Role of Metformin in the Treatment of Patients with Thyroid Nodules and Insulin Resistance: A Systematic Review and Meta-Analysis

He, Xiaowei; Wu, Dan; Hu, Cao; Xu, Ting; Liu, Yuanxin; Liu, Chao; Xu, Bo; Tang, Wei

doi:10.1089/thy.2017.0707

Cited by 29 publications

(39 citation statements)

References 58 publications

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“…In a recently published meta-analysis study that included 240 patients from three randomized control trials and four prospective studies, metformin treatment caused a decrease in nodular volume, TSH level and improvement in the insulin resistance in these patients (Sui et al 2018). Another very recent meta-analysis, including 189 patients fulfilling the analysis criteria, provided similar conclusions (He et al 2019).…”

Section: Clinical Trialsmentioning

confidence: 75%

The role of an anti-diabetic drug metformin in the treatment of endocrine tumors

Thakur

Daley

Kłubo-Gwieździńska

2019

Journal of Molecular Endocrinology

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Incidence of endocrine cancers is rising every year. Over the last decade, evidence has accumulated that demonstrates the anti-cancer effects of an anti-diabetic drug, metformin, in endocrine malignancies. We performed a literature review utilizing the PubMed, Medline and clinicaltrials.gov databases using the keyword ‘metformin’ plus the following terms: ‘thyroid cancer’, ‘thyroid nodules’, ‘parathyroid’, ‘hyperparathyroidism’, ‘adrenal adenoma’, ‘Cushing syndrome’, ‘hyperaldosteronism’, ‘adrenocortical cancer’, ‘neuroendocrine tumor (NET)’, ‘pancreatic NET (pNET)’, ‘carcinoid’, ‘pituitary adenoma’, ‘pituitary neuroendocrine tumor (PitNET)’, ‘prolactinoma’, ‘pheochromocytoma/paraganglioma’. We found 37 studies describing the preclinical and clinical role of metformin in endocrine tumors. The available epidemiological data show an association between exposure of metformin and lower incidence of thyroid cancer and pNETs in diabetic patients. Metformin treatment has been associated with better response to cancer therapy in thyroid cancer and pNETs. Preclinical evidence suggests that the primary direct mechanisms of metformin action include inhibition of mitochondrial oxidative phosphorylation via inhibition of both mitochondrial complex I and mitochondrial glycerophosphate dehydrogenase, leading to metabolic stress. Decreased ATP production leads to an activation of a cellular energy sensor, AMPK, and subsequent downregulation of mTOR signaling pathway, which is associated with decreased cellular proliferation. We also describe several AMPK-independent mechanisms of metformin action, as well as the indirect mechanisms targeting insulin resistance. Overall, repositioning of metformin has emerged as a promising strategy for adjuvant therapy of endocrine tumors. The mechanisms of synergy between metformin and other anti-cancer agents need to be elucidated further to guide well-designed prospective trials on combination therapies in endocrine malignancies.

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Section: Clinical Trialsmentioning

confidence: 75%

The role of an anti-diabetic drug metformin in the treatment of endocrine tumors

Thakur

Daley

Kłubo-Gwieździńska

2019

Journal of Molecular Endocrinology

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“…Given its vital role in both insulin resistance and thyroid metabolism, the AMPK pathway should be extensively studied as a potential new therapeutic target in T2DM complicated with NAFLD. It is an established fact that metformin, the most widely used antidiabetic drug, attenuates T2DM-induced insulin resistance by acting on the AMPK pathway [ 21 ]. Huang et al found that metformin treatment decreased liver lipid accumulation by inhibiting the expression of ROCK1, leading to the activation of the downstream AMPK pathway [ 11 ].…”

Section: Discussionmentioning

confidence: 99%

Association between Thyroid Function and Nonalcoholic Fatty Liver Disease in Euthyroid Type 2 Diabetes Patients

