Table 1.
Summary of the genes and variants involved in metformin pharmacogenomics
| Genes | Variant | Associated phenotype |
|---|---|---|
| SLC22A1 (OCT1) | Reduced function alleles: R61C (rs12208357), G401S (rs34130495), 420del (rs142448543 or rs34305973 or rs35191146), and G465R (rs34059508) | High AUC, higher Cmax, and lower oral volume of distribution (V/F) [47] |
| Impaired response to a glucose tolerance test [47] | ||
| Increased CLr and decreased hepatic uptake, no exposure changes (AUC) [22] | ||
| Reduced lipid response (total CHO and triglycerides) and insulin responses to metformin in women with PCOS [48] | ||
| rs72552763 deletion, rs34130495 and other reduced function alleles | Reduced trough metformin steady-state concentration, and association with the initial absolute decrease in HbA1c [7] | |
| SLC22A2 (OCT2) | 596C>T, 602C>T, and 808G>T (rs316019) | Increase in AUC and Cmax and a decrease in CLr [49] |
| rs316019 (808G>T) | Reduced CLr but no effect on overall drug exposure [28] | |
| rs316019 (808G>T) | Higher metformin CLrs [50] | |
| SLC22A3 (OCT3) | T400I (rs8187725), V423F and T44M (rs8187715) | Impacted metformin uptake and AMPK activation in skeletal muscle cells [11] |
| SLC47A1 (MATE1) | rs2289669 | Reduction in HbA1c [51] |
| No observed association with metformin CLr or other pharmacokinetic parameters [51] | ||
| rs8065082 | Reduced diabetes incidence [52] | |
| SLC47A2 (MATE2K) | rs12943590 (–130G>A) | Poorer response to metformin treatment, assessed by the relative change in glycated hemoglobin [53] |
| SRR | rs391300 | Associated with levels of FPG, PPG, and CHO [54] |
| ATM | rs11212617 | Associated with metformin treatment success (Hba1c<7%) [55] |
| LKB/STK11 | rs8111699 | C allele associated with a significantly decreased chance of ovulation in PCOS women [56,57] |
AMPK, AMP-activated protein kinase; AUC, area under the concentration–time curve; Cmax, maximal plasma concentration; CHO, cholesterol; CLr, renal clearance; FPG, fasting plasma glucose; HbAlc, hemoglobin A1c; PCOS, polycystic ovary syndrome; PPG, postprandial plasma glucose.