Effect of Fibrate-Statin Combination Therapy on Lipid Profiles in Patients with Type 2 Diabetes: A Systematic Review and Meta-Analysis

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While statin monotherapy is known to effectively modify lipid parameters in T2DM, recent evidence suggests that combination therapy may offer additional benefits in managing lipid levels and reducing cardiovascular risks. A systematic review of randomized clinical trials (RCTs) comparing statin monotherapy to statin-fibrate combination therapy was conducted. Data were sourced from PubMed and Embase, and studies published up to October 2023 were included. A total of 7 RCTs with 1,349 participants met the inclusion criteria. Of these, 676 participants (50%) received combination therapy, with follow-up durations ranging from 3 to 56.4 months. Results showed that combination therapy led to significant reductions in total cholesterol (TC) (-8.65 mg/dL), low-density lipoprotein cholesterol (LDL-C) (-5.52 mg/dL), and triglycerides (TG) (-53.59 mg/dL). Additionally, high-density lipoprotein cholesterol (HDL-C) levels were significantly higher in the combination therapy group (+ 2.33 mg/dL). The findings suggest that combining statins with fibrates significantly improves lipid parameters in T2DM patients. However, the high heterogeneity among studies indicates the need for further controlled trials to better assess the cardiovascular benefits of this combination therapy and provide more definitive conclusions. Health sciences/Cardiology Health sciences/Diseases Health sciences/Endocrinology Health sciences/Medical research Fibrates Statins Type 2 Diabetes Mellitus Systematic Review Dyslipidemia Figures Figure 1 Figure 2 Figure 3 Introduction Type 2 diabetes mellitus (T2DM) is a complex metabolic disorder characterized by chronic hyperglycemia resulting from impaired insulin secretion, insulin resistance, and excessive hepatic glucose production, as described by Galicia-Garcia et al. (2020). One of the major complications associated with T2DM is an elevated risk of cardiovascular disease (CVD), largely attributed to dyslipidemia—a condition characterized by high triglyceride (TG) levels, low levels of HDL cholesterol (HDL-C), and increased levels of LDL cholesterol (LDL-C). This link has been highlighted in earlier research by Almdal et al. (2004), Stamler et al. (1993), Haffner et al. (1998), and Miettinen et al. (1998). Given this risk profile, maintaining optimal lipid levels is critical for reducing cardiovascular events in diabetic patients​. Statins, inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, are well-established agents for lowering LDL-C. As noted by Malmborg et al. (2021), statins have been shown to significantly reduce cardiovascular events in patients with T2DM. However, despite their efficacy, a residual cardiovascular risk remains, particularly among those with atherogenic dyslipidemia characterized by elevated TG and low HDL-C levels. This residual risk indicates the need for additional therapeutic strategies to complement statin therapy. Fibrates, which act as agonists of peroxisome proliferator-activated receptor-alpha (PPAR-α), have been well documented to improve lipid profiles by substantially reducing TG levels and increasing HDL-C. Nevertheless, as reported by Jakob et al. (2016), the impact of fibrates on cardiovascular outcomes has been less conclusive. For instance, the Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) study, conducted by Keech et al. (2005), showed a reduction in nonfatal myocardial infarctions with fibrate therapy but failed to demonstrate a significant reduction in overall cardiovascular mortality. These outcomes raise questions about whether fibrates can help improve cardiovascular outcomes, especially when combined with the conventional statin monotherapy. Despite the growing body of research focused on minimizing cardiovascular risks, the clinical benefit of this combination therapy remains uncertain. A trial led by Ginsberg et al. in 2016—the Action to Control Cardiovascular Risk in Diabetes (ACCORD) Lipid trial—suggested a potential benefit of combining statins with fibrates in reducing heart failure hospitalizations. While statins and fibrates target different lipid abnormalities, their additive or synergistic effects on lipid parameters and cardiovascular outcomes—particularly in patients with T2DM—have yet to be fully elucidated. Moreover, heterogeneity in patient populations, baseline lipid profiles, and study designs across previous trials has contributed to the ongoing ambiguity surrounding this issue. The primary objective of this systematic review and meta-analysis is to assess the efficacy of combined statin and fibrate therapy in improving lipid profiles in patients with T2DM, when compared to statin monotherapy. By synthesizing evidence from randomized controlled trials, this study aims to provide a more comprehensive evaluation of the potential advantages of combination therapy in managing dyslipidemia in T2DM. Additionally, it seeks to address existing gaps in the literature regarding the long-term cardiovascular outcomes of such combination treatment in diabetic populations. Methods Eligibility Criteria For this meta-analysis, we included studies that met all of the following criteria: ( 1 ) RCTs; ( 2 ) studies comparing the efficacy of statin monotherapy against combination therapy with statins and fibrates for the management of plasma lipids; ( 3 ) studies specifically involving patients diagnosed with T2DM; and ( 4 ) studies that reported at least one of the following primary outcomes of interest: TC, LDL-C, HDL-C, or TG. Exclusion criteria were applied to studies that met any of the following conditions: ( 1 ) absence of a control group; ( 2 ) non-randomized study designs, including observational or cohort studies; and ( 3 ) failure to meet the predefined population or intervention specifications. Studies were also excluded if they did not provide adequate data on relevant lipid outcomes, as outlined in the inclusion criteria. Search Strategy and Data Extraction A comprehensive systematic search was conducted in the PubMed and Embase databases from their inception through October 2023. The search strategy utilized the following Medical Subject Headings (MeSH) terms: Type 2 Diabetes Mellitus, Hydroxymethylglutaryl-CoA Reductase Inhibitors, Statin, Simvastatin, Atorvastatin, Fluvastatin, Lovastatin, Rosuvastatin, Fibric Acid, Fibrate, Fenofibrate, Gemfibrozil, Fenofibric Acid, and Clofibrate. To ensure thoroughness, the reference lists of all included studies and relevant review articles were also manually