair capacity [116].

3.6. Emerging evidence for semaglutide

As evidence supporting semaglutide’s therapeutic versatility grows, so does the potential range of patients who may benefit from this medication. Current studies reveal semaglutide’s benefits beyond traditional glucose and weight management, with emerging data supporting its potential impact on AF, non-CV mortality, osteoarthritis, bone health, nonalcoholic fatty liver disease (NAFLD), and HIV-associated lipohypertrophy.

3.6.1. Atrial fibrillation

A meta-analysis of 10 RCTs involving 12,651 patients (7,285 on semaglutide [oral and subcutaneous] and 5,366 on placebo) with a median follow-up of 68 months found that semaglutide significantly reduces the risk of AF by 42% compared to placebo (RR 0.58; 95% CI: 0.40–0.85) [117]. Importantly, this risk reduction was observed consistently across different administration routes (oral and subcutaneous), irrespective of diabetes status and BMI, suggesting a robust cardioprotective role for semaglutide in AF prevention. It is also interesting that despite GLP-1 RAs increasing heart rate (2–3 beats per minute) [118–120], this class of medication has been consistently shown to have CV benefits.

3.6.2. Non-CV mortality

Further insights into semaglutide’s impact on mortality emerged from the SELECT trial. Scirica and colleagues reported a significant reduction in non-CV deaths, particularly those attributable to infection [121]. More specifically, once-weekly semaglutide (2.4 mg) appeared to lower the risk of death among patients who contracted COVID-19, although it did not impact the incidence of COVID-19 infection itself. This observation highlights semaglutide’s potential protective effect against severe infectious complications.

3.6.3. Osteoarthritis and bone health

In the STEP-9 trial, once-weekly semaglutide (2.4 mg) was evaluated for its effects on obesity and knee osteoarthritis pain in 407 participants over 68 weeks [122]. Compared to placebo, semaglutide led to a significant reduction in body weight (−13.7% vs. −3.2%; p < 0.001) and knee pain, as indicated by a statistically significant improvement in the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) pain score (−41.7 points vs. −27.5 points; p < 0.001). These findings suggest that semaglutide may aid in managing pain and improving mobility, which could be particularly beneficial for patients at elevated CV risk. However, in a related study by Hansen et al., semaglutide at a lower dose (1.0 mg QW) was found to increase bone resorption and reduce bone mass in 64 adults with increased fracture risk, potentially due to weight loss without increasing bone formation markers such as procollagen type I N-terminal propeptide (PINP) [123]. Further research is warranted to understand the long-term skeletal effects of semaglutide fully.

3.6.4. Non-alcoholic fatty liver disease and non-alcoholic steatohepatitis

MASLD, which encompasses conditions previously referred to as NAFLD and nonalcoholic steatohepatitis (NASH), remains highly prevalent and closely linked to obesity, metabolic syndrome, and T2D. Preliminary studies suggest that semaglutide (at doses ranging from 0. 25 mg to 2.4 mg weekly, and 0.1, 0.2, or 0.4 mg once-daily) may benefit patients with NAFLD by reducing body weight, improving glycemic control, and potentially improving liver parameters, such as reducing liver enzymes and liver stiffness [124–128]. Moreover, a recent Phase 3 trial evaluated semaglutide (2.4 mg QW) in 800 patients with MASLD and stage 2 or 3 fibrosis. At 72 weeks, semaglutide significantly improved liver histology compared with placebo: 62.9% of patients achieved resolution of steatohepatitis without worsening fibrosis (vs. 34.3% with placebo), and 36.8% experienced fibrosis improvement without worsening steatohepatitis (vs. 22.4%) [129]. Both primary endpoints met with high statistical significance (p < 0.001). At the time of writing, the European Association for the Study of the Liver (EASL) recommends emphasizing the potential advantages of GLP-1 RAs in treating NAFLD, particularly in patients with T2DM [130].

3.6.5. HIV-associated lipohypertrophy

Semaglutide is also emerging as a potential treatment for HIV-associated lipohypertrophy, a condition linked to an increased CKM risk. In a phase 2b trial of 108 participants with controlled HIV-1 infection, BMI ≥25 kg/m², and no diabetes, weekly semaglutide (1.0 mg) significantly reduced abdominal visceral and subcutaneous adipose tissue, as well as total body fat, over 32 weeks [131]. Improvements in glucose metabolism, insulin resistance, and lipid profiles were also noted, suggesting that semaglutide may improve adipose tissue distribution and metabolic health in this population.

These findings broaden semaglutide’s therapeutic landscape, underscoring its potential to address various health conditions with important implications for CV metabolic and overall health outcomes.

