How GLP-1 Receptor Agonists and SGLT2 Inhibitors Differ and Work Together to Lower Heart Disease Risk

GLP-1 receptor expression has been demonstrated in a wide range of organs and tissues, with the highest levels found in the beta cells of the pancreatic islets of Langerhans [14] and in specific regions of the central nervous system, including the amygdala, nucleus accumbens, and substantia nigra [15]. In the heart, GLP-1 is expressed in both atrial and ventricular tissues, including the sinoatrial node [14,16], and the presence of its receptors has also been detected on the surface of endothelial cells in blood vessels [17].

GLP-1 was first described in 1987 as an incretin hormone produced by the gastrointestinal tract after food intake that stimulates insulin secretion in a glucose-dependent manner [14,15]. Its beneficial effects on appetite regulation, energy intake, and body weight were identified later, in 1998 [16]. Similar to other incretin hormones, GLP-1 is present in the plasma at very low concentrations during fasting [17]. However, its production significantly increases after food intake, primarily in the L-cells of the small intestine—particularly the lower part of the jejunum—as well as in the colon and rectum. This production is mainly stimulated by carbohydrates and triglycerides absorbed during digestion and their breakdown products and, to a lesser extent, by proteins and amino acids. Among amino acids, glutamine has been shown to be a particularly strong stimulator of GLP-1 secretion [18]. GLP-1 concentrations begin to rise approximately 10–15 min after eating, reaching peak levels between 45 and 90 min post-meal. The stimulation of GLP-1 production triggered by food intake and absorption may also be mediated by glucose-dependent insulinotropic peptide (GIP), produced in the upper gastrointestinal tract, along with other enteroendocrine hormones [19] and neurotransmitters via the intramural plexus [20].

Under physiological conditions, GLP-1 is rapidly degraded within minutes by dipeptidyl peptidase-4 (DPP4). In contrast, GLP-1 RAs are resistant to DPP4-mediated degradation, resulting in significantly prolonged half-lives compared to native GLP-1. Sustained and meal-independent activation of the GLP-1 receptor enables prolonged glycemic control, appetite regulation, and continuous direct cardiovascular effects. Most GLP-1 RA-based therapies are administered via subcutaneous injection: twice daily (exenatide), once daily (lixisenatide and liraglutide), or once weekly (exenatide once weekly, dulaglutide, albiglutide, and semaglutide) [21]. The first oral formulation is oral semaglutide, which has demonstrated efficacy comparable to that of injectable GLP-1 RAs [22,23]. In addition to pure GLP-1 RAs, the first dual GLP-1/GIP receptor agonist, tirzepatide, has also been introduced. Furthermore, the development of several other dual- and triple-receptor agonist/antagonist therapies is currently underway (Table 1) [24].

Figure 1 summarizes the role of GLP-1 receptors and the mechanism of action of GLP-1 receptor agonists, focusing on their cardiovascular effects.

In healthy individuals, nearly all filtered glucose is reabsorbed, so glucose does not appear in the urine. Glucose reabsorption is partly mediated by glucose transporter proteins (GLUT) and partly through an active transport mechanism involving SGLT proteins, which are also involved in the transport of amino acids, certain ions, and vitamins alongside glucose [25]. SGLTs comprise a large protein family. Among them, the low-capacity isoform SGLT1 is present not only in the small intestine but also in the trachea, prostate, testes, skeletal muscle, heart, and certain regions of the brain (such as the hippocampus), as well as in the kidneys. In contrast, the high-capacity SGLT2 isoform is found almost exclusively in segment 1 of the proximal tubule of the kidneys, where it is responsible for 90% of total glucose reabsorption. It is also in much lower concentrations in the thyroid gland, heart, liver, and brain. Other members of the SGLT family, such as SGLT3, are widely distributed throughout the body and function mainly as glucose sensors, while the roles of other forms (SGLT4, SGLT5, and SGLT6) remain poorly understood in humans [26] (Figure 2).