Huang

Yang

2020

Journal of Diabetes Research

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Thyroid function and type 2 diabetes mellitus (T2DM) are both associated with increased risks of adverse clinical outcomes in nonalcoholic fatty liver disease (NAFLD). Our study is aimed at evaluating the association between thyroid function and NAFLD in T2DM patients with normal thyroid function (euthyroid) and analyzing the potential effects of metformin on the pathological process. Overall, 369 T2DM patients were enrolled between July 2017 and September 2018 and stratified into NAFLD and non-NAFLD groups. Data on age, gender, body mass index (BMI, kg/m2), metformin use, and basal metabolic rate (BMR) were obtained from participants’ records. All patients were tested for biochemical markers, indexes of glucose metabolism, lipid metabolism, bone metabolism, and thyroid function at baseline. Multivariate analyses detected increased odds of NAFLD among individuals with T2DM per unit increase in their BMI and free triiodothyronine (FT3) and thyroid stimulating hormone (TSH); the odds ratios (OR) were 1.25, 3.02, and 1.58, respectively (all p<0.05). Positive correlations were detected between alanine aminotransferase (ALT) and FT3 (r=0.221, p=0.010), and negative correlations were noted between TSH and BMR (r=−0.618, p<0.001) and between BMR and FT3 (r=−0.452, p<0.001) in T2DM subjects with NAFLD. A significant difference in serum FT3 (t=2.468, p=0.0167) and TSH (t=2.658, p=0.010) levels was found between obese individuals with NAFLD who used and did not use metformin. The pathological mechanism of T2DM complicated by NAFLD in euthyroid patients may be associated with insulin resistance and a thyroid hormone resistance-like manifestation, i.e., relevant hypothyroidism. Metformin can potentially decrease the double-resistance situation, especially in obese individuals.

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“…This effect was also found to be stronger in subjects with non‐autoimmune hypothyroidism than in hypothyroidism secondary to autoimmune thyroid disease probably because autoimmune process leads to the destruction of thyroid cells, impairing their secretory function 20 . Recent studies demonstrated that metformin therapy in subjects with insulin resistance significantly decreased also thyroid nodule size 7 . Shrinkage of thyroid nodules was accompanied by a fall in thyrotropin levels and an improvement in insulin sensitivity 21 .…”

Section: What Is Known and Objectivementioning

confidence: 98%

The impact of combination therapy with metformin and exogenous vitamin D on hypothalamic‐pituitary‐thyroid axis activity in women with autoimmune thyroiditis and high‐normal thyrotropin levels

Krysiak

Kowalcze

2020

J Clin Pharm Ther

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What is known and objective Metformin was found to decrease thyrotropin levels in subjects with non‐autoimmune but not with autoimmune hypothyroidism. Vitamin D reduced thyroid autoimmunity without affecting thyrotropin and thyroid hormone levels. The aim of the current study was to investigate whether exogenous vitamin D modulates the impact of metformin on hypothalamic‐pituitary‐thyroid axis activity in young women with autoimmune thyroiditis. Methods This case‐control study included 32 prediabetic women with Hashimoto's thyroiditis, high‐normal thyrotropin levels (2.5‐4.5 mIU/L) and vitamin D insufficiency. Based on patient preference, these individuals received either metformin (3 g daily) plus vitamin D (4000 IU daily) (n = 17) or were treated with only metformin (3 g daily) (n = 15). Plasma levels of glucose, serum levels of insulin, thyrotropin, total and free thyroid hormones and 25‐hydroxyvitamin D, as well as serum titres of thyroid antibodies, were assessed at baseline and 6 months later. Results and discussion Thirty‐one women completed the study. At baseline, there were no differences between the treatment groups. In both study arms, metformin reduced plasma glucose levels and improved insulin sensitivity but this effect was stronger in subjects receiving vitamin D. Only metformin administered with vitamin D decreased thyrotropin levels, increased 25‐hydroxyvitamin D levels and reduced thyroid antibody titres. The impact on thyrotropin and antibody titres correlated with the increase in 25‐hydroxyvitamin D levels and with the improvement in insulin sensitivity. What is new and conclusion This study has shown for the first time that exogenous vitamin D potentiates the impact of metformin on thyrotropin levels in women with autoimmune thyroiditis.

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Role of Metformin in the Treatment of Patients with Thyroid Nodules and Insulin Resistance: A Systematic Review and Meta-Analysis

Cited by 29 publications

References 58 publications

The role of an anti-diabetic drug metformin in the treatment of endocrine tumors

The role of an anti-diabetic drug metformin in the treatment of endocrine tumors

Association between Thyroid Function and Nonalcoholic Fatty Liver Disease in Euthyroid Type 2 Diabetes Patients

The impact of combination therapy with metformin and exogenous vitamin D on hypothalamic‐pituitary‐thyroid axis activity in women with autoimmune thyroiditis and high‐normal thyrotropin levels

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