JDBT

Introduction

Type 2 diabetes mellitus (T2DM) is a prevalent, chronic metabolic condition driven by insulin resistance and β-cell dysfunction with impaired glucose regulation. The burden of T2DM is increasing worldwide, and it has enormous implications on morbidity, mortality, and cost to healthcare [1-3]. Due to its chronic nature, early and effective intervention is essential to ensure long-term glycemic control and to prevent long-term complications [4,5].

The American Diabetes Association (ADA) guidelines recommend individualized treatment strategies based on comorbidities, patient preferences, and access, with metformin typically being the preferred first-line therapy. Owing to the inevitable progressive loss of β-cell function, monotherapy tends to prove inadequate, and early combination therapy is required to attain and maintain glycemic goals. Notably, in those with atherosclerotic cardiovascular disease (ASCVD), increased ASCVD risk, chronic kidney disease (CKD), or heart failure (HF), the guidelines stress the use of medications with established cardio-renal benefit, specifically sodium–glucose cotransporter-2 inhibitors (SGLT2is) and dipeptidyl peptidase-4 inhibitors (DPP-4is) [6-9].

Evidence from randomized clinical trials supports the early use of combination therapy in individuals with newly diagnosed T2DM. In addition to DPP-4is, SGLT2is have become a valuable therapeutic category in the management of T2DM. Through the inhibition of glucose reabsorption by the renal proximal tubule, these drugs enhance urinary glucose excretion, thereby decreasing blood glucose levels, reducing body weight, and lowering blood pressure. Increasing evidence suggests that SGLT2is are effective in cardiovascular and renal protection [10].

Large trials and real-world database analyses have demonstrated that SGLT2is treatment is linked to decreases in heart failure hospitalization, major adverse cardiovascular events, and allcause mortality, at times even when it is compared with metformin as initial therapy [11].  When used in combination with other antidiabetic medications, such as DPP-4is and SGLT2is, these can provide additive benefits. Recent meta-analysis and systematic review illustrated that body weight reduction, together with the improvement of glycemic control, was achieved by the combination of SGLT2i + DPP4i without raising the risk of hypoglycemia or urinary tract infections [12,13].

In the Asian-Indian population, combination therapy is especially relevant. The population is marked by higher insulin resistance, reduced β-cell function, abdominal obesity, and the concurrence of cardiovascular risk factors. The US FDA has licensed SGLT2i + DPP4i fixed-dose combinations and are extensively used in India to enhance patient compliance and therapeutic efficacy [14]. Nonetheless, real-world evidence concerning their use, especially for the fixed-dose combination of sitagliptin plus dapagliflozin, is limited in the Indian context. In light of these lacunae, the present study aims to analyse the usage pattern of the sitagliptin + dapagliflozin fixed-dose combination (FDC) in actual clinical practice. The results of this study can be useful for prescribers in making informed treatment decisions, enhancing glycemic and cardio-renal outcomes, and improving patient care among the Indian population with poorly controlled T2DM.

Methodology

This was a multicentric, cross-sectional, observational study conducted across 100 clinical sites in India. Data collection was done between January 2024 and June 2024. The study was designed to evaluate the real-world utilization patterns of the FDC of Sitagliptin and Dapagliflozin for the treatment of T2DM.

The study was conducted in accordance with the New Drugs and Clinical Trials Rules 2019 issued by the Government of India, ethical principles originating from the Declaration of Helsinki, International Council for Harmonization (ICH) Good Clinical Practice (GCP) guidelines, and all applicable local regulatory requirements. Ethics committee approval was obtained from the Good Society for Ethical Research (EC Registration: ECR/69/Indt/

DL/2013/RR-19). The study was approved by a CDSCO-registered Institutional Ethics Committee (Protocol No. NIS/2023/13). As this was a retrospective observational study using anonymised medical records, informed consent was not required

Data of 873 patients was captured electronically through a validated electronic data capture (EDC) platform. Medical records of patients who were prescribed with FDC of Sitagliptin + Dapagliflozin by the treating physician were included in the analysis. Incomplete information or missing essential data was excluded.

The primary endpoint of this study was to evaluate the clinical use of Sitagliptin + Dapagliflozin FDC in outpatient departments in India. Secondary endpoints were evaluation of demographic data, medical history, and concomitant medications of patients treated with the FDC.

Patient data were collected from medical records and entered into an electronic data capture (EDC) system by investigator staff at each site. All site investigators were provided with standardized training in the EDC process to ensure data accuracy and consistency of entry.

Statistical Analysis

All of the analyses were descriptive. Continuous data were reported as mean and standard deviation or median and interquartile range, depending on the data distribution. The categorical variables were

reported in frequencies and percentages. No inferential statistical testing was conducted due to the observational nature of the study.

Results

A total of 873 patients with T2DM were included in this cross-sectional analysis. The mean age of the patients was 55.26 ± 11.46 years, and the average duration of diabetes was 7.02 + 5.86 years. The male-to-female ratio was 66% to 34%. The average body weight was 74.25 ± 13.79 kg, average height 163.05 ± 15.70 cm^². The mean systolic blood pressure was 141.06 ±19.26 mmHg, diastolic blood pressure 87.83±11.36 mmHg, and mean pulse rate 82.44 ± 11.55/min. The sociodemographic profile of the study population is tabulated in (Table 1), and the overall enrolment pattern is shown in (Figure 1).