Approximately 80–90% of filtered glucose is reabsorbed in the S1 segment of the proximal tubule by the SGLT2 protein, while the remaining 10–20% is reabsorbed in the S2 segment via SGLT1. In diabetes, due to increased SGLT2 expression, the amount of reabsorbed glucose significantly rises. However, even with complete SGLT2 inhibition, around 50–60% of filtered glucose is still reabsorbed due to the enhanced activity of SGLT1 proteins [27,28,29]. In both proteins, the energy required for active glucose transport is provided by the Na⁺/K⁺ ATPase pump located in the basolateral membrane of the proximal tubule. Following active transport, glucose exits into the interstitial space and then into the peritubular capillaries through glucose transporter (GLUT) proteins. Specifically, SGLT2 works in conjunction with GLUT2, while SGLT1 functions alongside GLUT1 [26]. Due to this mechanism, glucose reabsorption is coupled with sodium (Na⁺) reabsorption. The increased Na⁺ reabsorption activates the renin–angiotensin system, which leads to vasodilation of the afferent arteriole and vasoconstriction of the efferent arteriole. This raises intraglomerular pressure and the glomerular filtration rate (GFR), contributing to glomerular damage [30,31].

Currently, there are three main representatives of selective SGLT2 inhibitors: empagliflozin, dapagliflozin, and canagliflozin (Table 1). Their main mechanism of action is to inhibit SGLT2 in the proximal portion of the nephron, with consequent glycosuria and natriuretic effects, attenuation of glomerular hyperfiltration, improvement of blood pressure levels, and weight reduction [32]. Furthermore, these agents have antioxidant, antifibrotic, and anti-inflammatory actions due to the reduction in glycosylation products and the expression of inflammatory molecules [33].

The cardiorenal benefits of SGLT2 transporter inhibitors, introduced as antidiabetic agents, far exceed the clinical gains expected from their antihyperglycemic effects alone (a 0.6–1% reduction in HbA1c levels). Although the full spectrum of the mechanism of action of SGLT2 inhibitors is likely still not fully understood, their introduction has led to the discovery of several previously unknown physiological effects [34].

The anti-inflammatory and anti-atherosclerotic effects of GLP-1 RAs are highly multifaceted [41]. Circulating GLP-1 RAs bind to GLP-1 receptors on the endothelial cell surface, activating adenylate cyclase. This leads to an increase in intracellular cAMP levels, which in turn reduces the expression of monocyte chemoattractant protein-1 (MCP-1), intercellular adhesion molecule-1 (ICAM-1), and vascular cell adhesion molecule-1 (VCAM-1), thereby inhibiting the adhesion and transmigration of myeloid cells into the vascular wall [42]. By reducing the uptake of oxidized LDL, GLP-1 RAs suppress foam cell formation [43]. Additionally, they inhibit vascular smooth muscle cell proliferation and platelet activation, thus reducing intravascular thrombus formation [42]. Through activation of the phosphoinositide 3-kinase (PI3K) signaling pathway, they suppress the expression of various pro-inflammatory cytokines, including interleukin-6 (IL-6), interleukin-1β (IL-1β), C-reactive protein (CRP), and tumor necrosis factor-alpha (TNF-α). Concurrently, by activating endothelial nitric oxide synthase (eNOS), they increase the production of the vasodilator nitric oxide (NO) [44]. A further beneficial effect is the downregulation of matrix metalloproteinase (MMP) expression, which may enhance the stability of existing atherosclerotic plaques [45] (Figure 3).

Among immune system cells, intraepithelial lymphocytes of the gastrointestinal tract express the highest levels of the GLP-1 receptor [46]. Modulation of gastrointestinal immune function is thought to contribute significantly to the favorable alterations in gut microbiome composition observed with GLP-1 RA therapy. However, the impact of these changes on the cardiovascular system is likely indirect [47,48].

