Efficacy and safety of fixed-dose dapagliflozin–pioglitazone in Indian adults with type 2 diabetes: a phase 3 PRO-1 trial

Abstract

Background

To assess the efficacy and safety of a fixed-dose combination (FDC) of dapagliflozin and pioglitazone versus a loose combination (LC) in Patients with Type 2 Diabetes Mellitus inadequately controlled on earlier metformin containing mono therapy.

Materials and methods

This 12-week PRO-1 study was a randomized, open-label, multicenter phase 3 trial that enrolled 180 Indian adults with T2DM, Glycated Hemoglobin (HbA1c) > 7.5% to 10% inadequately controlled with metformin. The participants received once-daily FDC (dapagliflozin 10 mg/pioglitazone 15 mg) or equivalent LC therapy (1:1 randomization). The primary endpoint was the HbA1c change (non-inferiority margin, 0.3). The secondary endpoints included fasting plasma glucose (FPG), postprandial glucose (PPG), and HbA1c < 7.5%.

Results

At week 12, the least-squares mean HbA1c reduction was − 1.20% (FDC) versus − 1.02% (LC). A between-group difference of − 0.18% (95% CI: −0.56 to 0.20) demonstrated non-inferiority. FPG decreased by − 8.6 mg/dL (FDC) and − 12.0 mg/dL (LC); PPG decreased by − 28.2 mg/dL and − 29.5 mg/dL, respectively. Target HbA1c < 7.5% was achieved in 52.9% (FDC) versus 54.8% (LC) of patients. (mITT population; p = 0.877). Both regimens were generally well tolerated; adverse events were more frequent with the fixed-dose combination than with the loose combination (8.9% versus 1.1%, p = 0.034), but were mild and self-limiting, with no serious events, hypoglycemia, or treatment discontinuation in either group.

Conclusions

The fixed-dose combination of dapagliflozin and pioglitazone was non inferior to separate administration with respect to glycemic efficacy in Indian adults with inadequately controlled type 2 diabetes mellitus receiving metformin, with a favorable and comparable safety profile.

Trial registration

CTRI/2024/09/073221.

Supplementary Information

The online version contains supplementary material available at 10.1186/s13098-026-02086-3.

Highlights

What is known about this topic?

Fixed-dose combinations improve adherence and reduce pill burden in T2DM management.

Dapagliflozin (an SGLT2 inhibitor) and pioglitazone (a thiazolidinedione) have complementary mechanisms that target different pathophysiological pathways.

Global evidence supports the efficacy of dapagliflozin–pioglitazone, but real-world Indian data are limited.

What this study adds and its future implications?

The randomized controlled trial demonstrated the non-inferiority of dapagliflozin–pioglitazone FDC versus loose combination in Indian T2DM patients.

Establishes clinical equivalence between formulations, enabling simplified prescribing and improved compliance.

Confirms favorable safety with no hypoglycemia, supporting use across diverse Indian settings.

This study provides an evidence base for incorporating this dual therapy into Indian diabetes management.

Supplementary Information

The online version contains supplementary material available at 10.1186/s13098-026-02086-3.

Background

India faces a growing epidemic of type 2 diabetes mellitus (T2DM), with more than 100 million affected adults and a parallel rise in metabolic complications such as metabolic dysfunction–associated steatotic liver disease (MASLD), atherosclerotic cardiovascular disease (ASCVD), and diabetic kidney disease [1–3]. The South Asian phenotype—marked by early-onset diabetes, increased visceral adiposity at lower body mass index (BMI), and high insulin resistance even among non-obese individuals—exacerbates this burden [4–6]. Despite the widespread availability of oral antidiabetic therapies, many Indian patients fail to achieve durable glycemic control with monotherapy or sequential drug escalation [7]. Conventional approaches may insufficiently address the underlying pathophysiological drivers, such as hepatic steatosis, chronic inflammation, and adipose dysfunction [8].

Dapagliflozin, a sodium–glucose co-transporter 2 inhibitor (SGLT2i), and pioglitazone, a thiazolidinedione (TZD), possess complementary mechanisms that may offer synergistic metabolic benefits. Dapagliflozin lowers plasma glucose through glycosuria and induces modest weight loss and blood pressure reduction [9], whereas pioglitazone improves insulin sensitivity and exerts anti-inflammatory and anti-fibrotic effects, particularly in hepatic and adipose tissues [10, 11]. When combined, these agents may mitigate each other’s limitations, for example, pioglitazone’s risk of fluid retention and dapagliflozin’s limited efficacy in hepatic steatosis [8, 12]. Meta-analyses and randomized trials suggest additive glycemic efficacy and potential benefits for cardiovascular and liver-related outcomes, especially in high-risk subgroups with MASLD or metabolic syndrome [13–15].

Given these advantages, a fixed-dose combination (FDC) of dapagliflozin 10 mg and pioglitazone 15 mg was approved by the Drug Controller General of India (DCGI) in Sept 2024 as an adjunct to metformin in patients with inadequately controlled T2DM. FDCs may enhance treatment adherence, simplify regimens, and reduce pill burden, factors of particular relevance in Indian settings with polypharmacy and limited health literacy [16, 17]. However, to date, no published randomized phase 3 trial has evaluated the efficacy and safety of this FDC in Indian adults or compared it head-to-head with the same agents administered as a loose combination (LC).

