Type 2 diabetes mellitus (T2DM) is a significant problem in public health and an important modifiable risk factor for cardiovascular disease (CVD).[1] The International Diabetes Federation (IDF) estimates that there were around 589 million adults aged 20-79 with diabetes worldwide in 2024, around 1 in 9 adults, and that this would rise to 853 million by 2050.[2] Around 81% of adults with diabetes reside in low- and middle-income countries, and it is estimated that 43% of people with diabetes are undiagnosed.[3] In 2024, there were approximately 3.4 million deaths linked to diabetes, underscoring the significant burden of diabetes on global health and the economy.[4]

Cardiovascular disease is one of the most relevant complications of T2DM, and hyperglycemia, hypertension, dyslipidemia, obesity, chronic kidney disease (CKD), and systemic metabolic dysfunction are associated with accelerated atherosclerosis and heart failure.[5] This has led to the current approach to diabetes management to focus more on decreasing cardiovascular and renal risk rather than just glycemic control.[6] In patients with T2DM and established or high risk of atherosclerotic cardiovascular disease (ASCVD), heart failure, or CKD, the American Diabetes Association (ADA) advises that glucose-lowering agents with proven cardiovascular benefit be used (taking into account whether further HbA1c reduction is needed).[7]

Sodium-glucose cotransporter-2 inhibitors (SGLT2i) and glucagon-like peptide-1 receptor agonists (GLP-1 RAs) are two newer glucose-lowering therapies that are important for cardiovascular risk reduction.[8] Empagliflozin, dapagliflozin, and canagliflozin are put into use not just to reduce blood glucose but additionally to have a cardiometabolic effect and renal impact.[9] Clinical outcome trials have shown benefits in terms of reduced heart failure mortality, heart failure hospitalization, cardiovascular mortality, and improved kidney disease progression. For instance, empagliflozin reduced hospitalization for heart failure by 35% in the EMPA-REG OUTCOME trial, and canagliflozin and dapagliflozin reduced heart failure hospitalization by similar amounts.[10]

The therapeutic profile of GLP-1 RAs such as liraglutide, semaglutide, and dulaglutide is somewhat different and yields significant glucose lowering, weight loss, and decreases in atherosclerotic cardiovascular events.[11] In the LEADER trial, liraglutide decreased the primary composite endpoint of cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke from 14.9% to 13.0% compared with placebo, and cardiovascular death was reduced significantly.[11] , or

Both the drugs decrease the risk of cardiovascular disease, but they can have very different patterns of benefit. There is evidence that GLP-1 RAs and SGLT2 inhibitors offer similar protection against major adverse cardiovascular events (MACE), with specific heart failure hospitalization and renal effects for SGLT2 inhibitors.[12] In contrast, GLP-1 RAs seem to be more effective for atherosclerotic events, especially stroke, and offer more weight loss.[11] The most recent systematic review and meta-analysis included 12 trials and 99,261 people and indicated that both classes were effective at reducing MACE compared to placebo; that SGLT2 inhibitors showed larger benefits for patients with heart failure and renal outcomes; and that GLP-1 RAs showed larger benefits for atherosclerotic events and weight loss.[13]

It is therefore clinically important to directly compare SGLT2 inhibitors to GLP-1 RAs in T2DM patients with cardiovascular risk, as cardiovascular protection is now increasingly becoming part of the decision-making regarding which treatment to select. Comparative evaluation of glycaemic control, weight loss, cardiovascular events, heart failure, renal outcome, and treatment-related adverse effects can be useful to delineate the comparative overall clinical profile of the different therapeutic strategies. This information could be used to better individualise prescribing and to improve cardiovascular risk management of patients with T2DM. Therefore, the present study aimed to compare the efficacy and clinical outcomes of SGLT2 inhibitors versus GLP-1 receptor agonists in patients with type 2 diabetes mellitus who had cardiovascular risk.

A comparative analytical prospective cohort study was carried out at the Department of Internal Medicine, King Edward Medical University/Mayo Hospital, Lahore, for one year i-e, from 1^st July 2025 to 30^th June 2026, and the participants were followed in a prospective manner during the study period.

The sample size was determined with OpenEpi version 3.01, with a 95% confidence level, 80% statistical power, and a ratio of 1:1 between the two treatment groups. In a previous real-world study, the incidence of major adverse cardiovascular events (MACE) was reported to be lower for patients using SGLT2 inhibitors than GLP-1 receptor agonists (HR =0.68).[14] Based on an anticipated difference in cardiovascular outcome between the two treatment groups, the OpenEpi cohort sample-size calculation yielded a minimum required sample of approximately 200 participants, including 100 participants in each group.

