Type 2 diabetes mellitus (T2DM) is a chronic metabolic disorder characterized by insulin resistance and hyperglycemia. It is often accompanied by dyslipidemia, a condition marked by elevated triglycerides (TG), low high-density lipoprotein cholesterol (HDL-C), and increased small, dense low-density lipoprotein (LDL) particles. ^[1] Dyslipidemia in T2DM significantly contributes to the increased risk of cardiovascular diseases (CVD), which remains the leading cause of morbidity and mortality in this population. ^[2]

Statins, particularly atorvastatin, are the cornerstone of lipid-lowering therapy due to their efficacy in reducing LDL-C and cardiovascular events. ^[3] However, statins alone may not adequately address the complex lipid abnormalities in T2DM, particularly elevated TG and low HDL-C. Combination therapy with agents that target these residual lipid abnormalities is often necessary to achieve comprehensive lipid control. ^[4]

Fenofibrate, a peroxisome proliferator-activated receptor-alpha (PPAR-α) agonist, is commonly used in combination with statins to lower TG and increase HDL-C. ^[5] However, its use is limited by potential side effects, including hepatotoxicity and myopathy, especially when combined with statins. ^[6] Saroglitazar, a novel dual PPAR-α/γ agonist, has shown promise in improving lipid profiles and glycemic control in T2DM patients. ^[7] Its unique mechanism of action allows for simultaneous modulation of lipid and glucose metabolism, making it a potentially superior option for combination therapy with statins.

This study aims to compare the efficacy and safety of atorvastatin plus fenofibrate versus atorvastatin plus saroglitazar in T2DM patients with dyslipidemia. By evaluating changes in lipid profiles and monitoring adverse events, we seek to identify the optimal combination therapy for managing dyslipidemia in this high-risk population.

A randomized, open-label study was conducted on 90 T2DM patients with dyslipidemia. Patients were recruited from a tertiary care hospital and randomized into two groups: Group A (n=45) received atorvastatin (20 mg) plus fenofibrate (160 mg), and Group B (n=45) received atorvastatin (20 mg) plus saroglitazar (4 mg). The study duration was 12 weeks.

Inclusion Criteria

1. Patients aged 18-65 years with a diagnosis of T2DM.
2. Dyslipidemia defined as TG ≥150 mg/dL and HDL-C <40 mg/dL for men or <50 mg/dL for women.
3. Stable glycemic control (HbA1c ≤8.5%) for at least three months.
4. Willingness to provide informed consent.

Exclusion Criteria

1. History of statin or fibrate intolerance.
2. Severe renal or hepatic impairment.
3. Pregnancy or lactation.
4. Active liver disease or unexplained persistent elevations in serum transaminases.
5. History of myopathy or rhabdomyolysis.

Data Collection

Baseline and post-treatment lipid profiles (total cholesterol [TC], LDL-C, HDL-C, TG) were measured. Safety was assessed through regular monitoring of liver function tests (LFTs), renal function tests (RFTs), and muscle enzymes (creatine kinase [CK]). Adverse events were recorded and categorized as mild, moderate, or severe.

Statistical Analysis

Descriptive statistics were used to summarize demographic and clinical characteristics. Continuous variables were expressed as mean ± standard deviation (SD), while categorical variables were expressed as frequencies and percentages. Comparative analyses were performed using paired t-tests for within-group comparisons and independent t-tests for between-group comparisons. A p-value of <0.05 was considered statistically significant.

Ethical Considerations

The study was approved by the institutional review board, and informed consent was obtained from all participants. Patient confidentiality was maintained by anonymizing data and using secure storage systems.

Table 1: Demographic Characteristics

Table 2: Baseline Lipid Profiles

Table 3: Post-Treatment Lipid Profiles

T

able 4: Percentage Change in Lipid Parameters

Table 5: Adverse Events

Table 6: Safety Parameters

The findings of this study highlight the superior efficacy of atorvastatin plus saroglitazar in managing dyslipidemia in T2DM patients compared to atorvastatin plus fenofibrate. The significant reductions in TG and increases in HDL-C observed in Group B are clinically relevant, as these lipid abnormalities are strongly associated with increased cardiovascular risk in T2DM patients. ^[8-11]

