Metformin Gastrointestinal Intolerance: Measurement of Mitochondrial Complex I
NCT ID: NCT03445702
Last Updated: 2020-10-28
Study Results
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Basic Information
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COMPLETED
EARLY_PHASE1
15 participants
INTERVENTIONAL
2018-10-15
2020-10-27
Brief Summary
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Aims:
1. To determine if the GI intolerance to metformin is associated with post meal elevations of lactic acid.
a. The test will measure the inhibition of mitochondrial complex 1 levels of lactate to pyruvate compared with non- intolerant subjects.
2. To determine if individuals with gastrointestinal symptoms and elevated lactate/pyruvate ratios have genetic variation in the organic cation transporters.
Detailed Description
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The incidence of gastrointestinal intolerance to the drug can range between 10% and 30%. It is postulated that the gastrointestinal enterocyte may accumulate the metformin. It is postulated that metformin uptake and accumulation may be exacerbated in those with genetic predispositions for certain organic transporters which are involved in the uptake and removal of metformin in cells. Metformin appears to be taken up from the intestine by plasma monoamine transporter (PMAT; SLC29A4), organic cation transporter 1 (OCT1; SCLC22A1) and organic cation transporter 3 (OCT3; SLC22A3) and actively removed from target tissues by multi-antimicrobial extrusion protein 1 (MATE1; SLC47A1) and eliminated by the urinary multi-antimicrobial extrusion protein 2 (MATE2; SCL47A2). Although certain genotypes are associated with a high incidence of intolerance, the gene low gene frequency does not explain the high degree of intolerance in the population.
ii) Innovation: The plan is to develop a test to evaluate whether there is accumulation of lactic acid after a therapeutic dose of metformin and whether the levels of lactic acid are higher in subjects with GI intolerance than those not intolerant. The hypothesis is that there is increased generation of lactic acid in those intolerant individuals, independent of glucose lowering effect on liver metabolism. Investigators propose to measure the generation of lactate/pyruvate (L/P, mitochondrial complex 1), in those with and without clinically known metformin gastrointestinal symptoms. Investigators will correlate gastrointestinal symptoms with L/P ratios. Investigators will also evaluate for genomic susceptibility for the origin transporters with comparison to the metformin tolerance test generation of lactic acid.
iii) Approach: Investigators wish to develop a pilot project of 24 subjects who will complete the protocol. Subject will be seen in the Endocrinology clinic of St. Louis University, and investigators will recruit 12 subjects who have clinical symptoms of gastrointestinal symptoms (diarrhea or bloating) and 12 subjects who are tolerant. Subjects will be randomized to receive a fasting standard dose of 1000 mg brand metformin (Glucophage) or comparable placebo on day one and then the alternate medicine on a second day. The study drug will be given with Diabetasourse meal (standard meal) which will provide carbohydrates to challenge the mitochondrial system \[2\]. Bloods for glucose, L/P, will be obtained at 0, 30 60 90 and 120 minutes. Symptoms of gastrointestinal effects will be documented by a Likert type questionnaire. Outcomes will be 1) the effect of metformin vs. placebo on the meal tolerance glucose levels 2) the effect of metformin on post meal challenge levels of L/P, in intolerant vs. tolerant individual and 3) the correlation of gastrointestinal symptoms with changes in L/P. From animal data, metformin causes a 2 fold increase in lactic acid at 60 minutes. In our laboratory with a normal reference lactic acid of 1.0 mmol/L and a SD=0.725. Twelve pairs would be sufficient for a pilot study to determine a difference at an alpha of 0.05 and beta of 0.80.
Conditions
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Study Design
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RANDOMIZED
CROSSOVER
SCREENING
QUADRUPLE
Study Groups
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Metformin intolerant & metformin
Metformin 1000mg once
Metformin
Metformin 1000mg once
Metformin intolerant & placebo
Placebo 1000mg once
Placebo
Sugar pill manufactured to mimic metformin 1000mg
Metformin tolerant & metformin
Metformin 1000mg once
Metformin
Metformin 1000mg once
Metformin tolerant and placebo
Placebo 1000mg once
Placebo
Sugar pill manufactured to mimic metformin 1000mg
Interventions
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Metformin
Metformin 1000mg once
Placebo
Sugar pill manufactured to mimic metformin 1000mg
Other Intervention Names
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Eligibility Criteria
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Inclusion Criteria
2. Tolerance to meformin
3. Intolerance to metformin
Exclusion Criteria
2. Those not competent to provide informed consent
3. Known systemic allergy (not intolerance) to metformin
4. Congestive heart failure NYHA class III-IV
5. Renal impairment,EGFRr\<45ml/min
6. Liver cirrhosis
40 Years
70 Years
ALL
Yes
Sponsors
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Washington University School of Medicine
OTHER
St. Louis University
OTHER
Responsible Party
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Alexis McKee, MD
MD
Locations
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Saint Louis University
St Louis, Missouri, United States
Countries
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References
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Ferrannini E. The target of metformin in type 2 diabetes. N Engl J Med. 2014 Oct 16;371(16):1547-8. doi: 10.1056/NEJMcibr1409796. No abstract available.
Madiraju AK, Erion DM, Rahimi Y, Zhang XM, Braddock DT, Albright RA, Prigaro BJ, Wood JL, Bhanot S, MacDonald MJ, Jurczak MJ, Camporez JP, Lee HY, Cline GW, Samuel VT, Kibbey RG, Shulman GI. Metformin suppresses gluconeogenesis by inhibiting mitochondrial glycerophosphate dehydrogenase. Nature. 2014 Jun 26;510(7506):542-6. doi: 10.1038/nature13270. Epub 2014 May 21.
Bailey CJ, Wilcock C, Scarpello JH. Metformin and the intestine. Diabetologia. 2008 Aug;51(8):1552-3. doi: 10.1007/s00125-008-1053-5. Epub 2008 Jun 5. No abstract available.
Bailey CJ, Wilcock C, Day C. Effect of metformin on glucose metabolism in the splanchnic bed. Br J Pharmacol. 1992 Apr;105(4):1009-13. doi: 10.1111/j.1476-5381.1992.tb09093.x.
Buse JB, DeFronzo RA, Rosenstock J, Kim T, Burns C, Skare S, Baron A, Fineman M. 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 Feb;39(2):198-205. doi: 10.2337/dc15-0488. Epub 2015 Aug 18.
Tarasova L, Kalnina I, Geldnere K, Bumbure A, Ritenberga R, Nikitina-Zake L, Fridmanis D, Vaivade I, Pirags V, Klovins J. 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 Sep;22(9):659-66. doi: 10.1097/FPC.0b013e3283561666.
Pawlyk AC, Giacomini KM, McKeon C, Shuldiner AR, Florez JC. Metformin pharmacogenomics: current status and future directions. Diabetes. 2014 Aug;63(8):2590-9. doi: 10.2337/db13-1367.
Wang L, Weinshilboum R. Metformin pharmacogenomics: biomarkers to mechanisms. Diabetes. 2014 Aug;63(8):2609-10. doi: 10.2337/db14-0609. No abstract available.
Davidson J, Howlett H. New prolonged-release metformin improves gastrointestinal tolerability. British Journal of Diabetes & Vascular Disease 2004; 4: 273.
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 Apr;20(4):565-72. doi: 10.1185/030079904125003278.
Other Identifiers
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25319
Identifier Type: -
Identifier Source: org_study_id