A non-probability consecutive sampling technique was used. The inclusion criteria included a diagnosis of type 2 diabetes mellitus in patients 18 years of age or older.

Patients were needed to have known cardiovascular disease or at least one of the major cardiovascular risk factors: hypertension, dyslipidemia, obesity, chronic kidney disease, smoking, and previously documented cardiovascular disease. Eligible patients were those who were taking an SGLT2 inhibitor or GLP-1 receptor agonist to treat diabetes. Patients had to be provided with adequate clinical and laboratory baseline data and consent in written form to participate and for follow-up after 12 months. Patients who had type 1 diabetes mellitus, gestational diabetes, or other specific types of diabetes were excluded. Patients who presented with acute diabetic emergencies at the time of enrollment, severe acute illness and required intensive care, advanced liver failure and end-stage renal disease receiving dialysis were excluded. Patients receiving both an SGLT2 inhibitor and a GLP-1 receptor agonist at baseline were also excluded to allow comparisons between the two treatment strategies. Patients were excluded if there was incomplete baseline clinical information, were not able to have follow-up, or refused informed consent.

Ethical approval was obtained from the relevant institutional ethical review committee, followed by an approach and elaboration of the aim and procedures of the study to eligible participants. Informed written consent was obtained prior to recruitment. A structured data-collection proforma was used for baseline demographic and clinical information. The variables recorded were age, sex, diabetes duration, BMI, smoking status, hypertension, dyslipidaemia, history of cardiovascular disease, chronic kidney disease, and other comorbidities.

 Details of the type and dose of glucose-lowering therapy, such as SGLT2 inhibitor or GLP-1 receptor agonist, were recorded.

Baseline laboratory parameters were HbA1c, fasting blood glucose, serum creatinine, estimated glomerular filtration rate, and lipid profile, among others, relevant for the clinical situation. Blood pressure and body weight were measured at baseline and follow-up. Patients were then followed up prospectively to determine the level of response and cardiovascular outcomes.

The main outcome was major adverse cardiovascular events (MACE), which included cardiovascular death, nonfatal myocardial infarction, and nonfatal stroke. Secondary outcomes included changes in HbA1c, fasting blood glucose, body weight/BMI, SBP, DBP, lipid profile, hospitalization for HF, renal outcomes, and treatment-related adverse events. The definition of MACE was chosen because it has been used in many comparative cardiovascular outcome studies of SGLT2 inhibitors and GLP-1 receptor agonists. Major cardiovascular endpoints used in previous real-world, comparative studies include cardiovascular death, myocardial infarction, and stroke.

Assessment of patients was conducted at baseline and at follow-up after 12 months, and clinical events were documented from hospital records, outpatient visits, laboratory investigations, and patient/caregiver reports, as needed. All cardiovascular hospitalizations, myocardial infarction, stroke, heart failure admission, and death during follow-up were documented and independently adjudicated to the pre-established outcome criteria. The data collected were entered and analyzed using IBM SPSS Statistics version 26. The Shapiro-Wilk test was used to test continuous variables for normality. Data on continuous variables that were normally distributed were presented as mean ± SD values, while those that were not normally distributed were presented as median (interquartile range). Frequencies and percentages were used for categorical variables.

The independent-samples t-test was used for normally distributed continuous variables, and the Mann-Whitney U test was used for non-normally distributed continuous variables in the two groups (SGLT2 and GLP-1). The Pearson chi-square test was used to compare categorical variables, and Fisher's exact test was used when the cell frequencies were low.

Statistically, differences in the baseline to follow-up HbA1c, body weight, BMI, blood pressure, and laboratory parameters were compared between treatment groups with appropriate paired and independent statistical tests. The incidence of each cardiac event and MACE was compared between the two groups by chi-square and Fisher's exact test, whichever was applicable. Kaplan-Meier survival analysis was performed to compare cardiovascular event-free survival between the treatment groups, and the log-rank test was used to assess differences between survival curves.

Multivariable Cox proportional-hazards regression analysis was used to account for possible baseline differences between non-randomized treatment groups for time-to-MACE outcomes. All variables that are clinically relevant and those that were associated with the outcome in the univariable analyses were included in the multivariable model. Hazard ratios (HRs) and 95% confidence intervals (CIs) are reported. A p-value < 0.05 was considered statistically significant.

