Understanding and overcoming metformin gastrointestinal intolerance

Diabetes, Obesity and Metabolism

Volumn 19, Issue 4, 2017, Pages 473-481

  Bonnet, Fabrice ^a   Scheen, André ^b,c  

^a RENNES UNIVERSITY HOSPITAL   (France)

^b UNIVERSITY OF LIÈGE   (Belgium)

^c UNIVERSITY OF LIÈGE   (Belgium)

Author keywords

gastrointestinal intolerance; metformin; microbiota; type 2 diabetes mellitus

Indexed keywords

2,4 THIAZOLIDINEDIONE DERIVATIVE; GLUCAGON LIKE PEPTIDE 1 RECEPTOR AGONIST; INSULIN; METFORMIN; SODIUM GLUCOSE COTRANSPORTER 2 INHIBITOR; SULFONYLUREA; ANTIDIABETIC AGENT;

ABDOMINAL DISCOMFORT; BARIATRIC SURGERY; COMORBIDITY; DIARRHEA; DRUG DOSE TITRATION; DRUG EFFICACY; DRUG MECHANISM; DRUG RELEASE; DRUG TOLERABILITY; FLATULENCE; GASTROINTESTINAL SYMPTOM; GENOTYPE; HUMAN; INDIGESTION; INTESTINE FLORA; MONOTHERAPY; NAUSEA; NON INSULIN DEPENDENT DIABETES MELLITUS; OBSERVATIONAL STUDY; RANDOMIZED CONTROLLED TRIAL (TOPIC); REVIEW; TREATMENT RESPONSE; VOMITING; CHEMICALLY INDUCED; DIABETES MELLITUS, TYPE 2; GASTROINTESTINAL DISEASE;

DIABETES MELLITUS, TYPE 2; GASTROINTESTINAL DISEASES; HUMANS; HYPOGLYCEMIC AGENTS; METFORMIN;

EID: 85013499877     PISSN: 14628902     EISSN: 14631326     Source Type: Journal    
DOI: 10.1111/dom.12854     Document Type: Review

References (97)

