European Journal of Cardiovascular Medicine

Type 2 Diabetes Mellitus (T2DM) represents a major global health challenge, with its prevalence escalating at an alarming rate. The International Diabetes Federation estimates that over 537 million adults are living with diabetes worldwide, a number projected to rise to 783 million by 2045 [1]. The cornerstone of T2DM management is achieving optimal glycemic control to mitigate the risk of microvascular and macrovascular complications, including nephropathy, retinopathy, neuropathy, and cardiovascular disease [2].

Metformin, a biguanide, is universally recommended as the first-line pharmacological agent for T2DM due to its robust efficacy, low cost, weight-neutral profile, and established safety record [3]. However, due to the progressive nature of T2DM, characterized by declining β-cell function and increasing insulin resistance, a significant proportion of patients eventually fail to maintain their target glycated hemoglobin (HbA1c) levels with metformin monotherapy [4]. This necessitates the addition of second-line antihyperglycemic agents with complementary mechanisms of action.

Among the numerous classes of available agents, dipeptidyl peptidase-4 (DPP-4) inhibitors and sodium-glucose cotransporter-2 (SGLT2) inhibitors have become prominent choices. DPP-4 inhibitors, such as sitagliptin, enhance glycemic control by preventing the degradation of incretin hormones (glucagon-like peptide-1 and glucose-dependent insulinotropic polypeptide), thereby stimulating glucose-dependent insulin secretion and suppressing glucagon secretion [5]. This class is known for its efficacy, low risk of hypoglycemia, and neutral effect on body weight.

In contrast, SGLT2 inhibitors, such as empagliflozin, offer an insulin-independent mechanism of action. They reduce renal glucose reabsorption by inhibiting SGLT2 in the proximal convoluted tubules, leading to increased urinary glucose excretion and a subsequent reduction in plasma glucose levels [6]. Beyond their glycemic benefits, SGLT2 inhibitors have demonstrated significant non-glycemic advantages, including reductions in body weight, blood pressure, and, most notably, a decreased risk of major adverse cardiovascular events and hospitalization for heart failure [7].

While previous studies have established the efficacy of both sitagliptin and empagliflozin as add-on therapies to metformin [8, 9], there remains a clinical need for direct, head-to-head comparative studies within routine clinical practice settings. Much of the existing evidence comes from large, industry-sponsored trials that may not fully reflect the heterogeneity of patient populations encountered daily. The research gap lies in a comprehensive, direct comparison that simultaneously evaluates glycemic efficacy, anthropometric changes (body weight), and metabolic parameters (lipid profile) between these two distinct classes when added to metformin.

Therefore, the aim of this study was to directly compare the efficacy and safety of adding empagliflozin versus sitagliptin to ongoing metformin therapy in patients with T2DM who were sub-optimally controlled. We hypothesized that while both combinations would be superior to metformin monotherapy, empagliflozin would demonstrate greater efficacy in reducing both HbA1c and body weight.

Study Design and Participants
This was a 24-week, prospective, single-center, randomized, open-label, parallel-group controlled trial conducted at the Department of Endocrinology, University City Hospital, from June 2022 to December 2023.

Inclusion and Exclusion Criteria
Eligible participants were male and female adults aged 18 to 70 years, with a confirmed diagnosis of T2DM for at least one year. They were required to be on a stable dose of metformin monotherapy (≥1500 mg/day or maximum tolerated dose) for at least three months prior to screening, with an HbA1c level between 7.5% and 10.0% (inclusive).

Exclusion criteria included: diagnosis of Type 1 diabetes or secondary forms of diabetes; a history of diabetic ketoacidosis; severe renal impairment, defined as an estimated glomerular filtration rate (eGFR) < 45 mL/min/1.73m²; a history of pancreatitis; active liver disease (transaminases > 3 times the upper limit of normal); New York Heart Association (NYHA) Class III-IV heart failure; pregnancy or lactation; or use of any other glucose-lowering agent besides metformin within the previous three months.

