Ten years of progress in type 2 diabetes and heart disease: advances in SGLT2 inhibitors and GLP-1 receptor agonists

The most common side effect of SGLT-2 inhibitors is polyuria, resulting from osmotic diuresis. Genital tract infections, affecting approximately 10-15% of women and less frequently in men, are another potential adverse effect (31, 32). Euglycemic diabetic ketoacidosis (euDKA), a rare but serious complication, has been primarily reported in patients with type 1 diabetes and may be precipitated by acute illnesses, inappropriate insulin dose reductions, or omissions (31).

Skin infections, such as Fournier’s gangrene, have been reported; their association with SGLT-2 inhibitors requires further confirmation through large, randomized trials (31). Genital fungal infections are up to four times more common in patients using SGLT-2 inhibitors (31, 32). The results of the CANVAS study showed a possible increased risk of amputations; however, neither this result nor the increased risk of fractures has been documented in other clinical trials of canagliflozin or other SGLT2 inhibitors, so further studies are required to establish a definitive link (32–35).

SGLT2 inhibitors should be discontinued in specific clinical scenarios to mitigate potential adverse events. Severe or recurrent genital mycotic infections and urinary tract infections warrant treatment suspension if they become problematic (36, 37). Patients presenting with euglycemic diabetic ketoacidosis require immediate cessation of SGLT2i therapy (36). Furthermore, it is recommended that SGLT2 inhibitors be discontinued during the perioperative period due to the risk of euDKA. This risk increases during the physiological stress associated with surgery and preoperative fasting, which can precipitate euDKA even in the absence of significant hyperglycemia. Additionally, treatment should be halted in elderly or frail individuals experiencing severe dehydration or orthostatic hypotension (36, 38).

Canagliflozin specifically should be discontinued in patients with a heightened risk of amputations, including those with a history of amputations, severe peripheral neuropathy, severe peripheral arterial disease, or active lower-limb ulcers or infections, as well as in individuals with an increased fracture risk, particularly those with previous osteoporotic fractures (34, 36, 37, 39). Although SGLT2 inhibitors do not typically increase the risk of AKI, their use should be halted during episodes of acute renal impairment (39). Although rare, cases of Fournier’s gangrene also necessitate immediate discontinuation of SGLT2 inhibitors to prevent further complications.

GLP-1 is a hormone belonging to the incretins that is produced in the gastrointestinal tract, by L cells, in response to the intake of nutrients, especially fat and glucose (40). Its release stimulates an increase in insulin secretion when stimulated by glucose at sufficient plasma levels (40). The effects of GLP-1 are not limited to the endocrinological component; there are receptors for these at the brain, liver, and gastrointestinal tract (41). It can influence renal function by increasing diuresis and natriuresis, and it can impact cardiac function by enhancing contractility and promoting cardiomyocyte survival. Additionally, GLP-1 can improve muscle insulin sensitivity and glucose uptake (42). These effects, including hemodynamic, metabolic, and anti-inflammatory actions, contribute to the cardio and renoprotective properties of GLP-1 RAs. By reducing intraglomerular pressure, decreasing inflammation, and mitigating oxidative stress, GLP-1 RAs can help preserve renal function, independent of glycemic control (43).

GLP-1 RAs like liraglutide and semaglutide, offer a therapeutic advantage over native GLP-1 by being resistant to degradation by dipeptidyl peptidase-4 (DPP-4). This resistance allows for prolonged exposure to GLP-1, resulting in sustained physiological effects. By activating GLP-1 receptors in the hypothalamus and brainstem, these analogs promote satiety, leading to reduced food intake and weight loss (40, 44).

Studies as Network Meta-analysis and clinical trials have shown that GLP1-RA can achieve a statistically significant decrease in HbA1C compared to placebo, as well as a weight reduction ranging between 1.3 and 8.65 kg (40, 45, 46). Furthermore, these analogues have the ability to stimulate natriuresis by inhibiting sodium reabsorption by decreasing the activity of sodium-hydrogen exchanger 3 (NHE3), resulting in a reduction in blood pressure in patients with diabetes (40, 46). In animal models, a modulatory effect has also been observed at the level of the carotid sinus, suggesting that this pharmacological class may influence sympathetic tone regulation during hyperglycemic states (47).

With regard to cardioprotection, several mechanisms have been proposed. GLP-1 RAs reduce macrophage adhesion to the endothelium, thereby inhibiting the formation of atherosclerotic plaques; they also suppress platelet activity, which may further contribute to cardiovascular protection (40). Moreover, these agents enhance cardiac glucose uptake and ATP production by increasing GLUT-1 translocation (40), and they modulate antioxidant, anti-inflammatory, and anti-apoptotic pathways (48).

