Improving Tolerability : Metformin

• Up to 30% of patients have gastrointestinal (GI) adverse effects when taking metformin
• Generally these adverse effects are mild and transient, but about 5% of patients are unable to tolerate metformin at all
• And almost half may not be able to tolerate the drug at a target dose of 2000 mg/day.

Initiating

• It is generally accepted that slow dose escalation increases GI tolerability but evidence for this is lacking.
• Start with either immediate-release (IR) or extended-release (ER) tablets.
• If using IR, give 500 mg once daily
• If a patient has a history of GI intolerance, consider starting with 250 mg once daily.
• If using ER, start with 500 mg once daily
• For even greater flexibility, metformin 100 mg/mL liquid can be used, allowing a patient to start at a lower dose and increase by smaller increments.
• Suggest starting with single-ingredient metformin for easier titration. Once dose is established, patient can be switched to a combination product with another glucose-lowering agent if that is indicated.

Dose Titration

• For IR or ER, increase by 500 mg per day every one to two weeks.
• Advise patients not to break, crush, or chew the ER tablets.
• If there is a history of GI intolerance increase more slowly, and maybe by only 250 mg at a time.
• If GI symptoms occur, decrease the dose back to the last tolerated dose and wait at least two weeks before further increases, in a smaller increment if possible
• It may take four to eight weeks, or longer to reach the target dose of 2000 mg/day.1 The benefit vs risk for adverse reactions does not support doses >2000 mg/day.

Tips to Improve Tolerance

• Take with food, during or right after meals.
• Recommend taking with the evening meal, typically the largest meal of the day
• Dividing the daily dose may improve tolerability. Consider giving the IR product three times per day or the ER product twice daily. Some reports indicate splitting the dose has no effect on the rate of adverse effects

Patient Education

• Let the patient know what to expect. It can be easier to tolerate some of these adverse effects if they know they’ll likely subside.
• Persistent diarrhea will subside quickly if metformin is stopped.
• Metformin can have an undesirable odor. Patients might even complain the odor makes them nauseous. Try a different brand or generic tablet if patients complain.
• Let patients know that they should be patient during the titration as it will take weeks and maybe a month or two to reach the target dose.

Managing Complaints

• Symptoms are generally transient, resolve over several months of treatment, and are reduced by slow dose titration and administration with food.
• It is unusual for GI symptoms from metformin to begin after prolonged therapy.
• Recommend a trial off metformin to see if symptoms resolve. You should see a resolution of symptoms within two to three days if the cause was metformin.
• Be aware that GI symptoms that developed later in therapy may need further investigation as they could be symptoms of lactic acidosis or other serious conditions
•  If patients cannot tolerate IR metformin at optimal doses, consider switching to a trial of ER.    
• There have been some retrospective and observational studies that report improved GI tolerability with ER over IR tablets.  However, large, direct comparative studies are lacking.

If Can't Achieve Target Dose?

• In most patients, there is some efficacy at a minimum dose of 500 mg/day, with a maximal effect at 2000 mg/day
• There may be some patients who see more benefit with doses up to 2500 mg/day but there is likely to be a higher incidence of GI adverse effects.21
• Up to 85% of the maximal effect is seen at a dose of 1500 mg/day.
• If a patient cannot tolerate metformin IR or ER at target dose, consider adding a second agent to the maximum metformin dose they can tolerate

Adapted from

• Improving Tolerability to Metformin. (PL Detail-Document #311202). PHARMACIST’S LETTER / PRESCRIBER’S LETTER. December 2015