To address this gap, the Pioglitazone–SGLT2i Combination Research Outcomes (PRO) program was initiated as a real-world clinical trial platform. The present PRO-1 trial is the first in this series: a randomized, open-label, multicenter, phase 3 study designed to evaluate whether the FDC of dapagliflozin–pioglitazone is non-inferior to its loose co-administration in improving glycemic outcomes among Indian adults with inadequately controlled T2DM on stable metformin therapy.

Methods

Study design and setting

The PRO-1 trial was a phase 3, multicenter, randomized, open-label, active controlled study comparing a fixed-dose combination of dapagliflozin 10 mg and pioglitazone 15 mg with the corresponding loose combination as an add-on therapy to stable metformin in adults with type 2 diabetes. This study was conducted at seven hospital- and clinic-based sites across India, including medical colleges, multispecialty hospitals, and high-volume diabetes clinics. The protocol was approved by the Institutional Ethics Committees of all participating sites and followed the Declaration of Helsinki, International Council for Harmonization Good Clinical Practice guidelines, and applicable Indian regulatory requirements. The trial was sponsored by USV Private Limited, and prospectively registered with the Clinical Trials Registry India (CTRI/2024/09/073221). This trial used a prospective, randomized, open-label, blinded endpoint (PROBE) design. Although treatment allocation was open, all laboratory assessments, adverse event coding, and statistical analyses were performed by personnel blinded to the treatment assignment. Adverse events were collected using standardized definitions and structured case report forms to reduce potential subjective bias in clinical assessments. Selected sections of the study protocol and Statistical Analysis Plan, with operational and proprietary details redacted, are provided as Supplementary Material S2 to enhance transparency.

Participants

Eligible participants were adults aged 18 to 65 years with a confirmed diagnosis of T2DM, inadequately controlled with a stable dose of metformin (≥ 1000 mg/day) for at least 3 months prior to screening. Key inclusion criteria included an HbA1c level between 7.5% and 10%, a BMI ≥ 18.5 kg/m², and willingness to provide written informed consent and comply with the study procedures.

Major exclusion criteria included type 1 diabetes or latent autoimmune diabetes in adults (LADA); prior use of glucose-lowering agents (other than metformin) within 3 months; history of diabetic ketoacidosis, pancreatitis, or severe hypoglycemia; clinically significant hepatic impairment (ALT or AST > 3× upper limit of normal); renal dysfunction (estimated glomerular filtration rate [eGFR] < 60 mL/min/1.73 m²), symptomatic congestive heart failure (NYHA class III/IV) or other major cardiovascular diseases; active malignancy within the past 5 years; pregnancy or lactation; and any condition deemed by the investigator to compromise patient safety, compliance, or study integrity.

Interventions

Participants were randomized in a 1:1 ratio to receive one of the two study treatments for 12 weeks, in addition to their background metformin regimen.

FDC arm

One tablet containing dapagliflozin 10 mg and pioglitazone 15 mg, administered orally once daily in the morning.

LC arm

Concomitant administration of dapagliflozin 10 mg and pioglitazone 15 mg, administered orally once daily in the morning.

All participants continued their pre-study metformin dose without modification unless indicated clinically. Adherence to the study medication was assessed at each follow-up visit (weeks 2, 6, and 12) using pill counts, patient diaries, and investigator verification. Self-monitoring of blood glucose was encouraged throughout the study and glucometers were provided to participants to support adherence and reinforce education on lifestyle and safety monitoring.

Randomization and blinding

Randomization was performed centrally using a computer-generated schedule with stratification by study site to ensure a balanced allocation across centers. Owing to differences in the physical appearance of FDC and LC tablets, the study was conducted in an open-label manner. However, to minimize bias, laboratory personnel and statisticians remained blinded to the treatment assignments, and efficacy and safety analyses were conducted independently of the clinical investigators.

Endpoints

Primary endpoint

The primary efficacy endpoint was the change in HbA1c from baseline to week 12, with the objective of demonstrating the non-inferiority of the FDC versus LC dose regimen. The non-inferiority margin was set at 0.3, consistent with international regulatory standards for glucose-lowering therapies [18].

Secondary endpoints

Secondary endpoints included changes from baseline to week 12 in fasting plasma glucose (FPG), 2-hour postprandial plasma glucose (PPG), and proportion of participants achieving HbA1c < 7.5%.

Safety endpoints

Safety endpoints included the incidence of adverse events (AEs), serious AEs (SAEs), symptomatic hypoglycemia, peripheral edema, and study drug discontinuation as well as changes in vital signs, electrocardiogram parameters, and routine laboratory measures. Peripheral edema was assessed at each scheduled visit by clinical examination and adverse event reporting, and any findings were recorded in the case report forms. AEs and SAEs were defined according to the study protocol in alignment with the guidelines of the International Council for Harmonization. An AE was any unfavorable medical occurrence temporally associated with study treatment, regardless of causality, and an SAE was an event that resulted in death, was life-threatening, required or prolonged hospitalization, resulted in persistent or significant disability/incapacity, or involved a congenital anomaly or birth defect. Symptomatic hypoglycemia was defined as typical autonomic or neuroglycopenic symptoms with a capillary glucose value < 70 mg/dL when available; severe episodes were those requiring assistance from another person. Hypoglycemic events were captured through patient self-reports and a review of home glucose readings at scheduled visits; continuous glucose monitoring was not used.