A total of 200 type 2 diabetes mellitus patients with cardiovascular risk were included, 100 of whom received SGLT2 inhibitors and 100 received GLP-1 receptor agonists. There were no significant differences between the two groups in terms of age, sex, diabetes duration, BMI, smoking, hypertension, dyslipidaemia, history of cardiovascular disease, chronic kidney disease, previous myocardial infarction, stroke, or heart failure (all p>0.05). (Table 1) Baseline metabolic and laboratory values were also similar in both groups. At enrollment, there were no significant differences in either systolic or diastolic blood pressure, HbA1c, fasting blood glucose, lipid profile, serum creatinine, eGFR or body weight (all p>0.05). (Table 2) At follow-up, both treatments resulted in marked glycemic and anthropometric improvements. The GLP-1 receptor agonists, however, were associated with significantly greater HbA1c, fasting blood glucose, body weight, and BMI reductions than SGLT2 inhibitors (p=0.006, p=0.018, p=0.021, and p=0.034, respectively). There were no significant differences in the reduction in blood pressure between groups. (Table 3) Lipid parameters showed moderate changes in both groups, but no significant differences between groups in total cholesterol, LDL-C, HDL-C, or triglycerides. There was no significant difference in renal function between the treatment groups at follow-up and renal function change was also similar between groups (all p>0.05). (Table 4) The rate of MACE was 8.0% in patients on SGLT2 inhibitors, and 11.0% in patients on GLP-1 receptor agonists, but this was not statistically different (p=0.468). Cardiovascular death, nonfatal myocardial infarction, stroke, hospitalization for heart failure, progression of CKD, cardiovascular hospitalization, and all-cause mortality were also more common, but not significantly different, with SGLT2 inhibitors. (Table 5) The incidence of side effects related to the treatment was not significantly different between the groups (p=0.472). There was a significant higher prevalence of genital mycotic infections in SGLT2 inhibitor users (p=0.030), and gastrointestinal symptoms were more prevalent with GLP-1 receptor agonists (p=0.012). (Table 6) The Kaplan-Meier analysis showed slightly better MACE-free survival in patients taking SGLT2 inhibitors compared to those taking GLP-1 receptor agonists (92.0% vs. 89.0%), but the difference in event-free survival was not significant on log-rank testing (p=0.471). (Table 7) SGLT2 inhibitor therapy had a numerically smaller risk for MACE than GLP-1 receptor agonist therapy on Cox regression analysis. The relationship was not significant after adjustment for age, sex, diabetes duration, hypertension, dyslipidemia, established CVD, CKD, HbA1c, and smoking (p=0.446). The strongest association in the univariable model was for established CVD which was not statistically significant after adjustment. (Table 8) Table 1. Baseline Demographic and Clinical Characteristics of Study Participants (n=200) Variable SGLT2 inhibitor (n=100) n(%)/mean ± SD GLP-1 RA (n=100) n(%)/mean ± SD p-value Age, years 57.8 ± 9.6 56.9 ± 10.1 0.519† Male sex 61 (61.0) 57 (57.0) 0.568‡ Duration of diabetes, years, median (IQR) 8 (5-12) 9 (6-13) 0.284§ BMI, kg/m² 29.1 ± 4.2 30.0 ± 4.6 0.152† Current smoker 19 (19.0) 17 (17.0) 0.712‡ Hypertension 72 (72.0) 76 (76.0) 0.508‡ Dyslipidemia 66 (66.0) 71 (71.0) 0.438‡ Established CVD 43 (43.0) 47 (47.0) 0.571‡ Chronic kidney disease 28 (28.0) 24 (24.0) 0.508‡ Previous myocardial infarction 18 (18.0) 21 (21.0) 0.585‡ Previous stroke 11 (11.0) 13 (13.0) 0.660‡ Heart failure 15 (15.0) 13 (13.0) 0.683‡ † Independent-samples t-test; ‡ Pearson chi-square test; § Mann-Whitney U test. Table 2. Baseline Clinical and Laboratory Parameters Variable SGLT2 inhibitor (n=100) Mean ± SD/Median (IQR) GLP-1 RA (n=100) Mean ± SD/Median (IQR) p-value Systolic BP, mmHg 139.6 ± 15.2 141.2 ± 16.1 0.469† Diastolic BP, mmHg 82.8 ± 9.3 83.6 ± 9.7 0.550† HbA1c, % 8.4 ± 1.2 8.5 ± 1.3 0.575† Fasting blood glucose, mg/dL 166 (145-198) 