What is the phenotype of patients with gastrointestinal intolerance to metformin?

A substantial minority of type 2 diabetes mellitus (T2DM) patients treated with metformin develop severe gastrointestinal (GI) symptoms leading to drug discontinuation, depriving them of the potentially cardioprotective pleiotropic effects of this first-line oral agent. At present, it is unclear whether treating diabetes without being able to ever use metformin alters cardiovascular outcomes.

From a population of 773 consecutive T2DM outpatients, the cardiometabolic phenotypes of 83 patients who discontinued metformin due to GI intolerance (Met-Intol cases) were compared with those of 332 age- and gender-matched metformin-tolerant (Met-Tol) controls, amounting to a case: control ratio of 1:4.

Mean age (SD) was 70 (13) (male:female: 46:54). Metformin intolerance was associated with a reduced prevalence of macroangiopathy (P=0.0486), mainly due to a lower prevalence of CAD (-34%; P=0.0374). Met-Intol cases more often belonged to blood group A and subgroup A Rh+, with 50% and 66% relative increases (P=0.0039 and P=0.0005), respectively. There were twice as many non-right-handers among the Met-Intol (18% vs. 9%; P=0.0262), and this group also had significantly higher serum ferritin and LDL cholesterol levels. Statins/fibrates were used by 66%/19% of Met-Tol vs. 48%/18% of Met-Intol (P=0.0051 for statins). On the other hand, there were no differences between groups as regards smoking, diabetes duration, HbA1c, BMI, blood pressure, waist size, fat mass, visceral fat, liver steatosis, the metabolic syndrome, eGFR, albuminuria, erectile dysfunction and microangiopathy.

Intolerance to metformin represents an unforeseen phenotype in T2DM patients characterized by a low rate of ischaemic heart disease, left-handedness, ABO group imbalance and an iron load.