screened for additional eligible studies. Data extraction was conducted independently by two authors (V.B. and A.F.) in accordance with predefined criteria and quality assessment protocols. Any discrepancies were resolved through discussion or consultation with a third reviewer, if necessary. The protocol for this meta-analysis was prospectively registered with PROSPERO under the registration number 513572. Quality Assessment The risk of bias in the RCTs included in this meta-analysis was evaluated using Version 2 of the Cochrane Risk of Bias Assessment Tool, as conducted by Higgins et al. (2011). Two independent reviewers performed the assessments, with any discrepancies or disagreements resolved through discussion and consensus. In cases where consensus could not be reached, a third reviewer was consulted to finalize the evaluation. Statistical analysis These systematic review and meta-analysis were conducted in strict accordance with the guidelines established by the Cochrane Collaboration and the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA), as described by Page et al. (2021). Treatment effects across the studies were analyzed using mean differences (MD) with corresponding 95% confidence intervals (CIs). To assess heterogeneity among studies, the Cochrane Q test and I² statistics were applied. A p-value 25% were used to identify significant heterogeneity. In cases where I² was less than 25%, indicating low heterogeneity, a fixed-effect model was employed for the analysis. All statistical analyses were conducted using Review Manager (RevMan) version 5.4 (Nordic Cochrane Centre, The Cochrane Collaboration, Copenhagen, Denmark). Results Study Selection and Characteristics The initial search yielded 2,044 results. After removing duplicates and irrelevant studies, 49 studies remained for full-text review to assess eligibility ( see Fig. 1 ). Of these, 7 studies met the inclusion criteria and were incorporated into both the qualitative and quantitative analyses. Baseline characteristics of the included studies are summarized in Table 1 . In the ACCORD trial by Ginsberg et al. (2010), only data from patients who completed the full seven-year follow-up were analyzed, rather than data from the entire study population, although Table 1 provides characteristics for the overall cohort. All included studies compared statin monotherapy with combination therapy involving statins and fibrates, though the specific dosages and types of drugs varied across the trials ( Table 1 ). Simvastatin was used in the studies by Derosa et al. (2009)​, Ginsberg et al. (2010) ​, and Krysiak et al. (2011]​. Atorvastatin was administered in the studies by Athyros et al. (2002), and Lella et al. (2013)​, while fluvastatin was utilized in Derosa et al. (2004)​. The study by Jones et al. (2010)​ did not specify the type of statin used for each patient, instead, participants were allocated into four treatment arms: low-dose statin (rosuvastatin 10 mg/day, simvastatin 20 mg/day, or atorvastatin 20 mg/day); fenofibric acid 135 mg/day plus low-dose statin; moderate-dose statin (rosuvastatin 20 mg/day, simvastatin 40 mg/day, or atorvastatin 40 mg/day); and fenofibric acid 135 mg/day plus moderate-dose statin. Baseline plasma lipid parameters and blood glucose levels for the patients were also extracted and are presented in Table 2 . For statistical analysis, values reported as medians in the original studies were converted to means. Pooled Analysis of All Studies The pooled results from all included studies demonstrate a significant impact of the combined fibrate/statin therapy on various lipid parameters (Figs. 2 and 3). Specifically, the combination therapy was associated with a substantial reduction in TG levels (mean difference [MD]: -53.59 mg/dL; 95% CI: -56.79 to -50.40; p < 0.0001; I² = 96%), total cholesterol (TC) levels (MD: -8.65 mg/dL; 95% CI: -10.87 to -6.52; p < 0.0001; I² = 87%), and LDL-C levels (MD: -5.52 mg/dL; 95% CI: -6.90 to -4.13; p < 0.0001; I² = 96%). In addition, combination therapy was associated with a notable increase in HDL-C levels (MD: 2.33 mg/dL; 95% CI: 1.66 to 3.00; p < 0.0001; I² = 88%). Quality assessment The quality of the included studies was evaluated using the Risk of Bias 2 (RoB 2) tool, as described in the publication by Sterne et al. (2019). One study—Athyros et al. (2002)—was flagged as having a high risk of bias, as shown in the bias assessment figure provided in the supplementary appendix. Another study, conducted by Jones et al. (2010), raised concerns due to its design as a pooled subgroup analysis derived from three separate randomized controlled trials, with limited information regarding the randomization processes. Despite these limitations, the remaining studies were considered to be of acceptable quality and performed satisfactorily in the bias assessment. Discussion The findings of this meta-analysis provide valuable insights into the effects of combining fibrates with statins on lipid profiles in patients with T2DM. In line with previous studies, such as the FIELD (Keech et al. 2005) and ACCORD (Ginsberg et al. 2010) trials, our results demonstrate improvements in lipid parameters but leave unresolved questions regarding long-term cardiovascular outcomes. The FIELD study showed that fibrate therapy reduced the incidence of non-fatal myocardial infarctions, yet did not significantly impact overall cardiovascular mortality. Similarly, the ACCORD Lipid trial observed reductions in TG and increases in HDL-C when fibrates were combined with statins, though evidence for reductions in cardiovascular events remained inconclusive. Our analysis corroborates these findings, particularly in the context of lipid improvements, but raises the crucial question of whether these changes translate into meaningful cardiovascular benefits. This meta-analysis confirmed that combination therapy with fibrates and statins significantly improved lipid profiles in T2DM patients, showing greater reductions in TC, LDL-C, and TG levels compared to statin monotherapy. The substantial reduction in triglycerides (mean difference: -53.59 mg/dL) is especially noteworthy, given that elevated TG levels are a well-established risk factor for cardiovascular events in T2DM. The observed increase in HDL-C levels (mean difference: 2.33 mg/dL) further supports the potential of combination therapy, as low HDL-C is a key contributor to atherosclerosis, particularly in diabetic populations. These data suggest that dual therapy may offer a more comprehensive lipid-lowering approach for high-risk individuals, particularly those with persistent hypertriglyceridemia despite statin therapy