3.6.6. Other emerging potential benefits

Evidence is also evolving to highlight the benefits of GLP-1 RAs in conditions such as polycystic ovarian syndrome [132] and obstructive sleep apnea (potentially linked to weight loss) [133,134], as well as in neurodegenerative diseases [135,136], addictive behaviors and substance misuse [137,138]. Compared to insulins, GLP-1 RAs may also reduce the risk of specific obesity-associated cancers (OACs) [139]. In a recent cohort study of more than 1.6 million people with T2D who had no prior diagnosis of 13 OACs, Wang et al., found that individuals with T2D treated with GLP-1 RAs versus insulin had a significant risk reduction in 10 of 13 OACs, including esophageal, colorectal, endometrial, gallbladder, kidney, liver, ovarian, and pancreatic cancer as well as meningioma and multiple myeloma. Notably, the observed reduction in pancreatic cancer risk contrasts with ongoing concerns about a potential link between GLP-1 RAs and pancreatic cancer [140], suggesting a need for further research to clarify this relationship.

3.7. Real-world evidence supporting the CKM benefits of semaglutide

Results from real-world studies are generally consistent with those observed in RCTs and highlight semaglutide’s efficacy and safety in diverse patient populations. Regarding the management of obesity, Tzoulis et al. evaluated the effectiveness and safety of once-weekly semaglutide (1 mg and 2 mg) in 40 adults without T2D, reporting a median weight loss of 14.9 kg (13.3% of baseline weight) over a six month period [141]. Similarly, Wang et al. performed a meta-analysis of 10 prospective real-world studies with once-weekly subcutaneous semaglutide (n = 3,558). They revealed significant reductions in HbA1c (−1.10%) and weight loss (−4.88 kg), consistent across patient subgroups [142]. Singh et al. further corroborated these outcomes with a systematic review of four prospective and ten retrospective real-world studies of oral semaglutide in patients with T2D [143]. The four prospective studies showed HbA1c and weight loss reductions of 0.9% to 1.6% and 4.7 kg to 8.2 kg, respectively, while glycemic targets of < 7% were achieved in 30%-64% of patients. In the ten retrospective studies, HbA1c reductions of 0.4% to 1.8% were achieved, with weight losses between 1.4 kg and 9.0 kg. Overall, 30%-41% of patients achieved ≥ 5% weight loss. These data confirm the broad applicability of semaglutide for managing weight loss and T2D in routine care.

In another real-world study, Perez-Belmonte and colleagues evaluated the efficacy and safety of once-weekly semaglutide (0.5 mg or 1.0 mg) in 136 obese patients with T2D and chronic HF over 12 months [144]. The authors reported significant improvements in KCCQ symptom scores, a reduction in the proportion of patients with New York Heart Association functional class III, and reductions in NT-proBNP levels. They also noted a de-intensification of T2D treatment, as measured by a reduction in the number of daily glucose-lowering drugs and insulin doses.

A multicenter retrospective study in 122 patients with T2D and CKD (n = 122) found significant reductions in UACR (51% in those with macroalbuminuria) without declines in eGFR, following once-weekly semaglutide for 12 months [145]. Furthermore, another real-world comparative study of oral and subcutaneous formulations in patients with CKD (n = 38) revealed similar efficacy for glucose and weight management, with stable renal parameters and comparable safety profiles [146].

Regarding the safety of once-weekly semaglutide in adults with T2D in routine clinical practice, Yale et al. performed a post hoc analysis of nine studies from the SemaglUtide Real-world Evidence (SURE) program (n = 3505) [147]. The results were generally consistent with observations from phase III once-weekly semaglutide RCTs: 24.3% of patients reported adverse events (AEs), with most patients reporting non-serious (22.3%) and mild (17.1%) AEs. AEs mainly belonged to the gastrointestinal (GI) disorders system organ class (16.3% of patients). In total, 5.1% of patients reported AEs that led to treatment discontinuation.

Overall, the consistency between real-world and RCT data reinforces semaglutide’s efficacy and safety for managing obesity, glycemia, HF, and CKD across diverse populations and further strengthens its position as a cornerstone in treating CKM syndrome in clinical practice.

3.8. Safety of semaglutide

The safety profile of semaglutide is mainly consistent with that of the GLP-1 RAs, where GI events predominate. Key safety outcomes from clinical trial programs are presented in Table 4. Across the STEP trials, GI side effects such as nausea, vomiting, diarrhea, and constipation were the most reported AEs [148]. However, they were generally transient and mild to moderate in severity. Notably, the frequency of GI symptoms was highest during initiation and dose escalation but tended to decrease over time with continued use. Consistency in the safety profile between the subcutaneous and oral formulations was also observed in the SUSTAIN and PIONEER programs, with 39.1% to 41.9% of participants on semaglutide experiencing GI events [149].

