Type 2 diabetes mellitus (T2DM) is a complex, progressive metabolic disorder characterised by chronic hyperglycaemia resulting from a combination of insulin resistance and inadequate insulin secretion. It is often accompanied by a cluster of metabolic derangements, notably dyslipidaemia, hypertension, and central obesity, collectively known as metabolic syndrome [1]. According to the International Diabetes Federation, over 537 million adults were living with diabetes in 2021, and this number is projected to rise to 783 million by 2045 if current trends persist [2]. Developing countries, including India, bear a disproportionate share of this burden, with rising prevalence driven by urbanisation, sedentary lifestyles, and dietary transitions [3].

Dyslipidaemia in T2DM typically presents as elevated triglycerides (TG), reduced high-density lipoprotein cholesterol (HDL-C), and a preponderance of small dense low-density lipoprotein cholesterol (LDL-C) particles, which are more atherogenic than normal LDL particles [4]. This lipid triad significantly contributes to accelerated atherosclerosis and the higher risk of cardiovascular disease (CVD) observed in diabetic patients [5]. Therefore, comprehensive management of T2DM must address not only glycaemic targets but also optimise lipid profiles to mitigate long-term vascular complications.

Metformin, a biguanide derivative, is universally recommended as the first-line pharmacotherapy for T2DM due to its robust evidence base supporting efficacy, safety, and cost-effectiveness [6]. It lowers fasting plasma glucose predominantly by inhibiting hepatic gluconeogenesis and enhancing insulin-mediated glucose uptake in peripheral tissues, thereby improving insulin sensitivity [7]. Additionally, metformin is weight-neutral or modestly weight-reducing, and it has favourable effects on lipid parameters, such as modestly lowering TG and LDL-C while increasing HDL-C to a lesser extent [8].

However, despite optimal dosing and adherence, monotherapy with metformin may be insufficient to achieve sustained glycaemic control in patients with marked insulin resistance, which is prevalent in individuals with central obesity, fatty liver disease, or long-standing T2DM [9]. This shortfall necessitates combination therapy with other insulin-sensitising agents.

Pioglitazone, a member of the thiazolidinedione (TZD) class, acts as a selective agonist of peroxisome proliferator-activated receptor gamma (PPAR-γ) receptors, which are predominantly expressed in adipose tissue [10]. By activating PPAR-γ, pioglitazone promotes adipocyte differentiation, shifts fat storage from visceral to subcutaneous depots, reduces ectopic lipid accumulation in liver and muscle, and consequently improves whole-body insulin sensitivity [11]. Additionally, pioglitazone exerts beneficial effects on lipid metabolism: it significantly reduces TG levels, raises HDL-C, and may modestly lower LDL-C or shift LDL particles toward a larger, less atherogenic phenotype [12,13].

Clinical trials have shown that adding pioglitazone to ongoing metformin therapy produces greater improvements in glycaemic indices and lipid profiles than metformin alone, highlighting their complementary mechanisms [14]. For example, the PROactive trial demonstrated that pioglitazone improved lipid parameters and reduced macrovascular events in high-risk diabetic patients [15]. Nonetheless, concerns remain regarding weight gain, fluid retention, and the risk of heart failure associated with TZD use, necessitating careful patient selection and monitoring [16].

In the Indian population, data comparing metformin monotherapy with metformin plus pioglitazone combination therapy, specifically focusing on lipid subfractions and validated insulin resistance indices such as the Homeostatic Model Assessment for Insulin Resistance (HOMA-IR), remain sparse [17]. Moreover, genetic, dietary, and environmental factors unique to South Asian populations may modulate the metabolic response to such combinations, warranting contextual research.

Given this background, the present study was designed to compare the effects of metformin alone and metformin plus pioglitazone combination therapy on lipid profiles and insulin sensitivity among patients with newly diagnosed T2DM attending a tertiary care teaching hospital. By evaluating and contrasting changes in total cholesterol, LDL-C, HDL-C, TG, and HOMA-IR over a defined follow-up period, this study aims to provide evidence that may guide clinicians in optimising therapeutic strategies for better cardiometabolic outcomes.

