Metformin Seasonal Use Considerations: A Clinical Guide

Does metformin act differently in hot or cold weather?

Metformin is a biguanide taken by mouth [1]. It is not metabolized, is negligibly bound to plasma proteins, and is cleared unchanged by the kidneys through tubular secretion; plasma half-life is about 6.2 hours and roughly 90% of an absorbed dose is gone within 24 hours [1]. Oral bioavailability is about 50% to 60%, and an 850 mg tablet taken with food has a peak about 40% lower and an AUC 25% lower than the same tablet taken fasting [1]. Clearance falls and half-life lengthens when kidney function falls [1].

Lactic acidosis: the risk factors the label names

The boxed warning covers lactic acidosis, and the label states that postmarketing cases primarily occurred in patients with significant renal impairment [1]. Metformin decreases liver uptake of lactate, increasing blood lactate levels, which the label says may raise lactic acidosis risk especially in patients at risk [1]. Named risk factors are renal impairment, certain drugs such as carbonic anhydrase inhibitors, age 65 or older, radiologic studies with contrast, surgery and other procedures, hypoxic states such as acute congestive heart failure, excessive alcohol intake, hepatic impairment and mitochondrial disease [1].

The presentation is often subtle: malaise, myalgias, respiratory distress, somnolence and abdominal pain, with blood lactate above 5 mmol/L, an anion gap acidosis and metformin levels generally above 5 mcg/mL [1]. The label says to educate patients and families about these symptoms and to instruct them to stop metformin and report the symptoms if they occur; suspected cases are managed in hospital, with prompt hemodialysis recommended [1].

How often does it happen? A review of the literature puts the reported incidence below 10 cases per 100,000 patient-years, with mortality approaching 50% once it occurs [3]. Pooled data from 347 comparative trials and cohort studies found no cases of fatal or nonfatal lactic acidosis across 70,490 patient-years of metformin use, with a statistical upper limit of 4.3 cases per 100,000 patient-years [4].

Volume depletion appears in the procedures section: withholding food and fluids during surgery or other procedures may increase the risk of volume depletion, hypotension and renal impairment, and the label says to discontinue metformin temporarily while intake is restricted [1].

Kidney checks: what the label requires

Before metformin is started, the label requires an eGFR, and it says to obtain one at least annually in everyone taking the drug [1]. Metformin is contraindicated below an eGFR of 30 mL/min/1.73 m²; starting is not recommended at 30 to 45; benefit and risk should be reassessed if eGFR later falls below 45; and the drug should be discontinued if it falls below 30 [1]. The label recommends assessing renal function more often in patients at risk of renal impairment, including older adults [1]. It also notes that lactic acidosis risk rises with age because older patients are more likely to have hepatic, renal or cardiac impairment [1].

Contrast scans and procedures

For iodinated contrast, the label says to stop metformin at the time of, or before, the procedure in patients with an eGFR of 30 to 60 mL/min/1.73 m², in those with a history of hepatic impairment, alcoholism or heart failure, or when contrast is given intra-arterially; eGFR is re-evaluated 48 hours after the study and metformin is restarted if renal function is stable [1]. A liver history, heavy alcohol use, heart failure or an intra-arterial route brings the hold instruction into play on its own, separate from the kidney cutoff [1].

For surgery and other procedures with restricted food and fluid, the label says to discontinue the drug temporarily [1].

Flu season: what changes for people with diabetes

The CDC states that people with type 1, type 2 or gestational diabetes, even when well managed, are at higher risk of serious flu complications, and that about 30% of adults hospitalized with flu have diabetes [2]. It recommends annual injectable flu vaccination for people with diabetes and says they should generally not receive the nasal spray vaccine; it also recommends prompt antiviral treatment for anyone with diabetes who has flu or suspected flu [2]. CDC reports that flu vaccination has been associated with reduced flu-related hospitalizations among people with diabetes (79%) [2]. Flu can raise blood sugar, or lower it when eating and drinking fall off, and CDC directs people with diabetes to sick-day guidance and to keeping at least a two-week supply of regular medicines on hand [2].

On the metformin side, the label lists hypoxic states, cardiovascular collapse, acute myocardial infarction and sepsis among the events that call for discontinuation [1].

GI side effects and the extended-release option

The label's immediate-release trial, 141 patients on metformin up to 2,550 mg per day versus 145 on placebo, reported diarrhea in 53% versus 12%, nausea or vomiting in 26% versus 8%, and flatulence in 12% versus 6%; diarrhea led to discontinuation in 6% [1]. In placebo-controlled extended-release trials, 781 patients on metformin extended-release versus 195 on placebo, diarrhea was 10% versus 3% and nausea or vomiting 7% versus 2%, with diarrhea leading to discontinuation in 0.6% [5]. The label cautions that adverse reaction rates from different trials cannot be directly compared [1]. A published observational study states that 20% to 30% of people develop gastrointestinal side effects on metformin and about 5% cannot tolerate it because of them [6].

Extended-release tablets are swallowed whole and never crushed, cut or chewed; the label starts them at 500 mg once daily with the evening meal and increases by 500 mg weekly to a maximum of 2,000 mg once daily, and a patient on immediate-release can switch at the same total daily dose up to 2,000 mg once daily [5].

Vitamin B12: a check every few years, not every season

In 29-week trials, subnormal vitamin B12 levels were seen in approximately 7% of patients, and the label says to measure hematologic parameters annually and vitamin B12 every 2 to 3 years [1]. It adds that the decrease appears rapidly reversible with discontinuation of metformin or with B12 supplementation [1]. In the Diabetes Prevention Program Outcomes Study, low B12 (203 pg/mL or less) occurred in 4.3% of the metformin group versus 2.3% of the placebo group at 5 years, and 7.4% versus 5.4% at 13 years, which was not significant. Combined low and borderline-low B12 (298 pg/mL or less) was more common with metformin at 5 years (19.1% versus 9.5%) and at 13 years (20.3% versus 15.6%), and the odds of deficiency rose 13% per year of metformin use (OR 1.13) [7].

Interactions the label lists

Corticosteroids are on the label's list of drugs that tend to produce hyperglycemia and loss of glycemic control, with instructions to observe patients closely while they are given and, for hypoglycemia, when they are withdrawn [1]. Carbonic anhydrase inhibitors (topiramate, zonisamide, acetazolamide and dichlorphenamide) frequently lower serum bicarbonate and may increase the risk of lactic acidosis; the label says to consider more frequent monitoring [1]. Ranolazine, vandetanib, dolutegravir and cimetidine can raise metformin exposure and may increase lactic acidosis risk [1]. Alcohol potentiates metformin's effect on lactate metabolism, and the label warns against excessive intake [1].