Statistical analysis

All statistical analyses were conducted according to a pre-specified and finalized statistical analysis plan (SAP). The primary objective was to evaluate the efficacy of an FDC of dapagliflozin and pioglitazone versus the corresponding LC in adults with T2DM that was inadequately controlled with metformin monotherapy.

Analysis populations

The Full Analysis Set (FAS), aligned with the modified intention-to-treat (mITT) principle, included all randomized participants who received at least one dose of study medication and had at least one valid post-baseline HbA1c measurement (n = 169). The Per Protocol (PP) population included participants from the FAS who completed the study without any major protocol deviations. The Safety Analysis Set (SAS) consisted of all randomized participants who received at least one dose of the study medication and were analyzed according to the treatment received.

Sample size determination

A sample size of 74 participants per arm was calculated to provide 80% power to demonstrate non-inferiority in the change in HbA1c from baseline to week 12, assuming a standard deviation of 1.0%, a non-inferiority margin of 0.3, and a one-sided alpha level of 0.025. To account for an estimated 15% dropout rate, 180 participants (90 per arm) were planned and enrolled.

Primary endpoint

The primary efficacy endpoint was the mean change in HbA1c level from baseline to week 12. The primary analysis employed an analysis of covariance (ANCOVA) model, with treatment as a fixed effect, and baseline HbA1c and study site as covariates. Non-inferiority was established if the upper bound of the two-sided 95% confidence interval (CI) for the treatment difference (FDC minus LC) was less than the prespecified non-inferiority margin of 0.3. A one-sided alpha of 0.025 was used. Sensitivity analysis using a two-sample t-test was also conducted for robustness.

Secondary endpoints

Secondary continuous endpoints, including changes in FPG, PPG, were analyzed using ANCOVA models adjusted for baseline values and study site. The proportion of participants achieving HbA1c < 7.5% at week 12 was compared using a proportion test. Safety data, including AEs, serious AEs, laboratory findings, ECGs, and vital signs, were summarized descriptively. Group comparisons for categorical safety endpoints were conducted using Fisher’s exact test as appropriate.

Exploratory analysis

Post-hoc Exploratory Pooled Analysis included changes in HbA1c, fasting plasma glucose, postprandial plasma glucose, and the proportion of participants achieving HbA1c < 7.5% at week 12. These analyses were not prespecified in the study protocol or Statistical Analysis Plan and were conducted post hoc as exploratory evaluations outside the primary and secondary efficacy assessments, without altering the prespecified endpoint hierarchy.

Data management and handling of missing data

Prior to analysis, all study data underwent a structured data cleaning and validation process involving range and consistency checks, resolution of missing or duplicate entries, and cross-verification with source documents (eCRF). Discrepancies were addressed collaboratively with site teams and were documented in a centralized query system. A database lock occurs only after full query resolution and quality assurance, as per the data management plan. Missing values for efficacy endpoints were handled using multiple imputations under the assumption of missing at random (MAR). The imputation model incorporated baseline values, age, sex, study site, and available postbaseline data. Fifty imputations were generated per endpoint and pooled estimates were computed using Rubin’s rules. Sensitivity analyses, including complete-case ANCOVA and tipping-point analyses, were performed to test robustness to violations of the MAR assumption. All analyses were performed using SAS^® version 9.4 (SAS Institute Inc., Cary, NC, USA) with a two-sided significance level of 0.05, unless otherwise specified.

Ethical considerations

Prior to study initiation, the study protocol, informed consent form, and all participant-facing materials were reviewed and approved by the IECs of all participating centers. Written informed consent was obtained from all participants prior to enrollment. The trial was prospectively registered in the Clinical Trials Registry, India (CTRI/2024/09/073221). All study procedures were conducted in accordance with the ethical principles outlined in the Declaration of Helsinki (2013 revision), the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use—Good Clinical Practice (ICH-GCP E6[R2]) guidelines, and applicable Indian regulatory requirements.

Results

Participant disposition and baseline characteristics

A total of 345 individuals were screened, of whom 180 were randomized equally to the FDC (dapagliflozin 10 mg plus pioglitazone 15 mg; n = 90) or LC (same agents administered separately; n = 90) groups. All randomized patients received the allocated intervention. At Week 12, 85 patients (94.4%) in the FDC arm and 84 patients (93.3%) in the LC arm completed the study, and loss to follow-up was the primary reason for discontinuation (FDC, n = 5; LC, n = 6). No discontinuation occurred owing to adverse events. Thus, 169 participants were included in the modified intention-to-treat (mITT) analysis, whereas all 180 randomized patients comprised the intention-to-treat (ITT) population. The baseline demographic and clinical characteristics were well balanced between the groups, including age, sex distribution, duration of diabetes, HbA1c, FPG, and BMI. The mean baseline HbA1c level was approximately 8.6% in both groups. Participant disposition is summarized in the CONSORT flow diagram, Fig. 1.

