CTIM

Introduction

Type 2 diabetes mellitus (T2DM) is a major and growing publichealth concern in India. According to the International Diabetes Federation (IDF)’s 2025 Diabetes Atlas, 589 million adults (20-79 years) worldwide live with diabetes, roughly 1 in 9 adults, and this number is predicted to rise to 853 million by 2050 [1].  It is characterized by a non-autoimmune, heterogeneously progressive decline in pancreatic β-cell insulin secretion, often occurring in conjunction with insulin resistance (IR) and metabolic syndrome (MS) [2].  Impaired β-cell function reduces insulin secretion and limits the body’s ability to maintain normal glucose levels, while insulin resistance promotes excessive hepatic glucose production and diminishes glucose uptake in muscle, liver, and adipose tissue. Although both defects contribute early in disease development, β-cell dysfunction tends to be more pronounced. Several antidiabetic agents have been developed to address these underlying defects, thereby enhancing glycemic control in T2DM [3].

Metformin remains the cornerstone of initial pharmacological therapy for type 2 diabetes mellitus (T2DM) due to its efficacy, safety, weight neutrality, cardiovascular benefits, and costeffectiveness. However, because T2DM is a progressive disease characterized by declining β-cell function and increasing insulin resistance, metformin monotherapy often fails to sustain adequate glycemic control over time and frequently falls short of adequately correcting dyslipidemia [4]. Hyperglycemia and dyslipidemia are the major metabolic defects of focus in Type 2 diabetes mellitus patients, which cannot be addressed solely by a single drug [5,6].

The U.S. study found that approximately 42% of patients experienced secondary metformin failure over a 2- to 5-year period [7].  This rising incidence of secondary treatment failure underscores the growing need for early initiation of combination therapy, particularly with agents that have complementary mechanisms of action, such as DPP-4 inhibitors, SGLT-2 inhibitors, GLP-1 receptor agonists, thiazolidinediones, or basal insulin. Current international and Indian guidelines therefore recommend combination therapy in patients who do not achieve the target HbA1c with metformin alone, to improve long-term glycemic durability and reduce the risk of complications [4, 8].

Sitagliptin, a dipeptidyl peptidase-4 (DPP-4) inhibitor, increases the levels of active incretin hormones (GLP-1 and GIP), thereby stimulating glucose-dependent insulin secretion and suppressing glucagon release. This, in turn, reduces hepatic glucose production and improves postprandial glycemia [9,10].  Pioglitazone, a thiazolidinedione, acts as a peroxisome proliferator-activated receptor-γ (PPAR-γ) agonist, improving insulin sensitivity in adipose tissue, skeletal muscle, and the liver, while also preserving β-cell function and reducing hepatic glucose output [11, 12].Thus, pioglitazone is frequently prescribed as an add-on therapy when metformin, DPP-4 inhibitors, GLP-1 receptor agonists, or their combinations fail to achieve adequate glycemic control [13].

A 16-week randomized controlled trial in patients inadequately controlled on metformin demonstrated that both sitagliptin (100 mg) and pioglitazone (30 mg) as add-on therapies significantly lowered HbA1c from baseline, with sitagliptin showing additional benefits in body weight control compared with weight gain with pioglitazone [14].  Additionally, the recent IMPACT study conducted in India compared a fixed-dose combination of triple therapy (FDC, metformin/sitagliptin/pioglitazone) vs. dual therapy (metformin/sitagliptin) in patients with HbA1c between 8-11% who were insufficiently controlled with metformin alone; triple therapy showed a greater HbA1c reduction (−1.64% vs. −1.32%) and superior fasting and postprandial glucose improvements [15].

Although randomized controlled trials, including the Indian IMPACT study [16], have demonstrated the efficacy and tolerability of the sitagliptin, metformin, and pioglitazone combination, largescale, multicentre real-world data evaluating its effectiveness and safety in routine Indian clinical practice remain limited.

Given the substantial burden of T2DM in India and the common f inadequacy of monotherapy or dual therapy to achieve optimal glycemic control, it is essential to assess the clinical effectiveness, safety, and metabolic impact of the combination of sitagliptin, pioglitazone, and metformin. The present study seeks to fill this gap by providing real-world evidence derived from a large, multicentric cohort.

Materials and Methods Study Details

We conducted a retrospective, observational, single-arm, multicentre study to evaluate the effectiveness and safety of a triple combination of sitagliptin, pioglitazone, and metformin in patients diagnosed with T2DM across India. The study was conducted in compliance with the International Conference on HarmonizationGood Clinical Practice Guidelines (ICH-GCP), the Declaration of Helsinki, and local regulatory requirements (Indian Good Clinical Practice, the Indian Council of Medical Research (ICMR), and the New Drugs & Clinical Trials Rules, 2019).

