Metformin Regret, Stopping, and Restarting: What Real Patients and Clinicians Say

What long-term treatment showed

In UKPDS 34, 753 overweight adults with newly diagnosed type 2 diabetes were randomized to a conventional diet-based policy (411) or intensive blood-glucose control with metformin (342). Over a median 10.7 years, metformin reduced any diabetes-related endpoint by 32% (95% CI 13 to 47), diabetes-related death by 42% (95% CI 9 to 63) and all-cause mortality by 36% (95% CI 9 to 55) [3]. These are group-level results of a treatment policy, not a prediction for one person, and the trial did not examine what happens after metformin is stopped.

What the label's trials show about side effects

The label's US trial of immediate-release metformin gave 141 patients up to 2,550 mg a day and 145 patients placebo [1]. Diarrhea occurred in 53% versus 12%, nausea or vomiting in 26% versus 8%, flatulence in 12% versus 6%, asthenia in 9% versus 6%, indigestion in 7% versus 4%, abdominal discomfort in 6% versus 5% and headache in 6% versus 5%; diarrhea led to discontinuation in 6% of patients [1].

The extended-release label reports a different trial: 781 patients on extended-release metformin against 195 on placebo, with diarrhea in 10% versus 3% and nausea or vomiting in 7% versus 2%, and diarrhea leading to discontinuation in 0.6% [2]. The label states that adverse reaction rates from different trials cannot be directly compared, because trial conditions vary and rates in practice may differ [1].

The DPP Outcomes Study, which followed participants for years, reported that gastrointestinal symptoms were more common with metformin than placebo and declined over time, with no significant safety issues identified [4].

How the label schedules the dose

For adults on immediate-release metformin, the label gives a starting dose of 500 mg twice a day or 850 mg once a day with meals, with increases of 500 mg a week or 850 mg every two weeks up to a maximum of 2,550 mg a day in divided doses; it says doses above 2,000 mg may be better tolerated given three times a day with meals [1]. For children 10 and older, it gives a start of 500 mg twice a day with meals, increased by 500 mg a week to a maximum of 2,000 mg a day [1].

For extended-release, the label gives a start of 500 mg once a day with the evening meal, rising by 500 mg a week to a maximum of 2,000 mg once a day; it says the tablets are swallowed whole and never crushed, cut or chewed [2]. Extended-release is labeled for adults only [2].

Kidney function and lactic acidosis

The boxed warning covers metformin-associated lactic acidosis, a postmarketing event whose onset is often subtle, with malaise, myalgias, respiratory distress, somnolence and abdominal pain; laboratory findings include blood lactate above 5 mmol/L and metformin plasma levels generally above 5 mcg/mL [1]. Named risk factors are renal impairment, certain drugs such as carbonic anhydrase inhibitors, age 65 or older, contrast studies, surgery and other procedures, hypoxic states such as acute heart failure, excessive alcohol intake and hepatic impairment [1].

The kidney rules are the practical part. The label contraindicates metformin at an eGFR below 30 mL/min/1.73 m2, does not recommend starting at 30 to 45, says to assess the benefit and risk of continuing if eGFR later falls below 45, and says to discontinue if eGFR falls below 30 [1]. It notes that the postmarketing lactic acidosis cases occurred primarily in patients with significant renal impairment [1].

On frequency, a 2010 Cochrane systematic review pooled 347 comparative trials and cohort studies and found no cases of fatal or nonfatal lactic acidosis in 70,490 patient-years of metformin use or in 55,451 patient-years without it; the statistical upper limit for the true incidence was 4.3 cases per 100,000 patient-years with metformin and 5.4 without [5].

On alcohol, the label says it potentiates metformin's effect on lactate metabolism and warns patients against excessive intake [1].

What metformin does to blood sugar while it is taken

The label says metformin lowers both fasting and post-meal glucose, decreases hepatic glucose production, decreases intestinal absorption of glucose and improves insulin sensitivity by increasing peripheral glucose uptake and utilization [1].