In T2DM, the associated atherogenic dyslipidemia—characterized by elevated triglyceride levels; decreased high-density lipoprotein cholesterol (HDL-C) levels; and an increased proportion of small, dense low-density lipoprotein (LDL) particles—represents a significant risk factor for the development of cardiovascular complications. Therefore, managing these lipid abnormalities is of high importance [49,50]. Reducing total cholesterol and LDL cholesterol (LDL-C) levels is also a key component of cardiovascular risk reduction in T2DM [51]. GLP-1 RAs exert favorable effects on lipid parameters through multiple mechanisms [52]. They have a direct impact on hepatic lipid metabolism by downregulating the expression of several key enzymes involved in lipogenesis, including sterol regulatory element-binding protein-1c (SREBP-1c), fatty acid synthase (FAS), stearoyl-CoA desaturase 1 (SCD1), and acetyl-coenzyme A carboxylase (ACC), thereby reducing de novo hepatic triglyceride synthesis [53]. Moreover, by inhibiting intestinal microsomal triglyceride transfer protein (MTP) and Apolipoprotein B48 (ApoB48) synthesis, GLP-1 RAs attenuate hepatic very low-density lipoprotein (VLDL) secretion [54]. Additionally, liraglutide has been shown to decrease proprotein convertase subtilisin kexin 9 (PCSK9) expression, which contributes to a reduction in plasma cholesterol levels [55]. The enteric nervous system is also likely to be influenced by GLP-1 RA therapy; however, its specific effects on lipid metabolism remain to be elucidated. Activation of the GLP-1 receptor pathway in the central nervous system, via portal afferent vagal fibers, reduces sympathetic nervous system activity, which in turn decreases chylomicron and VLDL secretion, thereby attenuating postprandial hyperlipidemia [56]. According to a recently published meta-analysis including 76 studies and a total of 39,246 patients with T2DM, only PEG-loxenatide was found to significantly increase HDL-C levels, while only semaglutide significantly reduced LDL-C and total cholesterol levels. A significant reduction in triglyceride levels was observed specifically with tirzepatide treatment [57]. Furthermore, a recent one-year follow-up study showed that once-weekly semaglutide administration promotes favorable remodeling of atherogenic lipoprotein subfractions in T2DM [58].

The beneficial effect of GLP-1 RAs on body weight is well established in patients with T2DM, and this weight reduction also contributes to cardiovascular risk mitigation. The weight-lowering effect is mediated by complex mechanisms [59]. In the central nervous system, GLP-1 RAs suppress appetite, enhance satiety, positively influence food preferences, and increase energy expenditure [60]. Peripherally, they delay gastric emptying [61], improve glucose control by enhancing insulin secretion and reducing glucagon production, and modulate enteric hormonal regulation [62] and gut microbiota composition [63]. Additionally, they reduce adipose tissue inflammation and ectopic fat deposition [64].

According to a meta-analysis that included data from 53 studies, Cagrilintide/semaglutide was identified as having the most potent weight-reducing effect [57]. However, tirzepatide, retatrutide, orforglipron, semaglutide, and liraglutide also induced statistically significant weight loss compared to a placebo [57].

Cardiovascular safety trials have reported a moderate increase in heart rate and a variable but clinically significant reduction in blood pressure following GLP-1 RA treatment. In patients with diabetes, this effect is more pronounced, resulting in an additional average reduction of 2–3 mmHg [65].

The urinary excretion of glucose leads to a daily caloric loss of approximately 200–300 kcal, which, based on clinical observations, results in a body weight reduction of 3–5 kg, with considerable inter-individual variation [70]. This initial weight loss is counteracted by the development of compensatory hyperphagia, leading to a plateau in weight reduction after approximately six months. The total weight loss consists of approximately 55–75% body fat (predominantly subcutaneous, with a smaller proportion of visceral fat), 15–35% fluid loss, and around 10% loss of mineral content [71].