Procedures and Interventions
Following a 2-week screening period, eligible patients were randomized in a 1:1:1 ratio using a computer-generated block randomization sequence to one of three treatment arms:

1. MET Mono Group: Continued on metformin, with the dose uptitrated to 2000 mg/day if not already at maximum dose.
2. MET+SITA Group: Continued their stable metformin dose and received add-on sitagliptin 100 mg once daily.
3. MET+EMP Group: Continued their stable metformin dose and received add-on empagliflozin 10 mg once daily.

Study visits were scheduled at baseline (Week 0), Week 12, and Week 24. At each visit, data on medication adherence, adverse events, and concomitant medications were collected. Participants received standardized counseling on diet and exercise at baseline.

Outcome Measures
The primary efficacy outcome was the absolute change in HbA1c from baseline to Week 24.

Secondary efficacy outcomes included:

• Change from baseline in fasting blood glucose (FBG) and 2-hour postprandial glucose (PPG) after a standardized meal.
• Change from baseline in body weight and body mass index (BMI).
• Change from baseline in lipid profile: total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), and triglycerides (TG).
• Proportion of patients achieving an HbA1c target of <7.0%.

Safety and tolerability were assessed by monitoring and recording all adverse events (AEs), serious adverse events (SAEs), and laboratory abnormalities throughout the study. Hypoglycemic events were defined as any episode with symptoms of hypoglycemia confirmed by a self-monitored blood glucose reading of <70 mg/dL (<3.9 mmol/L).

Statistical Analysis
The sample size was calculated to provide 80% power to detect a 0.5% difference in HbA1c change between the combination therapy groups, with a standard deviation of 0.8%, at a two-sided alpha level of 0.05. This calculation yielded a required sample size of approximately 45 patients per group; we enrolled 50 per group to account for potential dropouts.

Participant Disposition and Baseline Characteristics
A total of 182 patients were screened for eligibility, of whom 150 were randomized: 50 to the MET Mono group, 50 to the MET+SITA group, and 50 to the MET+EMP group. During the 24-week study, 7 patients discontinued (3 in MET Mono, 2 in MET+SITA, 2 in MET+EMP) due to personal reasons or loss to follow-up. All 150 randomized patients were included in the ITT analysis. The baseline demographic and clinical characteristics were well-balanced across the three treatment groups, with no statistically significant differences observed (Table 1). The mean age of participants was 56.4 years, mean duration of diabetes was 7.1 years, and the overall mean baseline HbA1c was 8.6%.

Table 1. Baseline Demographic and Clinical Characteristics of the Study Population.

Efficacy Outcomes
As shown in Table 2, both combination therapy groups achieved a significantly greater reduction in HbA1c from baseline compared to the MET Mono group at week 24. The mean adjusted change from baseline HbA1c was -0.7% for MET Mono, -1.3% for MET+SITA, and -1.5% for MET+EMP (p<0.001 for both MET+SITA and MET+EMP vs. MET Mono). The HbA1c reduction in the MET+EMP group was also significantly greater than that in the MET+SITA group (p=0.041). Consequently, a significantly higher proportion of patients in the combination groups achieved the HbA1c target of <7.0% (MET+SITA: 44%, MET+EMP: 52%) compared to the monotherapy group (14%) (p<0.001).

Regarding secondary outcomes, the MET+EMP group experienced a substantial and statistically significant mean weight loss of -2.8 kg. In contrast, the MET+SITA group was weight-neutral (-0.4 kg), and the MET Mono group had a slight weight gain (+0.2 kg). The difference in weight change between the MET+EMP group and the other two groups was highly significant (p<0.001). Similar patterns were observed for changes in BMI. Reductions in FBG and PPG were also significantly greater in the two combination therapy groups compared to the monotherapy group.

Table 2. Changes in Glycemic and Anthropometric Parameters from Baseline to Week 24.

Lipid Profile and Safety
Changes in lipid profiles were modest (Table 3). The MET+EMP group showed a slight increase in both LDL-C and HDL-C, while the MET+SITA group showed a small reduction in triglycerides. However, none of these between-group differences reached statistical significance.

