• Predict patient-specific response to metformin

Metformin, an oral glucose-lowering drug, is widely used to treat type 2 diabetes and to delay or prevent its onset in people at high risk of the disease.¹ Metformin acts primarily by inhibiting glucose production in the liver, but it also reduces gastrointestinal glucose absorption and improves glucose utilization. Although metformin is considered a first-line treatment for type 2 diabetes, approximately one-third of patients don’t respond.² Preliminary evidence suggests that this may be due to certain single-nucleotide polymorphisms (SNPs) in genes that mediate metformin transport.^2-5

Metformin is actively transported into the liver, where it exerts its primary action, and then is actively transported from the liver into bile and blood stream. Elimination from the liver is mediated in part by the multidrug and toxin extrusion protein (MATE1), a membrane-bound transporter protein.⁶ Thus, genetic changes that affect MATE1 activity could influence the concentration and, presumably, effectiveness of metformin in the liver cells.^3,5

Two recent studies have found that a SNP in the gene encoding MATE1 (SLC47A1) may affect the clinical effectiveness of metformin. In a post-hoc analysis of the Rotterdam Study, the minor “A” allele of the SNP rs2289669 G/A was associated with enhanced metformin response: hemoglobin A1C concentration decreased by 0.3% in patients with the GA genotype and by 0.7% in patients with the AA genotype.⁴ A second study examined whether SNPs in 40 candidate genes affect the ability of metformin to prevent diabetes in nearly 3,000 high-risk individuals.⁵ This study found that a SNP that is in tight linkage disequilibrium with rs2289669 affects metformin response: individuals with at least one minor allele benefited from metformin therapy, while those homozygous for the major allele did not.⁵

• Individuals being considered for, or receiving, metformin therapy

• PCR amplification of rs2289669 of the SLC47A1 gene

• Detection of fluorescent extension products on an automated DNA sequencer

Metformin response is likely to be optimal in patients with 2 A alleles (ie, minor variant) in the MATE1 rs2289669 SNP. Patients with 1 A allele are likely to respond less favorably, and those with the GG genotype may not respond at all or show suboptimal response.^4,5

Metformin response may be affected by genetic variations other than those tested for in this assay. Results should be interpreted in light of relevant clinical and familial data.  Having the A alleles would make a person a better responder to Metformin.