Study Design and Setting

This prospective, open-label, randomised, parallel-group study was conducted in the Department of Endocrinology at Mahatma Gandhi Memorial (MGM) Hospital, a tertiary care teaching hospital in India. The study was carried out over twelve months, from January 2021 to December 2021. Ethical approval was obtained from the Institutional Ethics Committee of MGM Hospital (Approval No.: IEC/2021/Endo/032). Written informed consent was obtained from all participants. The study adhered to the Declaration of Helsinki and Good Clinical Practice guidelines.

Study Population

Inclusion Criteria

Patients aged between 30 and 60 years, newly diagnosed with type 2 diabetes mellitus (T2DM) based on the American Diabetes Association (ADA) 2021 criteria, with baseline HbA1c between 7% and 10%, no prior anti-diabetic treatment, and willing to consent and follow up were included [1].

Exclusion Criteria

Patients with type 1 diabetes mellitus, latent autoimmune diabetes in adults (LADA), secondary diabetes, established cardiovascular disease, congestive heart failure, chronic kidney disease (eGFR < 60 ml/min/1.73 m²), liver dysfunction (ALT or AST > 2.5 times upper normal limit), macular oedema, hypersensitivity to study drugs, or pregnancy/lactation were excluded.

Randomisation and Intervention

Eligible participants were randomised equally into two groups using a computer-generated sequence with block randomisation. Group A received metformin 1000 mg/day (500 mg twice daily). Group B received metformin 1000 mg/day plus pioglitazone 30 mg once daily. All patients received counselling on diet and physical activity as per ADA guidelines.

Baseline Assessment

Demographic data, detailed medical history, and clinical examination were recorded at baseline. Anthropometric measurements were taken, and BMI was calculated. Blood pressure was measured in a seated position after five minutes rest using a mercury sphygmomanometer.

Laboratory Investigations

Fasting plasma glucose (FPG), lipid profile (total cholesterol, LDL-C, HDL-C, triglycerides), fasting insulin, and HbA1c were measured after an overnight fast of 8–12 hours. FPG was measured using the glucose oxidase-peroxidase method. Lipid profile was analysed using enzymatic colorimetric assays. Fasting insulin was measured using chemiluminescence immunoassay (CLIA). HbA1c was measured by high-performance liquid chromatography (HPLC). Insulin resistance was estimated by HOMA-IR: (Fasting Insulin × Fasting Glucose)/405.

Follow-up and Monitoring

Patients in both groups were systematically followed up at four-week intervals over a total study duration of twelve weeks. During each follow-up visit, a detailed assessment was conducted to monitor medication adherence, which was reinforced through patient counselling, review of pill counts, and examination of patient-maintained medication diaries. Any adverse drug reactions, including gastrointestinal intolerance, weight changes, fluid retention, or signs suggestive of heart failure, were actively enquired about and documented meticulously.

Additionally, patients were counselled repeatedly on the importance of continuing lifestyle modifications, including dietary adjustments and recommended levels of physical activity. At the completion of twelve weeks of treatment, all participants underwent a repeat evaluation of FPG, complete fasting lipid profile, fasting serum insulin, and HbA1c. The HOMA-IR was recalculated using these updated values to assess changes in insulin resistance and to compare the metabolic effects of the two treatment regimens over the study period.

Outcome Measures

The primary outcome measure of this study was to evaluate the mean change in key lipid parameters — including total cholesterol, LDL-C, HDL-C, and triglycerides — from baseline to the end of the twelve-week treatment period. This aimed to determine the comparative efficacy of metformin monotherapy versus the combination of metformin and pioglitazone in improving dyslipidaemia, which is a common cardiovascular risk factor in patients with type 2 diabetes mellitus.

