Abstract
Background
Uncontrolled type 2 diabetes mellitus warrant the utilization of different combination antidiabetic therapies, however, the addition of these newer agents as add-on therapy increases the risk of side effects and needs to be further investigated in terms of their risk to benefit to the patient. Therefore, the current study aims to evaluate the clinical and safety outcomes in patients taking empagliflozin and Sitagliptin in addition to metformin.
Method
A cross-sectional study was conducted using a non-probability consecutive sampling technique to gather data at the Diabetes and Foot Care Clinic in Abbottabad from July 2023 to December 2023. This is an exploratory observational study in which a total of 155 study participants were selected and divided into two groups: Group A, treated with Sitagliptin add-on Metformin (n = 79), and Group B, treated with Empagliflozin add-on Metformin (n = 76), Biochemical parameters (HbA1c, serum creatinine) were collected and eGFR was calculated at baseline and after a 3-month follow-up. All statistical analyses were performed using IBM SPSS version 23.
Results
Among the participant’s majority (53.5%) were males whereas the mean age of the participants was 51.7 ± 10.5 years. Baseline HbA1c and serum creatinine of all the patients were found to be 9.5 ± 1.8% and 1.02 ± 0.2 mg/dL respectively. There was a statistically significant decrease in mean HbA1c values in both the groups at baseline and follow-up (p < 0.001) whereas both the groups were found to be similar in their ability to reduce HbA1c (p = 0.25). Furthermore, there was a statistically significant decrease in serum creatinine values in both the groups at baseline and follow-up (p = 0.002) whereas Empagliflozin add-on Metformin was found to have more ability to reduce serum creatinine (p = 0.01) as compared to Sitagliptin add-on Metformin (p = 0.06). As a result, Empagliflozin add-on Metformin improved the patients’ eGFR significantly (p = 0.001).
Conclusion
Empagliflozin as add on therapy in uncontrolled T2DM provided improvements in patients HbA1c, serum creatinine, and eGFR hence improving overall clinical outcomes and patient safety.
Keywords: Assessment, Treatment outcome, Sitagliptin, Metformin, Type 2 diabetes mellitus
Introduction
Type 2 Diabetes Mellitus (T2DM) is a global epidemic. It is a metabolic syndrome which accounts for 1.5 million deaths per annum. Globally, 463 million people are suffering from diabetes mellitus, and 90% of whom suffer from type 2 diabetes mellitus. It is becoming the seventh largest driving reason for deaths worldwide. T2DM accounts for > 95% of diabetes. It is characterized by high levels of glucose in plasma, with a chronic and progressive course causing end-organ damage. Diabetes is specifically high in the Southeast-Asian (SEA) region with an increment projection to 123 million till 2035 [1].
Its prevalence in Pakistan was 11.77%, 16.98%, and 17.1% in 2016, 2018, and 2019 respectively. As per International Diabetes Federation (IDF), 26.7% of adults are affected by diabetes, in 2022, in Pakistan approximating to 33,000,000 cases. An alarmingly high prevalence is being observed and there is a constant increase with each passing year with an unaccounted probability of people who are still undiagnosed. Pakistan reports the third highest prevalence in the world [2].
Metformin is the drug of choice and is recommended as first-line therapy for T2DM patients, who are unable to achieve target glycemic control via lifestyle modifications [3]. Initially effective, monotherapy of metformin fails to provide glycemic control with the progress of disease [4]. New therapies are being considered to help attain glycemic targets. Sodium-glucose co-transporter type 2 (SGLT-2) in the management of diabetes is an emerging target. SGLT-2 inhibitors act independently of insulin and can be used as monotherapy or in addition to antidiabetic drugs (ADs) to control hyperglycemia. Glucose is reabsorbed in the in proximal convoluted tubule (PCT) via passive transport, also facilitatively through glucose transporters (GLUT) and actively using sodium glucose co-transporters (SGLT) [5]. Situated at the proximal tangled tubules, SGLT-2 has a significant physiological function in renal glucose reabsorption. Pharmacological hindrance of SGLT-2 increments urinary glucose discharge and diminishes plasma glucose levels [6]. SGLT2 reabsorbs more than 90% of the filtered glucose. Thus, a reduced risk of hypoglycemia, with weight loss and blood pressure (BP) reduction benefits. Drugs in this class include dapagliflozin, canagliflozin, empagliflozin, and ertugliflozin. They are indicated as an adjunct to monotherapy to improve glycemic control in adults with T2DM along with diet and exercise. Empagliflozin, a synthetic glucoside derivative, which is orally active, potent, and selective inhibitor of SGLT2 [1].
