Miriam E Tucker

October 05, 2015

STOCKHOLM — Genetic variants and certain common medications that interfere with gut absorption of metformin may both be tied to severe intolerance of the drug, new research shows.

Metformin is a first-line treatment for type 2 diabetes, used by over 120 million people worldwide. But about 20% of people who take it experience gastrointestinal side effects such as nausea, diarrhea, vomiting, bloating, and abdominal pain. For about 5% of people taking metformin, those symptoms are severe enough to require discontinuation of therapy.

"The pathophysiology isn't known but is hypothesized to be related to a high concentration of metformin in the intestine following oral administration," explained Tanja Dujic, PhD, who presented the findings at the recent European Association for the Study of Diabetes (EASD) 2015 Meeting. Dr Dujic was with the faculty of pharmacy at the University of Sarajevo, Bosnia and Herzegovina, at the time the study was conducted but is now a postdoctoral researcher at the University of Dundee, Scotland.

In a paper published in May in Diabetes (Diabetes. 2015;64:1786-1793), Dr Dujic and colleagues found associations between severe metformin intolerance and specific genetic variants of a carrier protein involved in the oral absorption, hepatic uptake, and renal elimination of metformin, the organic cation transporter 1 (OCT1).

They also found that certain commonly prescribed medications appear to inhibit transport of metformin via OCT1, including tricyclic antidepressants, proton-pump inhibitors (PPIs), and calcium-channel blockers.

In her EASD presentation, Dr Dujic summarized the earlier paper and also presented some new data related to the genetic variants.

In the earlier study of over 2000 patients with type 2 diabetes who were newly prescribed metformin, approximately 8% of the population was found to have two inactive OCT1 alleles, and these individuals had more than twice the risk for severe metformin intolerance as did those with other variants. When those individuals took OCT1-inhibiting medications, their risk for severe metformin intolerance increased fourfold.

The second study, of 92 patients, further confirmed the link between the specific OCT1 polymorphisms and severe metformin intolerance, but the numbers were too small to show the medication associations.

Taken together, Dr Dujic told Medscape Medical News that the findings have potential clinical implications, but she urged caution. "Especially for the 8% of patients carrying the two alleles, if they receive the drugs it's even worse. Clinically you can switch the PPIs to another drug, but this needs to be confirmed in a clinical trial. These were retrospective studies."

Session moderator Guntram Schernthaner, MD, head of the department of medicine at Rudolfstiftung Hospital, Vienna, Austria, called the earlier study "a very good paper." Regarding the new findings, he said, "It's very interesting, but still more data are needed. It should be repeated in a larger study."

Medications and Metformin Intolerance

The published observational cohort study included a total of 2166 new users of metformin from a large type 2 diabetes database that included genetic information. Of those, 251 were defined as intolerant based on having been switched from metformin to another oral glucose-lowering agent within 6 months. The 1915 who had been prescribed a daily dose of 2000 mg of metformin or more for longer than 6 months were deemed tolerant.

At baseline, the intolerant patients were about 10 years older on average (P < .001) and more likely to be female (P < .001); had lower weight and body mass index (P < .001), lower creatinine clearance levels (P < .001), lower HbA1c values (P = .003); and were using a lower metformin dose (P < .001).

Almost half of the metformin-intolerant patients (48%) were taking an OCT1-inhibiting drug, compared with 33% of tolerant patients (P < .001).

In logistic regression analysis adjusting for age, sex, and weight, the use of any OCT1-inhibiting medication was significantly associated with metformin intolerance, with an odds ratio (OR) of 1.63 (P = .001). Verapamil had the strongest association, with an odds ratio of 7.44. Codeine was next (OR, 4.03), followed by citalopram (OR, 3.22), doxazosin (OR, 1.97), and PPIs (OR, 1.84).

Because more of the intolerant patients were using PPIs prior to metformin initiation, which could have confounded the results, Dr Dujic and colleagues also analyzed the data for histamine H2-receptor antagonists, which are used for the same gastrointestinal indications but don't inhibit OCT1.

There were no significant differences in histamine-receptor–antagonist use between the metformin-tolerant and intolerant patients, suggesting that the result seen for PPIs does reflect OCT1 inhibition, the authors say in their paper.

When genotype was added to the model, the presence of two OCT1 reduced-function alleles was independently associated with metformin intolerance, with an odds ratio of 2.41 (P < .001). Moreover, that risk was approximately doubled among patients with two of the low-activity alleles who were also taking an OCT1-inhibiting drug, compared with those with just one or no deficient alleles and not taking any OCT1 inhibitor drugs (OR, 4.13, P < .001).

Genetic Predisposition to Intolerance?

In the new prospective observational study, genotyping was conducted in 92 adults prescribed metformin as initial diabetes therapy: half of the patients (52%) had no OCT1 reduced-transport gene variants, 40% had one, and 8% had two reduced-function alleles.

After adjustment for age, sex, weight, and use of OCT1-inhibiting medications, the 43 patients with gastrointestinal side effects were significantly less likely than the 49 without to have no reduced-function alleles (42% vs 61%) and more likely to have one (46.5% vs 35%) or two alleles (12% vs 4%) (P = .048 for the entire association).

In logistic regression, the number of reduced-function alleles was a significant predictor of metformin GI side effects (OR, 2.31; P = .034). But use of OCT1-inhibiting drugs was not significantly different (P = .912), although only six of the tolerant group and eight of the group with GI side effects were taking them.

"Studies in larger cohorts are needed to explore possible interaction between OCT1-inhibiting drugs and metformin side effects to replicate our findings," Dr Dujic told Medscape Medical News.

The data come from the Wellcome Trust United Kingdom Type 2 Diabetes Case Control Collection (GoDARTS) cohort, which was funded by the Wellcome Trust, with informatics support provided by the Chief Scientist Office, Scotland. Dr Dujic received a European Foundation for the Study of Diabetes Albert Renold Travel Fellowship award. Dr Dujic and Dr Schernthaner have no relevant financial relationships.

European Association for the Study of Diabetes 2015 Meeting; Stockholm, Sweden. Abstract 218, presented September 18, 2015.

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