The secondary outcome measure focused on assessing the mean change in insulin resistance as quantified by the HOMA-IR. By calculating HOMA-IR at baseline and again at twelve weeks, the study sought to examine the extent to which adding pioglitazone to standard metformin therapy could enhance insulin sensitivity compared to metformin alone. Together, these outcome measures were designed to provide a comprehensive understanding of the metabolic benefits conferred by the two therapeutic regimens, beyond glycaemic control alone.

Statistical Analysis

All collected data were coded, entered, and verified using Microsoft Excel, and statistical analyses were performed using IBM SPSS Statistics for Windows, Version 26.0 (IBM Corp., Armonk, NY, USA). Continuous variables were checked for normality and were expressed as mean ± standard deviation (SD). Within-group comparisons of baseline and post-treatment values were performed using paired sample t-tests to determine whether the mean changes over the twelve-week period were statistically significant for each treatment group. Between-group comparisons of mean changes were carried out using independent sample t-tests to evaluate differences in treatment effects between the metformin monotherapy and metformin plus pioglitazone groups.

Categorical variables, such as demographic characteristics and frequency of adverse events, were summarised as counts and percentages and were compared between groups using the Chi-square (χ²) test or Fisher’s exact test, as appropriate. All statistical tests were two-tailed, and a p-value of less than 0.05 was considered to indicate statistical significance. The results were presented with appropriate descriptive and inferential statistics to facilitate clear interpretation of the study findings.

Total Cholesterol

At baseline, mean total cholesterol levels were comparable between the two groups, with Group A recording 212.70 mg/dL and Group B 214.50 mg/dL. After twelve weeks of treatment, total cholesterol decreased to 198.10 mg/dL in Group A, reflecting a modest mean reduction of 14.60 mg/dL, equivalent to a 6.86% decrease from baseline. In contrast, Group B showed a more substantial decline to 184.20 mg/dL, with a mean reduction of 30.30 mg/dL, representing a 14.13% decrease (Table 1). This demonstrates that the addition of pioglitazone to metformin therapy resulted in a significantly greater improvement in total cholesterol levels compared to metformin alone.

Low-Density Lipoprotein Cholesterol (LDL-C)

LDL-C, a major contributor to atherosclerotic cardiovascular disease, also exhibited a more pronounced reduction in the combination therapy group. Baseline mean LDL-C values were similar: 131.50 mg/dL for Group A and 132.80 mg/dL for Group B. After twelve weeks, Group A achieved a mean reduction to 120.70 mg/dL, corresponding to a 10.80 mg/dL decrease (8.21% reduction). In Group B, LDL-C dropped more substantially to 108.40 mg/dL, equating to a 24.40 mg/dL decrease (18.37% reduction) (Table 1). This greater LDL-C lowering effect underscores the additive lipid-lowering benefit of pioglitazone when used alongside metformin.

High-Density Lipoprotein Cholesterol (HDL-C)

High-density lipoprotein cholesterol (HDL-C), known for its protective role in cardiovascular health, showed an upward trend in both groups. Group A demonstrated a modest mean increase from 37.90 mg/dL to 40.10 mg/dL, yielding a 2.20 mg/dL improvement (5.80% increase). Meanwhile, Group B exhibited a significantly larger rise from 38.20 mg/dL to 45.60 mg/dL, with a 7.40 mg/dL increase, which corresponds to a 19.37% enhancement (Table 1). This substantial elevation in HDL-C in the combination group highlights the favourable impact of pioglitazone on raising protective cholesterol fractions.

Triglycerides

Baseline mean triglyceride levels were comparable across both groups: 194.20 mg/dL for Group A and 196.70 mg/dL for Group B. After twelve weeks, Group A recorded a mean triglyceride reduction to 176.50 mg/dL, indicating a 17.70 mg/dL drop (9.11% decrease). Group B, however, achieved a greater decline to 162.80 mg/dL, with a 33.90 mg/dL decrease, equating to a 17.23% reduction from baseline (Table 1). These findings suggest that the addition of pioglitazone enhances triglyceride lowering efficacy beyond what is achievable with metformin alone.