170 (148-201) 0.390§ Total cholesterol, mg/dL 188.4 ± 38.6 192.7 ± 40.2 0.438† LDL-C, mg/dL 108.7 ± 28.9 111.9 ± 30.1 0.441† HDL-C, mg/dL 42.8 ± 8.1 41.9 ± 7.7 0.420† Triglycerides, mg/dL 168 (132-214) 174 (138-220) 0.472§ Serum creatinine, mg/dL 1.02 (0.86-1.24) 1.00 (0.84-1.21) 0.716§ eGFR, mL/min/1.73 m² 76.4 ± 18.3 77.8 ± 17.9 0.586† Body weight, kg 82.1 ± 12.4 84.6 ± 13.1 0.166† † Independent-samples t-test; § Mann-Whitney U test. Table 3. Changes in Glycemic, Anthropometric, and Blood Pressure Parameters During Follow-up Outcome SGLT2 inhibitor baseline n(%)/mean ± SD SGLT2 inhibitor follow-up n(%)/mean ± SD GLP-1 RA baseline n(%)/mean ± SD GLP-1 RA follow-up n(%)/mean ± SD Between-group p-value* HbA1c (%), 8.4 ± 1.2 7.4 ± 1.0 8.5 ± 1.3 7.0 ± 0.9 0.006 Fasting glucose (mg/dL), median (IQR) 166 (145-198) 132 (114-156) 170 (148-201) 124 (108-149) 0.018 Body weight (kg) 82.1 ± 12.4 78.9 ± 11.8 84.6 ± 13.1 79.5 ± 12.4 0.021 BMI (kg/m²) 29.1 ± 4.2 28.0 ± 4.0 30.0 ± 4.6 28.2 ± 4.3 0.034 Systolic BP (mmHg) 139.6 ± 15.2 133.1 ± 13.4 141.2 ± 16.1 135.8 ± 14.0 0.241 Diastolic BP (mmHg) 82.8 ± 9.3 79.8 ± 8.5 83.6 ± 9.7 80.9 ± 8.7 0.367 *Between-group comparison of change from baseline to follow-up using independent-samples t-test and Mann-Whitney U test. Table 4. Changes in Lipid and Renal Parameters Outcome SGLT2 inhibitor baseline Mean ± SD /Median (IQR) SGLT2 inhibitor follow-up Mean ± SD/Median (IQR) GLP-1 RA baseline Mean ± SD/ Median (IQR) GLP-1 RA follow-up Mean ± SD/ Median (IQR) p-value* Total cholesterol, mg/dL 188.4 ± 38.6 181.7 ± 35.4 192.7 ± 40.2 183.9 ± 36.8 0.518 LDL-C, mg/dL 108.7 ± 28.9 103.2 ± 26.7 111.9 ± 30.1 105.1 ± 27.9 0.671 HDL-C, mg/dL 42.8 ± 8.1 44.0 ± 8.2 41.9 ± 7.7 43.1 ± 7.9 0.843 Triglycerides, mg/dL 168 (132-214) 154 (120-196) 174 (138-220) 157 (123-199) 0.763 eGFR, mL/min/1.73 m² 76.4 ± 18.3 77.1 ± 18.5 77.8 ± 17.9 76.8 ± 18.2 0.734 Creatinine, mg/dL 1.02 (0.86-1.24) 1.00 (0.84-1.22) 1.00 (0.84-1.21) 1.01 (0.85-1.23) 0.619 *Between-group comparison of changes using independent-samples t-test or Mann-Whitney U test. Table 5. Cardiovascular and Renal Clinical Outcomes during Follow-up Outcome SGLT2 inhibitor (n=100) n (%) GLP-1 RA (n=100) n (%) p-value MACE 8 (8.0) 11 (11.0) 0.468‡ Cardiovascular death 2 (2.0) 3 (3.0) 0.651‡ Nonfatal myocardial infarction 3 (3.0) 4 (4.0) 0.701‡ Nonfatal stroke 3 (3.0) 5 (5.0) 0.471‡ Hospitalization for heart failure, 4 (4.0) 9 (9.0) 0.155‡ New/worsening CKD 5 (5.0) 8 (8.0) 0.391‡ Cardiovascular hospitalization 9 (9.0) 14 (14.0) 0.267‡ All-cause mortality 3 (3.0) 4 (4.0) 0.701‡ ‡ Pearson chi-square/Fisher's exact test Table 6. Treatment-Related Adverse Events Adverse event SGLT2 inhibitor (n=100) n (%) GLP-1 RA (n=100) n (%) p-value Any adverse event 17 (17.0) 21 (21.0) 0.472‡ Genital mycotic infection 7 (7.0) 1 (1.0) 0.030‡ Urinary tract infection 5 (5.0) 3 (3.0) 0.471‡ Gastrointestinal symptoms 3 (3.0) 13 (13.0) 0.012‡ Nausea/vomiting 2 (2.0) 9 (9.0) 0.030‡ Symptomatic hypoglycemia 2 (2.0) 3 (3.0) 0.651‡ Treatment discontinuation due to adverse event 4 (4.0) 6 (6.0) 0.515‡ ‡ Pearson chi-square/Fisher's exact test. Table 7. Kaplan-Meier Analysis of MACE-Free Survival Parameter SGLT2 inhibitor n (%) GLP-1 RA n (%) MACE events 8 (8.0) 11 (11.0) MACE-free survival 92.0 89.0 Log-rank test p=0.471 Table 8. Univariable and Multivariable Cox Regression Analysis for MACE Predictor Univariable HR (95% CI) p-value Adjusted HR (95% CI) p-value SGLT2 inhibitor vs GLP-1 RA 0.71 (0.27-1.86) 0.489 0.68 (0.25-1.82) 0.446 Age, per year 1.03 (0.99-1.07) 0.116 1.02 (0.98-1.07) 0.284 Male sex 1.21 (0.50-2.93) 0.672 1.18 (0.47-2.95) 0.728 Diabetes duration, per year 1.05 (1.00-1.11) 0.047 1.04 (0.99-1.10) 0.109 Hypertension 1.48 (0.55-3.99) 0.438 1.31 (0.47-3.66) 0.603 Dyslipidemia 1.39 (0.61-3.19) 0.431 1.27 (0.53-3.04) 0.593 Established CVD 2.64 (1.10-6.35) 0.030 2.38 (0.96-5.89) 0.061 CKD 2.19 (0.91-5.27) 0.080 1.87 (0.73-4.80) 0.193 Baseline HbA1c, per 1% 1.28 (0.99-1.65) 0.058 1.22 (0.93-1.60) 0.145 Smoking 1.74 (0.69-4.38) 0.241 1.51 (0.56-4.06) 0.414