1. Chinese Diabetes Society. China Guideline for Type 2 Diabetes [in Chinese]. 2010. Available at: http://www.diab.net.cn/uploadfile/T2dmguideline2010.pdf. Accessed December 29, 2016.
2. NICE guidelines. Type 2 diabetes in adults: management. 2015. Available at: http://www.nice.org.uk/guidance/ng28/chapter/1-Recommendations#drug-treatment-2. Accessed December 29, 2016.
3. International Diabetes Federation. Global Guideline for Type 2 Diabetes. 2012. Available at: http://www.idf.org/sites/default/files/IDF-Guideline-for-Type-2-Diabetes.pdf. Accessed December 29, 2016.
4. The Royal Australian College of General Practitioners and Diabetes Australia. General practice management of type 2 diabetes – 2014–15. Melbourne. 2014. http://www.racgp.org.au/your-practice/guidelines/diabetes/. Accessed December 29, 2016.
5. Garber AJ, Abrahamson MJ, Barzilay JI, et al. Consensus statement by the American Association of Clinical Endocrinologists and American College of Endocrinology on the comprehensive type 2 diabetes management algorithm – 2016 executive summary. Endocr Pract. 2016;22:84–113.
6. Inzucchi SE, Bergenstal RM, Buse JB, et al. Management of hyperglycaemia in type 2 diabetes, 2015: a patient-centred approach. Update to a position statement of the American Diabetes Association and the European Association for the Study of Diabetes. Diabetologia. 2015;58:429–442.
7. Maruthur NM, Tseng E, Hutfless S, et al. Diabetes medications as monotherapy or metformin-based combination therapy for type 2 diabetes: a systematic review and meta-analysis. Ann Intern Med. 2016;164:740–751.
8. Palmer SC, Mavridis D, Nicolucci A, et al. Comparison of clinical outcomes and adverse events associated with glucose-lowering drugs in patients with type 2 diabetes: a meta-analysis. JAMA. 2016;316:313–324.
9. Graham GG, Punt J, Arora M, et al. Clinical pharmacokinetics of metformin. Clin Pharmacokinet. 2011;50:81–98.
10. Scheen AJ. Clinical pharmacokinetics of metformin. Clin Pharmacokinet. 1996;30:359–371.
11. Andujar-Plata P, Pi-Sunyer X, Laferrere B. Metformin effects revisited. Diabetes Res Clin Pract. 2012;95:1–9.
12. Foretz M, Guigas B, Bertrand L, Pollak M, Viollet B. Metformin: from mechanisms of action to therapies. Cell Metab. 2014;20:953–966.
13. Rena G, Pearson ER, Sakamoto K. Molecular mechanism of action of metformin: old or new insights? Diabetologia. 2013;56:1898–1906.
14. Rojas LB, Gomes MB. Metformin: an old but still the best treatment for type 2 diabetes. Diabetol Metab Syndr. 2013;5:6.
15. Viollet B, Guigas B, Sanz Garcia N, et al. Cellular and molecular mechanisms of metformin: an overview. Clin Sci (Lond). 2012;122:253–270.
16. McCreight LJ, Bailey CJ, Pearson ER. Metformin and the gastrointestinal tract. Diabetologia. 2016;59:426–435.
17. Glucophage® [metformin hydrochloride tablets] and Glucophage® XR [metformin hydrochloride extended-release tablets] Product Information B-MSC, Princeton, NJ, USA, Revised 2009.
18. Schwartz S, Fonseca V, Berner B, et al. Efficacy, tolerability, and safety of a novel once-daily extended-release metformin in patients with type 2 diabetes. Diabetes Care. 2006;29:759–764.
19. Garber AJ, Duncan TG, Goodman AM, Mills DJ, Rohlf JL. Efficacy of metformin in type II diabetes: results of a double-blind, placebo-controlled, dose-response trial. Am J Med. 1997;103:491–497.
20. Kahn SE, Haffner SM, Heise MA, et al. Glycemic durability of rosiglitazone, metformin, or glyburide monotherapy. N Engl J Med. 2006;355:2427–2443.
21. Hermans MP, Delibasi T, Farmer I, et al. Effects of saxagliptin added to sub-maximal doses of metformin compared with uptitration of metformin in type 2 diabetes: the PROMPT study. Curr Med Res Opin. 2012;28:1635–1645.
22. UK Prospective Diabetes Study (UKPDS) Group. Effect of intensive blood-glucose control with metformin on complications in overweight patients with type 2 diabetes (UKPDS 34). Lancet. 1998;352:854–865.
23. DeFronzo RA, Goodman AM. Efficacy of metformin in patients with non-insulin-dependent diabetes mellitus. The Multicenter Metformin Study Group. N Engl J Med. 1995;333:541–549.
24. Ji LN, Pan CY, Lu JM, et al. Efficacy and safety of combination therapy with vildagliptin and metformin versus metformin uptitration in Chinese patients with type 2 diabetes inadequately controlled with metformin monotherapy: a randomized, open-label, prospective study (VISION). Diabetes Obes Metab. 2016;18:775–782.