Table 4.

Summary of key safety outcomes from semaglutide clinical trial programs.

	STEP 1–5 and 8 [148]		SUSTAIN [149]		PIONEER [149]		SELECT [10]		FLOW [13]		SOUL [12]
	Semaglutide* (% range)	Comparators† (% range)	Semaglutide* %	Comparators‡ %	Semaglutide* %	Comparators§ %	Semaglutide %	Placebo %	Semaglutide %	Placebo %	Semaglutide %	Placebo %
Serious AEs	7.7–9.9	2.9–11.8	7.0	5.8	8.6	9.0	33.4	36.4	49.6	53.8	47.9	50.3
AEs leading to discontinuations	2.4–7.0	2.2–12.6	7.8	3.0	8.7	4.2	16.6	8.2	13.2	11.9	15.5	11.6
Cholelithiasis	0.2–4.9	0.7–3.7	1.0	0.5	0.7	0.8	2.8	2.3	1.8	2.2	2.8	2.2
Acute pancreatitis	0.0–0.2	0.0–0.8	0.3	0.2	<0.1	0.2	0.2	0.3	0.6	0.4	0.4	0.4
Diabetic retinopathy	2.7–4.0ǁ	2.7ǁ	1.0	1.5	3.3	3.0	–	–	22.8	22.5	22.8	22.4
Kidney disorders	0.0–1.0	0.0–1.2	0.2	<0.1	0.3	0.4	1.9	2.3	9.7	10.3
Hypoglycemia	0.0–5.7	0.0–3.0	0.4	0.4	0.2	0.1	–	–	2.1	2.1	1.6	1.7
Malignant neoplasms	0.7–2.4	0.4–2.6	1.0	0.6	1.4	1.1	4.8	4.7	6.8	5.8	6.9	6.1

Comparisons across studies should be made cautiously due to differences in study design (e.g., patient populations included, background medications, outcomes measured).

*All doses.

^†Comparators include placebo and liraglutide (STEP 8).

^‡Comparators include placebo, sitagliptin, exenatide, and insulin glargine.

^§Comparators include placebo, empagliflozin, sitagliptin, liraglutide, dulaglutide.

^ǁData is from STEP 2.

AE, adverse event; GI, gastrointestinal.

In the SELECT and FLOW trials, semaglutide demonstrated a favorable safety profile. In SELECT, the incidence of serious AEs was lower with semaglutide compared to placebo, though treatment discontinuations due to GI issues were more common among those on semaglutide [10]. Gallbladder-related disorders were also slightly more prevalent with semaglutide. Importantly, there was no significant difference between semaglutide and placebo in the incidence of serious AEs related to GI disease, kidney injury, pancreatitis, cancers, or psychiatric disorders. In the FLOW trial, semaglutide had a lower rate of serious infections and CV disorders than placebo; however, serious eye disorders were slightly more frequent in the semaglutide group (3.0% vs. 1.7%) [13].

All GLP-1 RAs, semaglutide included, are associated with a low risk of hypoglycemia, particularly when used as monotherapy or combined with other glucose-lowering agents that do not directly promote insulin secretion, such as metformin or SGLT2 inhibitors [150]. However, hypoglycemia risk may increase when GLP-1 RAs are co-administered with insulin or sulfonylureas, necessitating dose adjustments to mitigate this potential adverse effect [150].

While the safety profile of semaglutide aligns with the broader GLP-1 RA class, some emerging concerns warrant ongoing monitoring and discussion. Among these are the potential risks of suicidal ideation [151], exacerbation of diabetic retinopathy [152], development of non-arteritic optic neuropathy [153], and excessive muscle mass loss accompanying significant weight reductions [154]. Suicidal ideation, in particular, has gained attention following isolated reports in patients treated with GLP-1 RAs, prompting regulatory bodies to monitor this risk closely, especially in individuals with a history of psychiatric illness [155]. Similarly, the relationship between rapid weight loss and its impact on muscle integrity underscores the need for clinicians to encourage strategies to preserve lean body mass during therapy (e.g., adequate intake of high-quality protein and micronutrients, concurrent physical activity, especially resistance training) [154].