alone. While the improvements in lipid profiles are significant, this study faces similar limitations to previous trials, particularly in its ability to demonstrate conclusive cardiovascular outcomes. Both the ACCORD and FIELD trials, despite showing favorable lipid changes, failed to definitively prove that these changes led to reductions in long-term cardiovascular events. Similarly, our meta-analysis found limited reporting of clinical events such as myocardial infarctions, strokes, or cardiovascular mortality, underscoring the need for future research to focus on these critical outcomes. Notably, only the Ginsberg et al. 2010 study in our review specifically evaluated whether fibrate-statin combination therapy provided additional cardiovascular protection compared to statin monotherapy, but indicated no significant difference in major cardiovascular event rates observed over a 4.7-year follow-up. Without robust data on clinical endpoints, it remains difficult to fully endorse combination therapy based solely on improvements in surrogate markers such as lipid levels, despite the promising changes observed. Further insight is provided by a secondary analysis of the ACCORDION study by Zhu et al. (2020), which included 940 participants with hypercholesterolemia. The study found that the combination of simvastatin and fenofibrate improved survival over a 5-year follow-up period, when compared to simvastatin plus placebo (adjusted HR 0.65, 95% CI: 0.45–0.94, p = 0.02). This survival benefit may be mediated, in part, by an increase in plasma adiponectin, a molecule with known cardioprotective properties through mechanisms such as stimulation of nitric oxide, improved endothelial function, enhanced reverse cholesterol transport, reduction of C-reactive protein, inhibition of foam cell formation, and prevention of thrombus formation. Kishida et al. (2012) highlight that low adiponectin levels are also associated with insulin resistance and atherosclerosis in patients with T2DM, underscoring the hormone’s potential anti-diabetic and anti-atherogenic properties. A systematic review and meta-analysis comparing fibrates and statins on adiponectin levels further favored fibrate therapy in terms of adiponectin induction, as described in the study by Sahebkar et al. 2013. The lipid-lowering effect of fibrates appears more pronounced in patients with elevated baseline lipoprotein levels, as shown in Sahebkar et al. 2017. However, due to the lack of studies specifically designed to investigate this outcome, we were unable to include this endpoint in our statistical analysis. A major limitation of this meta-analysis is the substantial heterogeneity across the included studies (I² >80% in most comparisons). Variability in study designs, patient populations, and treatment regimens complicates the interpretation of pooled results. It is possible that the benefits of combination therapy may be more pronounced in specific subgroups, such as those with higher baseline TG or lower HDL-C levels. Future studies should focus on stratifying patients according to these characteristics to better identify which populations are most likely to benefit from dual therapy. Moreover, the relatively short follow-up duration in most of the included studies limits the ability to assess long-term outcomes. Cardiovascular benefits from lipid modifications may take years to manifest, necessitating longer follow-up periods to adequately capture these effects. Another critical consideration is the safety of fibrate and statin combination therapy, particularly with regard to potential adverse effects such as hepatotoxicity and myopathy. Although earlier research suggests that these risks are minimal when fenofibrate is used, larger-scale trials should include comprehensive safety assessments, especially in high-risk populations such as older adults or those with comorbidities. The studies in this meta-analysis reported no significant differences in adverse events between combination therapy and statin monotherapy, but the limited data available on safety warrant further investigation (Table 3). Despite these limitations, this meta-analysis offers several strengths. The significant improvements in lipid profiles observed in the combination therapy group underscore the clinical importance of addressing residual dyslipidemia in T2DM patients. For individuals who continue to exhibit elevated TG and low HDL-C levels despite statin therapy, adding a fibrate may represent a viable strategy to further reduce lipid-related cardiovascular risk. Additionally, the findings highlight the potential role of combination therapy in specific high-risk populations, particularly those with atherogenic dyslipidemia. Conclusion This This meta-analysis demonstrates that combination therapy with fibrates and statins significantly improves lipid profiles in patients with T2DM, leading to greater reductions in total cholesterol, triglycerides, and LDL-C levels, along with increases in HDL-C, compared to statin monotherapy. These findings underscore the potential utility of dual therapy in addressing residual dyslipidemia, particularly in patients with atherogenic profiles who do not respond adequately to statins alone. However, the clinical relevance of these improvements remains uncertain due to a lack of robust evidence linking combination therapy to reductions in long-term cardiovascular events. The limited number of high-quality, long-term randomized controlled trials focused on cardiovascular outcomes—and the considerable heterogeneity in existing studies—highlight the need for more targeted research. Future investigations should prioritize longer follow-up periods, stratified analyses by baseline lipid subtypes, and comprehensive safety evaluations. Until such data are available, the routine use of fibrate-statin combination therapy should be considered on a case-by-case basis. As the therapeutic landscape for T2DM continues to evolve, particularly with the growing use of cardiometabolic agents such as SGLT2 inhibitors and GLP-1 receptor agonists, the role of lipid-targeted strategies like fibrate-statin combination therapy may need to be reconsidered within a broader, integrated approach to cardiovascular risk management. Declarations Declaration of No Funding I hereby declare that the research and work presented in the article titled “Effect of Fibrate-Statin Combination Therapy on Lipid Profiles in Patients with Type 2 Diabetes: A Systematic Review and Meta-Analysis” have been conducted without any financial support or funding from external sources. This statement is made to affirm the independence and integrity of the research. Ethics