A 2012 meta-analysis of 35 trials found metformin monotherapy lowered HbA1c by 1.12 percentage points versus placebo (95% CI 0.92 to 1.32) [6]. In the Diabetes Prevention Program, 3,234 adults with elevated fasting and post-load glucose were randomized to placebo, metformin 850 mg twice daily, or an intensive lifestyle program; over an average 2.8 years, diabetes incidence was 11.0, 7.8 and 4.8 cases per 100 person-years respectively, a 31% reduction with metformin (95% CI 17 to 43) and 58% with lifestyle (95% CI 48 to 66) [7]. At 15 years the metformin reduction had shrunk to 18% (HR 0.82, 95% CI 0.72 to 0.93) versus placebo, with cumulative incidence of 56% versus 62%; lifestyle was 55% [8].

Weight moves modestly too. During the DPP, body weight fell 2.06% with metformin versus 0.02% with placebo, and waist circumference fell 2.13 cm versus 0.79 cm [4].

Restarting: what the label sets out

The label gives starting doses and kidney-function limits [1]. It says to obtain an eGFR before starting and at least annually afterward, and to assess renal function more often in people at risk, such as the elderly [1].

Iodinated contrast has its own rule. The label says to stop metformin at or before an iodinated contrast imaging procedure in patients with eGFR 30 to 60, a history of hepatic impairment, alcoholism or heart failure, or when intra-arterial contrast is used. It says to re-evaluate eGFR 48 hours after the procedure and restart metformin only if renal function is stable [1].

Interactions the label lists:

• Carbonic anhydrase inhibitors (topiramate, zonisamide, acetazolamide, dichlorphenamide) can lower bicarbonate and raise lactic acidosis risk, so the label advises more frequent monitoring [1].
• Drugs that reduce metformin clearance through OCT2 and MATE transporters (ranolazine, vandetanib, dolutegravir, cimetidine) raise metformin exposure, and the label says to weigh benefits and risks [1].
• Insulin or an insulin secretagogue raises hypoglycemia risk, and a lower dose of either may be needed [1].
• Drugs that raise blood glucose (thiazides and other diuretics, corticosteroids, phenothiazines, thyroid products, estrogens, oral contraceptives, phenytoin, nicotinic acid, sympathomimetics, calcium channel blockers, isoniazid) call for close observation for loss of glycemic control [1].

Switching from immediate-release to extended-release

The extended-release label allows a switch at the same total daily dose, up to 2,000 mg once daily [2].

A 24-week double-blind trial randomized adults with type 2 diabetes to extended-release metformin at 1,500 mg once daily, 1,500 mg twice daily or 2,000 mg once daily, or immediate-release metformin 1,500 mg per day taken in two doses; HbA1c fell 0.73%, 0.74%, 1.06% and 0.70% respectively, and overall adverse events were similar across groups, though fewer extended-release patients discontinued for nausea during the initial dosing period [9].

The FDA reported voluntary recalls of certain extended-release metformin lots between July 2020 and January 2021 because of NDMA above its acceptable intake limit, and its testing has not shown NDMA in immediate-release metformin [10].

Vitamin B12 over years of use

The label says that in 29-week trials, a decrease to subnormal levels of previously normal vitamin B12 was seen in about 7% of patients, possibly from interference with B12 absorption from the B12-intrinsic factor complex, and that it appears to be rapidly reversible with discontinuation or B12 supplementation [1]. It says to measure hematologic parameters annually and vitamin B12 every 2 to 3 years [1].

In the DPP Outcomes Study, low B12 (203 pg/mL or less) occurred in 4.3% of metformin users versus 2.3% of placebo users at 5 years, and 7.4% versus 5.4% at 13 years, which was not statistically significant; combined low and borderline-low B12 (298 pg/mL or less) was 19.1% versus 9.5% at 5 years and 20.3% versus 15.6% at 13 years, and the odds of deficiency rose 13% per year of metformin use (OR 1.13, 95% CI 1.06 to 1.20) [11]. A nested case-control study of 155 cases and 310 controls found each 1 g/day step in metformin dose carried an odds ratio of 2.88 for B12 deficiency (95% CI 2.15 to 3.87) [12].