Diabetes

Improving Tolerability to Metformin

Posted on by Melvin Moose
11
Feb

Up to 30% of patients have gastrointestinal (GI) adverse effects when taking metformin.1-3 Generally these adverse effects are mild and transient, but about 5% of patients are unable to tolerate metformin at all.1,3 And almost half may not be able to tolerate the drug at a target dose of 2000 mg/day.4 Metformin is an important first-line glucose lowering medication due to its low cost, efficacy for glycemic control, possible cardiovascular benefits, and well-established safety.5,9 Consider using the strategies and tips below to improve patient tolerance of metformin so they can continue therapy with this important medication.

…Things to consider when starting metformin and handling gastrointestinal adverse effects…

Initiating Metformin

a)   How should metformin be started?

  • It is generally accepted that slow dose escalation increases GI tolerability but evidence for this is lacking.1,2,6
  • Start with either immediate-release (IR) or extended-release (ER) tablets.
    • If using IR, give 500 mg once daily.1

      • 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.7 (See next section for more about the available ER products, cost considerations, etc.)
  • 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.

b)   How should metformin dose be increased?

  • For IR or ER, increase by 500 mg per day every one to two weeks.1,7
  • Advise patients not to break, crush, or chew the ER tablets.7,8
  • 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.1
  • Allow the patient to titrate themselves up and down during this initiation period. Be sure to keep in touch with the patient to monitor their progress.
  • 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.21

c)   Tips for improving tolerance of metformin

  • Take with food, during or right after meals.7,23
  • Recommend taking with the evening meal, typically the largest meal of the day.1,8
  • Dividing the daily dose may improve tolerability.8 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.10 Customize dosing to your patient. Consider patient adherence with more frequent dosing before switching.

d)   What the patient needs to know

  • 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.6
  • 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.11
  • 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 about Metformin’s Adverse Effects

a)   What are the most common complaints?

  • Diarrhea and nausea are the most common gastrointestinal adverse effects.8
  • Also reported are flatulence, abdominal pain with cramps, abdominal swelling, taste distortions, vomiting, constipation, dyspepsia, fecal incontinence, and weight loss.2,3,6,12
  • Symptoms are generally transient, resolve over several months of treatment, and are reduced by slow dose titration and administration with food.8,13

b)   What about GI adverse effects that begin months or years after initiating metformin?

  • It is unusual for GI symptoms from metformin to begin after prolonged therapy.14
  • 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.14
  • 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.7

c)   How do immediate-release (IR) and extended-release (ER) products compare?

  • 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.6,15 However, large, direct comparative studies are lacking.
  • The product information for Glucophage ER reports an incidence of diarrhea of around 10% and nausea of around 7%. Glucophage reports an incidence of almost 50% for diarrhea and 25% for nausea.7 Direct comparisons of these two products have not been made within the same study.
  • The ER tablets have a slower time to peak plasma concentration and smoother plasma peak/trough levels which has been theorized to lead to improved tolerability, compared to the IR tablets.15,16
  • Incidence of nausea has been reported as being lower with ER tablets, compared to IR tablets, during the first week of therapy.8,12
  • More discontinuations have been reported with metformin IR vs ER products.12
  • A retrospective cohort study in 468 patients found reduced GI adverse effects with ER vs IR in metformin-naïve patients, but no difference between groups for those switched from IR to ER for improved tolerability.6
  • A small study in 35 patients showed switching from IR to ER resulted in 25% of patients becoming symptom free with marked reductions in diarrhea and nausea.17
  • There are several extended-release metformin products available.

    • Glucophage XR (U.S. only) 500 mg, 750 mg; Fortamet (U.S. only) 500 mg, 1000 mg; and Glumetza 500 mg, 1000 mg. There is no evidence that one ER product is better tolerated than another.
    • Glucophage XR and Fortamet both have generics available but Glumetza does not. 
    • Cost differences between these products can be substantial. 
    • Be sure to check what is covered by a patient’s insurance plan.
    • The cost difference between generic IR and generic Glucophage XR is small, as they are both less than $10 per month (U.S.).

d)   Can other medications improve metformin tolerability?

  • There are many different theories about how metformin causes GI adverse effects but no conclusion has been reached as to the exact mechanism. Many believe it is a physiological/functional disturbance.3 Some theories include:3
    • Malabsorption of bile salts and vitamin B12.
    • Agonist at the 5-HT3 (serotonin) receptors within the GI system.
    • Alterations of levels of other peptides: ghrelin, VIP, GLP-1.
  • Ondansetron, a 5-HT3 antagonist, did not improve GI adverse effects in one clinical trial.18
  • In a study in just over 400 patients, there were significantly more GI symptoms in patients positive for H. pylori on metformin.19 Treatment of H. pylori infections, as appropriate, may help improve a patient’s tolerance to metformin.
  • There is a GI microbiome modulator (NM505) in development. One small study has shown promising results for improved metformin tolerance.20

How Should Temporary Interruptions in Metformin Therapy be Managed?

a) How many missed doses constitute an interruption?