Fig. 1.

CONSORT Flow Diagram of Patient Disposition. FDC = Fixed-dose combination; LC = Loose combination; ITT = Intention-to-treat; FAS = Full analysis set; PP = Per protocol

The baseline demographic and clinical characteristics are summarized in Table 1. Participants were well-matched across treatment arms, with no clinically meaningful differences in age, sex distribution, BMI, HbA1c, glucose values, or duration of diabetes at baseline. This supports the validity of the treatment comparisons.

Table 1.

Baseline demographic and clinical characteristics (ITT population)

Characteristic	FDC (n = 90)	LC (n = 90)	Total (n = 180)
Age, years (SD)	47.1 (11.0)	48.3 (10.2)	47.7 (10.6)
Male sex, n (%)	44 (48.9)	44 (48.9)	88 (48.9)
Body weight, kg (SD)	69.2 (11.1)	68.5 (10.4)	68.9 (10.5)
BMI, kg/m² (SD)	26.7 (4.1)	26.6 (3.6)	26.6 (3.9)
HbA1c, % (SD)	8.5 (0.8)	8.6 (0.7)	8.5 (0.8)
FPG, mg/dL (SD)	152.9 (46.5)	156.8 (48.7)	154.8 (47.5)
2-h PPG, mg/dL (SD)	199.6 (78.4)	200.1 (84.3)	200.0 (81.2)
Duration of Diabetes, years (SD)	2.3 (3.2)	2.3 (2.3)	2.3 (2.7)
Systolic BP, mmHg (SD)	125.4 (9.0)	124.1 (10.0)	124.8 (9.5)
Diastolic BP, mmHg (SD)	81.2 (6.8)	80.5 (6.8)	80.8 (6.8)

ITT = Intention to Treat; FDC = Fixed-dose combination; LC = Loose combination; SD = Standard deviation; BMI = Body mass index; HbA1c = Glycated hemoglobin; FPG = Fasting plasma glucose; PPG = Postprandial plasma glucose; BP = Blood pressure

Primary and secondary efficacy outcomes

For the primary endpoint (Fig. 2a), the least-squares mean reduction in HbA1c from baseline to week 12 was − 1.20% (SE 0.14) in the FDC arm and − 1.02% (SE 0.14) in the LC arm based on ANCOVA adjusted for baseline HbA1c. The between-group difference of − 0.18% (95% CI: −0.56 to 0.20; p = 0.356) favored the FDC arm, but was not statistically significant. However, the upper bound of the confidence interval remained below the prespecified non-inferiority margin of 0.30, thereby meeting the criterion for non-inferiority. Sensitivity analyses using a complete-case ANCOVA and unadjusted comparisons confirmed the robustness of these findings.

Fig. 2.

Efficacy outcomes of FDC versus LC at Week 12: (a) Change in HbA1c from baseline; (b) Change in fasting plasma glucose (FPG) and postprandial plasma glucose (PPG) from baseline; (c) Proportion of patients achieving HbA1c targets (< 7.5% and < 7.0%). FDC = Fixed-dose combination; LC = Loose combination; HbA1c = Glycated hemoglobin; FPG = Fasting plasma glucose; PPG = Postprandial plasma glucose

For the secondary endpoints (Fig. 2b), both treatment groups demonstrated modest improvements in FPG and PPG levels, with no statistically significant differences between the FDC and LC arms. The adjusted mean change in FPG was − 8.58 mg/dL (SE 6.32) in the FDC group and − 12.01 mg/dL (SE 6.28) in the LC group, yielding a between-group difference of 3.43 mg/dL (95% CI: −14.17 to 21.01; p = 0.700). For PPG, the mean reduction was − 28.23 mg/dL (SE 7.64) in the FDC group versus − 29.51 mg/dL (SE 7.64) in the LC group (between-group difference: −1.28 mg/dL; 95% CI: −20.06 to 22.62; p = 0.906). These findings indicate comparable glycemic effects between the two regimens.

For target achievement (Fig. 2c), the response rates at week 12 were comparable between the FDC and LC groups for the protocol-defined threshold of HbA1c < 7.5%—52.9% (45/85) vs. 54.8% (46/84), respectively (p = 0.877). For the more stringent target of HbA1c level < 7.0%, 35.3% of FDC-treated patients and 31.8% of LC-treated patients achieved this goal (p = 0.828). These results confirm that target attainment was clinically meaningful and statistically similar between the treatment strategies.

