Metformin After Bariatric Surgery: What Clinicians and Patients Need to Know

What does the metformin label say about surgery?

The boxed warning on metformin covers lactic acidosis, a postmarketing event that has included fatal cases [1]. The label lists the risk factors it wants watched: renal impairment, certain drugs such as carbonic anhydrase inhibitors like topiramate, age 65 or older, radiological studies with contrast, surgery and other procedures, hypoxic states such as acute congestive heart failure, excessive alcohol intake, hepatic impairment, and mitochondrial disease [1]. Onset is often subtle, with malaise, myalgias, respiratory distress, somnolence or abdominal pain, and the laboratory picture is blood lactate above 5 mmol/L, anion gap acidosis and metformin plasma levels generally above 5 mcg/mL [1]. If lactic acidosis is suspected, the label says to discontinue metformin and institute supportive measures in hospital, with prompt hemodialysis recommended [1].

For procedures, the label says withholding food and fluids during surgical or other procedures may increase the risk of volume depletion, hypotension and renal impairment, and that metformin should be temporarily discontinued while patients have restricted food and fluid intake [1].

Does bariatric surgery change how metformin is absorbed?

Metformin's labeled pharmacokinetics are worth keeping in mind. Oral bioavailability is about 50% to 60%, food lowers absorption (an 850 mg tablet taken with food gives a peak about 40% lower and an AUC 25% lower), the drug is not metabolized, it is cleared unchanged by the kidneys, and plasma half-life is about 6.2 hours [1]. It also acts partly in the gut: a 2016 review describes increased intestinal glucose uptake and lactate production, higher GLP-1 concentrations and an altered microbiome, and proposes that metformin response and tolerance are linked with the gut [5].

A 2010 systematic review of drug absorption after bariatric surgery found 26 studies across a range of agents. The effect was drug-specific, evidence of diminished absorption was strongest for cyclosporine, thyroxine, phenytoin and rifampin, and only three studies examined gastric bypass or gastroplasty [3]. The review's abstract does not report metformin-specific findings.

The extended-release label says to swallow the tablet whole and never crush, cut or chew it [2].

What about vitamin B12?

The label has a dedicated warning. In 29-week trials, about 7% of patients with previously normal serum B12 fell to subnormal levels; the decrease may be due to interference with B12 absorption from the B12-intrinsic factor complex, may be associated with anemia, and appears rapidly reversible with discontinuation of metformin or B12 supplementation [1]. The label directs hematologic parameters annually and vitamin B12 every 2 to 3 years, with abnormalities managed [1].

Longer follow-up comes from the Diabetes Prevention Program. In a secondary analysis, low B12 (203 pg/mL or less) was more common with metformin than placebo at 5 years (4.3% vs 2.3%) but not at 13 years (7.4% vs 5.4%); combined low and borderline-low B12 (298 pg/mL or less) was more common at both points (19.1% vs 9.5%, and 20.3% vs 15.6%) [6]. The odds of deficiency rose 13% per year of metformin use (OR 1.13, 95% CI 1.06 to 1.20), and neuropathy was more common in metformin users with low B12 [6].

A small 2000 study of 21 patients with type 2 diabetes on a sulfonylurea, 14 of whom switched to metformin, found that oral calcium supplementation reversed the metformin-induced fall in holotranscobalamin, which the authors attributed to a calcium-dependent effect at the ileal membrane [7]. It did not study bariatric surgery.

The 2019 multisociety guideline on perioperative care of bariatric patients states that a team approach to perioperative care is mandatory, with special attention to nutritional and metabolic issues [8].

Gastrointestinal side effects and dosing

Gastrointestinal effects dominate the label's adverse reaction tables. In a US trial of immediate-release metformin up to 2,550 mg a day (141 patients on metformin, 145 on placebo), diarrhea occurred in 53% vs 12%, nausea or vomiting in 26% vs 8% and flatulence in 12% vs 6%; diarrhea led to discontinuation in 6% [1]. For extended-release metformin (781 patients vs 195 on placebo), diarrhea was 10% vs 3% and nausea or vomiting 7% vs 2%, with discontinuation for diarrhea in 0.6% [2]. The label cautions that rates from different trials cannot be compared directly [1].