Study Population and Sample Size

Patients aged 18 years and older diagnosed with type 2 diabetes mellitus were assessed for eligibility during their first visit. The inclusion criteria comprised adults with T2DM who had been prescribed the FDC of Sitagliptin, Pioglitazone, and Metformin for at least 3 months and who had inadequate glycemic control at initiation, defined as an HbA1c level of ≥8.0% prior to starting the triple combination therapy.

Patient case records that were incomplete and deemed unsuitable for inclusion in the study by the investigator were excluded from the trial. Since there was no hypothesis to be proven, no formal sample size calculation was made for the study.

Study Conduct

The FDC used was Sitazit-Trio (Sitagliptin 100 mg, Pioglitazone 15 mg, and Metformin 1000 mg), administered as a single tablet once daily. This retrospective, observational, single-arm, multicentre study aimed to evaluate the effectiveness and safety of the triple combination of sitagliptin, pioglitazone, and metformin in patients diagnosed with T2DM.

After the eligibility criteria were confirmed, patient-level data were analysed. Data on demographic characteristics, medical history, and switch patterns from mono- or dual-therapy to the FDC were evaluated against predefined efficacy and safety endpoints.

Data were collected using an Electronic Case Report Form (eCRF) within a secure Electronic Data Capture (EDC) system. The system provided role-based access to authorized users, including Principal Investigators (PIs) and study coordinators. Each investigator was responsible for completing a predefined number of patient cases at their respective study sites.

Efficacy analysis

The primary endpoint was the mean change in glycemic parameters, including Glycosylated hemoglobin (HbA1C), Fasting plasma glucose (FPG), and Postprandial plasma glucose (PPG), at 3 months from the first visit (baseline). Secondary endpoints were mean change in lipid parameters like LDL, HDL, Triglycerides (TG) and Total cholesterol (TCH) at 3 months from 1st visit (baseline), mean change in hepatic parameters like Alanine transaminase (ALT), Aspartate transaminase (AST), Alkaline phosphate (ALP), Gamma-glutamyl transferase (GGT), Albumin and Total bilirubin at 3 months from 1st visit (baseline) and mean change in renal parameters like eGFR, serum creatinine, serum albumin, Creatinine clearance, Blood urea nitrogen at 3 months from 1st visit (baseline).

Safety Analysis

The safety assessment included analyses of treatment-emergent adverse events, serious adverse events, and laboratory parameters. It also consisted of the percentage of patients experiencing serious adverse events (SAE) leading to discontinuation of the treatment.

Statistical Analysis

All data will be summarized using descriptive statistics, including the number of subjects, mean, standard deviation (SD), minimum, median, and maximum for continuous variables, and frequency and percentage for categorical variables. Descriptive statistics were used to summarize the data. Categorical variables were presented as absolute numbers and percentages, while continuous variables were expressed as mean ± standard deviation (SD). A t-test for two samples assuming unequal variances (Welch’s t-test) was performed to compare pre- and post-treatment values for continuous variables, including Glycaemic Parameters, renal and hepatic parameters, and lipid profile markers. Statistical significance was determined using a two-tailed test, with a p-value of <0.05 considered significant.

Results Demographic and Baseline Characteristics

Data from 1380 patients were collected across 186 clinical sites across India. The mean age was 55.81 ± 10.59 years, and the average weight was 73.80 ± 19.60 kg. The gender distribution comprised 1031 males (74.71%) and 349 females (25.29%). The mean duration of T2DM was 7.71 ± 5.59 years, indicating that most patients had a long-standing history of diabetes. Baseline vitals showed a mean systolic blood pressure (SBP) of 135.48 ± 19.26 mmHg, a mean diastolic blood pressure (DBP) of 91.36 ± 16.61 mmHg, and a mean pulse rate of 86.04 ± 30.02 bpm. Baseline demographic and vital characteristics of the study population are summarized in (Table 1 and 2).

Table 1: Demographic characteristics of the study participants

Table 2: Vital characteristics of the study participants

Treatment History

Among the study population, 711 (51.52%) patients were on dual therapy, and 632 (45.80%) were on monotherapy before switching to the triple fixed-dose combination (FDC) of Sitagliptin, Pioglitazone, and Metformin. Treatment adjustments were common, with 788 (57.10%) patients having switched medications 2 to 5 times, and 27 (1.96%) patients requiring more than 5 switches before initiating with the FDC. Lifestyle modifications were advised to 950 (68.84%) patients, with dietary changes (449, 47.26%) and physical exercise (408, 42.95%) being the most frequently recommended interventions. Details of prior treatment history, medication switching, and lifestyle advice provided to patients are summarized in (Table 3).