Inadequate glycemic control often presents as a problem in patients taking metformin monotherapy and warrants the use of additional antidiabetic medications, but those agents are associated with safety and tolerability issues. Therefore, other antidiabetic medications including either sitagliptin or new agents such as empagliflozin are added to metformin when its monotherapy fails to maintain optimum glycemic control. Sitagliptin is a β-Amino acid-based triazolopiperazine, a DPP-IV inhibitor that mimic the actions of incretins. Dipeptidyl peptidase - IV (DPP-IV) enzyme is present in plasma soluble form and membrane bound form [1, 2, 5]. The enzyme deactivates GLP-1. Inactivation of DPP-IV increases the half-life of GLP-1. Selective, competitive DPP-4 inhibition, increasing active GLP-1/GIP half-life by 2-3-fold, enhancing glucose-dependent insulin secretion [7].
Several studies have evaluated empagliflozin and sitagliptin as add-on therapies to metformin in uncontrolled Type 2 Diabetes Mellitus (T2DM), there is limited real-world comparative data available from Pakistan. There are significant disparities between Western and Pakistani populations in context of diabetes prevalence and management, that includes earlier onset of diabetes (often < 30 years), distinct metabolic profiles, and higher prevalence. This has necessitated early screening and adapted treatment strategies. There are modified international guidelines for local applicability (e.g., lowering screening age to 30) to address these differences. The driving reasons are socioeconomic, genetic, and healthcare-access factors. Evidence suggests variable antidiabetic drug responses in South Asians, underscoring the need for region-specific studies like ours to evaluate therapies such as Empagliflozin add-on Metformin in this high-risk population [8–10]. Our study is unique in that it provides evidence on the efficacy and safety of Empagliflozin add-on Metformin versus Sitagliptin add-on Metformin in our population, addressing a critical gap in region-specific data. Hence the current study aimed to evaluate the efficacy of empagliflozin as compared with sitagliptin in controlling glycated hemoglobin (HbA1c) in T2DM patients with dual therapy as well as on serum creatinine and estimated glomerular filtration rate (eGFR) in T2DM patients.
Methods
Study design and setting
A cross-sectional study was carried out at Abbottabad Diabetes Clinic and Foot Care Center, Abbottabad, Pakistan from July 2023 to December 2023. This is an exploratory observational study in which HbA1c levels were determined using an equipment (Quo-Lab analyzer, Werfen, Spain) employing boronate affinity method. The patients failing to achieve the goal HbA1c of ≤ 6.5% (48 mmol/mol) despite being on Metformin monotherapy were included in the study via nonprobability consecutive sampling technique. Based on the therapy they received from their healthcare professional (HCP), they were divided into two groups, i.e., Empagliflozin add-on Metformin and Sitagliptin add-on Metformin.
Study population
The study population included all the patients presenting to the clinic with uncontrolled diabetes. The patients were divided into two groups based on the combinations (Empagliflozin add-on Metformin and Sitagliptin add-on Metformin) they were taking.
Inclusion and exclusion criteria
Inadequately managed T2DM patients (patients who fail to achieve the goal HbA1c of ≤ 6.5% (48 mmol/mol) on metformin monotherapy) presenting to the clinic and age between 18 and 70 years were included in the study. Whereas patients with eGFR ≤ 30 mL/min/1.73 m2, Urinary tract infection (UTI), Diabetic Ketoacidosis (DKA), receiving treatment with anti-obesity drugs and having pregnancy were excluded from the study.