Common side effects associated with GLP-1 receptor agonists (GLP-1 RAs) include gastrointestinal symptoms such as nausea (25–60%), diarrhea, and vomiting (5–15%) (16, 46). Although these adverse effects can be bothersome, they rarely lead to treatment discontinuation. Importantly, clinical trials have not demonstrated an increased risk of hypoglycemia with GLP-1 RAs compared to placebo (16). Less frequent side effects include injection site reactions, headaches, and nasopharyngitis (16).

While some studies have suggested a possible association between GLP-1 RAs and acute kidney injury (AKI), this has not been confirmed and appears to occur primarily in patients with underlying risk factors such as dehydration or severe gastrointestinal symptoms (49). Reports of preneoplastic pancreatic ductal disease exist, but experimental findings in mice have not been consistently replicated in human clinical trials. Although a potential association between GLP-1 RAs and gastrointestinal tumors has been proposed, current evidence does not support an increased risk of colorectal neoplasia (50).

GLP-1 RA therapy should be discontinued under specific clinical conditions to minimize risk. While a definitive causal relationship has not been established, the occurrence of acute pancreatitis necessitates immediate drug withdrawal, as recommended by the American Diabetes Association and the American College of Cardiology (37, 51). These agents are contraindicated in patients with a personal or family history of medullary thyroid carcinoma or multiple endocrine neoplasia type 2, based on findings from preclinical studies (21).

Treatment cessation should also be considered in patients who develop gallbladder complications, such as acute cholecystitis. Caution and close monitoring are warranted in individuals with preexisting diabetic retinopathy, due to a higher incidence of retinopathy-related complications observed in clinical trials, particularly with semaglutide (21, 37). In rare instances, severe hypersensitivity reactions, including anaphylaxis, require immediate discontinuation of GLP-1 RA therapy (52). Additionally, although uncommon, reported cases of diabetic ketoacidosis (DKA) associated with GLP-1 RAs also warrant prompt treatment cessation (53).

The management of DM requires a long-term perspective, emphasizing the importance of medication safety over time. The Food and Drug Administration (FDA) mandates that clinical trials demonstrate the cardiovascular safety of anti-diabetic medications. To assess this, randomized trials typically evaluate the primary outcome of “major adverse cardiovascular events” (MACE), which includes cardiovascular death, non-fatal stroke, and non-fatal myocardial infarction (MI). This rigorous evaluation has led to the accelerated recognition of the cardioprotective, renoprotective, and vasoprotective effects of SGLT2i (54, 55) (Figure 1).

The cardiovascular benefits of SGLT-2i are particularly evident in reducing the risk of hospitalization for HF, both in patients with and without T2DM. The DAPA-HF trial, which included 4744 patients with LVEF ≤40%, demonstrated a 26% reduction in the RR of hospitalization or emergency room visits for HF within 28 days of randomization (54, 61). The cardiovascular benefits of SGLT-2i are particularly evident in reducing the risk of hospitalization for HF, both in patients with and without T2DM. The DAPA-HF trial, which included 4744 patients with LVEF ≤40%, demonstrated a 26% reduction in the RR of hospitalization or emergency room visits for HF within 28 days of randomization. Furthermore, patients treated with dapagliflozin experienced a lower rate of cardiovascular death (9.6% vs. 11.5%), reflecting an 18% reduction in RR. In addition to these objective outcomes, the DAPA-HF study assessed quality of life using the Kansas City Cardiomyopathy Questionnaire (KCCQ) and found a significant improvement in the dapagliflozin-treated group compared to placebo, indicating a positive impact on patient-reported symptoms (62).

The EMPEROR-REDUCED trial, which included 3730 patients with HF and a left ventricular ejection fraction (LVEF) ≤40%, demonstrated a 25% reduction in the RR of cardiovascular death and HF hospitalization with empagliflozin 10 mg daily compared to placebo; hospitalization from IC was reduced approximately 30% (RR 0,70; IC del 95%, 0,58 a 0,85; P <0,001). While empagliflozin did not significantly reduce all-cause mortality, it improved renal outcomes, with a slower decline in GFR compared to placebo (63). Regarding renal outcomes, the decline in GFR was slower in the empagliflozin group, with an estimated –0.55 ml per minute per 1.73 m², compared with placebo, which was –2.28 ml per minute per year. This led to a reduction in the incidence of the composite renal outcome, defined as chronic dialysis, kidney transplantation, and a sustained decline in GFR (63).