and Consent to Participate declarations: not applicable. Consent to Publish declaration: not applicable. Author Contribution V.B. drafted the main manuscript text and it's figures. V.B. drafted the methodology under the supervision of J.T., who also reviewed the manuscript.V.B. and A.F. performed the data extraction and analysis, while V.B. and A.L. conducted the study screening. T.S. and J.T. critically reviewed the manuscript. All authors reviewed and approved the final version of the manuscript. Data Availability Statement: This study did not generate any new data. All data used in this systematic review were secondary and obtained from the studies included in the analysis. The data underlying the findings of this study are available in the respective published articles of the included studies. For access to the data, please refer to the individual publications cited in the manuscript. References Galicia-Garcia U, Benito-Vicente A, Jebari S, et al. Pathophysiology of Type 2 Diabetes Mellitus. Int J Mol Sci 2020;21(17):6275. doi: 10.3390/ijms21176275 . Almdal T, Scharling H, Jensen JS, et al. The independent effect of type 2 diabetes mellitus on ischemic heart disease, stroke, and death: a population-based study of 13,000 men and women with 20 years of follow-up. Arch Intern Med 2004;164:1422–6. doi: 10.1001/archinte.164.13.1422 . Stamler J, Vaccaro O, Neaton JD, et al. Diabetes, other risk factors, and 12-yr cardiovascular mortality for men screened in the Multiple Risk Factor Intervention Trial. 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Fenofibrate, simvastatin and their combination in the management of dyslipidaemia in type 2 diabetic patients. Curr Med Res Opin 2009;25(8):1973–83. doi: 10.1185/03007990903073159 . Krysiak R, Gdula-Dymek A, Okopien B. Effect of simvastatin and fenofibrate on cytokine release and systemic inflammation in type 2 diabetes mellitus with mixed dyslipidemia. Am J Cardiol 2011;107(7):1010–1018.e1. doi: 10.1016/j.amjcard.2010.11.023 . Athyros VG, Papageorgiou AA, Athyrou VV, et al. Atorvastatin and micronized fenofibrate alone and in combination in type 2 diabetes with combined hyperlipidemia. Diabetes Care 2002;25(7):1198–202. doi: 10.2337/diacare.25.7.1198 . Lella M, Indira K. A comparative study of efficacy of atorvastatin alone and its combination with fenofibrate on lipid profile in type 2 diabetes mellitus patients with hyperlipidemia. J Adv Pharm Technol Res 2013;4(3):166–70. doi: 10.4103/2231-4040.116778 . Derosa G, Cicero AE, Bertone G, et al. Comparison of fluvastatin + fenofibrate combination therapy and fluvastatin monotherapy in the treatment of combined hyperlipidemia, type 2 diabetes mellitus, and coronary heart disease: a 12-month, randomized, double-blind, controlled trial. Clin Ther 2004;26(10):1599–607. doi: 10.1016/j.clinthera.2004.10.008 . Jones PH, Cusi K, Davidson MH, et al. Efficacy and safety of fenofibric acid co-administered with low or moderate-dose statin in patients with mixed dyslipidemia and type 2 diabetes mellitus: results of a pooled subgroup analysis from three randomized, controlled, double-blind trials. Am J Cardiovasc Drugs 2010;10(2):73–84. doi: 10.2165/10061630-000000000-00000 . Sterne JAC, Savović J, Page MJ, et al. RoB 2: a revised tool for assessing risk of bias in randomised trials. BMJ 2019;366:l4898. doi: 10.1136/bmj.l4898 . Zhu L, Hayen A, Bell KJL. Legacy effect of fibrate add-on therapy in diabetic patients with dyslipidemia: a secondary analysis of the ACCORDION study. Cardiovasc Diabetol 2020;19(1):28. doi: 10.1186/s12933-020-01002-x . Kishida K, Funahashi T, Shimomura I. Molecular mechanisms of diabetes and atherosclerosis: role of adiponectin. Endocr Metab Immune Disord Drug Targets 2012;12(2):118–31. doi: 10.2174/187153012800493468 . Sahebkar A. Head-to-head comparison of fibrates versus statins for elevation of circulating adiponectin concentrations: a systematic review and meta-analysis. Metabolism 2013;62(12):1876–85. doi: 10.1016/j.metabol.2013.08.017 . Sahebkar A, Simental-Mendía LE, Watts GF, et al Lipid and Blood Pressure Meta-Analysis Collaboration (LBPMC) Group. Comparison of the effects of fibrates versus statins on plasma lipoprotein(a) concentrations: a systematic review and meta-analysis of head-to-head randomized controlled trials. BMC Medicine 2017;15(1):22. doi: 10.1186/s12916-017-0787-7 . Tables Tables 1 to 3 are available in the Supplementary Files section. Additional Declarations No competing interests reported. Supplementary Files Supplementary.png SupplementaryMaterialPrismaChcklist.pdf Tabela1.png Tabela2.png Tabela3.png Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. 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legend.\u003c/p\u003e","description":"","filename":"Figura1ABC.png","url":"https://assets-eu.researchsquare.com/files/rs-7178196/v1/7c542fff318b42b43434da8b.png"},{"id":89281340,"identity":"85d4fe9d-b17e-41f7-ab23-ea378dcc0e39","added_by":"auto","created_at":"2025-08-18 10:38:22","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":427754,"visible":true,"origin":"","legend":"\u003cp\u003eSee image above for figure legend.\u003c/p\u003e","description":"","filename":"Figura2.png","url":"https://assets-eu.researchsquare.com/files/rs-7178196/v1/a5b113afcfc1c8d9028ba83a.png"},{"id":89281354,"identity":"6686d389-6acb-449e-9567-07addda99e52","added_by":"auto","created_at":"2025-08-18 10:38:23","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":652187,"visible":true,"origin":"","legend":"\u003cp\u003eSee image above for figure legend.\u003c/p\u003e","description":"","filename":"Figura3.png","url":"https://assets-eu.researchsquare.com/files/rs-7178196/v1/c3fe1905fae2bcc0e0bc9b06.png"},{"id":89593173,"identity":"be6ea92a-eccc-444b-ac1c-03f43f66b3c5","added_by":"auto","created_at":"2025-08-21 16:17:08","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1391786,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-7178196/v1/e590ab75-9d8d-45e1-9899-b82b829130c3.pdf"},{"id":89281359,"identity":"46caa8be-5d2c-499b-b986-f987ad298567","added_by":"auto","created_at":"2025-08-18 10:38:23","extension":"png","order_by":0,"title":"","display":"","copyAsset":false,"role":"supplement","size":130302,"visible":true,"origin":"","legend":"","description":"","filename":"Supplementary.png","url":"https://assets-eu.researchsquare.com/files/rs-7178196/v1/6ca02e96decd428c93b0fa35.png"},{"id":89281309,"identity":"4ffac370-6f25-45d5-8293-7035022d5368","added_by":"auto","created_at":"2025-08-18 