Fig. 1.
Flowchart depicting study cohort formation
Variables
Outcome variables
HbA1c (using Quo-Lab semiautomated analyzer), Serum creatinine, eGFR.
Independent variables
Age (years), gender, body weight (Kg).
Sampling technique and sample size calculation
Non-probability consecutive sampling technique was used. The following formula was used to calculate the sample size [11]:
 |
n = Sample size.
µ1 = Mean change in HbA1c in test drug.
µ2 = Mean change in HbA1c in standard drug.
σ = Population standard deviation.
Based on 95% confidence interval and 80% power, the sample size (n = 76) was included in each study group [12].
Data collection procedure
Patients were approached during their scheduled visit at the clinic and verbal consent was taken from each participant. Glycated hemoglobin (%), Systolic blood pressure (mm Hg), diastolic blood pressure (mm Hg), serum creatinine (mg/dl) and eGFR (ml/min/1.73m2) were obtained on two instances, i.e., at baseline and after 12 weeks’ visit using a data collection form.
Data analysis
SPSS (IBM SPSS Statistics 23) software was used for all statistical analyses. Continuous variables were presented as Mean and SD while categorical variables were presented as frequencies (n) and percentages (%). Mann-Whitney U test and Wilcoxon Signed-Ranks test were used to compare the two treatment groups. P-value < 0.05 was considered statistically significant.
Results
Patients’ demographics and clinical characteristics
Patients’ characteristics with respect to two treatment groups are illustrated in Table 1. Data from a total of n = 155 patients was included in the study. According to our findings, Empagliflozin add-on Metformin was frequently prescribed in males (59%) and elderly patients with mean age 53.2 ± 9.6, whereas prescription of Sitagliptin add-on Metformin was more common in young patients with mean age 50.2 ± 11.1, and in 62.5% female patients. The use of empagliflozin was more prevalent (58.2%) in T2DM patients with comorbid hypertension as compared with 41.8% patients taking Sitagliptin add-on Metformin. Based on clinical outcomes as revealed in Table 3, Group B showed an overall glycemic control from mean baseline values of HbA1c (mean = 9.4, SD = ± 1.5) and mean follow-up HbA1c values of (mean = 7.6, SD = ± 1.2), and Group A showed an overall glycemic control from mean baseline values of HbA1c (mean = 9.5, SD = ± 2) and mean follow-up HbA1c values of (mean = 7.4, SD = ± 1.5). Serum creatinine reduction in Group B from mean baseline values (mean = 1.08, SD = 0.24) to a mean follow-up value of (mean = 1.03, SD = 0.2) while serum creatinine reduction occurred in Group A was from a mean baseline value of (mean = 0.96, SD = 0.13) to a mean follow-up value of (mean = 0.96, SD = 0.12). Improvements in eGFR in both the groups were observed in such a manner that eGFR from a baseline value of (mean = 75.4, SD = 16.1) improved to a mean follow-up value of (mean = 78.1, SD = 23.1) in Group B, whereas in Group A, an improvement from a baseline value of (mean = 79.8, SD = 16.1) to a mean follow-up value of (mean = 81.9, SD = 19.3) was also observed.
Table 1.