Another trial that evaluated the efficacy and safety of empagliflozin was EMPEROR-Preserved; it included 5,988 patients with heart failure with preserved left ventricular ejection fraction, regardless of whether the patients had T2DM. Participants were randomly assigned to receive empagliflozin 10 mg or placebo once daily. There was a reduction in the RR in the primary outcome (cardiovascular death and hospitalization for heart failure) (RR 0.79, 95% CI 0.69-0.90). Highlighting the decrease in hospitalization for HF (0.71; 95% CI 0.60-0.83). In this study, it was unclear whether these benefits were preserved in subgroups of patients with higher left ventricular ejection fraction (>60%), as the result was not statistically significant (RR 0.87; 95% CI; 0.69-1.10) (64). It is also unclear whether this benefit was retained in patients who started treatment during the subacute phase, or in patients with an improved LVEF (54, 64).

In the DELIVER trial, in which participants were randomly assigned to receive dapagliflozin 10 mg or placebo once daily, 6263 patients with HF with LVEF >40% were enrolled. A significant reduction in RR was observed in the primary outcomes, such as cardiovascular death or worsening of HF, compared with placebo in the overall population (RR 0.82, 95% CI 0.73 to 0.92). Worsening of HF in the group of patients receiving dapagliflozin was 23% lower. These results were consistent both in patients with LVEF of 60% or more and in those <60%. In addition, the results were similar in prespecified subgroups, including patients with or without diabetes (65).

The SOLOIST-WHF trial evaluated the efficacy and safety of sotagliflozin in 1,222 patients with HF who were recently hospitalized for worsening of their baseline condition. This study demonstrated a significant risk reduction in a composite of cardiovascular death and worsening of HF (RR 0.67; 95% CI 0.52 to 0.85). Regarding hospitalizations and emergency department visits, the decrease in RR was 36%. These results were independent of LVEF (>50% or ≤50%) (66).

The DAPA-HF, EMPEROR-REDUCED, EMPEROR-Preserved, DELIVER and other trials mentioned above consistently demonstrate the efficacy of SGLT-2i in patients with HF, regardless of LVEF or the presence of diabetes. These studies establish SGLT-2i as a cornerstone therapy for HF across the disease spectrum (54, 61). Multiple meta-analyses performed on the most important studies have confirmed a significant risk reduction for a composite of cardiovascular death and hospitalization for heart failure, with the risk reduction for hospitalization being greater (67–69). In addition to the positive cardiovascular outcomes demonstrated in the studies discussed, early initiation of SGLT-2i is increasingly emphasized to reduce associated complications. This approach is supported by evidence on the results of studies such as the EMPULSE trial and the DICTATE-AHF trial (70–75).

SGLT2i have consistently demonstrated cardiovascular benefits in meta-analyses and recent studies, confirming their robust efficacy regardless of ejection fraction or the presence of diabetes. These findings support their role as a cornerstone therapy in the management of heart failure across the entire clinical spectrum (Table 1).

Several randomized clinical trials have demonstrated the cardiovascular benefits of GLP-1 RAs in patients with T2DM. Five of these trials have shown superiority in reducing MACE compared to placebo, while all have confirmed the cardiovascular safety of GLP-1 RAs (76).

A meta-analysis by Liu et al. (2022) suggests that GLP-1 RAs may be associated with a reduced risk of atrial arrhythmias. This analysis included five trials with a total of 31,314 patients. While the study found that semaglutide specifically reduced the risk of atrial arrhythmias and atrial fibrillation (AF), other studies have reported conflicting results regarding the arrhythmia risk associated with GLP-1 RAs (91).

GLP-1RAs have been shown to significantly reduce postprandial levels of triglycerides, apolipoprotein (Apo) B48 and ApoC-III, independently of gastric emptying. In addition, liraglutide has been shown to significantly modify lipoprotein metabolism by reducing chylomicron production. Additionally, they exert a neuroprotective effect independently of blood glucose levels (92). Some of the antiatherosclerotic effects that contribute to stroke prevention are increased plaque stability, reduced vascular smooth muscle proliferation, and increased nitric oxide, all of which translate into improved endothelial function (92). This effect has been observed in several cardiovascular outcome clinical trials. GLP-1RAs have been shown to exert a protective factor by reducing stroke (RR 0.84; 95% CI, 0.77-0.93) (93) (Table 2).