The present study aimed to compare the efficacy and cardiovascular outcomes of SGLT2 inhibitors and GLP-1 receptor agonists in 200 patients with T2DM and cardiovascular risk. The two treatment options both led to clinically significant improvements, though there seemed to be differences between them in terms of the outcomes. GLP-1 receptor agonists achieved significantly lower HbA1c, fasting glucose, body weight, and BMI, and numerically lower MACE, heart-failure hospitalizations, cardiovascular hospitalizations, and renal events, while SGLT2 inhibitors achieved lower renal events, without significant differences in the other measures. This pattern reflects the understanding that the two drug classes do not have equivalent (but complementary) cardiometabolic effects.

The larger HbA1c reduction we did find with GLP-1 receptor agonists mirrored those of Khan et al in their 2025 systematic review, which found GLP-1 receptor agonists to be more effective for glycemic control and MACE prevention, and SGLT2 inhibitors to be more effective for heart failure and renal outcomes. The larger weight loss was also consistent with the known effects of GLP-1 receptor agonists on appetite and caloric reduction and body weight.[15]

Our overall cardiovascular results closely matched those of the large population-based cohort study by Dong et al. that directly compared GLP-1 receptor agonists to SGLT2

inhibitors in T2DM patients in 2022. That study showed differences in cardiovascular effectiveness depending on particular outcomes and patient subgroups, which has led to the notion that the patient's primary cardiovascular phenotype should be taken into account, and not that there was a uniform benefit across both classes.[16]

Likewise, Fu et al. (2022) compared the two classes of medication in clinical practice and determined that SGLT2 inhibitors and GLP-1 receptor agonists could be distinguished by their different profiles of cardiovascular outcomes. Their findings are even more relevant to our results, as our observational comparison also showed a numerical advantage for SGLT2 inhibitors in cardiovascular outcomes without a statistically significant difference in MACE.[17]

The lower frequency of heart-failure hospitalization in our SGLT2 inhibitor group was consistent with the findings of Zhou et al. (2024). In their meta-analysis of 38 studies, they found that SGLT2 inhibitors were associated with a significantly greater reduction in cardiovascular death, heart-failure hospitalization, all-cause mortality, and myocardial infarction than GLP-1 receptor agonists. The beneficial impact of SGLT2 inhibitors on heart failure may be explained by their natriuresis, osmotic diuresis, decreased cardiac preload, decreased afterload, and beneficial ventricular remodeling effects.[18]

Similarly, our results were consistent with Patel et al. (2024) who conducted a collaborative meta-analysis of SMART-C, showing significant cardiovascular benefits of SGLT2 inhibitors in a wide range of patients. Their findings further reinforce the importance of SGLT2 inhibitors in reducing cardiovascular and heart failure outcomes, but the extent of these benefits might depend on the individual's underlying cardiovascular and renal risk profile.[19]

