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 1st July 2025 to 30th 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.