The natriuretic and glucosuric effects mediated by SGLT2 inhibitors lead to a reduction in preload, as well as pulmonary and systemic congestion [72]. However, the osmotic diuresis induced by SGLT2 inhibitors fundamentally differs from the mechanism of action of conventional diuretics. SGLT2 inhibitors promote the excretion of a larger volume of electrolyte-free water, primarily from the interstitial rather than the intravascular compartment. As a result, congestion is rapidly relieved without significant reductions in systemic blood pressure, arterial filling pressure, or organ perfusion [73]. In addition to reducing preload, SGLT2 inhibitors also decrease afterload, primarily through a 3–5 mmHg reduction in blood pressure and a decrease in arterial stiffness. Notably, the blood pressure and volume reductions associated with SGLT2 inhibitor use are not accompanied by an increase in heart rate, clearly suggesting a suppressive effect on sympathetic nervous system activity. Several in vivo and in vitro studies have demonstrated that the sympatholytic effects of SGLT2 inhibitors are mediated through reduced expression of norepinephrine and tyrosine hydroxylase in the kidneys and heart [74].

The administration of SGLT2 inhibitors induces a metabolic state in the body that closely resembles fasting, both at the molecular and cellular levels. These agents are unique among antidiabetic medications in that they enhance both gluconeogenesis and ketogenesis—mechanisms that play a key role in their beneficial effects observed in heart failure and renal insufficiency. A central component of these processes is the activation of silent information regulator 1 (SIRT1), a key regulator of genes involved in energy homeostasis and cellular equilibrium. During fasting, SIRT1 activation promotes ketone body production through increased free fatty acid oxidation and gluconeogenesis [75] (Figure 2).

The downstream effects of SIRT1 activation are mediated via pathways involving fibroblast growth factor 21 (FGF21) and peroxisome proliferator-activated receptor gamma coactivator-1 alpha (PGC-1α). SIRT1, PGC-1α, and FGF21 not only regulate genes and proteins involved in metabolism but also support the function of peroxisomes and mitochondria, thereby contributing to overall energy balance. In addition to these metabolic effects, SGLT2 inhibitors enhance antioxidant enzyme activity, reduce oxidative stress, and attenuate pro-inflammatory processes in both the heart and vasculature. SIRT1 signaling also stimulates autophagy, facilitating the removal of dysfunctional intracellular mitochondria, lysosomes, and other organelles, thereby reducing cellular stress [75]. Furthermore, the reduction in hyperglycemia leads to decreased activation of the renin–angiotensin–aldosterone system (RAAS) and a lower accumulation of advanced glycation end products (AGEs), which collectively reduce myocardial fibrosis, arterial stiffness, and improve diastolic relaxation [76]. Another cardioprotective mechanism of SGLT2 inhibitors involves the direct inhibition of sodium–hydrogen exchanger 1 (NHE1), which results in decreased cytoplasmic Na⁺ and Ca²⁺ levels, while increasing mitochondrial Ca²⁺ concentration—further contributing to improved myocardial function [77].

The effects of SGLT2 inhibitors on lipids may not be clinically significant. Most studies have reported that LDL-C and HDL-C increase and decrease triglyceride levels [78].

