Metformin Side Effects Severity Distribution by Patient Phenotype

Is there a severity distribution for metformin side effects?

Not in the form the question implies. The label reports adverse reactions as rates from placebo-controlled trials and handles the serious end separately in a boxed warning; it does not sort reactions into severity grades or give a separate distribution for each patient type [1]. Patient phenotype enters through the risk-factor list, which names renal impairment, certain drugs such as carbonic anhydrase inhibitors, 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].

In practice metformin's unwanted effects fall into three groups. Gastrointestinal reactions are common and are counted in the label's trial tables. Vitamin B12 loss is tied to length of use. Lactic acidosis is the rare, serious end and is described from postmarketing cases [1].

Long-term data from the Diabetes Prevention Program and its follow-up found no significant safety issues over 7 to 8 years of open-label treatment; gastrointestinal symptoms were more common with metformin than placebo and declined over time, and hemoglobin and hematocrit were slightly lower in the metformin group [5].

Gastrointestinal side effects: the numbers

In a US trial of immediate-release metformin up to 2,550 mg a day, 141 patients on metformin were compared with 145 on placebo: diarrhea 53% versus 12%, nausea or vomiting 26% versus 8%, flatulence 12% versus 6%, asthenia 9% versus 6%, indigestion 7% versus 4%, abdominal discomfort 6% versus 5%, and headache 6% versus 5% [1]. Diarrhea led to discontinuation in 6% of patients [1]. A second list covers reactions reported in 1% to 5% and more often than placebo: abnormal stools, hypoglycemia, myalgia, lightheadedness, dyspnea, nail disorder, rash, increased sweating, taste disorder, chest discomfort, chills, flu syndrome, flushing and palpitation [1].

The one severity marker the label provides for these reactions is discontinuation, which for diarrhea was 6% on the immediate-release tablet [1].

Does the extended-release tablet cause fewer GI effects?

Its label trial numbers are lower. Across placebo-controlled trials that gave extended-release metformin to 781 patients, diarrhea occurred in 10% versus 3% on placebo and nausea or vomiting in 7% versus 2%, with diarrhea leading to discontinuation in 0.6% [2].

Those figures come from different trials than the immediate-release numbers, and the label states that adverse reaction rates observed in the clinical trials of a drug cannot be directly compared with rates in the clinical trials of another drug and may not reflect the rates seen in practice [2]. A retrospective chart review compared 310 patients on extended-release metformin with 158 on immediate-release metformin: about 25% of the extended-release group had been switched from immediate-release because of gastrointestinal adverse events, and the frequency of any gastrointestinal adverse event was similar between the two formulations [6].

Vitamin B12: who loses it and how fast

The label reports that in metformin clinical trials of 29-week duration, a decrease to subnormal levels of previously normal serum vitamin B12 was seen in approximately 7% of patients, possibly through interference with B12 absorption from the B12-intrinsic factor complex. The label notes the change may be associated with anemia but appears to be rapidly reversible with discontinuation or B12 supplementation, that people with inadequate B12 or calcium intake or absorption appear predisposed, and that hematologic parameters should be measured annually and B12 every 2 to 3 years [1].

The Diabetes Prevention Program Outcomes Study gives the long-term numbers. At 5 years, low B12 (203 pg/mL or less) occurred in 4.3% of metformin users versus 2.3% of placebo users (P=0.02), and at 13 years in 7.4% versus 5.4%, which was not significant (P=0.12). 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%). The odds of B12 deficiency rose 13% for each year of metformin use (OR 1.13, 95% CI 1.06 to 1.20). Anemia was more common with metformin but did not track B12 status, and neuropathy was more common in metformin users with low B12 [3].

Longer metformin use was associated with higher odds of B12 deficiency: the odds rose 13% for each year of use [3].

Lactic acidosis: the rare serious end

The boxed warning describes postmarketing cases of metformin-associated lactic acidosis that resulted in death, hypothermia, hypotension and resistant bradyarrhythmias, with a subtle onset of malaise, myalgias, respiratory distress, somnolence and abdominal pain, a blood lactate above 5 mmol/L, anion gap acidosis, a raised lactate-to-pyruvate ratio and metformin levels generally above 5 mcg/mL. If it is suspected, the label says to stop metformin and treat in hospital, where prompt hemodialysis is recommended [1]. The label also states that these postmarketing cases primarily occurred in patients with significant renal impairment [1].

A review of comparative trials and observational cohorts found no cases of fatal or nonfatal lactic acidosis in 70,490 patient-years of metformin use or in 55,451 patient-years of non-metformin use; its calculated upper incidence limit was 4.3 per 100,000 patient-years with metformin and 5.4 without it [4]. The label separately identifies patients at higher risk [1].

Renal function and contrast: the sharpest cutoff

Metformin is not metabolized and is cleared by the kidneys, and its half-life lengthens and clearance falls in renal impairment [1]. For immediate-release metformin, the label calls for an eGFR check before treatment and at least yearly. It contraindicates use below 30 mL/min/1.73 m2, does not recommend starting at 30 to 45, calls for reassessing treatment if eGFR falls below 45, and says to discontinue if eGFR falls below 30 [1]. In patients at risk of renal impairment, such as the elderly, the label calls for renal function to be assessed more frequently [1].

For certain iodinated contrast procedures or patients with specified risk factors, the label calls for temporarily withholding metformin, checking eGFR 48 hours afterward, and restarting only when kidney function is stable [1].

A review of 17 observational studies associated metformin use with lower all-cause mortality in people with chronic kidney disease, congestive heart failure or chronic liver disease with hepatic impairment, and with fewer heart failure readmissions in those with kidney disease or heart failure, but the evidence was rated low strength [7].

Age 65 and older, liver disease, alcohol, heart failure

The label states that lactic acidosis risk rises with age because older patients are more likely to have hepatic, renal or cardiac impairment, and that renal function should be assessed more frequently in them [1]. In hepatic impairment it says to avoid metformin, because patients with hepatic impairment have developed lactic acidosis, possibly from impaired lactate clearance [1]. Alcohol potentiates metformin's effect on lactate metabolism, and the label warns against excessive intake [1]. Several postmarketing lactic acidosis cases occurred in acute congestive heart failure with hypoperfusion and hypoxemia, and the label says to discontinue metformin when such an event occurs; it also says to stop temporarily during surgery or other procedures with restricted food and fluid intake [1].

Drugs that shift a patient into a higher-risk group

Carbonic anhydrase inhibitors such as topiramate, zonisamide, acetazolamide and dichlorphenamide lower serum bicarbonate and can cause a non-anion gap acidosis, and the label advises more frequent monitoring when they are used with metformin [1]. Drugs that interfere with the renal transporters that handle metformin, including ranolazine, vandetanib, dolutegravir and cimetidine, raise metformin exposure and may increase lactic acidosis risk [1]. In a study of seven subjects, cimetidine increased the area under the plasma metformin concentration-time curve by an average of 50% [8]. Insulin and insulin secretagogues such as sulfonylureas raise hypoglycemia risk, and the label notes lower doses of those drugs may be required [1].

Pregnancy

The label reports that data on metformin in pregnancy are limited and not sufficient to determine a drug-associated risk for major birth defects or miscarriage, and that published studies have not reported a clear association; animal studies showed a partial placental barrier [1].

What adverse-event reports cannot tell you

Reported-event counts do not measure how often a side effect happens. The FDA's adverse event dashboard states that reports cannot be used to estimate the incidence of the events reported, that a report does not establish that the drug caused the event, and that reports are sometimes duplicated, incomplete or unverified [9].