Important Drug Interactions for the Type 2 Diabetes Drug Metformin

Patients taking metformin (FORTAMET, GLUMETZA and generics) should be aware that it has clinically important and potentially dangerous interactions with many other medications.

Metformin was approved by the Food and Drug Administration (FDA) in 1995 for use in combination with diet and exercise to control blood sugar in patients with type 2 diabetes.[1] It is recommended as the first-line treatment for patients with type 2 diabetes who are not able to control their blood sugar through diet and exercise alone. Metformin is one of the most effective drugs for lowering blood sugar, with relatively few adverse effects.[2]

However, metformin can cause a serious condition called lactic acidosis. Lactic acidosis (a buildup of lactic acid in the blood) can cause hypothermia (low body temperature), hypotension (low blood pressure), an abnormally slow heart rate and even death. For this reason, the FDA required a black-box warning (the most prominent warning that the agency can require) on the drug’s product labeling, and Public Citizen’s Health Research Group has designated metformin as a Limited Use drug.[3]

Dangerous drug interactions

The way metformin affects the body depends on several drug transporter proteins. These transporters play key roles in processes such as the absorption, elimination and distribution of drugs in the body.[4],[5],[6] When other drugs that are taken concomitantly (at the same time) with metformin block or use the same transporters as metformin, the safety and effectiveness of these drugs can be altered or lead to an accumulation of metformin in the body. Examples of such interactions include dofetilide (TIKOSYN and generics), a heart rhythm drug; tafenoquine (ARAKODA, KRINTAFEL) for the prevention or treatment of malaria; and trimethoprim (generic only), an antibiotic.[7],[8] Some drugs can reduce the elimination of metformin to such a degree that the increased blood concentrations of the drug can lead to a higher risk of lactic acidosis.

Increased risk of lactic acidosis

The onset of metformin-associated lactic acidosis is often subtle, with nonspecific symptoms such as malaise (a general feeling of discomfort or illness), muscle pain, trouble breathing, sleepiness and abdominal pain.[9] Although lactic acidosis is rare, it is a potentially fatal adverse reaction.

Metformin should not be used in patients with severe kidney impairment because they are at greatest risk of lactic acidosis.[10] Other risk factors include an age of 65 or older, exposure to injected dyes sometimes used to enhance medical images, undergoing surgery and other procedures including dental surgery, excessive alcohol intake and concomitant use of certain other drugs.[11] These medications include antiepileptic drugs, antiretrovirals and stomach-acid–suppressing drugs (see Table below, for examples).

Table. Examples of Oral Drugs That May Increase the Risk of Lactic Acidosis When Taken Concomitantly With Metformin[12]

Designated as Limited Use for epilepsy by Worst Pills, Best Pills News
**Designated as Do Not Use for migraine prevention by Worst Pills, Best Pills News

Increased risk of hyperglycemia or hypoglycemia

Concomitant use of several other medications with metformin can increase a patient’s risk of hyperglycemia (high blood sugar) or hypoglycemia (low blood sugar) and may lead to loss of glycemic control.[15] Such drugs include some diuretics (so-called water pills), medications for thyroid disease, oral contraceptives and calcium channel blockers. Specifically, risk of hyperglycemia is increased with concomitant use of the antiseizure medication phenytoin (DILANTIN, PHENYTEK and generics) and the calcium channel blocker verapamil (VERELAN and generics). Examples of drugs that can increase the risk of hypoglycemia include abiraterone (YONSA, ZYTIGA and generics), a drug for androgen-dependent prostate cancer; the antimalarial drug chloroquine (generic only)[16]; the antibiotic drug isoniazid (generic only); and sotagliflozin (INPEFA), a diabetes drug.[17]

Importantly, the concomitant use of other diabetes medications, such as insulin, also can increase the risk of hypoglycemia.

What You Can Do

If you need treatment with metformin, review all your other medications with your clinician to identify potentially significant drug interactions. If you are taking a medication that interacts with metformin, your clinician may recommend stopping or adjusting the dosage of the interacting drug or of metformin or may advise you to take another drug. Be aware that drugs not listed in this article also may have dangerous interactions with metformin.
 

References

[1] Teva Pharmaceuticals. Label: metformin hydrochloride (FORTAMET). November 2018. https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/021574s017lbl.pdf. Accessed January 11, 2024.

[2] Metformin: First choice drug for type 2 diabetes. Worst Pills, Best Pills News. August 2018. https://www.worstpills.org/newsletters/view/1210. Accessed January 11, 2024.

[3] Teva Pharmaceuticals. Label: metformin hydrochloride (FORTAMET). November 2018. https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/021574s017lbl.pdf. Accessed January 11, 2024.

[4] Maideen NM, Jumale A, Balasubramaniam R. Drug interactions of metformin involving drug transporter proteins. Adv Pharm Bull. 2017;7(4):501-505.

[5] Shugarts S, Benet LZ. The role of transporters in the pharmacokinetics of orally administered drugs. Pharm Res. 2009;26:2039-2054.

[6] Roberts AG. The structure and mechanism of drug transporters. Methods Mol Biol. 2021;2342:193-234.

[7] Stage TB, Brøsen K, Christensen MM. A comprehensive review of drug–drug interactions with metformin. Clin Pharmacokinet. 2015;54:811-824.

[8] IBM Micromedex. http://www.micromedexsolutions.com/home/dispatch. Search term: “metformin.” Accessed December 13, 2023.

[9] Teva Pharmaceuticals. Label: metformin hydrochloride (FORTAMET). November 2018. https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/021574s017lbl.pdf. Accessed January 11, 2024.

[10] Metformin: First choice drug for type 2 diabetes. Worst Pills, Best Pills News. August 2018. https://www.worstpills.org/newsletters/view/1210. Accessed January 11, 2024.

[11] MedlinePlus. Metformin. March 15, 2020. https://medlineplus.gov/druginfo/meds/a696005.html. Accessed January 11, 2024.

[12] Teva Pharmaceuticals. Label: metformin hydrochloride (FORTAMET). November 2018. https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/021574s017lbl.pdf. Accessed December 13, 2023.

[13] Medications that cause taste disorders. Worst Pills, Best Pills News. April 2019. https://www.worstpills.org/newsletters/view/1258. Accessed January 12, 2024.

[14] Lifestyle treatments to prevent or reduce the frequency of migraine headaches. Worst Pills, Best Pills News. November 2023. https://www.worstpills.org/newsletters/view/1564. Accessed January 12, 2024.

[15] Teva Pharmaceuticals. Label: metformin hydrochloride (FORTAMET). November 2018. https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/021574s017lbl.pdf. Accessed January 11, 2024.

[16] Important drug interactions for the stomach-acid–suppressing drug cimetidine. Worst Pills, Best Pills News. August 2023. https://www.worstpills.org/newsletters/view/1547. Accessed January 12, 2024.

[17] Risks but no benefits to taking newest drugs for type 2 diabetes. Worst Pills, Best Pills News. August 2015. https://www.worstpills.org/newsletters/view/981. Accessed January 12, 2024.