10:38:17","extension":"pdf","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":81357,"visible":true,"origin":"","legend":"","description":"","filename":"SupplementaryMaterialPrismaChcklist.pdf","url":"https://assets-eu.researchsquare.com/files/rs-7178196/v1/1fa7aa8710d9fa040bf75da9.pdf"},{"id":89282595,"identity":"00e9c1da-e51c-44e9-b675-bc98d53038fa","added_by":"auto","created_at":"2025-08-18 10:46:25","extension":"png","order_by":14,"title":"","display":"","copyAsset":false,"role":"supplement","size":414315,"visible":true,"origin":"","legend":"","description":"","filename":"Tabela1.png","url":"https://assets-eu.researchsquare.com/files/rs-7178196/v1/cc8597a4754a81f7475b90be.png"},{"id":89281352,"identity":"329d3833-7914-4179-9882-c0301fccb794","added_by":"auto","created_at":"2025-08-18 10:38:23","extension":"png","order_by":15,"title":"","display":"","copyAsset":false,"role":"supplement","size":403833,"visible":true,"origin":"","legend":"","description":"","filename":"Tabela2.png","url":"https://assets-eu.researchsquare.com/files/rs-7178196/v1/9a1d904031fdb314d78cc1e0.png"},{"id":89282592,"identity":"d4c2e38c-848b-4725-b28b-37238454f575","added_by":"auto","created_at":"2025-08-18 10:46:22","extension":"png","order_by":16,"title":"","display":"","copyAsset":false,"role":"supplement","size":358124,"visible":true,"origin":"","legend":"","description":"","filename":"Tabela3.png","url":"https://assets-eu.researchsquare.com/files/rs-7178196/v1/0cbea6fb3d81a37054472353.png"}],"financialInterests":"No competing interests reported.","formattedTitle":"Effect of Fibrate-Statin Combination Therapy on Lipid Profiles in Patients with Type 2 Diabetes: A Systematic Review and Meta-Analysis","fulltext":[{"header":"Introduction","content":"\u003cp\u003eType 2 diabetes mellitus (T2DM) is a complex metabolic disorder characterized by chronic hyperglycemia resulting from impaired insulin secretion, insulin resistance, and excessive hepatic glucose production, as described by Galicia-Garcia et al. (2020). One of the major complications associated with T2DM is an elevated risk of cardiovascular disease (CVD), largely attributed to dyslipidemia\u0026mdash;a condition characterized by high triglyceride (TG) levels, low levels of HDL cholesterol (HDL-C), and increased levels of LDL cholesterol (LDL-C). This link has been highlighted in earlier research by Almdal et al. (2004), Stamler et al. (1993), Haffner et al. (1998), and Miettinen et al. (1998). Given this risk profile, maintaining optimal lipid levels is critical for reducing cardiovascular events in diabetic patients​.\u003c/p\u003e\u003cp\u003eStatins, inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, are well-established agents for lowering LDL-C. As noted by Malmborg et al. (2021), statins have been shown to significantly reduce cardiovascular events in patients with T2DM. However, despite their efficacy, a residual cardiovascular risk remains, particularly among those with atherogenic dyslipidemia characterized by elevated TG and low HDL-C levels. This residual risk indicates the need for additional therapeutic strategies to complement statin therapy.\u003c/p\u003e\u003cp\u003eFibrates, which act as agonists of peroxisome proliferator-activated receptor-alpha (PPAR-α), have been well documented to improve lipid profiles by substantially reducing TG levels and increasing HDL-C. Nevertheless, as reported by Jakob et al. (2016), the impact of fibrates on cardiovascular outcomes has been less conclusive. For instance, the Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) study, conducted by Keech et al. (2005), showed a reduction in nonfatal myocardial infarctions with fibrate therapy but failed to demonstrate a significant reduction in overall cardiovascular mortality. These outcomes raise questions about whether fibrates can help improve cardiovascular outcomes, especially when combined with the conventional statin monotherapy.\u003c/p\u003e\u003cp\u003eDespite the growing body of research focused on minimizing cardiovascular risks, the clinical benefit of this combination therapy remains uncertain. A trial led by Ginsberg et al. in 2016\u0026mdash;the Action to Control Cardiovascular Risk in Diabetes (ACCORD) Lipid trial\u0026mdash;suggested a potential benefit of combining statins with fibrates in reducing heart failure hospitalizations. While statins and fibrates target different lipid abnormalities, their additive or synergistic effects on lipid parameters and cardiovascular outcomes\u0026mdash;particularly in patients with T2DM\u0026mdash;have yet to be fully elucidated. Moreover, heterogeneity in patient populations, baseline lipid profiles, and study designs across previous trials has contributed to the ongoing ambiguity surrounding this issue.\u003c/p\u003e\u003cp\u003eThe primary objective of this systematic review and meta-analysis is to assess the efficacy of combined statin and fibrate therapy in improving lipid profiles in patients with T2DM, when compared to statin monotherapy. By synthesizing evidence from randomized controlled trials, this study aims to provide a more comprehensive evaluation of the potential advantages of combination therapy in managing dyslipidemia in T2DM. Additionally, it seeks to address existing gaps in the literature regarding the long-term cardiovascular outcomes of such combination treatment in diabetic populations.\u003c/p\u003e"},{"header":"Methods","content":"\u003cp\u003e\u003cb\u003eEligibility Criteria\u003c/b\u003e\u003c/p\u003e\u003cp\u003eFor this meta-analysis, we included studies that met all of the following criteria: (\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e) RCTs; (\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e) studies comparing the efficacy of statin monotherapy against combination therapy with statins and fibrates for the management of plasma lipids; (\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e) studies specifically involving patients diagnosed with T2DM; and (\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e) studies that reported at least one of the following primary outcomes of interest: TC, LDL-C, HDL-C, or TG.\u003c/p\u003e\u003cp\u003eExclusion criteria were applied to studies that met any of the following conditions: (\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e) absence of a control group; (\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e) non-randomized study designs, including observational or cohort studies; and (\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e) failure to meet the predefined population or intervention specifications. Studies were also excluded if they did not provide adequate data on relevant lipid outcomes, as outlined in the inclusion criteria.