C l i n i c a l C a r e / E d u c a t i o n / N u t r i t i o n / P s y c h o s o c i a l R e s e a r c h
TSH-Lowering Effect of Metformin in
Type 2 Diabetic Patients
Differences between euthyroid, untreated hypothyroid, and euthyroid on
L-T4 therapy patients
METHODS — A pilot study was con-
tution (average dose 89.8 Ϯ 11.5 ␮g/day) MBERTO VALENTINI, MD
to examine the short- to mid-term (up to24 weeks) effects of metformin adminis-tration. Serum TSH, free T4 (FT4), free T3 OBJECTIVE — To assess the interplay between metformin treatment and thyroid function in
(FT3), total T4 (TT4), and total T3 (TT3) were measured at baseline and 6, 24, and72 h after starting metformin treatment, RESEARCH DESIGN AND METHODS — The acute and long-term effects of met-
as well as after 3 and 6 months of therapy.
formin on thyroid axis hormones were assessed in diabetic patients with primary hypothyroid-ism who were either untreated or treated with levothyroxine (L-T4), as well as in diabetic patients larger cohort of diabetic patients including29 euthyroid patients on L-T4 substitution RESULTS — No acute changes were found in 11 patients with treated hypothyroidism.
(group I), 18 subclinical hypothyroid pa- After 1 year of metformin administration, a significant thyrotropin (TSH) decrease (P Ͻ tients who did not receive L-T4 treatment 0.001) was observed in diabetic subjects with hypothyroidism who were either treated (n ϭ 29; from 2.37 Ϯ 1.17 to 1.41 Ϯ 1.21 mIU/l) or untreated (n ϭ 18; 4.5 Ϯ 0.37 vs. 2.93 Ϯ 1.48) with L-T4, but not in 54 euthyroid subjects. No significant change in free T4 (FT4) was clinical history, physical examination, mea- CONCLUSIONS
— Metformin administration influences TSH without change of FT4 in patients with type 2 diabetes and concomitant hypothyroidism. The need for reevaluation of and TPO-Ab, as well as thyroid ultrasonog- thyroid function in these patients within 6 –12 months after starting metformin is indicated.
raphy (group III). Type 2 diabetes was di-agnosed in accordance with American Diabetes Care 32:1589–1590, 2009
Metforminisawidelyuseddrugfor blelevothyroxine(L-T4)treatment(6,7). senttothestudy,whichwasperformedin
However, no data are available for untreated hypothyroid patients or for euthyroid dia- safe drug in that no clinically relevant phar- macologic interactions have been described when it is prescribed together with the most rences in diabetic patients (8), we aimed to further characterize the interplay between metformin and circulating thyroid function measures analysis (SPSS version 13; SPSS, formin is able to interfere with thyroid hor- Evanston, IL). A P value Ͻ0.05 was con- mone profile, as shown by a decrease in the axes in different categories of patients who serum levels of thyrotropin (TSH) to sub- were started on metformin because of a first normal levels in hypothyroid patients in sta- ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● From the 1Internal Medicine and Endocrinology Unit, Department of Medical and Surgical Sciences, Uni- versity of Brescia, Brescia, Italy; the 2Unit of Internal Medicine and Endocrinology, Fondazione Salvatore Maugeri Istituto di Ricovero e Cura a Carattere Scientifico, Istituto Superiore Prevenzione e Sicurezza and TT3 observed throughout the study.
Lavoro Laboratory for Endocrine Disruptors, University of Pavia, Pavia, Italy; and the 3Diabetic Unit, Spedali Civili di Brescia, Brescia, Italy.
Corresponding author: Carlo Cappelli,
Received 13 February 2009 and accepted 30 May 2009.
Published ahead of print at on 5 June 2009. DOI: 10.2337/dc09-0273.