Thyroid-related risks also remain a key concern with GLP-1 RAs. Medullary thyroid carcinoma (MTC) and other thyroid malignancies have been a focal point of safety surveillance. The FDA mandates a black-box warning for GLP-1 RAs regarding the risk of thyroid C-cell tumors, advising against their use in patients with a personal or family history of MTC or multiple endocrine neoplasia syndrome type 2 (MEN 2a or 2b) [156]. While direct evidence linking GLP-1 RAs to thyroid cancer remains limited, these precautions emphasize the importance of individual risk assessment before initiating therapy [157].

Pancreatic risks further highlight the need for cautious use of GLP-1 RAs in certain populations. Although evidence does not definitively link GLP-1 RAs to an increased incidence of pancreatitis or pancreatic cancer, these medications are generally avoided in individuals with a history of pancreatitis unless a clear reversible precipitant is identified [140,158,159]. It is also important to note that GLP-1 RAs are not licensed for use in type 1 diabetes; however, they may provide benefits as adjuvant therapies to address weight-related issues in this population [160].

Finally, recent comparative data suggest that SGLT2 inhibitors may be a preferred option to GLP-1RAs for the therapeutic management of frail individuals with T2D. A meta-analysis of two large cohort studies (n = 224,742) assessing GLP-1 RAs versus SGLT2 inhibitors found that while both drug classes were generally well tolerated, SGLT2 inhibitors were associated with a significantly lower risk of MACE in frail individuals [161]. Furthermore, GLP-1 RAs were linked to a higher risk of severe hyperglycemia, with no significant differences in rates of severe hypoglycemia or diabetic foot complications. Without head-to-head comparisons, this data should be viewed as hypothesis- generating only. However, the findings underscore the need for individualized risk – benefit assessments when prescribing GLP-1 RAs such as semaglutide in frail populations, considering factors such as tolerability, route of administration, and the overarching goals of therapy in older adults with limited physiological reserve.

3.9. Semaglutide compared with other GLP-1 receptor agonists

As of 2024, semaglutide, exenatide, liraglutide, dulaglutide, and lixisenatide are the globally available GLP-1 RAs [162,163]. Efpeglenatide is unavailable in the US, and albiglutide has been discontinued [164]. Significant disparities exist among medications regarding effectiveness, safety profiles, dosage regimens, and pharmacokinetic features. Although GLP-1 RAs have a similar mechanism of action, there are substantial differences between the various medications in this family. Understanding these distinctions is critical for providing optimal patient care and developing tailored treatment options (Table 5).

Table 5.

Key distinctions between GLP-1 RAs (and the dual agonist tirzepatide) in different categories. Adapted from [162] and [191]).

Category		Aspect	Details
Efficacy difference		Glycemic control	Research suggests that tirzepatide and semaglutide are more effective than other GLP-1 RAs in reducing HbA1c levels [191–193].
		Weight loss	In clinical trials, tirzepatide and semaglutide reduced body weight by up to 23.6% and 17.4%, respectively [58,194]. In comparison, liraglutide and dulaglutide typically result in reductions of 3% to 9% [195].
		Kidney outcomes	Kidney benefits have been reported with semaglutide [13], dulaglutide [196], liraglutide [197], and tirzepatide [198]. However, the only definitive data for kidney protection for GLP-1 RAs is from the FLOW trial with semaglutide [13].
		CV outcomes	Semaglutide, liraglutide, and dulaglutide improve CV outcomes. Semaglutide reduced MACE by 26%, while liraglutide and dulaglutide decreased MACE by 13% and 12%, respectively [10,82,83].
Safety and tolerability		GI side effects	The prevalence and severity of GI side effects caused by GLP-1 RAs can vary [199]. Compared to dulaglutide, other GLP-1 RAs are associated with a slightly higher incidence of nausea and vomiting [200].
		Injection site reactions	All agents are normally moderate; however, the frequency might vary substantially among agents [201].
		Pancreatitis and thyroid safety	No major differences exist between agents [202].
		Half-life and dosing frequency	Native exenatide is taken twice a day and has a short duration of effect (4–6 hours) [203]. Liraglutide is suggested to be taken OD [204]. Semaglutide, tirzepatide, dulaglutide, and exenatide extended-release are long-acting medications administered QW [201,205].
Pharmacokinetics and dosing		Route of administration	Most GLP-1-RAs are given subcutaneously [201]. Semaglutide is the sole oral GLP-1 RA available [206].
		Size and structure	Liraglutide, semaglutide and dulaglutide are based on the human GLP-1 sequence, while exenatide and efpeglenatide are based on the non-human exendin sequence [207,208]. Tirzepatide is based on the structure of human GLP-1 and GIP [208]. Semaglutide, dulaglutide, and tirzepatide utilize albumin binding and improved fatty acid attachment, which results in a longer half-life [44,205].
Cost difference			Newer medications, like semaglutide and tirzepatide are often more costly than older options, such as liraglutide and exenatide [209].
Special populations		Renal impairment	Exenatide dosing requires adjustment for patients with mild renal impairment, but it is not recommended for those with severe renal impairment [210]. Semaglutide, tirzepatide, liraglutide, and dulaglutide can be administered without additional dosage adjustments for individuals with reduced kidney function [205,210]. For all GLP-1 RAs, caution should be exercised in severe renal impairment.
Considerations		CV risk	Semaglutide, liraglutide, and dulaglutide offer CV benefits and may be preferred for high-risk CV complications [211].

