Metformin may be associated with low levels of thyroid-stimulating hormone, study finds

Metformin monotherapy may be linked to lower levels of thyroid-stimulating hormone (TSH) compared with sulfonylurea monotherapy in patients with type 2 diabetes, according to a new study.

Researchers used the Clinical Practice Research Datalink (CPRD) to identify 2 subcohorts of patients at least 40 years of age with treated hypothyroidism or euthyroidism who had started monotherapy with metformin or sulfonylurea from Jan. 1, 1988, to Dec. 31, 2012. The CPRD was established in 1987 and includes data from more than 680 practices in the United Kingdom. In each cohort, the researchers examined whether low TSH levels were associated with metformin compared with sulfonylurea. Low TSH levels were defined as those below 0.4 mIU/L. Patients were followed until March 31, 2013, or until a first TSH measurement below 0.4 mIU/L; until thyroid-related drugs were started or modified in euthyroid and treated hypothyroid patients, respectively; until a TSH measurement over 4.5 mIU/L; or until death or the end of registration with the CPRD practice. The study results were published early online Sept. 22 by CMAJ.

Overall, 5,689 hypothyroid patients and 59,937 euthyroid patients were included in the analysis. In the former group, 495 low TSH events were seen during follow-up versus 322 events in the latter group (incidence rates, 119.7/1,000 person-years vs. 4.5/1,000 person-years). Metformin monotherapy was associated with a 55% higher risk for low TSH levels in treated hypothyroid patients compared with sulfonylurea monotherapy (incidence rate, 125.2/1,000 person years vs. 79.5/1,000 person-years; hazard ratio, 1.55; 95% CI, 1.09 to 2.20). Risk for low TSH levels in treated hypothyroid patients was highest in the 90 to 180 days after metformin therapy began (adjusted hazard ratio, 2.30; 95% CI, 1.00 to 5.29), while no association was seen in euthyroid patients (adjusted hazard ratio, 0.97; 95% CI, 0.69 to 1.36).

The authors noted that data on medication use were based on prescriptions and that patient adherence was not known. In addition, TSH measurements in the CPRD were not validated and the study was observational, among other limitations. However, they concluded that although metformin therapy appeared to have no effect on TSH levels in euthyroid patients with type 2 diabetes, it was associated with increased risk for low TSH levels in patients with type 2 diabetes and treated hypothyroidism, especially 90 to 180 days after the start of treatment. “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,” the authors wrote.