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Metformin seemed to further diminish levels of thyroid-stimulating hormone (TSH) in diabetic patients who were already being treated for hypothyroidism, researchers found.

In an analysis of data from a longitudinal cohort, hypothyroid patients with type 2 diabetes had a 55% increased risk of having low TSH levels compared with hypothyroid diabetic patients who were taking a sulfonylurea instead, , of McGill University in Montreal, and colleagues

On the other hand, the association wasn't seen in diabetic patients who had normal thyroid function when they started getting diabetes treatment, they said.

Smaller, cross-sectional studies have suggested that metformin may lower TSH levels, especially in patients who have both diabetes and hypothyroidism when they start treatment.

To further explore the association, Azoulay and colleagues looked at data from the Clinical Practice Research Datalink, which tracks some 13 million patients at 680 practices in the U.K., for patients who started metformin or sulfonylurea between 1988 and 2012.

Among these patients, 59,937 had normal thyroid function, while 5,689 were being treated for hypothyroidism.

They found a significantly increased risk of low TSH levels among patients being treated for hypothyroidism if they were given metformin compared with sulfonylurea (adjusted HR 1.55, 95% CI 1.09- 2.20). The incidence rate of low TSH levels was 125.2 per 1,000 person-years with metformin compared with 79.5 per 1,000 person-years with sulfonylureas.

The highest risk of low TSH levels with metformin occurred in the 90 to 180 days after starting on the drug, they found (HR 2.30, 95% CI 1.00-5.29).

Azoulay and colleagues noted that they didn't see any of these associations among diabetic patients with normal thyroid function (adjusted HR 0.97, 95% CI 0.69-1.36).

The biological mechanisms linking metformin and low TSH aren't clear, the authors explained. Metformin may inhibit AMP kinase activity in the hypothalamus, which helps regulate the thyrotropin-releasing hormone/TSH axis. Or it may have something to do with modification of thyroid hormone receptor affinity or with thyroid hormone binding, bioavailability, and metabolism.

A digestive interaction with levothyroxine isn't likely, they added, given that metformin's TSH-lowering effect has also been described in patients with untreated hypothyroidism.

Azoulay said more study is needed to determine both the short- and long-term clinical consequences of a potential interaction, the need for monitoring TSH levels when starting metformin, and the appropriateness of adapting levothyroxine doses when low TSH levels are seen in these patients.

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