A longitudinal population based study conducted by Jean-Pascal Fournier Phd, Huiyin Msc, Laurent Azoulay Phd, published in Canadian Medical Association Journal showed that Metformin may not be suitable for patients with hypothyroidism.
Diabetes Mellitus type 2: also known as non-insulin dependent diabetes melliutus is a metabolic disorder which is characterized by hyperglycemia and is a consequence of inadequate insulin secretion, resistance to insulin action and increased or inappropriate secretion of glucagon. It can lead to health complications like cardiovascular risks, lipid abnormalities, increased risk of lower limb amputation, kidney failures, frequent infections, cognitive dysfunction.
Hypothyroidism: the deficiency of the thyroid hormone leads to an endocrine disorder called hypothyroidism. The cause could be primary, secondary or tertiary. Primary… inability of thyroid glands to produce adequate amounts of the hormone. Secondary… where thyroid gland is normal but is receiving insufficient stimulus due to the low levels or reduced secretion of thyrotropin which behaves as a thyroid stimulating hormone (TSH). Tertiary… lessened amount of secretion of thyrotropin releasing hormone (TRH) from the hypothalamus results in the reduced release of thyroid stimulating hormone which finally results in insufficient thyroid stimulation.
Metformin: is an anti diabetic agent belonging to biguanides class, used as a monotherapy or with sulfonylurea to treat type 2 diabetes mellitus.
Metformin reduces the blood glucose levels by decreasing the glucose production in liver and by reducing the absorption of glucose from GIT as well as increasing the sensitivity to insulin receptors, but some older researches have raised the questions whether metformin is actually decreasing the TSH levels in the body and these studies led to the newer ones as described below.
Objective: was to find out if the risk of low TSH levels (<0.4mIU/L) is present with the use of metformin monotherapy when compared to the sulfonylurea monotherapy.
Method: the Clinical Practice Research Data-link (CPRD) was used for the study. CPRD is involved in registering information on diagnoses, referrals, life style habits, prescriptions. CPRD was helpful in distinguishing the patients who were on metformin monotherapy or sulfonylurea monotherapy between January 1 1988 and December 31 2012.
A base cohort was established which incorporated patients at least of 40 years of age and were on metformin or sulfonyl monotherapies. Those patients were included in the study who had a medical record in CPRD for minimum of 1 year and were not receiving any other anti diabetic medicines at any time before these first prescriptions. Along with these parameters, patients who had also undergone TSH levels testing at least once in the year before cohort entry were finally selected.
Patients were then disintegrated into 2 sub-cohorts… with treated hypothyroidism and euthyroidism (normal thyroid functioning) and these groups were observed and studied till March 31 2013. Hypothyroidism group had total 5689 patients while euthyroid group constituted of 59937 patients.
Results of the study: during the follow up it was seen that 495 patients of hypothyroidism developed low TSH levels with incidence rate being 119.7/1000 person-years and in the euthyroid batch, 322 were observed with low TSH levels, incidence rate being 4.5/1000 person-years. When the results from metformin therapy were compared with sulfonylurea’s therapy, metformin showed 55% increased risk of low TSH levels in patients with treated hypothyroidism and presented with greatest risk within 90-180 days after the commencement of the metformin therapy. Euthyroid group revealed no association.
Metformin is responsible for lowering the TSH levels in patients who have been previously treated for hypothyroidism but not in euthyroid patients. Researchers also warned that low TSH levels can lead to broken bones and cardiac problems but the study did not provide any cause and effect link. The researchers believe that further investigation is required for the ascertaining these effects
Limitations of the study:
- The data involved records of prescriptions by physicians but the absolute certainty of patients following or adhering to their treatment was lacking. However, researchers stated that prescription renewals are good markers or indicators of therapy adherence.
- TSH measurements were not verified and only data/record from the lab testing ordered by general practitioners was present.
- The tests were also not conducted frequently during the study making it difficult to evaluate the connection between metformin and levels of triiodothyroxine and thyroxine.
According to Dr. Azoulay, the results of this study have given a clear cut picture of the use of metformin involved in increasing the risks of low TSH in patients with treated hypothyroidism.
Mechanism involved in reducing TSH: how metformin lowers the TSH levels in the body is still debatable and has not been properly identified yet but certain hypothesis are present. Following could be the role playing factors;
- metformin in periphery is an adenosine 5 monophosphete activated kinase (AMPK) activator but behaves as an inhibitor of hypothalamic AMPK which is believed to be involved in regulating thyrotropin releasing hormone.
- change in number of TSH receptors.
- change in affinity to TSH receptors.
- direct action of metformin on TSH regulatory mechanism.
- increase in central dopaminergic tone.
Dr Azoulay, ” given the relatively high incidence of low levels of TSH in patients taking metformin, it is crucial to conduct future studies to assess the clinical consequences of these effects.”
According to Dr Minisha Sood, endocrinologist at Lenox Hill Hospital NY, it is not yet clear whether this low TSH levels caused by metformin can lead patients to the danger of developing other health complications such as CVS diseases. So, further studies are highly required at this time.
According to Dr Gerald Bernstein, director of diabetes management at Friedman diabetes Institute NY city, this study poses a question that requires detailed answer that whether these reduced amounts of TSH are of any clinical significance or have any impact clinically?
Conclusion: Metformin is widely used for the treatment of patients suffering from diabetes mellitus type 2 and the involvement of this drug in reducing the thyroid stimulating hormone to dangerously low digits requires more intense studies to discover whether these effects are serious enough and clinically significant enough to change the recommending protocols of this agent in patients with hypothyroidism.
Patients on metformin should visit their endocrinologists periodically and should have their tests to keep track of their T4, T3 & TSH levels.
- CMAJ September 2014
- US Pharmacist.