Safety outcomes

Table 2 summarizes the safety outcomes during the 12-week treatment period. Both regimens were generally well-tolerated. Adverse events were more frequent in the FDC group than in the LC group (8.9% vs. 1.1%; safety population p = 0.034), corresponding to an odds ratio of 8.68 (95% CI 1.07–70.4). All events were mild, self-limiting, and required no clinical intervention. Reported events in the FDC group included fever, cold, joint pain, urinary tract infection, excessive thirst, acidity, dizziness, and weakness (one case each). In the LC group, a single episode of diarrhea was reported. No serious adverse events, hypoglycemia, or discontinuations due to adverse events were observed in either group. No hospitalizations due to urinary tract infections, cardiovascular events, or any other cause were reported during the 12-week study period. Laboratory parameters, vital signs, and ECG findings showed no clinically relevant changes. Overall, the safety profile was consistent with the known tolerabilities of dapagliflozin and pioglitazone. The distribution of adverse events by system organ classification is presented in Supplementary Table S1, which summarizes the SOC level and preferred term profiles of all mild events observed during the study. Adherence, assessed by pill counts, patient diaries, and investigator verification, was high and comparable in the fixed-dose and loose combination groups, with no meaningful between-group differences over the 12-week treatment period.

Table 2.

Adverse events

Adverse Events	FDC (n = 90)	LC (n = 90)	P-value	Odds Ratio (95% CI)
Any AE, n (%)	8 (8.9)	1 (1.1)	0.034*	8.68 (1.07–70.4)
Serious AEs, n (%)	0 (0.0)	0 (0.0)	NA	NA
Discontinuations due to AE, n (%)	0 (0.0)	0 (0.0)	NA	NA
Deaths, n (%)	0 (0.0)	0 (0.0)	NA	NA
Hypoglycemia, n (%)	0 (0.0)	0 (0.0)	NA	NA

*p-value from Fisher’s Exact Test. † All AEs were mild and resolved without sequelae. The safety population includes all participants who received at least one dose of study medication

AE = adverse event; CI = confidence interval; FDC = fixed-dose combination; LC = loose combination; NA = not applicable

Exploratory pooled efficacy analyses

To assess the overall therapeutic impact of dapagliflozin plus pioglitazone, post-hoc exploratory pooled analyses were performed across both treatment arms after confirming the statistical comparability at baseline. A multivariate analysis of variance (MANOVA) on key baseline variables yielded a Wilks’ lambda of 0.984 (p = 0.949), indicating no significant differences between the groups and validating the appropriateness of data pooling. Pooled analysis shows overall improvements in glycemic parameters across the cohort (Fig. 3a and b). From a baseline mean of 8.51%, HbA1c levels declined to 7.40% at week 12, reflecting a mean reduction of 1.11% (p < 0.001). Modest yet consistent improvements were also observed in FPG (− 10.3 mg/dL) and PPG (− 28.9 mg/dL), underscoring the complementary metabolic effects of SGLT2 inhibition and PPAR-γ activation.

Fig. 3.

Exploratory pooled efficacy outcomes at Week 12: (a) Change in HbA1c from baseline; (b) Mean reduction in fasting plasma glucose (FPG) and postprandial plasma glucose (PPG) from baseline; (c) Proportion of patients achieving HbA1c targets (< 7.5% and < 7.0%). HbA1c = Glycated hemoglobin; FPG = Fasting plasma glucose; PPG = Postprandial plasma glucose; T2DM = Type 2 diabetes mellitus

The target attainment is summarized in Fig. 3c. In the pooled cohort, 53.9% (n = 91) of the participants achieved the protocol-defined target of HbA1c < 7.5%, whereas 33.7% (n = 57) attained a more stringent threshold of HbA1c < 7.0%. These findings underscore the clinical effectiveness of this combination across a real-world spectrum of Indian adults with T2DM, supporting its applicability in routine care. The pooled safety profile was consistent with that of the individual arm analyses, and no new safety concerns were identified. Collectively, these exploratory outcomes reinforce the therapeutic value of dual SGLT2–TZD therapy, independent of the formulation type, in delivering meaningful glycemic control with favorable tolerability.

Weight and BMI showed a slight numerical increase in both groups with no significant between-group differences. The mean changes in hepatic, renal, lipid, and hematological parameters over 12 weeks were modest and clinically stable. There were no significant differences between the groups in hemoglobin, hematocrit, platelet counts, estimated glomerular filtration rate (eGFR), blood urea nitrogen, serum creatinine, alkaline phosphatase (ALP), total bilirubin, LDL-C, HDL-C, total cholesterol, or triglycerides. Hepatic parameters, including ALP, AST (SGOT), ALT (SGPT), total bilirubin, and Fib-4 score, showed small, non-clinically changes (Supplementary Table S3). Adjusted between-group changes from baseline to week 12, derived from the ANCOVA model adjusted for baseline values, are summarized in Supplementary Table S4.

In an exploratory pooled analysis across treatment groups, participants experienced modest increases in body weight and BMI, whereas ALP showed a reduction. Renal indices revealed a slight decline in eGFR with no consistent change in BUN levels. Lipid measurements and hematologic indices demonstrated directionally neutral or clinically stable changes. These findings are considered hypothesis-generating, given the pooled design and multiple unadjusted comparisons; however, they provide an overview of the net trajectory of non-glycemic measures in the study population (Supplementary Table S4).

Discussion

The PRO-1 trial demonstrated that the FDC of dapagliflozin and pioglitazone was non-inferior to that of LC for glycemic control in Indian adults with T2DM inadequately controlled with metformin. Reductions in HbA1c, FPG, and PPG levels were comparable, with favorable safety and no new renal or hepatic concerns. Pooled efficacy analyses support the durability of dual therapies. To our knowledge, this is the phase 3 randomized study from India that directly compared a dapagliflozin-pioglitazone FDC with its loose equivalent.