25. Dandona P, Fonseca V, Mier A, Beckett AG. Diarrhea and metformin in a diabetic clinic. Diabetes Care. 1983;6:472–474.
26. Florez H, Luo J, Castillo-Florez S, et al. Impact of metformin-induced gastrointestinal symptoms on quality of life and adherence in patients with type 2 diabetes. Postgrad Med. 2010;122:112–120.
27. Medical Dictionary for Regulatory Activities. Diarrhoea. 2016. http://bioportal.bioontology.org/ontologies/MEDDRA/?p=classes&conceptid=http%3A%2F%2Fpurl.bioontology.org%2Fontology%2FMEDDRA%2F10012735. Accessed October 13, 2016.
28. Foss MT, Clement KD. Metformin as a cause of late-onset chronic diarrhea. Pharmacotherapy. 2001;21:1422–1424.
29. Guo L, Guo X, Li Y, et al. Effects of body mass index or dosage on gastrointestinal disorders associated with extended-release metformin in type 2 diabetes: sub-analysis of a Phase IV open-label trial in Chinese patients. Diabetes Metab Syndr. 2016;10:137–142.
30. Hermans MP, Ahn SA, Rousseau MF. What is the phenotype of patients with gastrointestinal intolerance to metformin? Diabetes Metab. 2013;39:322–329.
31. Buse JB, DeFronzo RA, Rosenstock J, et al. The primary glucose-lowering effect of metformin resides in the gut, not the circulation. Results from short-term pharmacokinetic and 12-week dose-ranging studies. Diabetes Care. 2016;39:198–205.
32. Lee H, Ko G. Effect of metformin on metabolic improvement and gut microbiota. Appl Environ Microbiol. 2014;80:5935–5943.
33. Napolitano A, Miller S, Nicholls AW, et al. Novel gut-based pharmacology of metformin in patients with type 2 diabetes mellitus. PLoS One. 2014;9:e100778.
34. Shin NR, Lee JC, Lee HY, et al. An increase in the Akkermansia spp population induced by metformin treatment improves glucose homeostasis in diet-induced obese mice. Gut. 2014;63:727–735.
35. Bailey CJ, Wilcock C, Scarpello JH. Metformin and the intestine. Diabetologia. 2008;51:1552–1553.
36. Scarpello JH, Hodgson E, Howlett HC. Effect of metformin on bile salt circulation and intestinal motility in type 2 diabetes mellitus. Diabet Med. 1998;15:651–656.
37. Bahne E, Hansen M, Brønden A, et al. Involvement of glucagon-like peptide-1 in the glucose-lowering effect of metformin. Diabetes Obes Metab. 2016;18:955–961.
38. Forslund K, Hildebrand F, Nielsen T, et al. Disentangling type 2 diabetes and metformin treatment signatures in the human gut microbiota. Nature. 2015;528:262–266.
39. Gruszka A. New insight into the mechanisms of the anti-hyperglycemic action of metformin. Br J Med Med Res. 2016;13.
40. Hur KY, Lee MS. New mechanisms of metformin action: focusing on mitochondria and the gut. J Diabetes Invest. 2015;6:600–609.
41. Tucker GT, Casey C, Phillips PJ, et al. Metformin kinetics in healthy subjects and in patients with diabetes mellitus. Br J Clin Pharmacol. 1981;12:235–246.
42. Bonora E, Cigolini M, Bosello O, et al. Lack of effect of intravenous metformin on plasma concentrations of glucose, insulin, C-peptide, glucagon and growth hormone in non-diabetic subjects. Curr Med Res Opin. 1984;9:47–51.
43. Stepensky D, Friedman M, Raz I, Hoffman A. Pharmacokinetic-pharmacodynamic analysis of the glucose-lowering effect of metformin in diabetic rats reveals first-pass pharmacodynamic effect. Drug Metab Dispos. 2002;30:861–868.
44. Bybel B, Greenberg ID, Paterson J, Ducharme J, Leslie WD. Increased F-18 FDG intestinal uptake in diabetic patients on metformin: a matched case-control analysis. Clin Nucl Med. 2011;36:452–456.
45. Bailey CJ, Mynett KJ, Page T. Importance of the intestine as a site of metformin-stimulated glucose utilization. Br J Pharmacol. 1994;112:671–675.
46. Dujic T, Causevic A, Bego T, et al. Organic cation transporter 1 variants and gastrointestinal side effects of metformin in patients with type 2 diabetes. Diabet Med. 2016;33:511–514.
47. Dujic T, Zhou K, Donnelly LA, et al. Association of organic cation transporter 1 with intolerance to metformin in type 2 diabetes: a GoDARTS study. Diabetes. 2015;64:1786–1793.
48. Tarasova L, Kalnina I, Geldnere K, et al. Association of genetic variation in the organic cation transporters OCT1, OCT2 and multidrug and toxin extrusion 1 transporter protein genes with the gastrointestinal side effects and lower BMI in metformin-treated type 2 diabetes patients. Pharmacogenet Genomics. 2012;22:659–666.
49. Huang Y, Sun J, Wang X, et al. Asymptomatic chronic gastritis decreases metformin tolerance in patients with type 2 diabetes. J Clin Pharm Ther. 2015;40:461–465.