All treatments were generally well-tolerated. The overall incidence of adverse events was similar across the three groups. Mild hypoglycemia was rare and occurred in one patient in the MET+SITA group and one in the MET+EMP group. As anticipated, the incidence of genitourinary infections (primarily mycotic infections in women) was numerically higher in the MET+EMP group (8%) compared to the other groups (2%), although this difference did not reach statistical significance in our sample (p=0.171). No patient discontinued the study due to an adverse event.

Table 3. Changes in Lipid Profile and Incidence of Key Adverse Events.

This 24-week randomized controlled trial demonstrated that for patients with T2DM inadequately controlled by metformin, the addition of either the SGLT2 inhibitor empagliflozin or the DPP-4 inhibitor sitagliptin provides clinically and statistically significant improvements in glycemic control compared to uptitration of metformin alone. Our primary finding was that while both agents were effective, empagliflozin resulted in a superior reduction in HbA1c compared to sitagliptin.

The magnitude of HbA1c reduction observed in our combination therapy arms (-1.3% for sitagliptin and -1.5% for empagliflozin) from a high baseline of ~8.6% is consistent with findings from previous large-scale clinical trials [8, 10]. The incremental benefit of empagliflozin over sitagliptin, though modest (0.2%), was statistically significant and suggests a more potent glucose-lowering capacity in this patient population. This could be attributed to empagliflozin's insulin-independent mechanism of inducing glycosuria, which removes a substantial amount of glucose (approximately 70g/day) from the body, a pathway distinct from the insulin-sensitizing effects of metformin and the incretin-enhancing effects of sitagliptin [6].

Perhaps the most striking difference between the two combination therapies was their effect on body weight. The significant weight loss of 2.8 kg observed with empagliflozin is a well-established class effect of SGLT2 inhibitors, primarily driven by the caloric loss associated with urinary glucose excretion [11]. This contrasts sharply with the weight-neutral profile of sitagliptin, which aligns with the known pharmacology of DPP-4 inhibitors [5]. In an era where T2DM management is increasingly focused on a holistic approach that includes weight management, this finding has significant clinical implications. For the many patients with T2DM who are also overweight or obese, the dual benefit of glycemic control and weight reduction makes an SGLT2 inhibitor like empagliflozin a compelling therapeutic choice [12].

The effects on lipid profiles were not statistically significant, though trends were observed. The slight increase in LDL-C and HDL-C with empagliflozin has been reported previously and is thought to be related to hemoconcentration and altered lipid metabolism [13,14]. These changes are generally considered not to negate the profound cardiovascular benefits demonstrated by SGLT2 inhibitors in large cardiovascular outcome trials, such as the EMPA-REG OUTCOME trial, which showed a reduction in cardiovascular mortality with empagliflozin [7].

In terms of safety, our results confirm the favorable tolerability profiles of both agents. The risk of hypoglycemia was negligible, as neither drug class inherently causes hypoglycemia without concomitant insulin or sulfonylurea therapy. The numerically higher incidence of genitourinary infections with empagliflozin is a known side effect related to increased glucose in the urine, which can promote microbial growth [9]. In our study, these events were mild and easily managed, reinforcing that with proper patient education on hygiene, this risk can be effectively mitigated.

This study has several strengths, including its randomized, controlled design and its focus on a direct head-to-head comparison of two commonly used second-line agents. However, some limitations must be acknowledged. First, the 24-week duration is relatively short and does not allow for assessment of the long-term durability of the observed effects. Second, this was a single-center study, which may limit the generalizability of our findings to other populations. Third, the open-label design could have introduced a potential for bias, although the use of objective endpoints like HbA1c minimizes this risk.

In conclusion, this study demonstrates that for patients with Type 2 Diabetes Mellitus inadequately controlled on metformin, adding either empagliflozin or sitagliptin is a highly effective strategy to improve glycemic control. Empagliflozin was found to be superior to sitagliptin in reducing both HbA1c and body weight over a 24-week period. The significant weight reduction associated with empagliflozin offers a crucial non-glycemic benefit that can be particularly advantageous for the large proportion of T2DM patients with comorbid obesity. These findings support a personalized approach to T2DM management, where the selection of a second-line agent should be guided by individual patient characteristics, including the need for more potent glycemic lowering and the goal of weight management.

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