Comparative efficacy with global and Indian evidence

Global evidence consistently supports the efficacy of combining SGLT2i with TZDs. In a pivotal 48-week trial, dapagliflozin added to pioglitazone lowered HbA1c by up to − 0.97%, improved fasting and postprandial glucose levels, and attenuated weight gain compared with pioglitazone alone [19]. Subsequent multicenter RCTs in Asian populations reported additional HbA1c reductions (− 0.47% to − 0.83%) and improvements in insulin resistance indices when pioglitazone was combined with dapagliflozin and metformin, with more patients achieving HbA1c < 7% [13, 20]. These outcomes are particularly relevant in South Asians, who frequently present with lean diabetes and marked insulin resistance.

Indian data provide parallel evidence; the dapagliflozin–glimepiride trial by Sahay et al. (2025) highlighted the role of FDCs in achieving better glycemic control and adherence in real-world practice [21]. International findings reinforce that dual and triple FDC strategies maintain glycemic control without compromising safety [22], while meta-analyses confirm that combining pioglitazone with SGLT2i or glucagon-like peptide-1 (GLP-1) receptor agonists improves outcomes [23]. Consistent efficacy and tolerability have also been demonstrated across agents; canagliflozin plus pioglitazone showed durable glycemic benefits over 52 weeks [24], ipragliflozin add-on improved glycemia with good safety in a randomized, double-blind, placebo-controlled study [25], and empagliflozin add-on reduced HbA1c and weight in a 24-week RCT [26]. Most recently, a phase 3 trial confirmed the efficacy and safety of adding pioglitazone to metformin–dapagliflozin therapy, further validating the dual-agent approach [27]. Together, these findings establish dapagliflozin-pioglitazone FDC as a clinically effective, well-tolerated, and contextually relevant option in India, where reducing the pill burden and addressing insulin resistance remain critical to durable diabetes management.

Mechanistic rationale and synergistic benefits

The combination of dapagliflozin and pioglitazone draws on complementary biological pathways that address core defects in type 2 diabetes (Fig. 4). Pioglitazone enhances insulin sensitivity in adipose tissue, muscle, and the liver, and exerts anti inflammatory and antifibrotic effects. Dapagliflozin lowers glucose levels through insulin-independent glycosuria and natriuresis, which contributes to weight reduction and lower blood pressure. Together, these actions support durable improvements in HbA1c, fasting plasma glucose, and postprandial plasma glucose, with dapagliflozin helping counter pioglitazone-associated weight gain and fluid retention. Beyond glycemic effects, both agents improve hepatic steatosis, with dapagliflozin reducing fatty liver indices and pioglitazone providing antifibrotic benefits [12, 13, 15, 28]. Cardiovascular advantages such as lower left ventricular mass, reduced risk of heart failure, and favorable changes in remodeling and mitochondrial function have been reported in studies on individual drug classes [29, 30]. These findings are included in a mechanistic context rather than evidence of cardiovascular benefits in PRO 1, which was not designed to assess such outcomes.

Fig. 4.

Synergistic mechanisms of dapagliflozin (SGLT2 inhibitor) plus pioglitazone (PPAR-γ agonist) combination therapy. Adapted from Abdul-Ghani et al. [31], Blevins et al. [29], Böhm et al. [17], DeFronzo [10], Rosenstock et al. [19], and Seshadri et al. [15]. ↓ = decrease; ↑ = increase; BP = blood pressure; HF = heart failure; FDC = fixed-dose combination; PPAR-γ = peroxisome proliferator–activated receptor gamma; SGLT2 = sodium–glucose cotransporter 2.

Their complementary safety effects, with pioglitazone reducing the risk of ketosis sometimes seen with SGLT2 inhibitors and dapagliflozin attenuating fluid retention associated with thiazolidinediones, further support the overall tolerability [31]. Taken together, these mechanisms provide a strong rationale for the use of a fixed-dose combination in insulin-resistant phenotypes, particularly among Indian patients with MASLD and an elevated cardiometabolic risk.

Adherence, and pill Burden

FDCs simplify regimens and reduce pill burden, thereby improving adherence and persistence. Randomized and observational studies have shown 10–29% higher adherence and longer persistence with FDCs versus loose combination regimens [17, 32–34]. Meta-analyses confirm that regimen simplification enhances treatment satisfaction and reduces discontinuation [35–37]. Indian consensus statements also highlight the importance of structured education and adherence strategies for optimizing SGLT2i therapy [38–40]. Economic evaluations further suggest that FDCs lower out-of-pocket costs without raising overall expenditures, an important consideration in India’s largely patient-funded health system [33, 41, 42]. These findings are reinforced by Indian trial evidence showing that dapagliflozin-based FDCs improve glycemic control while facilitating adherence [21]. The 2024 CDSCO approval of dapagliflozin–pioglitazone FDC represents a regulatory milestone, translating global evidence into national guidelines and expanding access to rational, patient-centered therapy.