\u003c/p\u003e\u003cp\u003e\u003cb\u003eSearch Strategy and Data Extraction\u003c/b\u003e\u003c/p\u003e\u003cp\u003eA comprehensive systematic search was conducted in the PubMed and Embase databases from their inception through October 2023. The search strategy utilized the following Medical Subject Headings (MeSH) terms: Type 2 Diabetes Mellitus, Hydroxymethylglutaryl-CoA Reductase Inhibitors, Statin, Simvastatin, Atorvastatin, Fluvastatin, Lovastatin, Rosuvastatin, Fibric Acid, Fibrate, Fenofibrate, Gemfibrozil, Fenofibric Acid, and Clofibrate. To ensure thoroughness, the reference lists of all included studies and relevant review articles were also manually screened for additional eligible studies.\u003c/p\u003e\u003cp\u003eData extraction was conducted independently by two authors (V.B. and A.F.) in accordance with predefined criteria and quality assessment protocols. Any discrepancies were resolved through discussion or consultation with a third reviewer, if necessary. The protocol for this meta-analysis was prospectively registered with PROSPERO under the registration number 513572.\u003c/p\u003e\u003cp\u003e\u003cb\u003eQuality Assessment\u003c/b\u003e\u003c/p\u003e\u003cp\u003eThe risk of bias in the RCTs included in this meta-analysis was evaluated using Version 2 of the Cochrane Risk of Bias Assessment Tool, as conducted by Higgins et al. (2011). Two independent reviewers performed the assessments, with any discrepancies or disagreements resolved through discussion and consensus. In cases where consensus could not be reached, a third reviewer was consulted to finalize the evaluation.\u003c/p\u003e\u003cdiv id=\"Sec2\" class=\"Section2\"\u003e\u003ch2\u003eStatistical analysis\u003c/h2\u003e\u003cp\u003eThese systematic review and meta-analysis were conducted in strict accordance with the guidelines established by the Cochrane Collaboration and the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA), as described by Page et al. (2021). Treatment effects across the studies were analyzed using mean differences (MD) with corresponding 95% confidence intervals (CIs). To assess heterogeneity among studies, the Cochrane Q test and I\u0026sup2; statistics were applied. A p-value\u0026thinsp;\u0026lt;\u0026thinsp;0.10 and I\u0026sup2; \u0026gt;25% were used to identify significant heterogeneity. In cases where I\u0026sup2; was less than 25%, indicating low heterogeneity, a fixed-effect model was employed for the analysis. All statistical analyses were conducted using Review Manager (RevMan) version 5.4 (Nordic Cochrane Centre, The Cochrane Collaboration, Copenhagen, Denmark).\u003c/p\u003e\u003c/div\u003e"},{"header":"Results","content":"\u003cp\u003e\u003cb\u003eStudy Selection and Characteristics\u003c/b\u003e\u003c/p\u003e\u003cp\u003eThe initial search yielded 2,044 results. After removing duplicates and irrelevant studies, 49 studies remained for full-text review to assess eligibility (\u003cb\u003esee Fig.\u0026nbsp;1\u003c/b\u003e). Of these, 7 studies met the inclusion criteria and were incorporated into both the qualitative and quantitative analyses. Baseline characteristics of the included studies are summarized in \u003cb\u003eTable\u0026nbsp;1\u003c/b\u003e.\u003c/p\u003e\u003cp\u003eIn the ACCORD trial by Ginsberg et al. (2010), only data from patients who completed the full seven-year follow-up were analyzed, rather than data from the entire study population, although \u003cb\u003eTable\u0026nbsp;1\u003c/b\u003e provides characteristics for the overall cohort. All included studies compared statin monotherapy with combination therapy involving statins and fibrates, though the specific dosages and types of drugs varied across the trials (\u003cb\u003eTable\u0026nbsp;1\u003c/b\u003e).\u003c/p\u003e\u003cp\u003eSimvastatin was used in the studies by Derosa et al. (2009)​, Ginsberg et al. (2010) ​, and Krysiak et al. (2011]​. Atorvastatin was administered in the studies by Athyros et al. (2002), and Lella et al. (2013)​, while fluvastatin was utilized in Derosa et al. (2004)​. The study by Jones et al. (2010)​ did not specify the type of statin used for each patient, instead, participants were allocated into four treatment arms: low-dose statin (rosuvastatin 10 mg/day, simvastatin 20 mg/day, or atorvastatin 20 mg/day); fenofibric acid 135 mg/day plus low-dose statin; moderate-dose statin (rosuvastatin 20 mg/day, simvastatin 40 mg/day, or atorvastatin 40 mg/day); and fenofibric acid 135 mg/day plus moderate-dose statin.\u003c/p\u003e\u003cp\u003eBaseline plasma lipid parameters and blood glucose levels for the patients were also extracted and are presented in \u003cb\u003eTable\u0026nbsp;2\u003c/b\u003e. For statistical analysis, values reported as medians in the original studies were converted to means.\u003c/p\u003e\u003cp\u003e\u003cb\u003ePooled Analysis of All Studies\u003c/b\u003e\u003c/p\u003e\u003cp\u003eThe pooled results from all included studies demonstrate a significant impact of the combined fibrate/statin therapy on various lipid parameters (Figs.\u0026nbsp;2 and 3). Specifically, the combination therapy was associated with a substantial reduction in TG levels (mean difference [MD]: -53.59 mg/dL; 95% CI: -56.79 to -50.40; p\u0026thinsp;\u0026lt;\u0026thinsp;0.0001; I\u0026sup2; = 96%), total cholesterol (TC) levels (MD: -8.65 mg/dL; 95% CI: -10.87 to -6.52; p\u0026thinsp;\u0026lt;\u0026thinsp;0.0001; I\u0026sup2; = 87%), and LDL-C levels (MD: -5.52 mg/dL; 95% CI: -6.90 to -4.13; p\u0026thinsp;\u0026lt;\u0026thinsp;0.0001; I\u0026sup2; = 96%). In addition, combination therapy was associated with a notable increase in HDL-C levels (MD: 2.33 mg/dL; 95% CI: 1.66 to 3.00; p\u0026thinsp;\u0026lt;\u0026thinsp;0.0001; I\u0026sup2; = 88%).\u003c/p\u003e\u003cp\u003e\u003cb\u003eQuality assessment\u003c/b\u003e\u003c/p\u003e\u003cp\u003eThe quality of the included studies was evaluated using the Risk of Bias 2 (RoB 2) tool, as described in the publication by Sterne et al. (2019). One study\u0026mdash;Athyros et al. (2002)\u0026mdash;was flagged as having a high risk of bias, as shown in the bias assessment figure provided in the supplementary appendix. Another study, conducted by Jones et al. (2010), raised concerns due to its design as a pooled subgroup analysis derived from three separate randomized controlled trials, with limited information regarding the randomization processes. Despite these limitations, the remaining studies were considered to be of acceptable quality and performed satisfactorily in the bias assessment.