CV, cardiovascular; GI, gastrointestinal; GLP-1 RA, glucagon-like peptide 1 receptor agonist; HbA1c, hemoglobin A1c; MACE, Major Adverse Cardiovascular Events; OD, once-daily; QW, once-weekly.

In recent years, vigorous research has been conducted on developing dual and triple agonists related to GLP-1. Tirzepatide is a notable dual agonist that activates GLP-1 and gastric inhibitory polypeptide (GIP) receptors, enhancing insulin secretion, reducing glucagon secretion, delaying gastric emptying, and suppressing appetite [165,166]. The US Food and Drug Administration (FDA) has approved tirzepatide for T2D, and its major effects on promoting weight loss in the setting of obesity are also well-recognized [167]. The SURPASS-CVOT will provide definitive evidence on the impact of tirzepatide on CV risk relative to the GLP‐1 RA dulaglutide, which is also indicated for the reduction in CV risk for people with established CVD or multiple risk factors [168]. Clinical studies involving GLP-1 RAs therapy coupled with glucagon receptor (GCGR) agonists (survodutide) or amylin analogues (cagrilintide) are also demonstrating favorable metabolic-related outcomes [169–171].

The usefulness of triple agonists that target GLP-1 R, GIP, and the glucagon receptor is under investigation in clinical trials [163]. Examples include HM15211 and retatrutide (LY-3437943), which to date have shown excellent improvements glycemic control, outcomes related to metabolic dysfunction-associated liver dysfunction (MASLD), and significant weight reduction [172–175]. Triple agonists are still primarily in the development stage and have not been widely approved for use. In addition, oral non-peptide GLP-1 RAs, such as orforglipron [176] and danuglipron [177], are being tested in early phase clinical studies.

3.10. Practical considerations

The administration and management of semaglutide vary by formulation and indication, with each approach tailored to meet specific therapeutic goals, mitigate side effects, and ensure effective drug absorption. The subcutaneous formulation, provided as a pre-filled pen for QW administration, is used in chronic weight management with a gradual dosing schedule to help patients achieve a maintenance dose while minimizing GI side effects. Patients with comorbidities such as T2D or CVD may benefit from semaglutide’s positive metabolic effects, though regular monitoring of blood glucose and blood pressure is recommended. Additional guidance, including proper pen use, injection technique, rotation of injection sites, and protocols for missed doses, is critical for optimizing treatment adherence and minimizing local reactions.

For the oral formulation of semaglutide in T2D, specific instructions on administration – such as fasting before and after dosing – are essential to enhance absorption. Titration schedules are designed to help patients reach the therapeutic dose with minimal side effects, and close monitoring is advised for those with comorbid conditions like kidney impairment or CVD. Both formulations of semaglutide may carry risks of GI side effects, hypoglycemia (especially when combined with other antidiabetic medications), and gallbladder or pancreatitis concerns. Recently, concern has been raised about the risk of pulmonary aspiration during surgical procedures for people taking GLP-1 receptor agonist medications. The American Society of Anesthesiology (ASA) has released recommendations to mitigate this risk [178], and the FDA has added a warning to the label of GLP-1 RA medications to highlight the risk of aspiration [179].

Clinicians must also recognize that, despite their significant benefits, GLP-1 RA therapies are frequently discontinued, with real-world discontinuation rates ranging from 50% to 75% within the first 12 months [180]. This discontinuation often results in rapid weight regain and deterioration of cardiometabolic parameters. To enhance treatment persistence, proactive strategies are essential, including anticipatory counseling, timely management of adverse effects, and shared decision-making to educate patients about the potential consequences of discontinuation [180]. For a detailed breakdown of practical considerations and dosing protocols, please refer to Table 6.

Table 6.

Summary of practical guidance for initiating patients on semaglutide.

