Metformin May Lower TSH Levels in Those With Hypothyroidism

Miriam E. Tucker

September 26, 2014

Metformin use was associated with a reduction in thyroid-stimulating hormone (TSH) levels among patients with type 2 diabetes who also had treated hypothyroidism, a new large database analysis finds.

The results were published online September 22, 2014 in CMAJ by Jean-Pascal Fournier, MD, PhD, and colleagues at McGill University and Jewish General Hospital, Montreal, Quebec.

The study, from a UK general practice database comprising more than 74,000 patients, found a 55% increased risk for low TSH levels (below 0.4 mIU/L) among patients with treated hypothyroidism who were taking metformin monotherapy compared with those taking sulfonylurea monotherapy, but the same association was not seen among type 2 diabetes patients with normal thyroid function.

The clinical consequences of low TSH induced by metformin aren't clear, the authors say.

Subclinical hyperthyroidism is a theoretical concern, but a previous small study didn't find the expected changes in heart rate or electrocardiographic parameters among patients who developed low TSH while taking metformin, Dr. Fournier and colleagues note.

Nonetheless, "given the relatively high incidence of low TSH levels observed in our study in patients receiving metformin, there is a need for further research to determine the short- and long-term clinical consequences of this biochemical event, the necessity of monitoring TSH levels when starting metformin, and the appropriateness of adapting levothyroxine doses when low TSH levels are observed in patients starting metformin," they write.

Effect Strongest at 90 to 180 Days

The investigators initially looked at a total 74,300 patients who were at least 40 years of age and had begun receiving either metformin or sulfonylurea monotherapy between 1988 and 2012. Of those, 5689 had treated hypothyroidism and 59,937 were euthyroid.

Over a year, low TSH levels were recorded 495 times in the treated hypothyroid group (incidence 119.7/1000 person-years), compared with 322 times in the euthyroid group (4.5/1000 person-years). There were 445 low-TSH events in the metformin group (125.2/1000) and 40 among those taking a sulfonylurea (79.5/1000).

The adjusted hazard ratio (HR) for low TSH levels for metformin users vs sulfonylurea users was a significant 1.55 overall. The difference was not significant during the first 90 days (HR, 1.73) but increased significantly after 90 to 180 days of use (HR, 2.3) and returned to nonsignificance after 180 days (HR, 1.29).

In contrast, this effect of metformin was not seen in the euthyroid group, with an adjusted hazard ratio for low TSH of 0.97 compared with sulfonylurea use.

The exact biological mechanisms explaining the TSH-lowering properties are unclear, but metformin does activate adenosine 5'-monophosphate-activated kinase (AMPK) in the periphery and has been shown to inhibit hypothalamic AMPK, which is involved in the regulation of the thyrotropin-releasing-hormone–TSH axis, the researchers explain.

Other proposed mechanisms include modification of thyroid-hormone–receptor affinity, thyroid-hormone binding, bioavailability and metabolism, induced constitutive activation of the TSH receptor, and interference with the TSH assay.

"Given the relatively high incidence of low TSH levels in patients taking metformin, it is imperative that future studies assess the clinical consequences of this effect," Dr. Fournier and colleagues conclude.

CMAJ. Published online September 22, 2014. Article


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