The renal outcomes observed in our study, with a similar number of renal deterioration events and a numerical disadvantage to those using SGLT2 inhibitors, matched those observed in the 2021 network meta-analysis conducted by Yamada et al. in patients with T2DM and CKD. In that analysis, SGLT2 inhibitors showed significant advantages for cardiorenal outcomes and were proposed to have a benefit for renal protection over GLP-1 receptor agonists. The results support the concept of considering SGLT2 inhibitors as a preferred treatment option for patients with diabetes and CKD as well as a strong heart-failure phenotype.[20]

A 2021 network meta-analysis by Wei et al. also reported that each SGLT2 inhibitor (canagliflozin and empagliflozin) had significant effects on reducing HF hospitalization, and GLP-1 receptor agonists (semaglutide) had beneficial effects for MACE. The differential effect is similar to what we saw with GLP-1 receptor agonists and to the numerical CVS advantage seen with SGLT2 inhibitors.[21]

This is corroborated by Kilickap et al. (2023/2024), who performed a systematic review and meta-analysis of randomized cardiovascular outcome trials, which showed that there were broadly similar MACE rates between the two groups. Both GLP-1 receptor agonists and SGLT2 inhibitors resulted in a decrease in MACE, the analysis confirmed, and benefits were seen in patients with and without known cardiovascular disease. Therefore, the observed non-significant difference in MACE in our relatively small cohort does not provide evidence to support the absence of cardiovascular effectiveness of either class.[22]

The findings were supported by Lin et al. (2025), who evaluated 26 trials with 151,789 patients with ASCVD. They discovered that both drug classes were able to lower MACE by about 15%, but that the benefits differed depending on cardiovascular phenotype. In peripheral arterial disease and post-acute cardiovascular events, GLP-1 receptor agonists proved to have unique benefits, while SGLT2 inhibitors proved to have unique benefits in patients with CKD. Their results support our interpretation that treatment decisions should be individualized based on the predominant cardiovascular and renal risk.[23]

The most recent evidence from Alqurain et al. (2026) further supports our results. In a network meta-analysis of 14 trials with 117,633 participants, they concluded that there was no difference between the two classes in terms of MACE (HR 1.03, 95% CI 0.94-1.13), but that SGLT2 inhibitors were superior for heart-failure hospitalization and composite renal outcomes. This is similar to our results which indicate that MACE was not statistically different, but that the outcomes of heart failure and renal outcomes were in favor of SGLT2 inhibitors numerically.[24]

In contrast, the 2026 international study by Bu et al. showed a similar cardiovascular effectiveness in each of the GLP-1 receptor agonists compared with the SGLT2 inhibitors, including in patients with established CVD. In the case of 3-point or 4-point MACE for instance, the risks of the two drug classes were similar. The findings offer an important explanation for the absence of difference in MACE and indicate that differences between the classes could be more evident for specific outcomes than the composite endpoint of MACE.

In contrast, a large propensity-matched real-world cohort study by Ukita et al. (2026) found that GLP-1 receptor agonists had reduced risks for new onset atrial fibrillation, heart failure and ischemic stroke compared to SGLT2 inhibitors. They found different numbers than the ones I saw in our study when it came to the benefits of SGLT2 inhibitors on heart failure. This discrepancy could be due to differences in the populations studied, choice of treatments, outcome measurements, length of follow-up, or residual confounding factors in observational comparisons. Most importantly, their study was not a randomized head-to-head trial, but rather was used to generate hypotheses.[25]

In summary, the present results indicate GLP-1 receptor agonists to be more beneficial if intensive glycemic control and weight loss are principal therapeutic goals, while SGLT2 inhibitors appear to be more beneficial where heart failure or renal disease is the primary therapeutic focus. However, the lack of a significant difference between the two classes in terms of MACE shows that both groups can offer clinically relevant cardiovascular protection. Thus, the decision to use one class or the other should be made on an individual basis, depending on the cardiovascular phenotype, renal function, obesity, glycemic needs, susceptibility to adverse effects, availability of treatment, and the patient's preference. This interpretation is gaining more and more traction in light of the available contemporary comparative evidence, such as the 2026 network meta-analysis and the multinational real-world evidence.

LIMITATIONS

There were a number of limitations to this study. It was designed as a prospective observational study, and treatment was not randomly allocated, which may have resulted in selection bias and unaccounted-for confounding despite adjustment for important baseline variables. The study was carried out at a single tertiary care centre, narrowing the ability to generalise the study results to other populations and health care settings. The small number of patients in the study and relatively short follow-up period may have blunted the ability to detect differences in relatively rare outcomes of cardiovascular death and MACE. Moreover, variations in individual drugs in each therapeutic class, treatment doses, adherence, and socioeconomic factors were not fully evaluated. Lastly, clinical documentation and hospital records were required for some cardiovascular and adverse events, leading to underreporting.