Multiple clinical trials have demonstrated the renoprotective effects of SGLT-2i and GLP-1 RAs in patients with T2DM and CKD. Studies such as EMPA-REG, CANVAS and DECLARE-TIMI 58, while not primarily focused on renal outcomes, have consistently shown that these medications can help preserve renal function (89, 94). In the EMPA-REG study, empagliflozin significantly reduced the risk for the composite renal outcome, which included doubling of serum creatinine, progression of macroalbuminuria, initiation of renal replacement therapy, or renal death (56). The CANVAS trial was a cardiovascular safety study; however, it suggested the presence of the renoprotective effects of canagliflozin in patients with T2DM and CKD. Canagliflozin-treated patients experienced a slower decline in GFR and an 18% reduction in the urea-albumin-creatinine ratio. Additionally, the risk of sustained doubling of serum creatinine, end-stage renal disease, and renal death was lower in the canagliflozin group (34).

Subsequent studies, such as CREDENCE, DAPA-CKD, and EMPA-KIDNEY, were specifically designed to investigate the renoprotective effects of SGLT-2i. The CREDENCE clinical trial evaluated the effects of canagliflozin 100 mg daily versus placebo in 4401 patients with T2DM and chronic kidney disease (CKD). With a mean follow-up of 2.6 years, the study demonstrated a 34% reduction in the relative risk (RR) of a composite renal outcome, including dialysis requirement, a decline in glomerular filtration rate (GFR) <15 ml/m²/1.73 m², kidney transplant requirement, doubling of creatinine, and cardiovascular or renal death (58).

The DAPA-CKD trial, which specifically evaluated the efficacy of dapagliflozin in patients with CKD, regardless of T2DM status, found a 39% reduction in the relative risk of a composite renal outcome, including a decline in GFR by at least 50%, end-stage renal disease, or renal or cardiovascular death. Dapagliflozin-treated patients had a lower incidence of these events 6.6% vs. 11.3% in the placebo group (0.61; 95% CI, 0.51 to 0.72) (95).

The results of the EMPA-KIDNEY study showed that its primary endpoint was the first occurrence of the composite outcome of kidney disease progression, defined as end-stage kidney disease, a sustained decline in eGFR to <10 mL per minute per 1.73 m², a sustained decline in eGFR of ≥40% from baseline, renal death, or cardiovascular death. The study included 6,609 patients, who were followed for 2.0 years. Emplagliflozin demonstrated a 28% reduction in the risk of the primary endpoint. In addition, it also showed a reduction in the risk of kidney disease progression by 29% (0.71; 95% CI; 0.62–0.81) (96).

Regarding GLP-1 RAs, the LEADER, SUSTAIN-6, REWIND, PIONEER 6 and AMPLITUDE-O studies have shown nephroprotective effect, especially in preventing the occurrence of macroalbuminuria. In the LEADER study, the group treated with liraglutide had a lower risk of nephropathy, with a reduction of 26% (78). In the SUSTAIN-6 trial, it was observed that semaglutide reduced the risk of nephropathy in patients treated with the drug compared to those treated with placebo (79). On the other hand, in the AMPLITUDE-O study, which included 4,076 patients, was shown that efpeglenatide significantly reduced the composite renal outcomes by 32% (a decrease in renal function or the occurrence of macroalbuminuria according to criteria defined in the study) (0.68; 95% CI, 0.57-0.79). This significant difference between the GLP-1 and placebo groups was mainly driven by a marked reduction in the incidence of macroalbuminuria (59). The REWIND trial also provided results consistent with previous studies. This study showed that the dulaglutide treated group had a lower risk of a composite renal outcome, (which includes the occurrence of macroalbuminuria, a 30% decrease in estimated glomerular filtration rate (eGFR) or the need for renal replacement therapy, (0.85, 95% CI 0 77–0.93), and the strongest statistically significant outcome was the reduction in the occurrence of macroalbuminuria (97).

The FLOW trial enrolled 3533 patients with T2DM and chronic kidney disease at high risk for kidney failure, cardiovascular events, and death. Participants were randomly assigned to receive subcutaneous semaglutide 1.0 mg weekly or placebo. The primary outcome was major kidney disease events. The semaglutide group experienced a 24% lower risk of the primary outcome compared to the placebo group (p<0.001). Additionally, the semaglutide group had an 18% lower risk of MACE (98). However, the SOUL trial, evaluating oral semaglutide, did not demonstrate a statistically significant reduction in major kidney disease events (90).

