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Metformin and Triglycerides: A Comprehensive Overview
Introduction to Metformin and Triglycerides
Metformin is widely recognized as a first-line treatment for type 2 diabetes due to its effective antihyperglycemic properties. However, its impact extends beyond glucose regulation, notably influencing lipid metabolism, particularly triglycerides (TG). This article synthesizes current research on how metformin affects triglyceride levels, drawing from various studies to provide a cohesive understanding.
Metformin's Mechanism in Lowering Triglycerides
Enhanced VLDL-Triglyceride Clearance by Brown Adipose Tissue
One of the primary mechanisms by which metformin lowers plasma triglycerides is through the promotion of very low-density lipoprotein (VLDL)-triglyceride clearance. Research conducted on APOE*3-Leiden.CETP mice, a model for human-like lipoprotein metabolism, demonstrated that metformin significantly reduced plasma total cholesterol and TG levels. This reduction was primarily due to enhanced clearance of VLDL-TG into brown adipose tissue (BAT), rather than a decrease in hepatic VLDL-TG production 1. The study highlighted increased activation of BAT, which facilitated greater uptake and intracellular lipolysis of TG, followed by mitochondrial fatty acid oxidation 1.
Reduction of Microsomal Triglyceride Transfer Protein (MTP) Expression
In insulin-resistant OLETF rats, metformin was shown to improve lipid metabolism disorders by reducing the expression of microsomal triglyceride transfer protein (MTP) in the liver. This reduction in MTP expression led to decreased levels of triglycerides and total cholesterol in the treated rats, suggesting that metformin's lipid-lowering effects are partly mediated through this pathway 3.
Clinical Evidence of Triglyceride Reduction
Meta-Analyses and Systematic Reviews
Several meta-analyses and systematic reviews have confirmed the triglyceride-lowering effects of metformin in both diabetic and non-diabetic populations. A comprehensive meta-analysis of randomized controlled trials found that metformin significantly reduced triglycerides, total cholesterol, and low-density lipoprotein (LDL) cholesterol, while also improving insulin resistance and reducing the incidence of new-onset diabetes 5. Another systematic review specifically focusing on type 2 diabetes patients corroborated these findings, showing significant reductions in plasma triglycerides and total cholesterol with metformin treatment 67.
Specific Populations: Gestational Diabetes and PCOS
In women with gestational diabetes mellitus (GDM), metformin treatment was associated with higher increases in maternal plasma triglycerides compared to insulin treatment. This increase was linked to factors such as glucose control and ethnicity, indicating that the triglyceride response to metformin may vary based on individual characteristics 2. Additionally, in non-diabetic adults with polycystic ovarian syndrome (PCOS), metformin significantly reduced triglyceride levels, highlighting its potential benefits in specific subgroups 9.
Timing and Administration of Metformin
The timing of metformin administration can also influence its effect on triglycerides. A pilot study investigating preprandial (before meal) administration of metformin in type 2 diabetes patients found that it significantly reduced postprandial (after meal) plasma triglyceride levels. This effect was attributed to reduced intestinal absorption of triglycerides through delayed gastric emptying 8.
Conclusion
Metformin's ability to lower triglycerides is well-supported by various studies, which highlight its multifaceted mechanisms, including enhanced VLDL-TG clearance by brown adipose tissue and reduced MTP expression in the liver. Clinical evidence further supports its efficacy in reducing triglycerides across different populations, including those with type 2 diabetes, GDM, and PCOS. Understanding these mechanisms and effects can help optimize metformin use for managing dyslipidemia and improving overall metabolic health.
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Most relevant research papers on this topic
Metformin Lowers Plasma Triglycerides by Promoting VLDL-Triglyceride Clearance by Brown Adipose Tissue in Mice
Metformin lowers plasma triglycerides by promoting VLDL-triglyceride clearance from brown adipose tissue in mice, suggesting targeting BAT as a potential future therapeutic strategy for treating dyslipidemia.
Non-RCT
Animal Study
Rigorous Journal
Highly CitedDeterminants of Maternal Triglycerides in Women With Gestational Diabetes Mellitus in the Metformin in Gestational Diabetes (MiG) Study
Maternal triglycerides in women with gestational diabetes are related to glucose control in insulin-treated women and ethnicity in metformin-treated women.
RCT
Large Human Trial
Very Rigorous JournalMetformin improves lipid metabolism disorders through reducing the expression of microsomal triglyceride transfer protein in OLETF rats.
Metformin improves lipid metabolism in insulin-resistant rats by reducing the expression of microsomal triglyceride transfer protein (MTP).
RCTAnimal StudyMeta-analysis: metformin treatment in persons at risk for diabetes mellitus.
Metformin treatment improves weight, lipid profiles, and insulin resistance, and reduces new-onset diabetes by 40% in individuals at risk for diabetes.
Meta-AnalysisHighly CitedThe effect of metformin on blood pressure, plasma cholesterol and triglycerides in type 2 diabetes mellitus: a systematic review
Metformin has a glucose-lowering independent effect on blood pressure and lipid profile in individuals with type 2 diabetes, potentially reducing macrovascular end-points and mortality.
Systematic ReviewHighly CitedThe effect of metformin on blood pressure, plasma cholesterol and triglycerides in type 2 diabetes mellitus: a systematic review.
Metformin has no significant effect on blood pressure, HDL cholesterol, and triglycerides in patients with type 2 diabetes, but significantly reduces total and LDL cholesterol.
Highly CitedEfficacy of metformin on postprandial plasma triglyceride concentration by administration timing in patients with type 2 diabetes mellitus: A randomized cross‐over pilot study
Preprandial metformin administration may effectively reduce postprandial plasma triglyceride levels in patients with type 2 diabetes mellitus by reducing intestinal absorption through delayed gastric emptying.
RCTRigorous JournalEffects of metformin on blood lipid profiles in nondiabetic adults: a meta-analysis of randomized controlled trials
Metformin effectively reduces total cholesterol and LDL-c in nondiabetic adults, with potential triglyceride-lowering effects in nondiabetics with PCOS status.
Meta-AnalysisRigorous JournalMetformin maintains intrahepatic triglyceride content through increased hepatic de novo lipogenesis
Metformin improves insulin sensitivity and promotes weight loss without affecting intrahepatic triglyceride content, partly due to increased hepatic de novo lipogenesis and a lack of change in fatty acid oxidation.
Non-RCTRigorous Journal