A frequently cited issue related to the underutilization of GLP-1 RAs is the need for dose titration, which requires increased attention from both physicians and patients, as well as more frequent clinical visits. In contrast, SGLT2 inhibitors are administered at fixed doses, simplifying their use [94]. Gastrointestinal side effects, including nausea, vomiting, diarrhea, abdominal discomfort, and bloating, are among the most common adverse effects of GLP-1 RAs [95]. These are usually transient and can be successfully managed with gradual dose titration. The association between GLP-1 RA therapy and the risk of acute pancreatitis remains inconclusive. As the condition is rare, it does not pose a significant limitation to the routine clinical use of these agents [95]. Other serious adverse events, including those related to suicidal ideation or behavior, have not been found to occur more frequently during GLP-1 RA therapy [96]. However, it is important to note that the overall benefit–risk ratio of GLP-1 RAs remains highly favorable, particularly given their proven efficacy in reducing cardiovascular events, promoting weight loss, and improving glycemic control [97]. The risk of hypoglycemia is minimal with GLP-1 RA monotherapy or in combination with metformin. However, the risk may increase when these agents are combined with insulin or sulfonylureas, necessitating careful adjustment of concomitant therapeutic doses [98,99]. Reluctance to use injectable therapy could be a barrier, but the availability of oral semaglutide has alleviated this concern for many patients [100]. However, economic considerations and reimbursement restrictions continue to limit access to GLP-1 RAs in some healthcare systems [101,102]. Furthermore, frequently changing reimbursement regulations are challenging for many physicians to navigate, creating potential risks of audits or penalties [103,104]. Nevertheless, practical strategies such as comprehensive patient education, careful titration protocols, and individualized therapy selection may optimize tolerability and adherence, thereby increasing the real-world efficacy of GLP-1 RAs.

The underutilization of SGLT2 inhibitors is primarily attributed to concerns regarding adverse effects. The most common adverse reactions to SGLT2 inhibitors are genital and urinary tract infections, particularly among women and elderly patients. These infections are usually mild to moderate and can be managed with basic preventive measures, such as good personal hygiene and patient counseling [105,106,107]. With the expansion of the treated patient population, including an increasing number of elderly, multimorbid individuals, reports of euglycemic ketoacidosis have become more frequent. Euglycemic diabetic ketoacidosis, although rare, has been reported, particularly during acute illness, the perioperative period, and prolonged fasting. Appropriate risk-mitigation strategies, such as discontinuing the drug in the event of catabolic states, ensuring adequate hydration, and monitoring patients, can effectively minimize this complication [108]. However, with appropriate caution and adherence to safety guidelines, this complication is generally avoidable [109]. Similar to GLP-1 RAs, SGLT2 inhibitors are associated with a low risk of hypoglycemia, which is clinically relevant only when combined with insulin or insulin secretagogues. In such cases, reducing the dose of the latter agents is recommended [110]. Although the cost of therapy is more favorable compared to GLP-1 RAs, the price of the medication may still limit its initiation in patients with disadvantaged socioeconomic status [102]. Furthermore, prescription regulations also pose practical limitations in routine clinical practice. While cost and the need for a prescription may limit their wider use, the prognostic and preventive benefits of SGLT2 inhibitors clearly outweigh the manageable risks, particularly in patients with concomitant cardiovascular or renal disease.

In everyday clinical practice, the decision regarding the optimal therapy for patients with T2DM is influenced by multiple factors, including scientific evidence, clinical guidelines, physician experience, treatment costs, prescribing restrictions, the presence of comorbidities and potential side effects, and the individual preferences of both the physician and the patient [111]. In alignment with professional recommendations, GLP-1 RAs are prioritized in patients with established atherosclerotic cardiovascular disease (such as coronary artery disease, stroke, or peripheral artery disease) and significant excess body weight. In contrast, SGLT2 inhibitors may be preferred in cases of chronic kidney disease or heart failure [13,112]. However, in most patients, these comorbid conditions frequently coexist—even if one predominates clinically—making therapeutic choices more complex. Therefore, when cost and reimbursement considerations allow, the combined use of a GLP-1 RA and an SGLT2 inhibitor should be considered in patients with T2DM. This approach aims to maximize the complementary cardiovascular, renal, and metabolic benefits offered by the two drug classes.

A comparison of the mechanisms of action of the two drug classes clearly demonstrates that both exert broad and substantial beneficial effects on cardiovascular function [113]. These effects are partly complementary and partly synergistic in nature, providing a strong rationale for their combined use [114] (Figure 5). It has now become evident that the concomitant administration of these two modern therapeutic classes offers significant clinical benefit for patients with T2DM.