SGLT2 inhibitors and GLP-1 receptor agonists had positive outcomes in patients with type 2 diabetes and cardiovascular risk. The GLP-1 receptor agonists demonstrated a significantly larger reduction in HbA1c, fasting glucose, body weight, and BMI compared with the SGLT2 inhibitors, which had a favorable numerical trend for MACE, heart-failure hospitalization, and renal outcomes. The groups had no significant difference in MACE-free survival and adjusted cardiovascular risk. Therefore, there was no cardiovascular superiority observed between the two classes, and individual selection of class based on glycemic needs, obesity, heart failure, renal disease, cardiovascular risk factors, tolerability, and patient preference.

The present study aimed to compare the efficacy and cardiovascular outcomes of SGLT2 inhibitors and GLP-1 receptor agonists in 200 patients with T2DM and cardiovascular risk. The two treatment options both led to clinically significant improvements, though there seemed to be differences between them in terms of the outcomes. GLP-1 receptor agonists achieved significantly lower HbA1c, fasting glucose, body weight, and BMI, and numerically lower MACE, heart-failure hospitalizations, cardiovascular hospitalizations, and renal events, while SGLT2 inhibitors achieved lower renal events, without significant differences in the other measures. This pattern reflects the understanding that the two drug classes do not have equivalent (but complementary) cardiometabolic effects.

The larger HbA1c reduction we did find with GLP-1 receptor agonists mirrored those of Khan et al in their 2025 systematic review, which found GLP-1 receptor agonists to be more effective for glycemic control and MACE prevention, and SGLT2 inhibitors to be more effective for heart failure and renal outcomes. The larger weight loss was also consistent with the known effects of GLP-1 receptor agonists on appetite and caloric reduction and body weight.[15]

Our overall cardiovascular results closely matched those of the large population-based cohort study by Dong et al. that directly compared GLP-1 receptor agonists to SGLT2

inhibitors in T2DM patients in 2022. That study showed differences in cardiovascular effectiveness depending on particular outcomes and patient subgroups, which has led to the notion that the patient's primary cardiovascular phenotype should be taken into account, and not that there was a uniform benefit across both classes.[16]

Likewise, Fu et al. (2022) compared the two classes of medication in clinical practice and determined that SGLT2 inhibitors and GLP-1 receptor agonists could be distinguished by their different profiles of cardiovascular outcomes. Their findings are even more relevant to our results, as our observational comparison also showed a numerical advantage for SGLT2 inhibitors in cardiovascular outcomes without a statistically significant difference in MACE.[17]

The lower frequency of heart-failure hospitalization in our SGLT2 inhibitor group was consistent with the findings of Zhou et al. (2024). In their meta-analysis of 38 studies, they found that SGLT2 inhibitors were associated with a significantly greater reduction in cardiovascular death, heart-failure hospitalization, all-cause mortality, and myocardial infarction than GLP-1 receptor agonists. The beneficial impact of SGLT2 inhibitors on heart failure may be explained by their natriuresis, osmotic diuresis, decreased cardiac preload, decreased afterload, and beneficial ventricular remodeling effects.[18]

Similarly, our results were consistent with Patel et al. (2024) who conducted a collaborative meta-analysis of SMART-C, showing significant cardiovascular benefits of SGLT2 inhibitors in a wide range of patients. Their findings further reinforce the importance of SGLT2 inhibitors in reducing cardiovascular and heart failure outcomes, but the extent of these benefits might depend on the individual's underlying cardiovascular and renal risk profile.[19]

The renal outcomes observed in our study, with a similar number of renal deterioration events and a numerical disadvantage to those using SGLT2 inhibitors, matched those observed in the 2021 network meta-analysis conducted by Yamada et al. in patients with T2DM and CKD. In that analysis, SGLT2 inhibitors showed significant advantages for cardiorenal outcomes and were proposed to have a benefit for renal protection over GLP-1 receptor agonists. The results support the concept of considering SGLT2 inhibitors as a preferred treatment option for patients with diabetes and CKD as well as a strong heart-failure phenotype.[20]

A 2021 network meta-analysis by Wei et al. also reported that each SGLT2 inhibitor (canagliflozin and empagliflozin) had significant effects on reducing HF hospitalization, and GLP-1 receptor agonists (semaglutide) had beneficial effects for MACE. The differential effect is similar to what we saw with GLP-1 receptor agonists and to the numerical CVS advantage seen with SGLT2 inhibitors.[21]