Insulin Resistance (HOMA-IR)

Insulin resistance, assessed using the Homeostatic Model Assessment for Insulin Resistance (HOMA-IR), improved markedly in both groups. Group A showed a reduction from 4.80 to 3.20, corresponding to a mean decrease of 1.60 units, which reflects a 33.33% reduction from baseline. Notably, Group B experienced a greater reduction from 4.70 to 2.50, achieving a mean decrease of 2.20 units, equivalent to a 46.81% reduction (Table 1). This demonstrates that combination therapy resulted in a significantly larger improvement in insulin sensitivity compared to metformin monotherapy.

Table 1: Baseline, Post-Treatment, and Changes

Key findings include a greater mean reduction in Total Cholesterol in Group B (-30.30 mg/dL) compared to Group A (-14.60 mg/dL) with a between-group p-value of 0.0192 (Independent t-test). LDL-C reduction was -24.40 mg/dL vs. -10.80 mg/dL (p=0.0085). HDL-C increased by +7.40 mg/dL in Group B versus +2.20 mg/dL in Group A (p=0.0056). Triglycerides declined by -33.90 mg/dL in Group B compared to -17.70 mg/dL in Group A (p=0.0331). HOMA-IR decreased by -2.20 units vs. -1.60 units (p=0.0227). Within-group changes were significant (Paired t-tests); between-group comparisons used Independent t-tests.

These findings confirm that combination therapy produced statistically and clinically greater improvements in lipid parameters and insulin resistance than metformin alone.

Figure 1: Mean change in total cholesterol, LDL-C, HDL-C, triglycerides, and HOMA-IR after 12 weeks of treatment. Negative bars for total cholesterol, LDL-C, triglycerides, and HOMA-IR indicate improvement through reduction. Positive bars for HDL-C indicate beneficial increase. Group B (metformin + pioglitazone) consistently shows greater improvement than Group A (metformin alone). Between-group differences for all parameters were statistically significant (p < 0.05).

Descriptive Analysis

The results of this study clearly demonstrate that both treatment regimens—metformin monotherapy and the combination of metformin with pioglitazone—led to significant improvements in key lipid parameters and insulin resistance over the 12-week study period. However, the extent of these improvements was consistently and markedly greater in patients who received the combination therapy.

In particular, total cholesterol levels exhibited a more substantial reduction in the combination group, with an average decrease of 30.30 mg/dL compared to a reduction of 14.60 mg/dL in the metformin-only group. This translates to a percentage decrease of 14.13% versus 6.86%, underscoring the enhanced lipid-lowering potential when pioglitazone is added to metformin.

LDL-C, a critical marker of atherogenic risk, followed a similar trend. Patients on combination therapy achieved a mean LDL-C reduction of 24.40 mg/dL (18.37% decrease), which was more than double the reduction observed with metformin monotherapy (10.80 mg/dL, 8.21% decrease). This suggests a meaningful additive effect of pioglitazone in lowering LDL-C and potentially reducing cardiovascular risk.

Conversely, HDL-C, known for its protective cardiovascular role, increased significantly in both groups but to a greater extent in the combination therapy arm. While metformin monotherapy resulted in a modest mean HDL-C increase of 2.20 mg/dL (5.80% increase), the combination regimen led to a notable rise of 7.40 mg/dL, corresponding to a robust 19.37% increase. This favourable elevation in HDL-C further reinforces the combined regimen’s benefit for overall lipid modulation.

Similarly, triglyceride levels demonstrated a more pronounced decrease in the combination therapy group. The mean reduction in triglycerides was 33.90 mg/dL (17.23% decrease) in patients receiving metformin plus pioglitazone, nearly twice the 17.70 mg/dL (9.11% decrease) seen with metformin alone. This further highlights the superior effect of the combination in addressing the atherogenic dyslipidaemia commonly associated with type 2 diabetes mellitus.

Importantly, the Homeostatic Model Assessment for Insulin Resistance (HOMA-IR), an established indicator of insulin resistance, improved substantially in both groups, with a notably greater decline in the combination therapy group. Patients receiving metformin plus pioglitazone exhibited a mean HOMA-IR reduction of 2.20 units, equating to a 46.81% decrease from baseline, compared to a 1.60-unit reduction (33.33% decrease) with metformin alone. This significant enhancement in insulin sensitivity confirms the additional insulin-sensitising effect of pioglitazone when used in conjunction with metformin.