SGLT2 inhibitors have demonstrated significant renoprotective effects in patients with type 2 diabetes and CKD, reducing the risk of renal disease progression, the need for dialysis or kidney transplantation, and renal or cardiovascular mortality. GLP-1 RAs also confer renal benefits, particularly by reducing macroalbuminuria and slowing the progression of nephropathy. Together, these findings underscore the important role both drug classes play in renal protection for patients with type 2 diabetes.

Subgroup analyses from the DAPA-HF trial revealed that women with heart failure experienced a reduction in the primary composite outcome with dapagliflozin (RR 0.79; 95% CI, 0.59–1.06), comparable to men (RR 0.73; 95% CI, 0.63–0.85), with no significant interaction by sex (62). Similar findings were reported in the CANVAS and EMPA-REG OUTCOME trials, where no significant sex-based differences were observed (34, 56). In contrast, a meta-analysis by Rivera et al. (2023) demonstrated a significant reduction in the primary composite outcome for both men (RR 0.77; 95% CI, 0.72–0.84; p < 0.00001) and women (RR 0.75; 95% CI, 0.67–0.84; p < 0.00001) receiving SGLT-2 inhibitors compared to placebo (99). Another meta-analysis evaluating three CVOTs with SGLT-2 inhibitors (N = 34,322) showed a reduction in MACE in men (RR 0.90; 95% CI, 0.83–0.97; p = 0.006), whereas in women, the risk reduction did not reach statistical significance (RR 0.88; 95% CI, 0.77–1.00; p = 0.06) (100).

Regarding safety, women experienced a higher incidence of genital infections while on SGLT-2 inhibitors, likely due to anatomical predisposition, which may impact treatment adherence (31).

For GLP-1 receptor agonists, the REWIND trial demonstrated a reduction in cardiovascular events with dulaglutide, with a trend toward greater benefit in women, although statistical significance was not achieved (RR 0.85; 95% CI, 0.71–1.02) vs. men (RR 0.90; 95% CI, 0.79–1.04; p = 0.60) (82). In the SUSTAIN-6 trial, no sex-based differences in cardiovascular outcomes were observed, indicating similar efficacy across genders (79). A meta-analysis including seven GLP-1 RA trials demonstrated significant MACE reduction in both men (RR 0.88; 95% CI, 0.82–0.93; p < 0.0001) and women (RR 0.88; 95% CI, 0.79–0.99; p = 0.03) (100).

In terms of safety, gastrointestinal adverse effects—particularly nausea—were common across both sexes, but women reported higher rates of intolerance, which may lead to treatment discontinuation (46). These observations underscore the importance of incorporating sex-specific factors when selecting GLP-1 RAs, favoring their use in women at elevated stroke risk, with potential dose adjustments to optimize adherence (8, 91).

The reduction in MACE with SGLT-2 inhibitors appears to be less consistent in women with type 2 diabetes than in men, while GLP-1 receptor agonists provide similar cardiovascular benefits across sexes.

Several studies have explored the combination of GLP-1 RAs and SGLT-2 inhibitors in patients with T2DM. Randomized clinical trials, such as DURATION-8, SUSTAIN-9, and AWARD-10, have documented the use of GLP-1 RAs in patients already receiving SGLT-2 inhibitors, demonstrating efficacy without adverse effects on the studied population (96, 97). Similarly, sub analyses of studies like EXSCEL, AMPLITUDE-O, HARMONY, CANVAS, DECLARE-TIMI 58, and VERTIS-CV have shown a positive impact with the concomitant use of GLP-1 RAs and SGLT-2 inhibitors, irrespective of whether the initial intervention involved GLP-1 RAs or SGLT-2 inhibitors (34, 57, 59, 80, 85, 101–105).

Among the studies evaluating GLP-1 RAs and SGLT-2 inhibitors, the study conducted by Riley et al. through the TriNetX network stands out. This study included approximately 2.2 million participants and compared cardiovascular outcomes among patients treated without GLP-1 RAs or SGLT-2 inhibitors, with one of these drug classes, or with a combination of both. After five years of follow-up in patients with T2DM, the GLP-1 RAs and SGLT-2 inhibitors groups demonstrated significant reductions in mortality, CHD, HF, AF, stroke, peripheral vascular disease, and CKD, regardless which one of the drugs or its combination were used. Notably, the simultaneous use of both pharmacological classes provided a significantly greater benefit in outcomes such as mortality, hospitalizations, heart failure, and CKD (106).