This is corroborated by Kilickap et al. (2023/2024), who performed a systematic review and meta-analysis of randomized cardiovascular outcome trials, which showed that there were broadly similar MACE rates between the two groups. Both GLP-1 receptor agonists and SGLT2 inhibitors resulted in a decrease in MACE, the analysis confirmed, and benefits were seen in patients with and without known cardiovascular disease. Therefore, the observed non-significant difference in MACE in our relatively small cohort does not provide evidence to support the absence of cardiovascular effectiveness of either class.[22]

The findings were supported by Lin et al. (2025), who evaluated 26 trials with 151,789 patients with ASCVD. They discovered that both drug classes were able to lower MACE by about 15%, but that the benefits differed depending on cardiovascular phenotype. In peripheral arterial disease and post-acute cardiovascular events, GLP-1 receptor agonists proved to have unique benefits, while SGLT2 inhibitors proved to have unique benefits in patients with CKD. Their results support our interpretation that treatment decisions should be individualized based on the predominant cardiovascular and renal risk.[23]

The most recent evidence from Alqurain et al. (2026) further supports our results. In a network meta-analysis of 14 trials with 117,633 participants, they concluded that there was no difference between the two classes in terms of MACE (HR 1.03, 95% CI 0.94-1.13), but that SGLT2 inhibitors were superior for heart-failure hospitalization and composite renal outcomes. This is similar to our results which indicate that MACE was not statistically different, but that the outcomes of heart failure and renal outcomes were in favor of SGLT2 inhibitors numerically.[24]

In contrast, the 2026 international study by Bu et al. showed a similar cardiovascular effectiveness in each of the GLP-1 receptor agonists compared with the SGLT2 inhibitors, including in patients with established CVD. In the case of 3-point or 4-point MACE for instance, the risks of the two drug classes were similar. The findings offer an important explanation for the absence of difference in MACE and indicate that differences between the classes could be more evident for specific outcomes than the composite endpoint of MACE.

In contrast, a large propensity-matched real-world cohort study by Ukita et al. (2026) found that GLP-1 receptor agonists had reduced risks for new onset atrial fibrillation, heart failure and ischemic stroke compared to SGLT2 inhibitors. They found different numbers than the ones I saw in our study when it came to the benefits of SGLT2 inhibitors on heart failure. This discrepancy could be due to differences in the populations studied, choice of treatments, outcome measurements, length of follow-up, or residual confounding factors in observational comparisons. Most importantly, their study was not a randomized head-to-head trial, but rather was used to generate hypotheses.[25]

In summary, the present results indicate GLP-1 receptor agonists to be more beneficial if intensive glycemic control and weight loss are principal therapeutic goals, while SGLT2 inhibitors appear to be more beneficial where heart failure or renal disease is the primary therapeutic focus. However, the lack of a significant difference between the two classes in terms of MACE shows that both groups can offer clinically relevant cardiovascular protection. Thus, the decision to use one class or the other should be made on an individual basis, depending on the cardiovascular phenotype, renal function, obesity, glycemic needs, susceptibility to adverse effects, availability of treatment, and the patient's preference. This interpretation is gaining more and more traction in light of the available contemporary comparative evidence, such as the 2026 network meta-analysis and the multinational real-world evidence.

LIMITATIONS

There were a number of limitations to this study. It was designed as a prospective observational study, and treatment was not randomly allocated, which may have resulted in selection bias and unaccounted-for confounding despite adjustment for important baseline variables. The study was carried out at a single tertiary care centre, narrowing the ability to generalise the study results to other populations and health care settings. The small number of patients in the study and relatively short follow-up period may have blunted the ability to detect differences in relatively rare outcomes of cardiovascular death and MACE. Moreover, variations in individual drugs in each therapeutic class, treatment doses, adherence, and socioeconomic factors were not fully evaluated. Lastly, clinical documentation and hospital records were required for some cardiovascular and adverse events, leading to underreporting.

SGLT2 inhibitors and GLP-1 receptor agonists had positive outcomes in patients with type 2 diabetes and cardiovascular risk. The GLP-1 receptor agonists demonstrated a significantly larger reduction in HbA1c, fasting glucose, body weight, and BMI compared with the SGLT2 inhibitors, which had a favorable numerical trend for MACE, heart-failure hospitalization, and renal outcomes. The groups had no significant difference in MACE-free survival and adjusted cardiovascular risk. Therefore, there was no cardiovascular superiority observed between the two classes, and individual selection of class based on glycemic needs, obesity, heart failure, renal disease, cardiovascular risk factors, tolerability, and patient preference.

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