Patients’ characteristics of both treatment groups
| Variables | Treatment Groups | ||
|---|---|---|---|
| Sitagliptin add-on Metformin | Empagliflozin add-on Metformin | ||
| n (%)* | n (%)* | ||
| Gender | |||
| Female | 45 (62.5) | 27 (37.5) | |
| Male | 34 (41) | 49 (59) | |
| Diagnosis | |||
| Type 2 Diabetes Mellitus | 51 (58) | 37 (42) | |
| Comorbidities | |||
| Hypertension | 28 (41.8) | 39 (58.2) | |
| IHD | 1 (25) | 3 (75) | |
| Years of Diagnosis | |||
| ≤ 3 | 32 (53.3) | 28 (46.7) | |
| 4–7 | 22 (57.9) | 16 (42.1) | |
| 8–10 | 11 (44) | 14 (56) | |
| > 10 | 12 (40) | 18 (60) | |
| Other Parameters | Mean ± SD | Mean ± SD | |
| Age (years) | 50.2 ± 11.1 | 53.2 ± 9.6 | |
| Systolic BP (mm Hg) | 139.1 ± 21.5 | 135.6 ± 24.7 | |
| Diastolic BP (mm Hg) | 85.3 ± 8.9 | 83.7 ± 10.4 | |
| Baseline HbA1c (%) | 9.5 ± 2 | 9.4 ± 1.5 | |
| Follow-up HbA1c (%) | 7.4 ± 1.5 | 7.6 ± 1.2 | |
| Baseline serum creatinine (mg/dl) | 0.96 ± 0.13 | 1.08 ± 0.24 | |
| Follow-up serum creatinine (mg/dl) | 0.94 ± 0.12 | 1.03 ± 0.2 | |
| Baseline eGFR (mL/min/1.73m2) | 79.8 ± 16.1 | 75.4 ± 23.7 | |
| Follow-up eGFR (mL/min/1.73m2) | 81.9 ± 19.3 | 78.1 ± 23.1 | |
*Row-wise percentages were calculated (total number of patients = 155)
i. n = 76 in Empagliflozin-Metformin group
ii. n = 79 in Sitagliptin-Metformin group
Table 3.
Comparison between baseline and follow-up values of HbA1c, serum creatinine and eGFR before and after initiating combination antidiabetic therapy
| Treatment Groups | N | HbA1c (%) | Serum creatinine (mg/dl) | eGFR (ml/min/1.73m2) | ||||||
|---|---|---|---|---|---|---|---|---|---|---|
| Sitagliptin add-on Metformin | Median (IQR) | Z Statistic | p-value* | Median (IQR) | Z Statistic | p-value* | Median (IQR) | Z Statistic | p-value* | |
| Baseline | 79 | 9.4 (2.8) | -7.723 | < 0.001 | 0.9 (0.1) | -1.905 | 0.057 | 80.3 (20.07) | -1.903 | 0.057 |
| After 3 months | 79 | 7 (2.2) | 0.9 (0.1) | 82.07 (20.9) | ||||||
| Empagliflozin add-on Metformin | ||||||||||
| Baseline | 76 | 9.4 (2.2) | -7.576 | < 0.001 | 1.0 (0.4) | -2.551 | 0.01 | 73.3 (32.08) | -2.734 | 0.006 |
| After 3 months | 76 | 7.2 (2.1) | 1.0 (0.2) | 78.3 (28.7) | ||||||
*p-value was calculated using the Wilcoxon Signed-Ranks test
Diabetic complications
Figure 2 illustrates frequencies of various diabetic complications. Diabetes is associated with several complications, including pain/burning of feet at night (76.8%), numbness of feet in night (75.5%), waking up at night for urination more than once (75.5%), diabetic neuropathy (61.9%), high blood pressure (45.2%) and deterioration of vision (26.5%). Other less frequent complications included shortness of breath on exertion (6.5%), wounds/ulcers in feet (3.2%), constipation/diarrhea (3.2%), chest pain on either exertion or rest (2.6%), diabetic nephropathy (1.3%) and diabetic foot (1.3%).
Fig. 2.
Patients with various diabetic complications at initial visit
Overall comparison between the two treatment groups with respect to follow-up HbA1c, serum creatinine, and subsequent eGFR levels
Data from two groups of patients was collected i.e. Group A took Sitagliptin add-on Metformin which had 79 patients, and Group B took Empagliflozin add-on Metformin combination consisting of 76 patients. The Mann-Whitney test was conducted to compare the two treatment groups with respect to follow-up HbA1c, serum creatinine, and eGFR levels as given in Table 2. Results indicated that there was no statistically significant association found between the HbA1c percentage reduction of the two treatment groups U (N = 79, N = 76,) = 2682, p = 0.25. Similarly, there was no significant reduction in the eGFR between the two treatment groups U (N = 79, N = 76,) = 2756.5, p = 0.4. However, a significant association was found between the creatinine reduction and the treatment groups, U (N = 79, N = 76,) = 2043, p < 0.001. The serum creatinine reduction of Group A (Mean Rank = 65.9; Median = 0.9) was more than that of Group B (Mean Rank = 90.6; Median = 0).