To date, three randomized clinical trials have assessed the combination of GLP-1 RA and SGLT2 inhibitor therapy. The DURATION-8 Study was a multicenter, double-blind, randomized controlled trial that aimed to compare the effects of exenatide once weekly plus dapagliflozin, exenatide once weekly alone, or dapagliflozin alone added to metformin monotherapy in patients with T2DM. The study proved that exenatide plus dapagliflozin provided sustained improvements in glycemia, weight, and systolic blood pressure over 52 weeks as well as over 2 years, with no unexpected safety findings [115,116,117].

AWARD-10 was a phase 3b, double-blind, parallel-arm, placebo-controlled, 24-week study on patients with inadequately controlled T2DM taking stable doses of an SGLT2 inhibitor with or without metformin. Based on the results, dulaglutide as an add-on treatment to SGLT2 inhibitors resulted in significant and clinically relevant improvements in glycemic control, with acceptable tolerability that is consistent with the established safety profile of dulaglutide [118].

The SUSTAIN 9 double-blind, parallel-group trial enrolled adults with T2DM and aimed to investigate the efficacy and safety of semaglutide when added to SGLT2 inhibitor therapy. The results showed that adding semaglutide to SGLT2 inhibitor therapy significantly improves glycemic control and reduces body weight in patients with inadequately controlled T2DM and is generally well tolerated [119].

According to the findings of a meta-analysis of eight randomized controlled trials, GLP-1 RA and SGLT2 inhibitor combination therapy showed superior effects in reducing HbA1c, body weight, fasting and postprandial serum glucose levels, systolic blood pressure, body mass index, and LDL-C, without major safety issues, when compared with monotherapy in patients with T2DM [120]. Several further trials and meta-analyses have been published in the last few years with similar conclusions [121,122,123,124,125].

Regarding the reduction in cardiovascular risk, less data is available. However, a meta-analysis of the AMPLITUDE-O and HARMONY Outcomes trials demonstrated that GLP-1 RA therapy reduced the risk of atherosclerotic cardiovascular events and hospitalization due to heart failure, independently of baseline SGLT2 inhibitor use, suggesting an additional risk-reducing effect of the combination therapy [126]. Subgroup analysis from the EXSCEL trial indicated that the addition of exenatide to SGLT2 inhibitor therapy improved cardiovascular outcomes and reduced mortality [127]. Furthermore, a meta-analysis including data from 12 trials showed that the addition of an SGLT2 inhibitor to GLP-1 RA therapy significantly reduced the risk of MACEs [128]. A study conducted in the United Kingdom supports the idea that adding an SGLT2 inhibitor to ongoing GLP-1 RA therapy—or vice versa—significantly reduces the risk of MACEs, as well as severe renal outcomes [129]. Although an increasing use of combination therapy can be observed in patients newly diagnosed with T2DM, it still falls short of the levels recommended by current clinical guidelines [130,131].

According to the available data, combination therapy is safe and well tolerated; the risk of adverse events does not exceed that observed with monotherapy [114].

In patients with T2DM mellitus, both quality of life and long-term prognosis are fundamentally influenced by whether they receive treatment with GLP-1 RAs and/or SGLT2 inhibitors. Despite compelling evidence and clear recommendations in current clinical guidelines, including ADA/EASD Consensus Reports [132] and ESC Guidelines 2023 [87] supporting their use as monotherapy and in combination, these agents remain underutilized in everyday clinical practice. The 2025 ADA/EAS update highlights the significance of the combined use of these two agents in the management of cardio-reno-metabolic (CKM) syndrome, a recommendation further supported by the results of the FLOW trial investigating the renal outcomes of semaglutide treatment [133,134]. In addition, metabolic dysfunction-associated steatohepatitis (MASH) is expected to emerge as a therapeutic target closely linked to cardiorenal–metabolic diseases in the near future [135].