Table 3: Treatment history of medication switching and lifestyle advice

Comorbidities in study participants

The study population of 1380 patients showed a wide range of comorbid conditions. The most prevalent condition was hypertension, affecting 350 (25.36%) patients, with a mean duration of 6.45 ± 4.46 years. Obesity was present in 235 (17.03%) patients, with a mean duration of 7.16 ± 5.54 years. Other common conditions included cardiovascular disease in 137 (9.93%) patients, with a mean duration of 7.05 ± 5.40 years, and dyslipidaemias in 78 (5.65%) patients, with a mean duration of 4.82 ± 3.25 years. Regarding chronic kidney disease (CKD), 15 (1.09%) patients were diagnosed with varying stages of CKD, with the percentage distribution across stages calculated based on the total CKD population. Among these, 8 (53.33%) were in CKD Stage G1, 1 (6.67%) in CKD Stage G2, 3 (20.00%) in CKD

Stage G3a, 1 (6.67%) in CKD Stage G3b, and 2 (13.33%) in CKD Stage G4. No patients were classified in CKD Stage G5. The mean duration of CKD in this cohort was 6.47 ± 4.78 years. Other notable conditions included asthma in 69 (5.00%) patients, with a mean duration of 6.63 ± 5.16 years, and anxiety/depression in 82 (5.94%) patients, with a mean duration of 3.68 ± 3.48 years. The prevalence of comorbidities among study participants is presented in (Table 4).

Table 4: Comorbidities in study participants

Clinical Outcomes Glycemic Control

Among the 921 patients, the mean Fasting Blood Glucose (FBG) level decreased from baseline (164.01 ± 38.84 mg/dL) to 139.28 ± 30.77 mg/dL at 3 months (P < 0.0001), indicating a significant improvement in fasting blood sugar levels. The Postprandial Blood Glucose (PPG, n=923) level also decreased from 244.88 ± 62.69 mg/dL to 202.98 ± 43.79 mg/dL (P < 0.0001), demonstrating a marked reduction in postprandial glucose levels. HbA1C levels significantly improved from 8.35 ± 0.96% to 7.57 ± 0.95% (n=905, P < 0.0001), indicating better long-term glycemic control. A significant reduction in HbA1c, FPG, and PPG levels was observed at 3 months compared to baseline (Figures 1 and 2).

Figure 1: HbA1c change from baseline to 3 months

Figure 2: FPG and PPG change from baseline to 3 months

Renal Function

In the analysed population (n = 165), eGFR declined slightly from 91.59 ± 16.15 to 87.53 ± 13.21 (P = 0.0102), although the difference was statistically significant. Serum Creatinine improved from 1.05 ± 0.25 mg/dl at baseline to 0.92 ± 0.24 mg/dl at 3 months (n=154, P < 0.0001), indicating better renal health. Other renal parameters, including Creatinine clearance (n=19) and Blood Urea Nitrogen (BUN, n=96), remained stable or improved, with BUN significantly decreasing from 18.54 ± 5.99 mg/dl to 14.46 ± 2.05 mg/dl (P < 0.0001). Renal function parameters, including serum creatinine and eGFR, remained stable over the study period (Figures 3 and 4).

Figure 3: Creatinine and BUN change from baseline to 3 months

Figure 4: Creatinine clearance and eGFR change from baseline to 3 months

Lipid Profile

Among 1560 patients, there was a significant improvement in serum cholesterol levels, with total cholesterol decreasing from 184.39 ± 37.49 mg/dL to 158.65 ± 36.23 mg/dL (n=153, P < 0.0001) and LDL cholesterol decreasing from 95.58 ± 18.94 mg/dL to 83.69 ± 22.55 mg/dL (n=150, P < 0.0001). HDL cholesterol, however, showed a decrease from 55.75 ± 28.53 mg/dl to 46.52 ± 25.88 mg/dl (n=149, P = 0.0019). Triglycerides significantly decreased from 148.59 ± 32.77 mg/dl to 123.50 ± 33.26 mg/dl (n=137, P < 0.0001), reflecting an improvement in lipid metabolism. Improvements in lipid parameters, including reductions in total cholesterol, LDL-C, and triglycerides, are presented in (Figure 5).

Figure 5: Lipid change from baseline to 3 months

Hepatic Parameters

Liver function markers, including ALT, AST, ALP, GGT, and Total bilirubin, showed minimal or no significant changes. Specifically, ALT (n=14) and AST (n=11) showed slight reductions, but these changes did not reach statistical significance (P > 0.05). Albumin levels slightly improved from 4.12 ± 0.89 g/dL to 4.43 ± 0.65 g/dL (n= 13, P = 0.2419), though this change was not statistically significant. Liver function tests showed no clinically significant changes (Figure 6).

Figure 6: Hepatic enzymes change from baseline to 3 months