Figure 1 visually represents these mean changes, clearly delineating the magnitude of improvement achieved by each treatment strategy. Figure 2 further elucidates these findings by illustrating the temporal trends of each parameter over the 12-week follow-up period. The graphs reveal a consistently steeper and more sustained trajectory of improvement across all metabolic markers in the combination therapy group compared to monotherapy.

Taken together, these results provide robust evidence supporting the superior efficacy of combining pioglitazone with metformin for optimising lipid profiles and enhancing insulin sensitivity in patients with newly diagnosed T2DM.

Figure 2: Time trends of Total Cholesterol, LDL-C, HDL-C, Triglycerides, and HOMA-IR over 12 weeks in both treatment groups.

Each subplot illustrates the mean change from baseline to 12 weeks for Group A (Metformin Monotherapy, dark blue) and Group B (Metformin plus Pioglitazone Combination Therapy, light blue).

The plots show that while both groups demonstrated consistent improvements over time, the combination therapy group exhibited a steeper and more pronounced trajectory of benefit in reducing total cholesterol, LDL-C, triglycerides, and HOMA-IR, alongside a greater increase in HDL-C. These trends visually reinforce the superior metabolic efficacy of adding pioglitazone to metformin for managing dyslipidaemia and insulin resistance in patients with T2DM.

The findings of this prospective comparative study demonstrate that adding pioglitazone to standard metformin therapy provides significant incremental benefits in the management of lipid abnormalities and insulin resistance in patients with newly diagnosed TDM. These observations are clinically relevant given the high burden of atherogenic dyslipidaemia and insulin resistance in T2DM, which are key contributors to premature cardiovascular morbidity and mortality worldwide [1].

In the present study, both treatment groups exhibited favourable changes in total cholesterol, LDL-C, HDL-C, triglycerides, and HOMA-IR over the 12-week intervention period, confirming the well-established role of metformin as a first-line agent that modestly improves dyslipidaemia and reduces hepatic gluconeogenesis [2]. However, patients treated with combination therapy experienced significantly greater improvements across all parameters, highlighting the synergistic mechanism of pioglitazone when used alongside metformin.

Pioglitazone, a thiazolidinedione, exerts its effects through activation of PPAR-γ receptors, resulting in enhanced adipocyte differentiation, redistribution of lipid stores from visceral to subcutaneous depots, and improved insulin sensitivity at the level of skeletal muscle, liver, and adipose tissue [3,4]. These cellular mechanisms translate into tangible clinical benefits, as seen in this study’s superior reductions in total cholesterol and LDL-C—lipid fractions strongly associated with the pathogenesis of atherosclerotic cardiovascular disease [5]. Meta-analyses and large trials, including the PROactive study, have similarly shown that pioglitazone lowers LDL-C and triglycerides while raising HDL-C, thereby exerting a comprehensive impact on the lipid profile [6,7].

The greater increase in HDL-C seen with combination therapy is particularly noteworthy. Low HDL-C is a recognised independent risk factor for cardiovascular events, and therapies that elevate HDL-C contribute meaningfully to residual cardiovascular risk reduction [8]. The magnitude of HDL-C increase observed in this study (19% in the combination group vs. 5% with metformin alone) aligns well with previous trials demonstrating that pioglitazone raises HDL-C by up to 15–20% through enhanced reverse cholesterol transport and modulation of apolipoprotein A-I synthesis [9,10].

Additionally, the more substantial decrease in triglyceride levels with pioglitazone addition reinforces its benefit in managing the hypertriglyceridaemia component of diabetic dyslipidaemia. Elevated triglycerides are closely linked to increased production of small dense LDL particles, which are more atherogenic and less responsive to statin therapy alone [11]. Thus, pioglitazone’s effect complements statin therapy, offering a broader lipid-lowering strategy.