Table 1: Baseline Demographic Characteristics of the Study Population (N = 873).

Values are expressed as mean ± Standard Deviation (SD) or n (%), unless otherwise specified.

 Figure 1: Gender distribution of study population.

Prescription Profile

The sitagliptin + dapagliflozin FDC was prescribed extensively in real-world clinical practice in India. Approximately 36.77% of the patients were treatment-naïve and were initiated directly on the FDC, whereas 62.77% were transitioned from previous oral antidiabetic regimens. Among FDCs used prior to switching, the most common were glimepiride + metformin, sitagliptin + metformin, glimepiride + metformin + voglibose, dapagliflozin + vildagliptin, linagliptin + dapagliflozin, and teneligliptin + dapagliflozin.

The main reasons for prescribing the FDC among switch patients were poor glycemic control on prior therapies and the occurrence of cardiovascular or metabolic comorbidities. FDC was most frequently prescribed in combination with metformin, although a large percentage was also prescribed as part of triple therapy (with sulfonylureas or other oral drugs) or in combination with insulin for more severe cases. The distribution of detailed prescription patterns is illustrated in Figure 2.

 Figure 2: Prescription profile of patients.

In our study, the analysis of drug utilization revealed that most patients (62.77%) received various combinations of antidiabetic agents. The drugs commonly used were sitagliptin, glimepiride, canagliflozin, dapagliflozin, metformin, vildagliptin, voglibose, linagliptin, remogliflozin, insulin, empagliflozin, gliclazide, pioglitazone, repaglinide, and teneligliptin. These results are indicative of the therapeutic strategy for T2DM in real-life settings, where clinicians tend to employ combination therapy to achieve the best possible glycemic control and counter the progressive nature of the disease.

In our current investigation, a high percentage of patients with T2DM were found to have comorbid diseases. The most common comorbidity was obesity, seen in 44.90% of the study group, which was followed very closely by cardiovascular disease in 44.79% of the patients.

Dyslipidemia was seen in 33.56%, chronic kidney disease and anxiety/depression in 10.42% of the patients each. The less prevalent comorbidities were obstructive sleep apnea (5.96%) and osteoporosis (5.61%). Also, 2.86% of patients reported other medical conditions. These results indicate the high comorbidity burden among T2DM patients, necessitating extensive management approaches beyond glycemic control. The prevalence of comorbid conditions is represented in (Figure 3).

 Figure 3: Comorbidities among the study population.

Medical, Personal, and Family History

The patients’ history was systematically collected to identify definitive indications related to their diabetic status. A history of recurrent Urinary Tract Infection (UTI) was noted in 63 patients (7.2%), and 61 patients (6.99%) had a history of shortness of breath. Chest pain was noted in 75 patients (8.59%), and restriction of physical activity was noted in 131 patients (15.01%). Hospitalization due to any reason in the past year was noted by 13 patients (1.49%).

165 patients (18.90%) reported a positive smoking status or a history of tobacco exposure. It emphasizes the role of modifiable lifestyle risk factors in the total disease burden of type 2 diabetes mellitus.

418 patients (47.88%) had a positive family history of diabetes, while 455 patients (52.12%) had no known familial risk. These results highlight the interaction between genetic susceptibility and environmental or lifestyle-related risk factors in the development and progression of type 2 diabetes. These results are shown in (Figure 4).

 Figure 4: Medical, Personal, and Family History.

Among the biochemical parameters measured, there was poor glycemic control, with mean fasting blood glucose (171.83 ± 54.96 mg/ dL), postprandial glucose (262.81 ± 67.71 mg/dL), and HbA1c (8.28 ± 1.25%) levels significantly above the desired values.

Renal function testing revealed a mean serum creatinine value of 1.89 ± 2.16 mg/dL and a blood urea nitrogen of 22.61 ± 7.45 mg/dL, with serum albumin levels maintained at 4.86 ± 1.59 g/dL.

A lipid profile was abnormal in a significant number of patients, as evidenced by elevated mean triglycerides (187.70 ± 91.04 mg/dL) and LDL cholesterol (112.79 ± 39.49 mg/dL), with an average HDL cholesterol level of 63.41 ± 36.57 mg/dL. These results collectively indicate suboptimal glycemic and metabolic control among study subjects, thereby emphasizing the elevated cardiovascular and renal risk load among type 2 diabetic patients. These findings are presented in (Table 2).

Table 2: Biochemical Parameters of the Study Population at the Time of Initiation of Sitagliptin + Dapagliflozin FDC.

In the current study, it was observed that a considerable number of patients needed drugs in addition to antidiabetic treatment to control concomitant comorbidities and complications. Antihypertensive drugs were prescribed to almost half (47.76%) of the patients as monotherapy or in combination due to the high incidence of hypertension in type 2 diabetes patients. Calcium channel blockers, beta blockers, Angiotensin-Converting Enzyme inhibitors, Angiotensin Receptor Blockers, and diuretics were the most commonly used medications.