A retrospective chart review of 471 charts included 310 eligible patients in the extended-release metformin group and 158 in the immediate-release group (mean daily doses about 1,258 mg and 1,282 mg). Overall gastrointestinal adverse event frequency was similar between the two formulations, even though about a quarter of the extended-release group had been switched from immediate-release because of gastrointestinal side effects [9].

The 2010 absorption review concluded that individual dose adjustment and therapeutic monitoring may be required for drugs whose absorption is reduced after bariatric surgery [3]. The labeled adult maximum is 2,550 mg a day for immediate-release tablets and 2,000 mg a day for extended-release tablets [1][2]. Immediate-release: start 500 mg twice daily or 850 mg once daily with meals, increase by 500 mg weekly or 850 mg every 2 weeks to a maximum of 2,550 mg a day in divided doses, with doses above 2,000 mg possibly better tolerated three times a day [1]. Extended-release: 500 mg once daily with the evening meal, increased by 500 mg weekly to a maximum of 2,000 mg once daily, and patients switching from immediate-release can move at the same total daily dose up to 2,000 mg [2].

Kidney function and contrast scans

The prescribing information sets the renal rules: an eGFR before starting and at least yearly; metformin is contraindicated below eGFR 30 mL/min/1.73 m2; starting is not recommended at eGFR 30 to 45; if eGFR later falls below 45, the label says to reassess the benefit and risk of continuing, and to discontinue metformin if eGFR falls below 30 [1].

Iodinated contrast has its own instruction. The label says to stop metformin at the time of or before the procedure in patients with eGFR 30 to 60 mL/min/1.73 m2, a history of liver disease, alcoholism or heart failure, or when intra-arterial contrast is used; eGFR is rechecked 48 hours afterward and metformin is restarted only if renal function is stable [1].

Does diabetes come back, and where does metformin fit?

Mingrone et al. randomly assigned 60 patients with type 2 diabetes of at least 5 years and a BMI of 35 or more to medical treatment, gastric bypass or biliopancreatic diversion; at 5 years, 19 of 38 surgical patients (50%) maintained remission versus none of 15 medically treated patients, and hyperglycemia relapsed in 8 of the 15 surgical patients who had achieved 2-year remission [10].

DiGiorgi et al. followed 42 RYGB patients with type 2 diabetes for at least 3 years: diabetes resolved in 64% and improved in 36%, and 10 patients (24%) later recurred or worsened, with recurrence associated with regaining a greater share of lost weight (37.7% vs 15.4%) [4].

Metformin's own prevention data come from people with elevated glucose who did not yet have diabetes. In the Diabetes Prevention Program, 3,234 adults took metformin 850 mg twice daily, placebo, or a lifestyle program: metformin cut diabetes incidence by 31% (95% CI 17 to 43%) over a mean 2.8 years, while the lifestyle program cut it by 58% [11]. At 15 years the metformin reduction was 18% (HR 0.82) [12]. Preventing diabetes this way is not a labeled use; the labeled indication is type 2 diabetes [1].

Label interactions

The label's interaction table covers several groups [1]:

• Carbonic anhydrase inhibitors (topiramate, zonisamide, acetazolamide, dichlorphenamide) can lower serum bicarbonate and raise lactic acidosis risk; the label says to consider more frequent monitoring.
• Drugs that reduce metformin clearance through OCT2/MATE transporters (ranolazine, vandetanib, dolutegravir, cimetidine) could increase metformin exposure.
• Alcohol potentiates metformin's effect on lactate metabolism, and the label says to warn patients against excessive alcohol intake.
• Insulin or insulin secretagogues raise hypoglycemia risk, and lower doses of those drugs may be needed.
• Drugs that raise blood glucose, including thiazides and other diuretics, corticosteroids, thyroid products, estrogens, oral contraceptives, phenytoin, nicotinic acid, sympathomimetics, calcium channel blockers and isoniazid, may cause loss of glycemic control.