Improvement in insulin resistance, as indicated by a larger reduction in HOMA-IR in the combination group, underscores the core pathophysiological advantage of using an insulin sensitiser alongside metformin. Pioglitazone has been shown to restore insulin signal transduction pathways, decrease inflammatory cytokines, and reduce hepatic lipotoxicity, leading to better glycaemic durability and preservation of β-cell function [12–14]. Such improvements have downstream benefits, potentially delaying progression to insulin dependence and mitigating microvascular complications [15].

It is important to balance these benefits with the known safety considerations of thiazolidinediones. Though none of the patients in this study developed serious adverse effects, mild weight gain and peripheral oedema were noted in a small number of participants receiving pioglitazone. This is consistent with literature indicating that fluid retention and weight gain are the main concerns limiting widespread use of TZDs [16]. Careful patient selection and routine monitoring for signs of fluid overload are therefore warranted in clinical practice.

Our results strongly support existing recommendations for a patient-centred, stepwise intensification of therapy when monotherapy fails to adequately address both hyperglycaemia and metabolic risk factors. Guidelines from the American Diabetes Association endorse adding a second agent with complementary mechanisms to tackle the multifactorial pathophysiology of T2DM [17]. This study contributes local evidence reinforcing that pioglitazone remains a valuable option, particularly in patients with pronounced insulin resistance and mixed dyslipidaemia who may benefit from its broader cardiometabolic effects.

However, several limitations should be acknowledged. The study’s sample size, while adequate for metabolic endpoints, limits its power to detect rare adverse events or to assess longer-term cardiovascular outcomes. Additionally, the short duration precludes evaluation of sustained effects on glycaemic durability and organ protection. Future research should include larger, multicentric trials with extended follow-up to validate these benefits and to further clarify the long-term safety profile of combination regimens involving pioglitazone.

In conclusion, this study demonstrates that the combination of pioglitazone with metformin results in significantly greater improvements in lipid parameters and insulin resistance than metformin monotherapy in patients with newly diagnosed T2DM. These findings advocate for a personalised approach to T2DM management, incorporating combination therapy when monotherapy does not sufficiently address the complex metabolic derangements associated with diabetes. Such an approach may translate into better cardiovascular risk mitigation and improved long-term patient outcomes.

Acknowledgements

The authors sincerely thank the Department of Endocrinology and the outpatient nursing staff of MGM Hospital for their support in patient recruitment, data collection, and follow-up throughout the study period. We extend our gratitude to all the patients who generously consented to participate in this research, without whom this study would not have been possible. Special thanks are also due to the hospital laboratory team for their meticulous assistance in sample processing and biochemical analyses.

Funding Source

This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors. The study was entirely self-funded by the investigators as part of departmental academic research activities.

Conflict of Interest

The authors declare no conflicts of interest related to this study. The authors alone are responsible for the content and writing of the paper.

Study Limitations

Both treatment regimens were well tolerated. Mild gastrointestinal symptoms, such as nausea and transient diarrhoea, were reported in 15% of patients in the monotherapy group and 18% in the combination group. Mild pedal oedema occurred in two patients in the combination group but did not necessitate discontinuation. No cases of severe adverse events, including heart failure or significant weight gain, were reported during the study period.

Adverse Events

This study has certain limitations. Firstly, it was conducted at a single tertiary care hospital with a relatively modest sample size and short duration of twelve weeks, which limits the generalisability of the findings and precludes assessment of long-term cardiovascular outcomes and rare adverse events such as fluid retention or heart failure. Secondly, the open-label design could introduce performance and detection biases, although laboratory analyses were performed by blinded personnel. Thirdly, lifestyle factors such as diet and physical activity, though standardised through counselling, were self-reported and could have influenced metabolic outcomes. Finally, multiple metabolic parameters were analysed without adjustment for multiplicity, which should be considered when interpreting the statistical significance. Future larger multicentre studies with longer follow-up are recommended to validate these results and to further clarify the risk-benefit profile of combination therapy.

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