Patient subgroup implications: Early-Onset, MASLD, High-Risk profiles

Clinical evidence highlights specific patient populations that may derive particular benefit from SGLT2i–pioglitazone therapy. In early-onset type 2 diabetes, randomized trials evaluating the addition of dapagliflozin or empagliflozin to pioglitazone have demonstrated sustained glycemic reductions with favorable weight and safety outcomes, supporting use in patients for whom lifelong disease burden necessitates durable and simplified regimens [19, 26]. In Asian cohorts, including individuals with relatively lean but insulin-resistant phenotypes, pooled analyses of ipragliflozin combined with pioglitazone have shown consistent improvements in HbA1c and body weight across BMI categories, along with favorable effects on liver enzymes, underscoring relevance for South Asian populations [25].

Patients with metabolic dysfunction–associated steatotic liver disease (MASLD) may also benefit; a large real-world study reported that SGLT2i–pioglitazone combination therapy was associated with the highest likelihood of regression in fibrosis risk scores compared with monotherapy [28]. Cardiovascular high-risk groups have similarly demonstrated improved outcomes, with nationwide database analyses from Taiwan showing the lowest rates of major adverse cardiovascular events and heart failure among patients treated with SGLT2i–pioglitazone combinations compared with either agent alone [14, 43].

In this context, it is noteworthy that the PRO-1 cohort had a relatively short mean duration of type 2 diabetes (approximately two years). Earlier disease stages are often associated with greater glycemic responsiveness to complementary insulin-independent and insulin-sensitizing mechanisms, which may partly explain the magnitude of glucose-lowering observed with dapagliflozin–pioglitazone in PRO-1. However, the study was not designed or powered to evaluate effect modification by disease duration, and these observations should be interpreted accordingly. In the present study, the absence of between-group differences across hepatic enzymes, renal indices, and lipid fractions indicates a neutral short-term profile for the fixed-dose combination, consistent with the known class effects of SGLT2 inhibitors and TZDs [10]. From a clinical standpoint, these data support pragmatic 3-month monitoring—glycemia, body weight, blood pressure, hepatic and renal panels, and hemoglobin/hematocrit—to confirm tolerability and detect outliers rather than to anticipate large mean changes.

Safety and tolerability profile

Adverse events were more frequent with the fixed-dose combination than with the loose combination (8.9% vs. 1.1%, p = 0.034), although all were mild, self-limiting, and did not require clinical intervention. No serious adverse events, hypoglycemia, or discontinuations due to adverse events were observed, and the laboratory parameters, vital signs, and ECG findings remained stable in both arms. These short-term findings indicate that despite a higher incidence of mild events with the fixed-dose combination, both regimens were generally well-tolerated in the PRO 1 population. The numerically higher reporting of mild adverse events with the fixed-dose combination may reflect early treatment-related effects following initiation of SGLT2 inhibitor–based therapy and closer symptom capture at treatment start, rather than indicating a formulation-specific safety signal.

The safety profile observed with PRO 1 is consistent with previous clinical and real-world evidence of dapagliflozin and pioglitazone. Rates of hypoglycemia with dapagliflozin based regimens have been low and comparable to placebo or other oral agents, with most events classified as mild and not leading to discontinuation [13, 19, 20, 44]. Genital infections have been reported more frequently with sodium glucose co transporter 2 inhibitor therapy but are typically mild, manageable, and rarely necessitate withdrawal [45]. Dapagliflozin may also mitigate pioglitazone-related fluid retention through its natriuretic effect, resulting in attenuated edema and less weight gain than pioglitazone alone in prior studies [19, 20]. Pharmacokinetic studies have shown no meaningful interaction between dapagliflozin and pioglitazone, supporting the rationale for fixed-dose co-formulations [46]. Additional evidence suggests hepatic safety, including improvements in liver enzymes and a lower risk of ketone related complications, as pioglitazone may counterbalance dapagliflozin induced ketone elevation [28, 31]. Taken together, PRO 1 safety findings, viewed alongside global evidence, support the short-term tolerability of dapagliflozin plus pioglitazone in a fixed-dose combination form. Nevertheless, the higher incidence of mild events with the fixed-dose combination and the 12 week duration of the trial highlight the need for continued pharmacovigilance and long-term evaluation of Indian adults with type 2 diabetes and cardiometabolic comorbidities.

Strengths and limitations

This study has several strengths. This is the multicenter, randomized trial in India to evaluate a fixed-dose combination of dapagliflozin and pioglitazone using doses reflective of real-world prescription, enhancing its relevance to routine clinical practice. The future PRO studies will also incorporate hepatic endpoints, thereby increasing the clinical applicability of the development strategy in a population with high metabolic risk.