\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eThe findings of this meta-analysis provide valuable insights into the effects of combining fibrates with statins on lipid profiles in patients with T2DM. In line with previous studies, such as the FIELD (Keech et al. 2005) and ACCORD (Ginsberg et al. 2010) trials, our results demonstrate improvements in lipid parameters but leave unresolved questions regarding long-term cardiovascular outcomes. The FIELD study showed that fibrate therapy reduced the incidence of non-fatal myocardial infarctions, yet did not significantly impact overall cardiovascular mortality. Similarly, the ACCORD Lipid trial observed reductions in TG and increases in HDL-C when fibrates were combined with statins, though evidence for reductions in cardiovascular events remained inconclusive. Our analysis corroborates these findings, particularly in the context of lipid improvements, but raises the crucial question of whether these changes translate into meaningful cardiovascular benefits.\u003c/p\u003e\u003cp\u003eThis meta-analysis confirmed that combination therapy with fibrates and statins significantly improved lipid profiles in T2DM patients, showing greater reductions in TC, LDL-C, and TG levels compared to statin monotherapy. The substantial reduction in triglycerides (mean difference: -53.59 mg/dL) is especially noteworthy, given that elevated TG levels are a well-established risk factor for cardiovascular events in T2DM. The observed increase in HDL-C levels (mean difference: 2.33 mg/dL) further supports the potential of combination therapy, as low HDL-C is a key contributor to atherosclerosis, particularly in diabetic populations. These data suggest that dual therapy may offer a more comprehensive lipid-lowering approach for high-risk individuals, particularly those with persistent hypertriglyceridemia despite statin therapy alone.\u003c/p\u003e\u003cp\u003eWhile the improvements in lipid profiles are significant, this study faces similar limitations to previous trials, particularly in its ability to demonstrate conclusive cardiovascular outcomes. Both the ACCORD and FIELD trials, despite showing favorable lipid changes, failed to definitively prove that these changes led to reductions in long-term cardiovascular events. Similarly, our meta-analysis found limited reporting of clinical events such as myocardial infarctions, strokes, or cardiovascular mortality, underscoring the need for future research to focus on these critical outcomes. Notably, only the Ginsberg et al. 2010 study in our review specifically evaluated whether fibrate-statin combination therapy provided additional cardiovascular protection compared to statin monotherapy, but indicated no significant difference in major cardiovascular event rates observed over a 4.7-year follow-up. Without robust data on clinical endpoints, it remains difficult to fully endorse combination therapy based solely on improvements in surrogate markers such as lipid levels, despite the promising changes observed.\u003c/p\u003e\u003cp\u003eFurther insight is provided by a secondary analysis of the ACCORDION study by Zhu et al. (2020), which included 940 participants with hypercholesterolemia. The study found that the combination of simvastatin and fenofibrate improved survival over a 5-year follow-up period, when compared to simvastatin plus placebo (adjusted HR 0.65, 95% CI: 0.45\u0026ndash;0.94, p\u0026thinsp;=\u0026thinsp;0.02). This survival benefit may be mediated, in part, by an increase in plasma adiponectin, a molecule with known cardioprotective properties through mechanisms such as stimulation of nitric oxide, improved endothelial function, enhanced reverse cholesterol transport, reduction of C-reactive protein, inhibition of foam cell formation, and prevention of thrombus formation. Kishida et al. (2012) highlight that low adiponectin levels are also associated with insulin resistance and atherosclerosis in patients with T2DM, underscoring the hormone\u0026rsquo;s potential anti-diabetic and anti-atherogenic properties. A systematic review and meta-analysis comparing fibrates and statins on adiponectin levels further favored fibrate therapy in terms of adiponectin induction, as described in the study by Sahebkar et al. 2013.\u003c/p\u003e\u003cp\u003eThe lipid-lowering effect of fibrates appears more pronounced in patients with elevated baseline lipoprotein levels, as shown in Sahebkar et al. 2017. However, due to the lack of studies specifically designed to investigate this outcome, we were unable to include this endpoint in our statistical analysis.\u003c/p\u003e\u003cp\u003eA major limitation of this meta-analysis is the substantial heterogeneity across the included studies (I\u0026sup2; \u0026gt;80% in most comparisons). Variability in study designs, patient populations, and treatment regimens complicates the interpretation of pooled results. It is possible that the benefits of combination therapy may be more pronounced in specific subgroups, such as those with higher baseline TG or lower HDL-C levels. Future studies should focus on stratifying patients according to these characteristics to better identify which populations are most likely to benefit from dual therapy. Moreover, the relatively short follow-up duration in most of the included studies limits the ability to assess long-term outcomes. Cardiovascular benefits from lipid modifications may take years to manifest, necessitating longer follow-up periods to adequately capture these effects.\u003c/p\u003e\u003cp\u003eAnother critical consideration is the safety of fibrate and statin combination therapy, particularly with regard to potential adverse effects such as hepatotoxicity and myopathy. Although earlier research suggests that these risks are minimal when fenofibrate is used, larger-scale trials should include comprehensive safety assessments, especially in high-risk populations such as older adults or those with comorbidities. The studies in this meta-analysis reported no significant differences in adverse events between combination therapy and statin monotherapy, but the limited data available on safety warrant further investigation (Table\u0026nbsp;3).\u003c/p\u003e\u003cp\u003eDespite these limitations, this meta-analysis offers several strengths. The significant improvements in lipid profiles observed in the combination therapy group underscore the clinical importance of addressing residual dyslipidemia in T2DM patients. For individuals who continue to exhibit elevated TG and low HDL-C levels despite statin therapy, adding a fibrate may represent a viable strategy to further reduce lipid-related cardiovascular risk. Additionally, the findings highlight the potential role of combination therapy in specific high-risk populations, particularly those with atherogenic dyslipidemia.