2009 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered. See http://creativecommons.
org/licenses/by-nc-nd/3.0/ for details.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. DIABETES CARE, VOLUME 32, NUMBER 9, SEPTEMBER 2009 TSH-lowering effect of metformin
Table 1—Demographic, drug treatment, and thyroid function data in the three groups of
abetic patients with hypothyroidism, both diabetic subjects
with L-T4 therapy and untreated, is associ-ated with a significant reduction in the se-rum levels of TSH, with no change in FT4.
Group III
No effect is detectable in patients with an intact pituitary-thyroid axis. A major clini- cally relevant consequence of our findings is within 6 –12 months after starting met- formin seems necessary in diabetic patients Acknowledgments — No potential conflicts of
interest relevant to this article were reported.
Noncategorical data are means Ϯ SD. Between-group differences: *P Ͻ 0.001 for group I vs. group III.
Within-group differences: †P Ͻ 0.001 for on treatment vs. baseline.
10.7 to 10.2 ␮g/dl), and TT3 (from 1.07 in this patient led to an increase of TSH 2. Schwartz S, Fonseca V, Berner B, Cramer level, which returned to the baseline (pre- M, Chiang Y-K, Lewin A. Efficacy, tolera- in diabetic patients may be dual: Although bility, and safety of a novel once-daily ex- no effect is detectable in patients with a nor- tended-release metformin in patients with Clinical characteristics and most relevant changes do occur in patients with an under- 3. Scheen AJ. Drug interactions of clinical im- data in the three groups of patients are sum- lining thyroid deficiency, both with L-T4 marized in Table 1. A significant decrease of therapy and untreated. This is a clinically TSH levels after 1 year of metformin treat- relevant observation, especially when con- 4. Stocker DJ, Vigersky RA. The effects of ment was observed in group I and group II sidering that hypothyroidism occurs in 10 – subjects but not in group III subjects. In detail, mean TSH level was significantly re- duced after 1 year on metformin in group I, (Abstract). Abstract book of the 87th An- 1.41 Ϯ 1.21 (P Ͻ 0.001). Furthermore, six formin lowers TSH level is still unclear, and patients in this group (20.7%) showed a se- the design of the present study does not al- 5. Wulffele MG, Kooy A, Lehert P, Bets D, Og- terop JC, Borger van der Burg B, Donker AJ, Stehouwer CD. Effects of short-term treat- the present data would exclude biological interferences of metformin with the TSH as- tions of homocysteine, folate and vitamin group II was 4.5 Ϯ 0.37 mIU/l and signif- B12 in type 2 diabetes mellitus: a random- icantly decreased to 2.93 Ϯ 1.48 after 1 gastrointestinal tract, or any influence of ized, placebo-controlled trial. J Intern Med year of metformin (P Ͻ 0.001); TSH re- 6. Vigersky RA, Filmore-Nassar A, Glass AR.
in individual patients of this group. Se- Thyrotropin suppression by metformin.
modulation of thyroid hormones on central 7. Isidro ML, Penín MA, Nemin˜a R, Cordido modify circulating FT3 or TSH levels when the closed-loop control system is normally CONCLUSIONS — The results of this
functioning, but may well explain the re- study showed that 1) the initiation of treat- duction of circulating TSH levels observed ment therapy. Endocrine 2007;32:79 – 82 ment with metformin was associated with a in subjects with altered thyroid-hypophy- significant reduction in the serum levels of seal feedback. Another explanatory hypoth- TSH in diabetic patients with primary hy- esis could be that metformin ameliorates the thyroid function reserve in those patients therapy and untreated; 2) TSH reduction was not associated with reciprocal changes treated. Future studies will be needed to in any other thyroid function parameter; 3) fully elucidate the mechanisms of the here- and Classification of Diabetes Mellitus. Re- port of the Expert Committee on the Diag- veloped slowly and was detectable after a few months of treatment; and 4) metformin had no effect on circulating thyroid func- show that metformin administration in di- DIABETES CARE, VOLUME 32, NUMBER 9, SEPTEMBER 2009


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