  • This will depend on your patient and could be a couple of days or more for some people. 

b) Is a full titration required to restart metformin?

  • Be more cautious with patients who needed a longer, slower titration initially.
  • If a patient experiences adverse effects when restarting after missed doses, lower the dose and increase every one to two weeks back to the target dose.

What if Patients Cannot Reach the Metformin Target Dose?

a) What is the efficacy of different doses of metformin?

  • In most patients, there is some efficacy at a minimum dose of 500 mg/day, with a maximal effect at 2000 mg/day.13,21
  • 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.1
  • 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.22

 

  1. Defronzo RA. Pharmacologic therapy for type 2 diabetes mellitus. Ann Intern Med 1999;131:281-303.
  2. Bouchoucha M, Uzzan B, Cohen R. Metformin and digestive disorders. Diabetes Metab 2011;37:90-6.
  3. Philpott HL, Nandurkar S, Lubel J, Gibson PR. Drug-induced gastrointestinal disorders. Postgrad Med J 2014;90:411-9.
  4. Bailey CJ, Turner RC. Metformin. N Engl J Med 1996;334:574-9.
  5. American Diabetes Association. Approaches to glycemic treatment. Diabetes Care 2015;38:S41-8.
  6. Blonde L, Dailey GE, Jabbour AS, et al. Gastrointestinal tolerability of extended-release metformin tablets compared to immediate-release metformin tablets: results of a retrospective cohort study. Curr Med Res Opin 2004;20:565-72.
  7. Product information for Glucophage and Glucophage XR. Bristol-Myers Squibb Company. Princeton, NJ 08543. January 2009.
  8. Foster RH, Keam SJ. Metformin Extended Release. Am J Drug Deliv 2006;4:177-86.
  9. Harper W, Clement M, Goldenberg R, et al. Policies, guidelines and consensus statements: pharmacologic management of type 2 diabetes-2015 interim update. Can J Diabetes 2015;39:250-2.
  10. Schwartz S, Fonseca V, Berner B, et al. Efficacy, tolerability, and safety of a novel once-daily ER metformin in patients with type 2 diabetes. Diabetes Care2006;29:759-64.
  11. Pelletier AL, Butler AM, Gillies RA, May JR. Metformin stinks, literally. Ann Intern Med 2010;152:267-8.
  12. Ali S, Fonseca V. Overview of metformin: special focus on metformin extended release. Expert Opin Pharmacother 2012;13:1797-805.
  13. Scarpello JH. Optimal dosing strategies for maximizing the clinical response to metformin in type 2 diabetes. Br J Diabetes Vasc Dis 2001;1:28-36.
  14. Raju B, Resta C, Tibaldi JT. Metformin and late gastrointestinal complications [letter]. Am J Med 2000;109:260-1.
  15. Kim CH, Han KA, Oh HJ, et al. Safety, tolerability, and efficacy of metformin extended-release oral antidiabetic therapy in patients with type 2 diabetes: an observational trial in Asia. J Diabetes 2012;4:395-406.
  16. Pala L, Rotella CM. The “slower” the better. J Endocrinol Invest 2014;37:497-8.
  17. Levy J, Cobas RA, Gomes MB. Assessment of efficacy and tolerability of once-daily extended release metformin in patients with type 2 diabetes mellitus. DiabetolMetab Syndr 2010;2:16.
  18. Hoffmann IS, Roa M, Torrico F, Cubeddu LX. Ondansetron and metformin-induced gastrointestinal side effects. Am J Ther 2003;10:447-51.
  19. Huang Y, Sun J, Wang X, et al. Helicobacter pylori infection decreases metformin tolerance in patients with type 2 diabetes mellitus. Diabetes Technol Ther2015;17:128-33.
  20. Burton JH, Johnson M, Johnson J, et al. Addition of a gastrointestinal microbiome modulator to metformin improves metformin tolerance and fasting glucose levels. J Diabetes Sci Technol 2015;9:808-14.
  21. Garber AJ, Duncan TG, Goodman AM, et al. Efficacy of metformin in type II diabetes: results of a double-blind, placebo-controlled, dose-response trial. Am J Med1997;103:491-7.
  22. Neutel JM, Zhao C, Karyekar CS. Adding saxagliptin to metformin extended release (XR) or uptitration of metformin XR: efficacy on daily glucose measures. Diabetes Ther 2013;4:269-83.
  23. Product monograph for Glucophage. Sanofi-Aventis Canada. Laval, QC H7V 0A3. October 2014.

 

Melvin Moose

X Close
0