Table 3.

Summary of the gene polymorphisms involved in the pharmacogenetics of biguanides.

SNP	Study population	Associated response phenotype	Reference
SLC22A1
R61C (Arg61Cys) (rs12208357) G401S (Gly401Ser) (rs34130495) 420del (rs72552763) G465R (Gly465Arg) (rs34059508)	Healthy volunteers (N = 21).	Lower effects of metformin in the oral glucose tolerance test.	Shu et al, 2007 (91)
	Healthy volunteers (N = 20).	Higher metformin AUC, higher maximal plasma concentration and lower oral volume of distribution.	Shu et al, 2008 (92)
	Healthy men (N = 103).	Additive increase in renal clearance of metformin with increasing number of reduced-function alleles.	Tzvetkov et al, 2009 (93)
	Prospective study: T2DM patients treated with metformin (N = 159).	Inverse correlation of metformin trough Css and reduction of HbA1c levels with the number of reduced-function SLC22A1 alleles.	Christensen et al, 2011 (96)
R61C (Arg61Cys) (rs12208357) 420del (rs72552763)	Population-based GoDARTS study: T2DM patients, incident users of metformin (N = 1.531).	No effects on initial glycemic response to metformin, the mid-term HbA1c control, and the rate of metformin monotherapy failure.	Zhou et al, 2009 (94)
rs622342 A>C	Population-based study: T2DM patients, incident users of metformin (N = 102).	Lower HbA1c reduction.	Becker et al, 2009 (95)
SLC22A2
T199I (Thr199Ile) (rs201919874) T201M (Thr201Met) (rs145450955) A270S (Ala270Ser) (rs316019) A270S (Ala270Ser) (rs316019)	Healthy subjects (N = 26).	Increased metformin Cmax and AUC and reduced renal clearance of metformin.	Song et al, 2008 (100)
	Healthy subjects (N = 15).	Reduced renal clearance of metformin.	Wang et al, 2008 (101)
	Healthy subjects (N = 23).	Increased metformin renal clearance.	Chen et al, 2009 (102)
SLC47A1
rs2289669 G>A	Population-based study: T2DM patients, incident users of metformin (N = 116).	Greater reduction of HbA1c levels.	Becker et al, 2009 (103)
rs8065082 C>T	DPP study: individulas at high risk for T2DM randomized to placebo (N = 1.000), metformin (N = 990) or lifestyle intervention program (N = 1.004).	Lower diabetes incidence in subjects treated with metformin.	Jablonski et al, 2010 (104)
SLC47A2
rs12943590 G>A	Retrospective study: T2DM patients initially treated with metformin (N = 253).	Lower HbA1c reduction.	Choi et al, 2011 (105)
ATM
rs11212617 A>C	GWA study (N = 1.024) and two replication cohorts (N = 1.783 and N = 1.113) of T2D patients, incident users of metformin.	Association with treatment success (achieving an HbA1c below 7% (53 mmol/mol)), the combined odds ratio = 1.35.	Zhou et al, 2011 (107)

AUC - area under the curve; C_ss - steady-state plasma concentration; C_max – peak plasma concentration.