Table 2.
Overall comparison between the two treatment groups with respect to follow-up HbA1c, serum creatinine and eGFR levels
| Glycated Hemoglobin (%) | ||||
|---|---|---|---|---|
| Treatment Groups | N | Mean Rank | U Statistic | p-value* |
| Sitagliptin add-on Metformin | 79 | 73.95 | 2682 | 0.25 |
| Empagliflozin add-on Metformin | 76 | 82.21 | ||
| Serum Creatinine (mg/dl) | ||||
|---|---|---|---|---|
| Treatment Groups | N | Mean Rank | U Statistic | p-value* |
| Sitagliptin add-on Metformin | 79 | 65.9 | 2043 | < 0.001 |
| Empagliflozin add-on Metformin | 76 | 90.6 | ||
| eGFR (ml/min/1.73 m2) | ||||
|---|---|---|---|---|
| Treatment Groups | N | Mean Rank | U Statistic | p-value |
| Sitagliptin add-on Metformin | 79 | 81.1 | 2756.5 | 0.4 |
| Empagliflozin add-on Metformin | 76 | 74.8 | ||
*p-value was calculated using Mann-Whitney U test
Comparison between baseline and follow-up values of HbA1c, serum creatinine and eGFR before and after initiating combination antidiabetic therapy
Table 3 illustrates the comparison between the baseline and follow-up values of HbA1c serum creatinine and eGFR for both groups (Sitagliptin add-on Metformin and Empagliflozin add-on Metformin) after 3 months using the Wilcoxon signed-rank test. The results showed a statistically significant difference (Z = -7.723, p < 0.001) with respect to HbA1c, whereas the Cohen d effect size calculated was 0.87 which showed a strong effect. Similarly, the results showed a statistically significant change between baseline and follow-up values of HbA1c after Empagliflozin add-on Metformin therapy (Z = -7.576, p < 0.001). The Cohen’s effect size calculated was 0.3 which was small effect. The results suggest that participants achieved significant glycemic control when combination antidiabetic therapy was initiated, with baseline and follow-up values.
The results did not reflect a statistically significant difference (Z = -1.905, p = 0.06) with respect to serum creatinine in patients taking Sitagliptin add-on Metformin therapy. However, there was a statistically significant change between the baseline and follow-up values of serum creatinine after Empagliflozin add-on Metformin therapy (Z = -2.551, p = 0.01). Cohen’s effect size calculated was 0.3 which was a small effect. The results suggest that participants achieved a serum creatinine reduction when a combination of antidiabetic therapy of Empagliflozin add-on Metformin was initiated with baseline and follow-up values.
Moreover, there was no statistically significant difference (Z = -1.903, p = 0.06) in Sitagliptin add-on Metformin therapy group with respect to eGFR values. However, the results showed a statistically significant change between the values of eGFR in baseline and Empagliflozin add-on Metformin (Group B) after 3 months of therapy (Z = -2.734, p = 0.006). Cohen’s effect size calculated was 0.3 which was a small effect. The results suggest that participants achieved an eGFR reduction when a combination of antidiabetic therapy of Empagliflozin add-on Metformin was initiated with baseline and follow-up values.
