Trial reportPloS one2014
Novel gut-based pharmacology of metformin in patients with type 2 diabetes mellitus.
Trial report in PloS one, 2014. The graph read 2 numbers from its abstract, feeding 2 cells of the map: it . An erratum has been issued. It reports registered trial NCT01357876. Cited by 151 papers, 6 of them syntheses that pooled it.
What it found
Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.
The plasma glucose concentrations were decreased by ∼21% (p<0.0001) from Visit 3 to Visit 4 when fasting CBG had returned to baseline levels following the reintroduction of metformin.
Read, but not usablea number the graph found but could not read as for or against
Following metformin withdrawal at Visit 1, the 12-hour mean venous plasma glucose levels increased by ∼15% (p = 0.0006) from baseline to Visit 3 when fasting CBG had increased by ∼25%.
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Where it lands on the map
Rows are treatments, columns are outcomes. The coloured squares are the cells this paper feeds, coloured by the vote it casts there. Click one to jump to what this paper adds to it.
What it adds to each cell
For every cell the paper feeds: the belief in the claim with and without this paper, and this paper's estimate drawn against every other readable study in the cell. The ringed dot is this paper.
Metformin×glycemic control
No readable resultOpen on the map →What to test next →40 readable studies in this cell: 41 favour the treatment, 12 find no difference, 8 favour the comparator.
Metformin×adverse events & safety
No readable resultOpen on the map →What to test next →22 readable studies in this cell: 9 favour the treatment, 8 find no difference, 5 favour the comparator.
This paper's own estimate is on a different scale from the rest of the cell, so it is not drawn here.
The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
Effect of Metformin on Gut Peptides , Bile Acids and Lipid Profiles in Type 2 Diabetics
Open the trial in the graphWho cites it
151 citing papers in PubMed, 6 syntheses or guidelines pooled it, 282 citations in OpenAlex.
- Comparing SGLT2i and Other Oral Antidiabetic Drugs as Dual Therapy Add-On to Metformin in Type 2 Diabetes: A Systematic Review and Meta-Analysis.Endocrinology, diabetes & metabolism · 2026Pooled it
- Interactions between Gut Microbiota and Oral Antihyperglycemic Drugs: A Systematic Review.International journal of molecular sciences · 2024Pooled it
- Pooled it
- Genomic editing of metformin efficacy-associated genetic variants in SLC47A1 does not alter SLC47A1 expression.Human molecular genetics · 2022Pooled it
- Effects of Non-insulin Anti-hyperglycemic Agents on Gut Microbiota: A Systematic Review on Human and Animal Studies.Frontiers in endocrinology · 2020Pooled it
- Variants in Pharmacokinetic Transporters and Glycemic Response to Metformin: A Metgen Meta-Analysis.Clinical pharmacology and therapeutics · 2017Pooled it
- Systemic and gut microbiome changes with metformin and liraglutide in youth-onset type 2 diabetes: the MIGHTY study.Gut microbes · 2025Trial
- The effects of prebiotics on gastrointestinal side effects of metformin in youth: A pilot randomized control trial in youth-onset type 2 diabetes.Frontiers in endocrinology · 2023Trial
- Metformin with Versus without Concomitant Probiotic Therapy in Newly Diagnosed Patients with Type 2 Diabetes or Prediabetes: A Comparative Analysis in Relation to Glycemic Control, Gastrointestinal Side Effects, and Treatment Compliance.The Turkish journal of gastroenterology : the official journal of Turkish Society of Gastroenterology · 2022Trial
- Effects of metformin and alogliptin on body composition in people with type 2 diabetes.Journal of diabetes investigation · 2019Trial
- Metformin-induced glucagon-like peptide-1 secretion contributes to the actions of metformin in type 2 diabetes.JCI insight · 2018Trial
- Gut microbiota and plasma metabolites associated with diabetes in women with, or at high risk for, HIV infection.EBioMedicine · 2018Trial
- Postprandial glucose-lowering effect of premeal consumption of protein-enriched, dietary fiber-fortified bar in individuals with type 2 diabetes mellitus or normal glucose tolerance.Journal of diabetes investigation · 2018Trial
- Association of metformin administration with gut microbiome dysbiosis in healthy volunteers.PloS one · 2018Trial
- Improved glycemic control with minimal systemic metformin exposure: Effects of Metformin Delayed-Release (Metformin DR) targeting the lower bowel over 16 weeks in a randomized trial in subjects with type 2 diabetes.PloS one · 2018 · on this mapTrial
- Trial
- Biliary effects of liraglutide and sitagliptin, a 12-week randomized placebo-controlled trial in type 2 diabetes patients.Diabetes, obesity & metabolism · 2016 · on this mapTrial
- Once-daily delayed-release metformin lowers plasma glucose and enhances fasting and postprandial GLP-1 and PYY: results from two randomised trials.Diabetologia · 2016 · on this mapTrial
- Trial
- Trial
91 more citing papers are in PubMed but not listed here.
Corrections and comments
- Erratum issued
Authors and funding
10 authors at 4 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
The marked sentences are the ones the graph read a number from.
unlabelledMetformin, a biguanide derivate, has pleiotropic effects beyond glucose reduction, including improvement of lipid profiles and lowering microvascular and macrovascular complications associated with type 2 diabetes mellitus (T2DM). These effects have been ascribed to adenosine monophosphate-activated protein kinase (AMPK) activation in the liver and skeletal muscle. However, metformin effects are not attenuated when AMPK is knocked out and intravenous metformin is less effective than oral medication, raising the possibility of important gut pharmacology. We hypothesized that the pharmacology of metformin includes alteration of bile acid recirculation and gut microbiota resulting in enhanced enteroendocrine hormone secretion. In this study we evaluated T2DM subjects on and off metformin monotherapy to characterize the gut-based mechanisms of metformin. Subjects were studied at 4 time points: (i) at baseline on metformin, (ii) 7 days after stopping metformin, (iii) when fasting blood glucose (FBG) had risen by 25% after stopping metformin, and (iv) when FBG returned to baseline levels after restarting the metformin. At these timepoints we profiled glucose, insulin, gut hormones (glucagon-like peptide-1 (GLP-1), peptide tyrosine-tyrosine (PYY) and glucose-dependent insulinotropic peptide (GIP) and bile acids in blood, as well as duodenal and faecal bile acids and gut microbiota. We found that metformin withdrawal was associated with a reduction of active and total GLP-1 and elevation of serum bile acids, especially cholic acid and its conjugates. These effects reversed when metformin was restarted. Effects on circulating PYY were more modest, while GIP changes were negligible. Microbiota abundance of the phylum Firmicutes was positively correlated with changes in cholic acid and conjugates, while Bacteroidetes abundance was negatively correlated. Firmicutes and Bacteroidetes representation were also correlated with levels of serum PYY. Our study suggests that metformin has complex effects due to gut-based pharmacology which might provide insights into novel therapeutic approaches to treat T2DM and associated metabolic diseases.
trial registrationwww.ClinicalTrials.gov NCT01357876.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the Socratic graph.