Metformin and Stomach Upset: Is This Normal?

Metformin does a large part of its work inside the gut itself, not only in the bloodstream. It reduces expression of the SGLT1 transporter on the lining of the jejunum, slowing glucose absorption there (Frontiers in Pharmacology, 2024), and reduced bile acid absorption in the ileum has been implicated in metformin-induced gastrointestinal effects (PMC / Medicine journal, 2024). Sugars and bile acids left in the bowel pull water with them, which is why loose stools are the typical pattern rather than a random one.

There is also a signalling side. A duodenal biopsy study in metformin-naive people found that metformin stimulated the release of serotonin from enterochromaffin cells, which the authors suggest may help explain metformin-induced nausea, vomiting and diarrhea (Allied Academies, undated). Research in animals also points to the gastrointestinal tract as a major source of the acute rise in GDF15 after an oral dose (PMC, 2024).

• Common early on. Beyond the trial figures in the label, one review describes metformin-associated gastrointestinal side effects as common in approximately 20% of patients, with approximately 5% discontinuing because of them (PMC, 2024); the FDA label reports diarrhea led to discontinuation in 6% of patients taking metformin hydrochloride tablets.
• Usually an adjustment-period effect. The FDA states that once a patient is stabilized on any dose level, the gastrointestinal symptoms that are common during initiation of therapy are unlikely to recur (FDA, 2017). Taking the tablets with meals is what the label advises to help lessen upset stomach.
• New symptoms after a stable stretch are different. The same FDA statement notes that later occurrence of gastrointestinal symptoms could be due to lactic acidosis or other serious disease — report these rather than assuming they are the old side effect returning. Metformin carries an FDA boxed warning, the strongest safety-related warning the agency issues, for lactic acidosis (Drugs.com, 2025).
• Formulation can matter. In a study of extended-release metformin, reported symptoms included diarrhea (6.9%), bloating (6.2%), abdominal pain (5.3%), vomiting (2.4%) and constipation (1.1%), with a lower incidence of adverse events than with immediate-release; the UK's NICE guidelines recommend the extended-release form for people intolerant of immediate-release (The Educated Patient, summarizing published study and NICE guidance). The difference is release speed — extended-release delivers the drug more gradually to the upper gut rather than all at once. Which formulation and what dose are your prescriber's decisions.

Usually not a concern

• Loose stools, gas or mild nausea in the first days or weeks after starting, or after a change your prescriber made, that eases as you continue.
• Nausea that settles when you take the dose with a meal, which is what the label advises for upset stomach.
• Passing a soft mass in your stool that looks like the tablet — the FDA label states this is not harmful.

Call your doctor

• Nausea and flatulence, diarrhea, stomach upset or constipation that persists or bothers you — MedlinePlus advises contacting your provider about these.
• Gastrointestinal symptoms that appear for the first time after months of being steady on the same dose.
• An illness causing severe vomiting, diarrhea or fever, or you are drinking much less liquid than normal — the FDA says to tell your doctor, as you may need to stop metformin for a short time. That decision is theirs, not yours.
• Diarrhea or vomiting severe enough that you cannot keep fluids down.
• Right away, not a routine call: feeling very weak and tired, unusual muscle pain, trouble breathing, unusual sleepiness, feeling cold especially in arms and legs, dizziness, or a slow or irregular heartbeat, with or without stomach or intestinal symptoms. The FDA label directs patients to stop metformin and call their provider right away for these. If breathing is difficult or you feel faint, go to the emergency department or call 911 rather than waiting for a callback.