A major finding of this study was the significant improvement in HDL-C levels in Group B compared to Group A (p = 0.02). The percentage increase in HDL-C was 9.9% in Group A versus 20.6% in Group B, indicating a nearly twofold greater improvement in the latter. This finding is clinically significant, as elevated HDL-C levels are associated with enhanced reverse cholesterol transport and a reduced risk of atherosclerotic cardiovascular disease (ASCVD). Studies such as the Framingham Heart Study and AIM-HIGH trial have consistently demonstrated the cardioprotective effects of increased HDL-C. ^[12]

Similarly, triglyceride levels showed a significantly greater reduction in Group B (-41.9%) compared to Group A (-30.8%), with a highly significant p-value (<0.001). Elevated triglycerides are an independent risk factor for cardiovascular disease, and their reduction is associated with improved insulin sensitivity and reduced residual cardiovascular risk. ^[13] This aligns with findings from the ACCORD Lipid Trial, where greater triglyceride reductions were associated with lower cardiovascular event rates in diabetic patients. ^[14]

The enhanced effects of Group B’s intervention on HDL-C and triglycerides suggest a mechanism beyond standard lipid-lowering therapy. ^[15] The most likely explanations include: Fibrate therapy, which selectively reduces triglycerides while increasing HDL-C, as seen in the FIELD study. ^[16] SGLT2 inhibitors, which have been shown in recent trials to lower TG and improve HDL-C via metabolic modulation. ^[17] Omega-3 fatty acids, which have demonstrated significant TG-lowering effects, as observed in the REDUCE-IT trial. ^[18]

The dual PPAR-α/γ agonism of saroglitazar likely contributes to its superior lipid-modifying effects. By simultaneously activating PPAR-α and PPAR-γ, saroglitazar enhances fatty acid oxidation and improves insulin sensitivity, leading to better control of TG and HDL-C levels. ^[19] In contrast, fenofibrate, as a PPAR-α agonist, primarily targets TG reduction without significant effects on HDL-C. ^[20]

The clinical implication of this finding is that Group B’s intervention may be preferable for T2DM patients with dyslipidemia characterized by high TG and low HDL-C, a common lipid profile in diabetic patients. This profile is associated with an increased risk of cardiovascular disease, making targeted therapy essential. ^[21]

The safety profiles of both combination therapies were comparable, with no significant differences in adverse events or changes in LFTs, RFTs, or CK levels. This suggests that saroglitazar is a safe alternative to fenofibrate when used in combination with atorvastatin, addressing concerns about hepatotoxicity and myopathy associated with fibrates. ^[22]

Safety assessments, including liver function tests (LFTs), renal function tests (RFTs), and creatine kinase (CK) levels, were comparable between groups, indicating no significant hepatic, renal, or muscular toxicity. The incidence of mild to moderate adverse events was similar, and no severe adverse events were reported, supporting the overall safety profile of both interventions. These findings are consistent with long-term safety studies on lipid-lowering therapies, such as JUPITER and PROVE-IT TIMI 22 trials, which demonstrated the tolerability of statins and other lipid-modifying agents. ^[23]

Strengths and Limitations

One of the strengths of this study is the well-matched baseline characteristics, which minimize potential confounding factors. Additionally, the statistically significant findings related to HDL-C and triglycerides provide strong evidence supporting the efficacy of Group B’s intervention.

However, limitations include the relatively small sample size (n=45 per group), which may limit the generalizability of findings. Additionally, long-term cardiovascular outcomes were not assessed, which would provide a clearer picture of the clinical benefits of these lipid changes. Future studies with larger cohorts and extended follow-up periods are warranted to validate these findings and assess their impact on major cardiovascular events.

Atorvastatin plus saroglitazar is a superior combination therapy for managing dyslipidemia in T2DM patients compared to atorvastatin plus fenofibrate. Its dual PPAR-α/γ agonism provides comprehensive lipid control, particularly in reducing TG and increasing HDL-C, with a favorable safety profile. Atorvastatin plus saroglitazar is more effective than atorvastatin plus fenofibrate in improving lipid profiles in T2DM patients with dyslipidemia, with a similar safety profile. This combination therapy offers a promising approach to managing dyslipidemia in this high-risk population, potentially reducing cardiovascular risk and improving overall outcomes.

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