The prescribing information for metformin ER tablets lists diarrhea, nausea/vomiting, flatulence, asthenia, indigestion, abdominal discomfort, and headache as the most common adverse reactions (> 5.0%). Studies that compare extended-release with immediate-release metformin report different stomach and bowel results, depending on design and population. A licensed provider decides what is appropriate.
What the label lists
The percentages below come from the label's Table 1. It covers adverse reactions occurring more than 5% and more common than placebo in adults with type 2 diabetes mellitus. The tablets group was n=781 and the placebo group was n=195.
| Question | What the source says |
|---|---|
| Most common adverse reactions (> 5.0%) | Diarrhea, nausea/vomiting, flatulence, asthenia, indigestion, abdominal discomfort, and headache |
| Diarrhea, tablets versus placebo | 10% versus 3% |
| Nausea/vomiting, tablets versus placebo | 7% versus 2% |
| Stopping the tablets because of diarrhea | Diarrhea led to discontinuation of the tablets in 0.6% of patients |
| Also more commonly reported than placebo | Abdominal pain, constipation, distention abdomen, dyspepsia/heartburn, flatulence, dizziness, headache, upper respiratory infection, taste disturbance |
What the patient information says about side effects
The patient information leaflet in the label says common side effects of the tablets include diarrhea, nausea, and upset stomach, and that these side effects generally go away after you take the medicine for a while. It also says to tell your doctor if the side effects bother you a lot, last for more than a few weeks, come back after they’ve gone away, or start later in therapy.
Low blood sugar and other medicines
The label's warnings section states that insulin and insulin secretagogues (e.g., sulfonylurea) are known to cause hypoglycemia. It states the tablets may increase the risk of hypoglycemia when combined with insulin and/or an insulin secretagogue.
The label's drug interactions table repeats that co-administration with an insulin secretagogue (e.g., sulfonylurea) or insulin may increase the risk of hypoglycemia. It also states that certain drugs tend to produce hyperglycemia and may lead to loss of glycemic control. A licensed provider decides about any combination of medicines.
Extended-release compared with immediate-release
A 2021 systematic review and meta-analysis of randomized controlled trials compared equal daily doses of extended-release (MXR) and immediate-release (MIR) metformin, with no single dose stated. It concluded that MXR was associated with statistically worse but likely clinically similar HbA1c lowering and minimal improvement of GI intolerance compared to MIR.
A randomized open-label phase IV trial in treatment-naive Chinese adults with type 2 diabetes reported incidences of drug-related AEs of 26.5% (n = 66) in the metformin IR-only group and 32.2% (n = 85) in the metformin XR-only group. GI AEs were 23.8% and 22.3% in those groups, respectively. The abstract does not state the mg doses. As a disclosure, the affiliations listed on that abstract include authors in Medical Affairs, Merck China Ltd, an affiliate of Merck KGaA, Darmstadt, Germany.
An observational prospective cohort study of newly diagnosed Saudi patients with type 2 diabetes reported that by 6 months, 45.2% of IR patients and 24.5% of XR patients reported any GI side effect (P <.05). The abstract does not state doses. Observational studies cannot show cause and effect.
A long-term safety report from the randomized Diabetes Prevention Program and its Outcomes Study states that no significant safety issues were identified. It also states that gastrointestinal symptoms were more common in metformin than placebo participants and declined over time. The abstract does not state the dose.
What this does not tell you
The label percentages come from adults with type 2 diabetes mellitus and compare the tablets with placebo. They are not a comparison of extended-release with immediate-release.
The three comparison sources differ in design, population and results, so this guide does not combine their figures. The cohort cannot show cause and effect. The company affiliation is a disclosure on an abstract, not a finding about the trial's results. The long-term report is the authors' own statement and sits beside its finding that gastrointestinal symptoms were more common with metformin.
None of these sources tells a reader which tablet type or dose to take. A licensed provider decides.