50. Huang Y, Sun J, Wang X, et al. Helicobacter pylori infection decreases metformin tolerance in patients with type 2 diabetes mellitus. Diabetes Technol Ther. 2015;17:128–133.
51. Rosenstock J, Brown A, Fischer J, et al. Efficacy and safety of acarbose in metformin-treated patients with type 2 diabetes. Diabetes Care. 1998;21:2050–2055.
52. Nauck M, Frid A, Hermansen K, et al. Long-term efficacy and safety comparison of liraglutide, glimepiride and placebo, all in combination with metformin in type 2 diabetes: 2-year results from the LEAD-2 study. Diabetes Obes Metab. 2013;15:204–212.
53. Padwal RS, Gabr RQ, Sharma AM, et al. Effect of gastric bypass surgery on the absorption and bioavailability of metformin. Diabetes Care. 2011;34:1295–1300.
54. Hazel-Fernandez L, Xu Y, Moretz C, et al. Historical cohort analysis of treatment patterns for patients with type 2 diabetes initiating metformin monotherapy. Curr Med Res Opin. 2015;31:1703–1716.
55. Pladevall M, Williams LK, Potts LA, et al. Clinical outcomes and adherence to medications measured by claims data in patients with diabetes. Diabetes Care. 2004;27:2800–2805.
56. Nichols GA, Rosales AG, Kimes TM, et al. Impact on glycated haemoglobin of a biological response-based measure of medication adherence. Diabetes Obes Metab. 2015;17:843–848.
57. Lawrence DB, Ragucci KR, Long LB, Parris BS, Helfer LA. Relationship of oral antihyperglycemic (sulfonylurea or metformin) medication adherence and hemoglobin A1c goal attainment for HMO patients enrolled in a diabetes disease management program. J Manag Care Pharm. 2006;12:466–471.
58. Reasner C, Olansky L, Seck TL, et al. The effect of initial therapy with the fixed-dose combination of sitagliptin and metformin compared with metformin monotherapy in patients with type 2 diabetes mellitus. Diabetes Obes Metab. 2011;13:644–652.
59. Davidson J, Howlett H. New prolonged-release metformin improves gastrointestinal tolerability. Br J Diabetes Vasc Dis. 2004;4:273–277.
60. Chacra AR. Evolving metformin treatment strategies in type-2 diabetes: from immediate-release metformin monotherapy to extended-release combination therapy. Am J Ther. 2014;21:198–210.
61. Jabbour S, Ziring B. Advantages of extended-release metformin in patients with type 2 diabetes mellitus. Postgrad Med. 2011;123:15–23.
62. Fujioka K, Brazg RL, Raz I, et al. Efficacy, dose-response relationship and safety of once-daily extended-release metformin (Glucophage XR) in type 2 diabetic patients with inadequate glycaemic control despite prior treatment with diet and exercise: results from two double-blind, placebo-controlled studies. Diabetes Obes Metab. 2005;7:28–39.
63. Blonde L, Dailey GE, Jabbour SA, Reasner CA, Mills DJ. Gastrointestinal tolerability of extended-release metformin tablets compared to immediate-release metformin tablets: results of a retrospective cohort study. Curr Med Res Opin. 2004;20:565–572.
64. Donnelly LA, Morris AD, Pearson ER. Adherence in patients transferred from immediate release metformin to a sustained release formulation: a population-based study. Diabetes Obes Metab. 2009;11:338–342.
65. Pala L, Rotella CM. The “slower” the better. J Endocrinol Invest. 2014;37:497–498.
66. DeFronzo RA, Buse JB, Kim T, et al. Once-daily delayed-release metformin lowers plasma glucose and enhances fasting and postprandial GLP-1 and PYY: results from two randomised trials. Diabetologia. 2016;59:1645–1654.
67. Greenway F, Wang S, Heiman M. A novel cobiotic containing a prebiotic and an antioxidant augments the glucose control and gastrointestinal tolerability of metformin: a case report. Benef Microbes. 2014;5:29–32.
68. 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;9:808–814.
69. Rebello CJ, Burton J, Heiman M, Greenway FL. Gastrointestinal microbiome modulator improves glucose tolerance in overweight and obese subjects: a randomized controlled pilot trial. J Diabetes Complications. 2015;29:1272–1276.
70. Defronzo RA. Banting Lecture. From the triumvirate to the ominous octet: a new paradigm for the treatment of type 2 diabetes mellitus. Diabetes. 2009;58:773–795.
71. Blonde L, San Juan ZT. Fixed-dose combinations for treatment of type 2 diabetes mellitus. Adv Ther. 2012;29:1–13.
72. Irons BK, Minze MG. Drug treatment of type 2 diabetes mellitus in patients for whom metformin is contraindicated. Diabetes Metab Syndr Obes. 2014;7:15–24.
73. Scheen AJ, Lefebvre PJ. Oral antidiabetic agents. A guide to selection. Drugs. 1998;55:225–236.