	Chronic weight management (subcutaneous: 0.25 mg, 0.5 mg, 1.0 mg, 1.7 mg, 2.4 mg QW) [52,54,55]	T2D or reduction of CV events (subcutaneous: 0.25 mg, 0.5 mg, 1.0 g, 2.0 mg QW) [45,47,48]	T2D (oral: 3 mg, 7 mg, 14 mg OD) [49,51]
Administration	The recommended approach for weight management includes the integration of semaglutide with a balanced diet and regular exercise. Administer semaglutide QW on the same day each week, with or without meals. Rotate injection sites between the abdomen, thigh, or upper arm to prevent irritation. Avoid injecting into areas with skin irritation or bruising. If a dose is missed, administer as soon as possible within 5 days of the missed dose. If more than 5 days have passed, skip the missed dose and resume the usual weekly schedule.	Administer semaglutide QW on the same day each week, with or without meals. Rotate injection sites between the abdomen, thigh, or upper arm to prevent site irritation. Avoid areas with inflammation, bruising, or scarring. If a dose is missed, administer as soon as possible within 5 days. If more than 5 days have passed, skip the missed dose and continue with the next scheduled dose.	Take semaglutide OD on an empty stomach at least 30 minutes before any food, drink, or other oral medications. This timing maximizes absorption. Swallow the tablet whole with no more than 120 mL of plain water. Avoid breaking, chewing, or crushing the tablet. To ensure adequate absorption, wait at least 30 minutes after taking semaglutide before eating, drinking, or taking other oral medications.
Dose titration	Begin with a 0.25 mg dose QW for the first 4 weeks to minimize GI side effects. To help patients adjust and reduce side effects, the dose is increased every four weeks to the next level (0.5 mg, then 1 mg, then 1.7 mg). Achieve the total maintenance dose of 2.4 mg by week 17. If patients cannot tolerate the 2.4 mg dose, consider maintaining the highest tolerated dose rather than discontinuing therapy.	Begin at 0.25 mg QW for 4 weeks. Note that this dose is intended for initial tolerance and does not effectively control blood glucose. After 4 weeks, increase to 0.5 mg QW. If additional glycemic control is needed, increase to 1 mg QW after at least 4 weeks on the 0.5 mg dose. The recommended maintenance dose for semaglutide in T2D management is up to 1 mg QW, though some patients may benefit from higher doses under close supervision.	Begin with 3 mg OD for the first 30 days. Note that this dose is for initial tolerance only and does not provide effective glucose control. After 30 days, increase to 7 mg OD. After 4 weeks on this dose, assess blood glucose control. If additional glycemic control is required, increase to the maximum recommended dose of 14 mg OD after at least 4 weeks on the 7 mg dose.
Comorbidities	Monitor blood glucose levels regularly, as semaglutide can improve glycemic control and may reduce the need for other antidiabetic medications, especially insulin and sulphonylureas Semaglutide may be beneficial for patients with CVD; however, monitor for symptoms like dizziness or dehydration, which can affect BP. Although dose adjustments are not required for mild or moderate kidney or liver impairment, renal and hepatic function should be monitored regularly, especially in patients with severe impairment.	Semaglutide has demonstrated CV benefits and is especially suitable for patients with T2D and CVD. Monitor BP and signs of dehydration, as semaglutide may lower BP. Dose adjustment is not required for mild to moderate kidney impairment. However, monitor renal function, especially in patients with severe impairment or those who experience significant nausea and vomiting. In patients on other diabetes medications, such as insulin or sulfonylureas, monitor for hypoglycemia, as adjustments may be necessary to reduce the risk of low blood sugar.	Monitor BP regularly, as some patients may experience a reduction. No dose adjustments are necessary for patients with mild or moderate renal impairment. Still, close monitoring is advised in those with severe impairment, especially if they experience dehydration due to GI side effects. As semaglutide may increase the risk of hypoglycemia when combined with insulin or sulfonylureas, monitor blood glucose closely and consider adjusting the dose of these agents if necessary.
Management of side effects	Common side effects include nausea, vomiting, diarrhea, and constipation. Advise patients to eat smaller meals, avoid rich or spicy foods, and stay hydrated. If symptoms persist, consider pausing the dose increase or reducing the dose temporarily. Though less common, patients on other hypoglycemic agents (e.g., insulin or sulfonylureas) should be monitored closely for hypoglycemia, with adjustments to other medications as needed. Inform patients of potential symptoms of gallbladder disease (e.g., abdominal pain, jaundice), as semaglutide may increase the risk. Evaluate any signs or symptoms promptly. Local reactions such as redness, swelling, or itching may occur. Encourage patients to rotate injection sites and apply a cold compress if irritation persists.	Common side effects include nausea, vomiting, diarrhea, and constipation, often seen during dose escalation. Advise patients to eat smaller meals and avoid heavy or fatty foods. Symptoms generally improve over time; if persistent, consider slowing dose escalation. Patients using semaglutide with insulin or sulfonylureas are at an increased risk for hypoglycemia. Adjust other diabetes medications as needed and educate patients on recognizing and managing symptoms of low blood sugar. Severe dehydration from prolonged vomiting or diarrhea can lead to kidney injury, especially in patients with preexisting kidney issues. Encourage patients to maintain hydration and seek medical help if they experience prolonged GI symptoms. Inform patients to watch for symptoms of pancreatitis (e.g., severe abdominal pain) or gallbladder disease. If pancreatitis is confirmed, discontinue semaglutide and manage symptoms promptly.	Nausea, vomiting, and diarrhea are common during initiation and dose escalation. Advise patients to eat smaller, less fatty meals and to remain hydrated. Symptoms often subside with continued use. When combined with insulin or sulfonylureas, there is an increased risk of hypoglycemia. Educate patients on recognizing symptoms and adjusting other diabetes medications as needed. Watch for symptoms of pancreatitis, such as persistent severe abdominal pain. If pancreatitis is suspected, discontinue semaglutide and manage symptoms promptly. Due to its unique absorption needs, semaglutide may interact with or be impacted by other oral medications. Review the patient’s medication list to avoid interactions and counsel on timing adjustments if needed.

