By Rahul Gupta, MD, MPH, FACP
Clinical Assistant Professor, West Virginia University School of Medicine, Charleston, WV
Dr. Gupta reports no financial relationships relevant to this field of study.
SYNOPSIS: In a longitudinal population-based study, metformin use was associated with an increased incidence of low thyroid-stimulating hormone (TSH) levels in patients with treated hypothyroidism.
SOURCE: Fournier JP, et al. Metformin and low levels of thyroid-stimulating hormone in patients with type 2 diabetes mellitus. CMAJ 2014;186:1138-1145.
In clinical practice, type 2 diabetes mellitus and hypothyroidism are among the most prevalent medical conditions encountered. While thyroid-stimulating hormone (TSH) testing is commonly utilized in both the diagnosis and management of hypothyroidism, metformin is an oral hypoglycemic biguanide that is often the first choice for oral treatment of type 2 diabetes when no contraindications exist. In recent years, some data have suggested that metformin may affect the thyroid profile in patients with type 2 diabetes.1,2 Specifically, studies suggest that the use of metformin may lower TSH levels in patients with diabetes and hypothyroidism. The reductions in TSH levels may even fall below the reference range, in which case, patients may develop risks associated with subclinical hyperthyroidism.3 Since metformin is commonly utilized in type 2 diabetics with hypothyroidism, it is importanta to evaluate the extent of this problem in clinical practice to determine whether it is clinically relevant.
In their research, Fournier et al conducted a large population-based study to determine whether the use of metformin monotherapy, when compared with sulfonylurea monotherapy, is associated with an increased risk of low TSH levels (< 0.4 mIU/L) in patients with treated hypothyroidism or euthyroidism and type 2 diabetes. Utilizing a United Kingdom general practice database, investigators identified patients with type 2 diabetes who had begun receiving either metformin or sulfonylurea monotherapy between 1988 and 2012 and divided them in two cohorts of 5689 treated hypothyroid patients and 59,937 euthyroid patients. Adjusted Cox proportional hazards models were used to estimate the hazard ratio (HR) of the association of low TSH level (< 0.4 mIU/L) and initiation of metformin, compared to sulfonylureas.
Researchers found that over 1 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). Therefore, compared with sulfonylurea monotherapy, metformin monotherapy was associated with a 55% increased risk of low TSH levels in patients with treated hypothyroidism (HR, 1.55; 95% confidence interval [CI], 1.09-2.20), with the highest risk in the 90-180 days after initiation (HR, 2.30; 95% CI, 1.00-5.29). No association was observed in euthyroid patients (HR, 0.97; 95% CI, 0.69-1.36).
This study supports the previous studies that the use of metformin is associated with an increased risk of low TSH levels in patients with treated hypothyroidism, with the highest risk observed in the first 180 days after treatment initiation. However, metformin did not appear to have any significant effects on TSH levels in euthyroid patients.
COMMENTARY
This study in a clinical practice setting not only found a relatively high incidence of low TSH levels in treated hypothyroid patients receiving metformin but also found that this risk increases to 2.3 times when patients continue to be treated for type 2 diabetes with metformin beyond the first 3 months. While the exact biological mechanisms explaining the TSH-lowering properties may be unclear, experts hypothesize that the mechanism of action for metformin on the thyrotropin releasing hormone–TSH axis may be complex and multifactorial.4, 5 Metformin may impact the affinity or the number of thyroid hormone receptors or both. It may also increase the central dopaminergic tone or may directly act on TSH regulation, thus enhancing the effect of thyroid hormones on the pituitary gland. Finally, metformin may also inhibit the adenosine 5’-monophosphate-activated kinase (AMPK) activity in the hypothalamus, leading to the inhibitory modulation of thyroid hormones on TSH secretion.
Certainly, further research needs to be conducted in this area as well to further assess the clinical consequences of low TSH levels induced by metformin.
Nevertheless, these findings raise a concern for the short- and long-term clinical consequences of these types of metabolic changes and perhaps may support additional monitoring of TSH levels when starting metformin. Until further research is conducted, this type of monitoring would allow more appropriate adjustments of the levothyroxine doses when lower TSH levels begin to be observed in clinical practice.
REFERENCES
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Oleandri SE, et al. J Endocrinol Invest 1999;22:134-40.
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Lupoli R, et al. J Clin Endocrinol Metab 2014;99: E143-E148.
- Cappelli C, et al. Eur J Endocrinol 2012;167:261-265.
- Vigersky RA, et al. J Clin Endocrinol Metab 2006;91:225-227.
- López M, et al. Nat Med 2010;16:1001–1008.
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