What time of day should I take metformin?

Manufacturers recommend all forms of metformin be taken at the same time every day with food.^1-4 Metformin comes in tablet and oral solution forms and in immediate-release and extended-release formulations. Manufacturers recommend taking metformin with food to avoid gastrointestinal side effects.

Immediate-release tablets and oral solution can be taken once, twice, or three times a day depending on dosage and tolerance.^1-4 Manufacturers recommend dividing the dose to twice a day for dosages 850 mg and above and dividing to three times a day for dosages 2,000 mg and above. Divided doses can minimize gastrointestinal side effects.

Extended-release tablets and oral solution are recommended to be taken once a day with the evening meal.^1,3,4

Pharmacology

Metformin immediate-release tablets and oral solution reaches maximum bioavailability within 1.79-3.32 hours.^1,2 Metformin extended-release tablets and oral solution reaches maximum bioavailability within 4-8 hours.^1,3,4

The plasma elimination half-life for all forms of metformin is approximately 6.2 hours, and the elimination half-life in blood is approximately 17.6 hours. Plasma elimination half-life is the time at which the total amount of the drug bound to plasma proteins is reduced by 50%, and blood elimination half-life is the time at which the total amount of drug bound to blood cells is reduced by 50%.⁵ In order to be metabolized and eliminated, metformin must be unbound from both blood and plasma.

The presence of food in the gastrointestinal tract changes the way that metformin is absorbed, however, the clinical relevance of this is unknown.^1-4,6 The effect of food on absorption of metformin are outlined below:

• Immediate-release tablets: food decreases absorption by 40% and delays peak absorption by 35 minutes.
• Extended-release tablts: food increase absorption by 50% but does not impact the speed of absorption.
• Immediate-release oral solution: food increase absorption 13-16% and delats peak absorption by 1.4 hours.
• Extended-release oral solution: decreases absorption by 20% and delats peak absorption by one hour.

Strategies to Improve Adherence

There are a variety of effective strategies that can help improve medication adherence, including use of reminder packaging such as labeled weekly or daily pill boxes to aid in taking medication consistently and habitually. A 2012 study (n=9,266) examining the impact of reminder packaging on antihypertensive medication adherence found that the cohort using reminder packaging had significantly higher levels of medication possession (80% vs 73%, p<0.001).⁷ Another 2005 study (n=2,081) found that use of a tablet dispenser similar to a pill box significantly improved outcomes among those with type 2 diabetes (HbA1c fell by 0.74 vs 0.53 for controls).⁸

A 2006 study (n=200) examined the adherence to antihypertensive agents before, during, and after an intervention involving medication education, pharmacist follow-up, and time-specific medication packaging.⁹ Before the intervention, baseline adherence was 61.2%. After 6 months of intervention, medication adherence increased to 96.9%. At 6 months, participants were randomized to continuing receipt of intervention or return to usual care. At 12 months, those who received the intervention had 95.5% adherence vs 69.1% for those receiving usual care.

References:

1. Glucophage (metformin hydrochloride) tablets, for oral use & Glucophage XR (metformin hydrochloride) extended-release tablets, for oral use. [Package insert]. Princeton, NJ: Bristol-Myers Squibb Company; 2018.
2. Riomet (metformin hydrochloride) oral solution. [Package insert]. Cranbury, NJ: Sun Pharmaceutical Industries; 2018.
3. Riomet ER (metformin hydrochloride for extended-release oral suspension). [Package insert]. Cranbury, NJ: Sun Pharmaceutical Industries; 2019.
4. Glumetza (metformin hydrochloride) extended-release tablets, for oral use. [Package insert]. Bridgewater, NJ: Valeant Pharmaceuticals; 2018.
5. Benet LZ, Zia-Amirhosseini P. Basic principles of pharmacokinetics. Toxicol Pathol. Mar-Apr 1995;23(2):115-23. doi:10.1177/019262339502300203
6. Sambol N, Brookes L, Chiang J, et al. Food intake and dosage level, but not tablet vs solution dosage form, affect the absorption of metformin HC1 in man. British Journal of Clinical Pharmacology. 1996;42(4):510-512. doi:https://doi.org/10.1111/j.1365-2125.1996.tb00017.x
7. Dupclay L, Eaddy M, Jackson J, Raju A, Shim A. Real-world impact of reminder packaging on antihypertensive treatment adherence and persistence. Patient Prefer Adherence. 2012;6:499-507. doi:10.2147/ppa.S31417
8. Maier C, Mustapic D, Schuster E, Luger A, Eher R. Effect of a pocket-size tablet-dispensing device on glycaemic control in Type 2 diabetic patients. Diabet Med. Jan 2006;23(1):40-5. doi:10.1111/j.1464-5491.2005.01721.x
9. Lee JK, Grace KA, Taylor AJ. Effect of a pharmacy care program on medication adherence and persistence, blood pressure, and low-density lipoprotein cholesterol: a randomized controlled trial. Jama. Dec 6 2006;296(21):2563-71. doi:10.1001/jama.296.21.joc60162