BP, blood pressure; CV(D), cardiovascular (disease); GI, gastrointestinal; OD, once-daily; QW, once-weekly; T2D, type 2 diabetes mellitus.

Finally, SGLT2 inhibitors and GLP-1 RAs should not be viewed as competing therapies but as complementary options that may offer additive benefits beyond those achieved with either medication alone. While no outcome RCTs have confirmed these synergistic effects, observational studies suggest that combination therapy is promising for enhancing patient outcomes [181,182]. For example, a recent meta-analysis by Karakasis et al., including over 39,000 individuals with T2D and established or high CV risk, found that combination therapy significantly reduced the risk of MACE, all-cause mortality, and CV mortality compared to monotherapy [183].

4. Contemporary approaches to optimizing cardiovascular protection

Despite endorsements from multiple organizations [2,37–41], GLP-1 RAs remain underutilized, particularly in high-risk CV populations. At the time of writing, three GLP-1 RAs – semaglutide, liraglutide, and dulaglutide – are FDA-approved for the prevention of CV events in adults with T2D and established CVD [45,184,185]. The collective evidence from a recent meta-analysis of RCTs suggests that GLP-1 RAs reduce the risk of MACE by 13%, CV death by 14%, non-fatal MI by 10%, and non-fatal stroke by 13% in patients with T2DM [186], while in patients with established CVD without T2DM, semaglutide reduces the risk of MACE by 20%, CV death by 15%, non-fatal MI by 28%, and non-fatal stroke by 7% [10]. However, a retrospective review from a major healthcare US institution (2013–2019) showed that only 1.6% of nearly 21,000 patients with both CVD and T2D were prescribed GLP-1 RAs, with cardiologists accounting for a mere 1.4% of those prescriptions [187]. This trend holds true on a larger scale; the Getting to an Improved Understanding of Low-Density Lipoprotein Cholesterol and Dyslipidemia Management (GOULD) registry revealed that only 7.9% of high-risk individuals with ASCVD and T2D received GLP-1 RAs [188].

This underutilization highlights a critical opportunity for cardiologists. Cardiologists are uniquely positioned as specialists in CV care to advocate for GLP-1 RAs and champion their integration into routine practice for eligible patients. Not only are patients with T2D more likely to see a cardiologist than an endocrinologist – especially those with ASCVD – but cardiologists are also trusted advisors in reducing CV risks [189]. Cardiology-led initiatives to inform, educate, and engage patients and other healthcare providers can dismantle barriers such as therapeutic inertia and lack of awareness of CV benefits.

The evidence underscores the importance of GLP-1 RAs, particularly semaglutide, in delivering cardioprotective benefits beyond glycemic control or weight loss alone. These therapies, redefined by some as comprehensive CKM risk-reduction agents [190], align directly with cardiologists’ goals and mark a paradigm shift in our approach to CVD. Now is the time for cardiologists to break down barriers to GLP-1 RA adoption.

5. Conclusion

Recent guidelines emphasize the importance of multidisciplinary approaches in the prevention, risk stratification, and management of individuals with CKM syndrome. Identifying therapies that benefit all three domains of this syndrome represents a pivotal advancement in CKM management. Semaglutide’s metabolic benefits, including significant weight loss and improved glycemic control, are well-established, alongside its CV benefits in individuals with diabetes. Its recent recognition as a fourth pillar in DKD treatment underscores its expanding role in CKM care.