Discussion
This exploratory observational study aimed to assess the HbA1c and eGFR in patients presenting with uncontrolled type 2 Diabetes Mellitus receiving combination therapy of Sitagliptin or Empagliflozin as adjuncts to Metformin to help our local Healthcare Practitioners to make an investigative decision when prescribing therapy for diabetes mellitus type 2. Among the study population, male patients with uncontrolled T2DM presented more frequently than females, which aligns with the findings of other studies, where they observed a high male-to-female ratio [13, 14]. However, some studies identified a high prevalence rate among females suggesting that factors such as lifestyle, ethnic differences, genetic predispositions, and/or environmental factors might contribute to these variations [15].The study also identified that uncontrolled T2DM was more frequently encountered in higher age groups, which was consistent with other previous studies [14, 16]. The higher prevalence of diabetes in older age groups can be attributed to various factors, including age related physiological changes such as decreased sensitivity to insulin and beta-cell impairment [17], increased prevalence of risk factors over time like obesity, sedentary lifestyle, unhealthy dietary habits [18] and genetic predisposition [19]. Moreover, the association between diabetes duration and uncontrolled T2DM was also evident in our findings which were consistent with similar studies that attributed prolonged disease duration with adherence to treatment and lifestyle modification [20].
Our study also showed that with an increase in systolic and diastolic blood pressure in T2DM mellitus patients reinforcing the link between T2DM mellitus patients and hypertension. Several studies have concluded a raised blood pressure increases in T2DM and also suggested various mechanisms that contribute to the association between diabetes and hypertension. The reasons maybe insulin resistance resulting in hyperinsulinemia, endothelial damage and dysfunction, arterial stiffness which is attributed to hyperglycemia, low-grade chronic inflammation and oxidative stress, central obesity, and renin-angiotensin aldosterone system (RAAS) dysfunction [21].
Our study suggested that patients with T2DM had serum creatinine in a higher normal range, thus indicating that kidney functions are compromised with T2DM. Literature suggests that impaired kidney function in T2DM can result from chronic low-grade inflammation leading to renal fibrosis and thus, impaired tissue repair mechanisms in kidney, increase in glomerular pressure and hyperfiltration resulting from altered renal hemodynamics which can cause structural and functional changes in the kidneys, and prolonged hyperglycemia leading to glomerular oxidative stress and inflammation, and hence contributing to renal damage [22]. Moreover, our study found that diabetic patients presented with several complications like pain/burning of feet at night, numbness in feet, waking up at night for urination, diabetic neuropathy, high blood pressure, and deterioration of vision (primarily from microvascular damage, neurodegeneration, inflammation, and metabolic dysregulation [23]. These are similar to those reported in previous studies [24–26].
After performing a comparative analysis between the two treatment groups with respect to baseline and follow-up HbA1c, we observed that there appeared no statistically significant difference between Group A and Group B in their ability to reduce HbA1c. Similar findings were demonstrated in a meta-analysis in which there was no statistically significant difference found between SGLT-2 inhibitors and DPP-4 inhibitors in their ability to reduce HbA1c, because the baseline HbA1c in the subgroup of patients was ≥ 8%, which is in agreement to our study population that had a mean baseline HbA1c 9.5 ± 1.8. Therefore, due to a high mean baseline HbA1c the results failed to appear statistically significant. However, there was statistically significant reduction in mean HbA1c when a comparison was performed between the baseline and three months’ follow-up of all the patients irrespective of their treatment group. This implies that both Empagliflozin add-on Metformin and Sitagliptin add-on Metformin treatment groups demonstrated reduction in the HbA1c level to a similar extent. Such findings have also been reported in other studies [27].
Findings in our study suggest a statistically significant reduction in HbA1c, when comparison between baseline and follow up values of mean HbA1c before and after initiating Sitagliptin add-on Metformin therapy. These results are in accordance with the data published in several studies, where a statistically significant reduction in mean HbA1c values were recorded for Sitagliptin add-on Metformin therapy [28]. A statistically significant reduction in mean HbA1c, when comparing between baseline and follow up values of mean HBA1C before and after initiating Empagliflozin add-on Metformin combination antidiabetic therapy. The result shows a significant reduction in mean HbA1c values, that is in agreement with the already existing literature [27]. A similar trend is seen in other literatures as well [29].