74. Morgan CL, Mukherjee J, Jenkins-Jones S, Holden SE, Currie CJ. Association between first-line monotherapy with sulphonylurea versus metformin and risk of all-cause mortality and cardiovascular events: a retrospective, observational study. Diabetes Obes Metab. 2014;16:957–962.
75. Phung OJ, Schwartzman E, Allen RW, Engel SS, Rajpathak SN. Sulphonylureas and risk of cardiovascular disease: systematic review and meta-analysis. Diabet Med. 2013;30:1160–1171.
76. Roumie CL, Hung AM, Greevy RA, et al. Comparative effectiveness of sulfonylurea and metformin monotherapy on cardiovascular events in type 2 diabetes mellitus: a cohort study. Ann Intern Med. 2012;157:601–610.
77. Tzoulaki I, Molokhia M, Curcin V, et al. Risk of cardiovascular disease and all cause mortality among patients with type 2 diabetes prescribed oral antidiabetes drugs: retrospective cohort study using UK general practice research database. BMJ. 2009;339:b4731.
78. Hemmingsen B, Schroll JB, Lund SS, et al. Sulphonylurea monotherapy for patients with type 2 diabetes mellitus. Cochrane Database Syst Rev. 2013;4:CD009008.
79. Scheen AJ. DPP-4 inhibitors in the management of type 2 diabetes: a critical review of head-to-head trials. Diabetes Metab. 2012;38:89–101.
80. Wu D, Li L, Liu C. Efficacy and safety of dipeptidyl peptidase-4 inhibitors and metformin as initial combination therapy and as monotherapy in patients with type 2 diabetes mellitus: a meta-analysis. Diabetes Obes Metab. 2014;16:30–37.
81. Gerich J. DPP-4 inhibitors: what may be the clinical differentiators? Diabetes Res Clin Pract. 2010;90:131–140.
82. Scheen AJ. A review of gliptins for 2014. Expert Opin Pharmacother. 2015;16:43–62.
83. Shyangdan DS, Uthman OA, Waugh N. SGLT-2 receptor inhibitors for treating patients with type 2 diabetes mellitus: a systematic review and network meta-analysis. BMJ Open. 2016;6:e009417.
84. Henry RR, Murray AV, Marmolejo MH, et al. Dapagliflozin, metformin XR, or both: initial pharmacotherapy for type 2 diabetes, a randomised controlled trial. Int J Clin Pract. 2012;66:446–456.
85. Umpierrez G, Tofe Povedano S, Perez Manghi F, Shurzinske L, Pechtner V. Efficacy and safety of dulaglutide monotherapy versus metformin in type 2 diabetes in a randomized controlled trial (AWARD-3). Diabetes Care. 2014;37:2168–2176.
86. Zinman B, Wanner C, Lachin JM, et al. Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes. N Engl J Med. 2015;373:2117–2128.
87. Scheen AJ. Reduction in cardiovascular and all-cause mortality in the EMPA-REG OUTCOME trial: a critical analysis. Diabetes Metab. 2016;42:71–76.
88. Marso SP, Daniels GH, Brown-Frandsen K, et al. Liraglutide and cardiovascular outcomes in type 2 diabetes. N Engl J Med. 2016;375:311–322.
89. Marso SP, Bain SC, Consoli A, et al. Semaglutide and cardiovascular outcomes in patients with type 2 diabetes. N Engl J Med. 2016;375:1834–1844.
90. Joshi SR, Standl E, Tong N, et al. Therapeutic potential of alpha-glucosidase inhibitors in type 2 diabetes mellitus: an evidence-based review. Expert Opin Pharmacother. 2015;16:1959–1981.
91. Yang W, Liu J, Shan Z, et al. Acarbose compared with metformin as initial therapy in patients with newly diagnosed type 2 diabetes: an open-label, non-inferiority randomised trial. Lancet Diabetes Endocrinol. 2014;2:46–55.
92. Richeldi L, du Bois RM, Raghu G, et al. Efficacy and safety of nintedanib in idiopathic pulmonary fibrosis. N Engl J Med. 2014;370:2071–2082.
93. Weng J, Soegondo S, Schnell O, et al. Efficacy of acarbose in different geographical regions of the world: analysis of a real-life database. Diabetes Metab Res Rev. 2015;31:155–167.
94. Goldman-Levine JD. Combination therapy when metformin is not an option for type 2 diabetes. Ann Pharmacother. 2015;49:688–699.
95. Montgomery AA, Fahey T. How do patients’ treatment preferences compare with those of clinicians? Qual Health Care. 2001;10(suppl 1):i39–i43.
96. Shillington AC, Col N, Bailey RA, Jewell MA. Development of a patient decision aid for type 2 diabetes mellitus for patients not achieving glycemic control on metformin alone. Patient Prefer Adherence. 2015;9:609–617.
97. Weymann N, Harter M, Petrak F, Dirmaier J. Health information, behavior change, and decision support for patients with type 2 diabetes: development of a tailored, preference-sensitive health communication application. Patient Prefer Adherence. 2013;7:1091–1099.