Metformin and Levothyroxine Interaction: What Patients and Clinicians Need to Know

What does the metformin label say about thyroid drugs?

Metformin is an oral biguanide used for type 2 diabetes, and its drug interaction table is short. It lists carbonic anhydrase inhibitors such as topiramate; drugs that reduce metformin clearance through OCT2 and MATE transporters (ranolazine, vandetanib, dolutegravir, cimetidine); alcohol; insulin and insulin secretagogues; and a group of drugs that affect glycemic control [2].

Thyroid products are one of the named examples in that last group. The label's instruction is to observe the patient closely for loss of blood glucose control when such a drug is given, and closely for hypoglycemia when it is withdrawn [2]. Levothyroxine is not listed as a drug that reduces metformin clearance [2].

What do the levothyroxine product labels say?

Levothyroxine sodium is synthetic T4 used for thyroid hormone replacement, and the administration instructions are written per product [1]. For Synthroid tablets and Tirosint capsules, the label directs a single daily oral dose on an empty stomach, one-half to one hour before breakfast, and at least 4 hours before or after drugs known to interfere with absorption [1]. Tirosint-SOL, the oral solution, is taken on an empty stomach 15 minutes before breakfast, with the same 4-hour rule [1].

Those labels name the drugs that interfere with absorption and what to do about each: calcium carbonate and ferrous sulfate at least 4 hours apart; bile acid sequestrants and ion exchange resins, with levothyroxine given at least 4 hours before them or with TSH monitoring; antacids, sucralfate and proton pump inhibitors with monitoring rather than a fixed time gap; and orlistat with thyroid function monitoring [1]. Certain foods (soybean flour, cottonseed meal, walnuts, dietary fiber and grapefruit juice) can bind, delay or reduce absorption [1]. Metformin is not one of the drugs named in those lists [1].

How strong is the evidence for the absorption warnings?

The evidence for levothyroxine's absorption interactions comes from small, mostly uncontrolled studies of other drugs. In an uncontrolled study of 20 adults with hypothyroidism, taking 1,200 mg a day of elemental calcium as calcium carbonate with levothyroxine for 3 months raised mean TSH from 1.6 to 2.7 mIU/L, and TSH returned to 1.4 after the calcium stopped [4]. In 14 patients, ferrous sulfate 300 mg daily taken with thyroxine for 12 weeks raised mean TSH from 1.6 to 5.4 mU/L, and nine patients had more hypothyroid symptoms [5]. In 10 patients taking thyroxine, omeprazole raised TSH in all of them, an effect reversed by a 37% dose increase [6].

The 4-hour spacing rule in the levothyroxine labels applies to the drugs those labels name, and metformin is not among them [1].

Do the two drugs need to be taken at different times?

For Synthroid tablets and Tirosint capsules, the label directs levothyroxine on an empty stomach, one-half to one hour before breakfast; Tirosint-SOL is taken 15 minutes before breakfast [1]. Metformin immediate-release is taken with meals, starting at 500 mg twice daily or 850 mg once daily, up to a maximum of 2,550 mg a day [2]. Extended-release metformin is taken once daily with the evening meal and swallowed whole [3]. Neither label sets a specific waiting period between levothyroxine and metformin [1][2].

Blood sugar is where the labels actually meet

Levothyroxine's labeling states that thyroid hormones may worsen glycemic control [1]. Metformin's label lists thyroid products among the drugs that tend to produce hyperglycemia and may lead to loss of glycemic control. It says to observe patients closely for loss of blood glucose control while such a drug is given, and for hypoglycemia when it is withdrawn [2].