Metformin Side Effects: Rare But Serious Adverse Events Explained

How common is lactic acidosis with metformin?

Metformin-associated lactic acidosis is the event the label warns about first. In postmarketing cases it has caused death, hypothermia, hypotension and resistant bradyarrhythmias, and its onset is often subtle [1]. The label describes nonspecific symptoms - malaise, myalgias, respiratory distress, somnolence and abdominal pain - and a characteristic laboratory picture: blood lactate above 5 mmol/L, anion gap acidosis without ketonuria or ketonemia, a raised lactate-to-pyruvate ratio, and metformin plasma levels generally above 5 mcg/mL [1]. The label also states that metformin decreases liver uptake of lactate, raising blood lactate levels, which may increase the risk of lactic acidosis in patients at risk [1].

The best frequency estimate comes from a Cochrane systematic review of 347 comparative trials and cohort studies in type 2 diabetes. Pooled data contained no fatal or nonfatal cases of lactic acidosis in 70,490 patient-years of metformin use, or in 55,451 patient-years of non-metformin treatment; Poisson statistics put the upper limit for the true incidence at 4.3 cases per 100,000 patient-years with metformin and 5.4 cases without it [2]. That does not prove the rate is zero, but it points to an uncommon event.

In a five-year single-center review of 197 patients admitted to intensive care with lactic acidosis, 10 had metformin-associated lactic acidosis; their median arterial pH was 6.78 and mean lactate 18.7 mmol/L, and mortality was 50%, against 74% in patients whose acidosis had another cause [3]. Ten patients is a small series, and its mortality figure is not a general prognosis.

Which risk factors does the label name?

The label states that postmarketing cases of metformin-associated lactic acidosis occurred primarily in patients with significant renal impairment, and lists these additional risk factors [1]:

• Age 65 or older
• Radiologic studies with contrast
• Surgery and other procedures, particularly with restricted food and fluid intake
• Hypoxic states, such as acute congestive heart failure, myocardial infarction or sepsis
• Excessive alcohol intake
• Hepatic impairment
• Mitochondrial disease
• Certain drugs, including carbonic anhydrase inhibitors such as topiramate

What the label says about suspected lactic acidosis

If lactic acidosis is suspected, the label says to stop metformin and start general supportive measures in hospital, with prompt hemodialysis recommended; metformin is dialyzable with a clearance of up to 170 mL/min under good hemodynamic conditions, and hemodialysis has often reversed symptoms [1].

Vitamin B12 deficiency

In metformin hydrochloride tablet trials of 29-week duration, a drop to subnormal levels of previously normal serum vitamin B12 was observed in approximately 7% of patients [1]. The label says the decrease may be associated with anemia but appears to be rapidly reversible with discontinuation of metformin or vitamin B12 supplementation, and it advises measuring hematologic parameters annually and vitamin B12 every 2 to 3 years [1].

Longer-term data come from the Diabetes Prevention Program Outcomes Study, in which participants were assigned to metformin 850 mg twice daily or placebo for 3.2 years; the metformin group then received open-label metformin for an additional 9 years [4]. Low B12 was found in 4.3% of the metformin group versus 2.3% of the placebo group at 5 years; the difference at 13 years was not statistically significant [4]. Combined low and borderline-low B12 (298 pg/mL or less) was more common at both 5 years (19.1% vs 9.5%) and 13 years (20.3% vs 15.6%), and the odds of deficiency rose 13% per year of metformin use [4]. Neuropathy was more common among metformin users with low B12 [4].

A separate systematic review of 26 papers found lower B12 levels in metformin users; pooling four trials, metformin lowered B12 by a mean of 57 pmol/L after 6 weeks to 3 months of use [5].

Hypoglycemia: mostly a combination problem

Metformin does not raise insulin secretion - the label states insulin secretion remains unchanged during therapy [1]. In the label's US trial of immediate-release metformin up to 2,550 mg daily, hypoglycemia was among the adverse reactions reported in 1% to 5% of patients and more often than with placebo [1].

The label carries a specific warning for combination use: coadministration with insulin or an insulin secretagogue such as a sulfonylurea increases the risk of hypoglycemia, and lower doses of the insulin or secretagogue may be required [1].

Kidney function and contrast scans

Metformin is cleared by the kidneys and is not metabolized [1]. The label calls for an eGFR check before starting metformin and at least once a year during treatment. It contraindicates metformin below an eGFR of 30 mL/min/1.73 m2, does not recommend starting it at 30 to 45, and calls for reassessing continued treatment if eGFR falls below 45 [1].

For iodinated contrast, the label says to stop metformin at the time of, or before, the procedure in patients with eGFR between 30 and 60, a history of hepatic impairment, alcoholism or heart failure, or when intra-arterial contrast is to be given. The label calls for another eGFR check 48 hours after the procedure and says to restart metformin only if renal function is stable [1].

Liver injury and hepatic impairment

The liver is not the route of metformin elimination; the drug is excreted unchanged in urine [1]. Cholestatic, hepatocellular and mixed hepatocellular liver injury have been reported in postmarketing use, and because these reports are voluntary, frequency cannot be reliably estimated and a causal relationship cannot be established [1].

Hepatic impairment is a different matter. The label says to avoid metformin in patients with clinical or laboratory evidence of hepatic disease, and notes that patients with hepatic impairment have developed metformin-associated lactic acidosis, possibly through impaired lactate clearance and higher blood lactate levels [1].

Interactions that raise the risk

The label's interaction table names four groups [1]:

• Carbonic anhydrase inhibitors (topiramate, zonisamide, acetazolamide, dichlorphenamide) can lower serum bicarbonate and cause a non-anion gap metabolic acidosis, and may increase the risk of lactic acidosis; more frequent monitoring is advised.
• Drugs that reduce metformin clearance through OCT2/MATE transporters - ranolazine, vandetanib, dolutegravir and cimetidine - can raise systemic exposure to metformin and may increase lactic acidosis risk; the label advises weighing benefits and risks.
• Alcohol potentiates metformin's effect on lactate metabolism, and the label warns against excessive intake.
• Insulin and insulin secretagogues raise hypoglycemia risk, and lower doses of those drugs may be needed.

The label also lists drugs that tend to raise blood glucose - thiazides and other diuretics, corticosteroids, phenothiazines, thyroid products, estrogens, oral contraceptives, phenytoin, nicotinic acid, sympathomimetics, calcium channel blockers and isoniazid - and advises watching for loss of glycemic control [1].

What long-term follow-up showed

In the Diabetes Prevention Program and its open-label extension, no significant safety issues were identified; gastrointestinal symptoms were more common with metformin than placebo and declined over time, and hemoglobin and hematocrit were slightly lower in the metformin group, with the drop occurring in the first year and no further change thereafter [6]. At 15 years, microvascular disease was 13.0% with metformin, 12.4% with placebo and 11.3% with lifestyle intervention, with no overall difference between groups [7].