Looking ahead, cardiologists and other healthcare professionals are monitoring semaglutide’s positioning as a CV-protective agent in non-diabetic individuals, as demonstrated by the SELECT trial. There is also interest in whether GLP-1 RAs might become a fifth pillar in HF management, particularly given promising results in HFpEF. Future research will likely refine dosing regimens and explore combining semaglutide with finerenone or SGLT2 inhibitors to enhance CKM outcomes. Trials of dual and triple receptor modulators offer exciting possibilities. The SURPASS-CVOT trial, expected in 2025, will assess whether tirzepatide (a dual GLP-1 and GIP RA) provides additive CV benefits over single-hormone modulation.

Adopting a holistic approach that recognizes the interconnected nature of CKM syndrome could improve patient outcomes. Semaglutide is poised to play a central role, delivering benefits across metabolic, CV, and kidney domains. Further research into its mechanisms will be crucial to unlocking its full potential.

Funding Statement

Novo Nordisk Pharmaceuticals Pty. Ltd. funded this manuscript. The funders had no role in design, data collection and analysis, publication decision, or manuscript preparation.

Article highlights

CKM syndrome

• CKM syndrome integrates obesity, T2D, CVD, and CKD under a unified framework due to shared biological and social risk factors.

• Semaglutide, a GLP-1 RA, is emerging as a cornerstone therapy for CKM syndrome by addressing weight loss, glycemic control, CV, and kidney protection.

CV benefits

• The SUSTAIN-6, SELECT, and SOUL trials demonstrated that semaglutide reduces MACE, including non-fatal MI, stroke, and CV death, in individuals with and without T2D.

• Semaglutide improves symptoms and reduces hospitalizations for HF, particularly in individuals with HFpEF and obesity.

Kidney benefits

• Semaglutide slows CKD progression, reduces albuminuria, and preserves kidney function in individuals with T2D or obesity. The FLOW trial confirmed a 24% reduction in major kidney events, underscoring its role as a fourth pillar of DKD management.

Metabolic and weight loss effects

• Semaglutide consistently delivers significant weight loss (up to 17%) and improves glycemic control in diabetic and non-diabetic populations. These benefits extend to reducing prediabetes progression and enhancing cardiometabolic risk factors.

Emerging benefits

• New research links semaglutide to improvements in AF, MASLD, osteoarthritis, and HIV-associated lipohypertrophy.

Safety profile

• Semaglutide’s side effects are primarily GI in nature and dose-related, including nausea and vomiting, but generally resolve over time. Emerging concerns include thyroid risks, progression of diabetic retinopathy, and loss of lean muscle mass with rapid weight reduction.

Real-world data and practical use

• Real-world studies validate semaglutide’s effectiveness and safety, mirroring trial outcomes across diverse populations.

• Practical considerations include semaglutide’s titration schedule, administration methods (subcutaneous or oral), and its integration with therapies like SGLT2 inhibitors.

Future perspectives and call to action

• Ongoing trials, like SOUL and SURPASS-CVOT, aim to refine semaglutide’s role in CV protection and assess the efficacy and safety of dual-acting medications like tirzepatide.

• Cardiologists, endocrinologists, and primary care providers should consider advocating for the use of semaglutide in high-risk CKM patients, given its potential to address interconnected metabolic, CV, and kidney disorders.

Disclosure statement

R MacIsaac has received research grants from Novo Nordisk, Servier, Medtronic, The Rebecca Cooper Medical Research Foundation, St Vincent’s Research Foundation, The Juvenile Diabetes Research Foundation, Grey Innovations, The Diabetes Australia Research Trust/Program and The National Health and Medical Research Council of Australia. He has also received honoraria for lectures from Eli Lilly, Novo Nordisk, Sanofi Aventis, Astra Zeneca, Merck Sharp & Dohme, Novartis and Boehringer Ingelheim. He is on the advisory boards for Novo Nordisk, Boehringer Ingelheim-Eli Lilly Diabetes Alliance, Astra Zeneca, and Merck Shape and Dohme. Novo Nordisk, Sanofi, Boehringer Ingelheim and Astra Zeneca have supplied travel support. He has been a principal investigator for industry-sponsored clinical trials by Novo Nordisk, Sanofi, Bayer, Johnson-Cilag and AbbVie. He was an investigator for the semaglutide trials SUSTAIN-6 and FLOW and was on the global expert panel for the FLOW trial. The author has no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Brad Dalton of medScript Communications provided medical writing and editorial support for this article, which Novo Nordisk funded.