\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eThis This meta-analysis demonstrates that combination therapy with fibrates and statins significantly improves lipid profiles in patients with T2DM, leading to greater reductions in total cholesterol, triglycerides, and LDL-C levels, along with increases in HDL-C, compared to statin monotherapy. These findings underscore the potential utility of dual therapy in addressing residual dyslipidemia, particularly in patients with atherogenic profiles who do not respond adequately to statins alone.\u003c/p\u003e\u003cp\u003eHowever, the clinical relevance of these improvements remains uncertain due to a lack of robust evidence linking combination therapy to reductions in long-term cardiovascular events. The limited number of high-quality, long-term randomized controlled trials focused on cardiovascular outcomes\u0026mdash;and the considerable heterogeneity in existing studies\u0026mdash;highlight the need for more targeted research.\u003c/p\u003e\u003cp\u003eFuture investigations should prioritize longer follow-up periods, stratified analyses by baseline lipid subtypes, and comprehensive safety evaluations. Until such data are available, the routine use of fibrate-statin combination therapy should be considered on a case-by-case basis.\u003c/p\u003e\u003cp\u003eAs the therapeutic landscape for T2DM continues to evolve, particularly with the growing use of cardiometabolic agents such as SGLT2 inhibitors and GLP-1 receptor agonists, the role of lipid-targeted strategies like fibrate-statin combination therapy may need to be reconsidered within a broader, integrated approach to cardiovascular risk management.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eDeclaration of No Funding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eI hereby declare that the research and work presented in the article titled \u0026ldquo;Effect of Fibrate-Statin Combination Therapy on Lipid Profiles in Patients with Type 2 Diabetes: A Systematic Review and Meta-Analysis\u0026rdquo; have been conducted without any financial support or funding from external sources.\u003c/p\u003e\n\u003cp\u003eThis statement is made to affirm the independence and integrity of the research.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthics and Consent to Participate declarations:\u0026nbsp;\u003c/strong\u003enot applicable.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent to Publish declaration:\u003c/strong\u003e not applicable.\u003c/p\u003e\u003ch2\u003eAuthor Contribution\u003c/h2\u003e\u003cp\u003eV.B. drafted the main manuscript text and it's figures. V.B. drafted the methodology under the supervision of J.T., who also reviewed the manuscript.V.B. and A.F. performed the data extraction and analysis, while V.B. and A.L. conducted the study screening. T.S. and J.T. critically reviewed the manuscript. All authors reviewed and approved the final version of the manuscript.\u003c/p\u003e\u003ch2\u003eData Availability Statement:\u003c/h2\u003e\u003cp\u003eThis study did not generate any new data. All data used in this systematic review were secondary and obtained from the studies included in the analysis. The data underlying the findings of this study are available in the respective published articles of the included studies. For access to the data, please refer to the individual publications cited in the manuscript.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eGalicia-Garcia U, Benito-Vicente A, Jebari S, et al. Pathophysiology of Type 2 Diabetes Mellitus. 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BMC Medicine 2017;15(1):22. doi: \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1186/s12916-017-0787-7\u003c/span\u003e\u003cspan address=\"10.1186/s12916-017-0787-7\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"},{"header":"Tables","content":"\u003cp\u003eTables 1 to 3 are available in the Supplementary Files section.\u003c/p\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"Fibrates, Statins, Type 2 Diabetes Mellitus, Systematic Review, Dyslipidemia","lastPublishedDoi":"10.21203/rs.3.rs-7178196/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-7178196/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eThis meta-analysis evaluates the efficacy of combining statins with fibrates for improving lipid profiles in patients with Type 2 Diabetes Mellitus (T2DM). While statin monotherapy is known to effectively modify lipid parameters in T2DM, recent evidence suggests that combination therapy may offer additional benefits in managing lipid levels and reducing cardiovascular risks. A systematic review of randomized clinical trials (RCTs) comparing statin monotherapy to statin-fibrate combination therapy was conducted. Data were sourced from PubMed and Embase, and studies published up to October 2023 were included. A total of 7 RCTs with 1,349 participants met the inclusion criteria. Of these, 676 participants (50%) received combination therapy, with follow-up durations ranging from 3 to 56.4 months. Results showed that combination therapy led to significant reductions in total cholesterol (TC) (-8.65 mg/dL), low-density lipoprotein cholesterol (LDL-C) (-5.52 mg/dL), and triglycerides (TG) (-53.59 mg/dL). Additionally, high-density lipoprotein cholesterol (HDL-C) levels were significantly higher in the combination therapy group (+\u0026thinsp;2.33 mg/dL). The findings suggest that combining statins with fibrates significantly improves lipid parameters in T2DM patients. However, the high heterogeneity among studies indicates the need for further controlled trials to better assess the cardiovascular benefits of this combination therapy and provide more definitive conclusions.\u003c/p\u003e","manuscriptTitle":"Effect of Fibrate-Statin Combination Therapy on Lipid Profiles in Patients with Type 2 Diabetes: A Systematic Review and Meta-Analysis","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-08-18 10:38:08","doi":"10.21203/rs.3.rs-7178196/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"852a35af-f99a-4a61-87dc-50b5a7c3c24f","owner":[],"postedDate":"August 18th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[{"id":53266352,"name":"Health sciences/Cardiology"},{"id":53266353,"name":"Health sciences/Diseases"},{"id":53266354,"name":"Health sciences/Endocrinology"},{"id":53266355,"name":"Health sciences/Medical research"}],"tags":[],"updatedAt":"2025-08-21T16:09:00+00:00","versionOfRecord":[],"versionCreatedAt":"2025-08-18 10:38:08","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-7178196","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-7178196","identity":"rs-7178196","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}