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The Mechanism for Metformin's (Glucophage) Improvement in the Lipid Profile Beyond its Glucose Lowering Effects in Diabetes Mellitus

Summary:

  • It is well known that type 2 diabetics may have uncontrolled glucose levels but are known to have dyslipidemia that has been characterized as being an "atherogenic" lipid profile.
  • Treating uncontrolled glucose levels can indirectly improve lipids, in particular TG. 
  • Metformin has been shown to decrease the activity and expression of several products involved in lipid synthesis, such as: acetyl CoA carboxylase, SREBP-1, fatty acid synthase, and HMG CoA reductase.
  • Metformin can decrease the TG's by 10% and LDL-C by 10 to 15% and increase the HDL-C by up to 7% beyond its glucose lowering properties while also contributing to weight lose and having a good history of safety in clinical practice.

Editor-in-Chief: Anthony J. Busti, MD, PharmD, FNLA, FAHA
Reviewers:
Jon D. Herrington, PharmD, BCPS, BCOP and Donald S. Nuzum, PharmD, BCACP, CDE
Last Reviewed: August 2015

Explanation

  • It is well known that patients with type 2 diabetes mellitus (T2DM) are characterized as having central obesity (or increased abdominal visceral fat), hepatic insulin resistance, decreased peripheral insulin mediated glucose uptake (despite elevated insulin levels), excessive or accelerated "basal rates" of hepatic glucose production (or hepatic gluconeogenesis), and abnormal lipid profiles that are considered to be more "atherogenic".1-3

    Unfortunately, several glucose lowering agents (sulfonylureas, thiazolidinediones, and insulin in particular) are also associated with an increase in weight - a problem already implicated in T2DM.  As it relates to cholesterol, many cases show that an improvement in the glucose levels will improve the lipid profile (generally through a reduction in very low density lipoprotein (VLDL) output from the liver since it is directly tied to blood glucose levels).2-4  However, not all glucose lowering medications have a beneficial and direct effect on the lipid profile beyond their glucose lowering properties.2,4  Given the characterization of most type 2 diabetics, any intervention that could not only significantly improve glucose control, but that would also cause weight loss or at least not weight gain, have a good history of safety, and improve the lipid profile beyond the glucose lowering properties would be ideal.  Fortunately, metformin is the only cost-effective, oral glucose lowering agent that meets all of these criteria.2,3,5-8 

    How does metformin improve cholesterol levels beyond its glucose lowering properties?
    Metformin can activate an upstream primary kinase called LKB1.9  LKB1 then phosphorylates and activates AMP-activated protein kinase (AMPK) which can then affect the transcription (production) of several key regulators of liver lipid production (lipogenesis) and hepatic gluconeogenesis.9,10  The first regulation of lipogenesis is a reduction in the expression and activity of sterol regulatory element binding protein-1 (SREBP-1) which leads to two beneficial effects on lipids.  One effect is a reduced expression of the enzyme fatty acid synthase, which leads to a reduction in fatty acid synthesis.  These are both essential steps in the formation of triacylglycerols (also known as triglycerides (TG)) that make up the majority of VLDL being produced by the liver.10  Another effect is the  phosphorylation of 3-hydroxy-3-methyl-glutary;-CoA reductase (HMG CoA Reductase) which reduces its cholesterol synthesis capabilities.3,11  The second regulation of lipogenesis is a phosphorylation of acetyl CoA carboxylase thereby inhibiting its activity.  As a result, malonyl CoA levels are reduced leading to a reduction in fatty acid synthesis (need for TG production) and an enhancement of fatty acid oxidation.10

                     Metfomin Mechanism for Lipid Lowering Effects

    Therefore, metformin improves the lipid profile beyond its glucose lowering effects by reducing triglyceride and cholesterol synthesis.  Metformin is known to reduce triglycerides (TG) by about 10% and low density lipoprotein cholesterol (LDL-C) by 10 to 15% and increase high density lipoprotein cholesterol (HDL-C) up to 7%.2,5,6,7,12,13  Given the level of difficulty in getting type 2 diabetics to their patient specific glucose and lipid goals, any additional beneficial effect can be helpful, especially when further weight gain can be avoided.

    References:

    1. Monnier L, Colette C, Owens DR.  Type 2 diabetes: a well-characterised but suboptimally controlled disease.  Can we bridge the divide?  Diabetes Metab  2008;34(3):207-16.   
    2. DeFronzo RA.  Pharmacologic therapy for type 2 diabetes mellitus.  Ann Intern Med  1999;131(4):281-303. 
    3. Leiberman M, Marks AD, eds.  Mark's Basic Medical Biochemistry A Clinical Approach.  3rd Ed.  Philadelphia, PA: Lippincott Williams & Wilkins; 2009:479-566.
    4. Jeppesen J, Zhou MY, Chen YD et al. Effect of glipizide treatment on postprandial lipaemia in patients with NIDDM. Diabetologia  1994;37(8):781-7.  
    5. Bristol-Myers Squibb Co.  Glucophage (metformin hydrochloride) package insert. Princeton, NJ; August 2008.  Link obtained on 11/24/2008. 
    6. DeFronzo RA, Goodman AM.  Efficacy of metformin in patients with non-insulin-dependent diabetes mellitus.  The Multicenter Metformin Study Group.  N Engl J Med 1995;333:541-9.   
    7. Cusi K, Consoli A, DeFronzo RA.  Metabolic effects of metformin on glucose and lactate metabolism in noninsulin-dependent diabetes mellitus.  J Clin Endocrinol Metab 1996;81:4059-4067.   
    8. Nathan DM, Buse JB, Davidson MB et al.  Management of hyperglycemia in type 2 diabetes: a consensus algorithm for the initiation and adjustment of therapy: a consensus statement from the American Diabetes Association and the European Association for the Study of Diabetes.  Diabetes Care  2009;32(1):193-203. 
    9. Shaw RJ, Lamia KA, Vasquez D et al. The kinase LKB1 mediates glucose homeostasis in liver and therapeutics effects of metformin.  Science  2005;310(5754):1642-1646.  
    10. Zhou G, Myers R, Li Y et al.  Role of AMP-activated protein kinase in mechanism of metformin action.  J Clin Invest  2001;108:1167-1174.  
    11. Clarke PR, Hardie DG.  Regulation of HMG-CoA reductase: identification of the site phosphorylated by the AMP-activated protein kinase in vitro and in intact rat liver.  EMBO J  1990;9:2439-46.   
    12. DeFronzo RA, Barzilai N, Simonson DC.  Mechanism of metformin action in obese and lean noninsulin-dependent diabetics subjects.  J Clin Endocrinol Metab  1991;73(6):1294-301.     
    13. Jeppesen J, Zhou MY et al. Effect of metformin on postprandial lipemia in patients with fairly to poorly controlled NIDDM.  Diabetes Care  1994;17(10):1093-9.

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MESH Terms & Keywords

  • Metformin, Glucophage, Type 2 Diabetes Mellitus, Metformin Lipid Lowering Effects