This study had several limitations that must be acknowledged. The twelve week duration restricts the assessment of long-term efficacy and safety, including the durability of glycemic control, possibility of glycemic rebound, and long-term outcomes such as cardiovascular events, heart failure, fracture risk, and hepatic measures. Patient-reported outcomes, quality of life assessments, and formal adherence metrics were not collected in this phase, and liver-specific endpoints were not evaluated. Although the fixed-dose combination group showed a higher proportion of mild adverse events, which were transient, non-serious, and did not lead to treatment discontinuation, they underlined the need for longer follow-up in subsequent PRO program studies. Hypoglycemia was assessed through patient self-reports and routine capillary glucose monitoring without the use of continuous glucose monitoring, which may detect asymptomatic or nocturnal episodes. Information on dietary intake and physical activity was not systematically collected, limiting the interpretation of lifestyle influences on glycemic and metabolic outcomes. The trial was conducted in hospital- and clinic-based settings in India, and the generalizability to primary care or non-Indian populations should be interpreted with caution. As the study was open-label, clinical assessments may have been subject to some degree of observation bias, although endpoint evaluation, laboratory measurements, and statistical analyses were all performed under blinded conditions.

Implications for practice and research

The clinical implications of this trial highlight the potential of dapagliflozin–pioglitazone FDC in adults with inadequately controlled T2DM on metformin, or high pill burden requiring regimen simplification. The complementary mechanisms of action of dapagliflozin and pioglitazone support their combined use for glycemic control; however, potential benefits beyond glycemia require further investigation. Future research should extend beyond glycemic endpoints to evaluate long-term outcomes in MASLD and cardiovascular disease, validate the benefits of adherence in pragmatic trials conducted in rural and resource-constrained populations, and explore the mechanistic effects on hepatic fibrosis regression and cerebrovascular protection.

Conclusion

In this multicenter phase 3 trial of Indian adults with T2DM inadequately controlled with metformin, FDC therapy with dapagliflozin and pioglitazone was non-inferior to the corresponding loose combination in terms of glycemic efficacy. Both treatment groups achieved clinically meaningful reductions in HbA1c, fasting plasma glucose, and PPG levels, with a favorable safety profile and no new concerns. AEs were infrequent, mild, and comparable across the groups. Longer and larger studies incorporating cardiovascular and metabolic outcomes are warranted to confirm the durability and to define the role of this combination in long-term disease modification.

Abbreviations

↑

Increase

↓

Decrease

AE

Adverse event

AEs

Adverse events

ANCOVA

Analysis of covariance

APRI

Aspartate aminotransferase-to-platelet ratio index

ASCVD

Atherosclerotic cardiovascular disease

BMI

Body mass index

BP

Blood pressure

CI

Confidence interval

CRO

Contract research organization

DCGI

Drug Controller General of India

ECG

Electrocardiogram

FAS

Full analysis set

FDC

Fixed-dose combination

FIB-4

Fibrosis-4 index

FPG

Fasting plasma glucose

GLP-1

Glucagon-like peptide-1

HbA1c

Glycated hemoglobin

HF

Heart failure

ICH-GCP

International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use—Good Clinical Practice

IECs

Institutional ethics committees

ITT

Intention-to-treat

LADA

Latent autoimmune diabetes in adults

LC

Loose combination

MANOVA

Multivariate analysis of variance

MAR

Missing at random

MASLD

Metabolic dysfunction–associated steatotic liver disease

NA

Not applicable

PP

Per protocol

PPAR-γ

Peroxisome proliferator–activated receptor gamma

PPG

Postprandial glucose

PRO

Pioglitazone–SGLT2i combination research outcomes

SAP

Statistical analysis plan

SAS

Safety analysis set

SD

Standard deviation

SE

Standard error

SGLT2

Sodium–glucose cotransporter 2

SGLT2i

Sodium–glucose co-transporter 2 inhibitor

T2DM

Type 2 diabetes mellitus

TZD

Thiazolidinedione

Author contributions

AKS: Conceptualization, Methodology, Formal analysis, Resources, Data curation, Writing—original draft, Visualization, Supervision, Project administration; KGS: Conceptualization, Methodology, Resources, Data curation, Writing – review & editing, Supervision; AGU: Conceptualization, Methodology, Data curation, Writing – review & editing; JK: Conceptualization, Methodology, Data curation, Writing – review & editing; SK: Analysis, Interpretation, Writing – review & editing; SRJ: Analysis, Interpretation, Writing – review & editing; KP: Analysis, Interpretation, Writing – review & editing; RKS: Analysis, Interpretation, Writing – review & editing; VKP: Analysis, Interpretation, Writing – review & editing; AM: Analysis, Interpretation, Writing – review & editing; SG: Writing – original draft, Visualization, Writing – review & editing; TA: Writing – original draft, Visualization, Writing – review & editing.

Funding

This study was funded by USV Private Limited (Mumbai, India). Clinical monitoring and statistical analyses were performed by an independent research contract organization.

Data availability

The datasets used and/or analyzed during the current study are available from the corresponding author upon reasonable request.

Declarations

Ethics approval and consent to participate

The study protocol, informed consent form, and participant-facing materials were approved by the Institutional Ethics Committees of all the participating centers. Written informed consent was obtained from all participants prior to enrollment. The trial was prospectively registered in the Clinical Trials Registry, India (CTRI/2024/09/073221).

AI use disclosure

Artificial intelligence tools were used only for language refinement and grammar editing during the preparation of the manuscript. No AI tools were used to develop scientific content, perform statistical analyses, generate results, or influence the study’s design or interpretation. All analyses, conclusions, and interpretations were performed independently by the authors.

Competing interests

The authors declare no competing interests.