As demonstrated in Table 3, both groups showed a clinically significant reduction in HBA1c. However, the amplitude of HbA1c reduction in both the groups was similar, empagliflozin as add on therapy to metformin did not prove superior to the Sitagliptin add-on Metformin group. Similar results were evident in other literatures as well where SGLT 2 inhibitors did not prove to be superior to DPP-4 inhibitors [27, 28]. A statistically significant difference was found after an overall comparison between the two treatment groups with respect to baseline and follow-up serum creatinine, and overall, clinically significant reduction in serum creatinine, irrespective of the treatment group, was observed. Sitagliptin add-on Metformin group failed to produce a statistically significant reduction in mean serum creatinine and eGFR, whereas Empagliflozin add-on Metformin therapy produced slight improvements in both serum creatinine and eGFR. This is in accordance with the EMPA-REG renal outcomes trial, in which empagliflozin group reduced time to doubling of serum creatinine, thus maintaining kidney functions and a significant improvement of eGFR, providing a better alternative in chronic diabetes mellitus patients to maintain kidney function [29, 30].
The current study addresses a significant research gap, as limited literature exists on the comparative outcomes of empagliflozin and sitagliptin as add-on therapies to metformin in Pakistan. It provides clinically relevant insights into improving glycemic control and patient outcomes in uncontrolled type 2 diabetes in this region with a high prevalence of the disease. The study’s findings may serve as supportive but not definitive evidence for clinical practice and contribute to future research and guidelines for diabetes management in Pakistan. Therefore, extensive studies are needed to produce more conclusive evidence.
This study was based on a single clinical setup and with a limited sample size. The limited time duration of the study has also left room for observing further parameters like long-term safety, efficacy, and tolerability and development of primary and secondary complications related to diabetes. Due to the limited nature of the data, various factors such as myocardial infarction in the previous six months, cancer, need for steroids, and rheumatic diseases have not been taken into account.
Conclusion
The study findings suggest that Sitagliptin add-on Metformin and Empagliflozin add-on Metformin therapies are associated with significant glycemic control as compared with Metformin monotherapy. However, minor differences in HbA1c reduction were observed between the Sitagliptin add-on Metformin and Empagliflozin add-on Metformin therapy groups. Moreover, there was a slight improvement in eGFR and serum creatinine levels in Empagliflozin add-on Metformin therapy group as compared with the Sitagliptin add-on Metformin group. Therefore, in uncontrolled T2DM patients, addition of Empagliflozin to first-line monotherapy with Metformin, can provide an equivalent glycemic control and slightly improved kidney function.
Acknowledgements
The authors of this study extend their appreciation to the Ongoing Research Funding Program ( ORF-2025-856), King Saud University, Riyadh 11451, Saudi Arabia.
Author contributions
“A.K.,M.S.,M.A and Q.K. wrote the main manuscript text and M.I.,A.I.,A.B.,N.A and W.S prepared figures and Tables and analyzed data and revised the entire mansucirpt . All authors reviewed the manuscript.”
Funding
This study was Funded by Ongoing Research Funding Program ( ORF-2025-856), King Saud University, Riyadh 11451 , Saudi Arabia.
Data availability
The datasets used and analyzed during the current study are available from the corresponding author upon reasonable request.
Declarations
Ethics approval and consent to participate
The ethical approval for this study, with reference number M02-09/1123 Phm, was obtained from the ethical committee of the Department of Pharmacy at COMSATS University Islamabad, Abbottabad Campus. Informed consent was obtained from all study participants before data collection. All study procedures were conducted in accordance with the Declaration of Helsinki guidelines for human research. Participants were informed that the data provided would only be used for research purposes, and that confidentiality would be maintained throughout the study. They were also informed of their right to withdraw from the study at any point in time.
Consent for publication
Not applicable.
Competing interests
The authors declare no competing interests.
Clinical trial number
Not applicable.
Footnotes
Publisher’s note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Contributor Information
Qasim Khan, Email: qasimmunir@cuiatd.edu.pk.
Naji Alqahtani, Email: alqnaji@KSU.EDU.SA.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Data Availability Statement
The datasets used and analyzed during the current study are available from the corresponding author upon reasonable request.