Building on the findings of the aforementioned trials, several meta-analyses have been conducted since 2019 to evaluate the safety and efficacy of combining GLP-1 RAs and SGLT-2 inhibitors. In 2019, Castellana et al. performed a meta-analysis focusing on patients with T2DM who required rescue medication for hyperglycemia and had a follow-up period of at least 24 weeks. This study demonstrated significant improvements in parameters such as HbA1c, body weight, and lipid profiles, along with a reduced need for rescue medications to control hyperglycemia (107), an effect that has been demonstrated again in other meta-analyses carried out subsequently (108). Additionally, to date it has been demonstrated to have an adequate safety profile by not increasing adverse effects with the combination of these pharmacological groups (108–111).

Among the prospective studies on this pharmacological combination, real-world evidence also plays a significant role. For instance, García-Vega et al. conducted a prospective study involving patients treated in Galicia between 2018 and 2022. The study included 15,549 patients who received either the combination therapy of GLP-1 RAs and SGLT-2 inhibitors or monotherapy with one of these drug classes. After an average follow-up of 19 months, the combination therapy did not demonstrate a reduction in coronary heart disease or ischemic stroke events compared to monotherapy. However, notable benefits were observed in other outcomes, including a 31% reduction in hospital admissions for heart failure and a 32% decrease in all-cause mortality (112).

Other high-profile studies on the use of GLP-1 RAs and SGLT-2 inhibitors combination therapy were conducted by Marfellas et al. (84, 96),. Marfellas et al. recruited patients with T2DM who had experienced acute myocardial infarction (AMI) and had been treated with one of these drug groups within the three months preceding the acute event. Patients with HbA1c >7% were initiated on the complementary drug to complete the GLP-1 RA + SGLT-2i combination therapy. The primary endpoint was a composite of cardiovascular death, recurrent acute coronary syndrome, and heart failure related to AMI after two years of follow-up. Among the 443 patients who completed the study, the combination therapy group demonstrated an ≈84% reduction in the primary endpoint (113).

Simms-Williams et al. conducted a population-based cohort study involving 15,638 patients receiving the combination therapy. Their findings revealed a ≈30% reduction in MACE compared to monotherapy. Regarding renal outcomes, the combination therapy showed a reduction in events that did not reach statistical significance when compared to SGLT-2i monotherapy. In contrast, when analyzing stroke outcomes, the effect was more pronounced with GLP-1 RAs, which provided the greatest contribution to the reduction of stroke events. However, a 57% reduction in renal events was observed compared to those receiving only GLP-1 RAs (114).

In 2024, Ahmad and Sabbour conducted a meta-analysis encompassing data from over 110,000 patients, encompassing 13 investigations that evaluated the combined use of GLP-1 RAs and SGLT-2 inhibitors. The findings demonstrated a significant reduction in all-cause mortality, with an odds ratio of 0.49 (95% CI [0.41–0.60]; p < 0.00001). Additional benefits included reductions in body mass index (BMI), blood pressure levels, HbA1c, and fasting blood glucose, observed after a minimum of six months of clinical follow-up (111).

Notably, the study by Marfellas et al. focused on a cohort of patients following a coronary event, providing insights into the cardiovascular benefits of the therapeutic combination in this high-risk population. In contrast, Simms-Williams et al. analyzed patients initially treated with GLP-1 RAs or SGLT2i, subsequently adding the second agent to evaluate the effects of combination therapy compared to monotherapy and differencing across groups (113, 114). The study by Riley et al., despite its retrospective design, represents the largest dataset to date, offering robust evidence on cardiovascular and renal outcomes associated with this therapeutic strategy (106). Lastly, the analysis by García-Vega et al. incorporated stroke outcomes, broadening the scope of evidence for this combination therapy in real-world settings (112). The meta-analyses reviewed highlight the favorable safety profile of the pharmacological therapy, alongside its efficacy in optimizing clinical parameters, particularly glycemic control and lipid profiles (Table 3).

With respect to the SOUL trial, oral semaglutide demonstrated a 14% reduction in MACE outcomes, independent of concurrent SGLT2 inhibitor use. The combination therapy also exhibited a favorable safety profile in this trial (115).

To date, current evidence suggests that the combination of SGLT2 inhibitors and GLP-1 receptor agonists is generally well-tolerated. The adverse events observed align with the known safety profiles of each class used individually, with no indication of synergistic toxicity. This combination represents a promising therapeutic strategy for improving cardiovascular, renal, and metabolic outcomes in patients with T2DM.