glucose tolerance responses were demonstrated, with carriers of SLC47A1 variants having increased and SLC47A2 variants having decreased responses to metformin. The authors also reported better HbA1c responses in patients with diabetes (n = 145) carrying the SLC47A1 promoter variant suggesting improved pharmacotherapeutic outcomes. Similarly, promoter variants (n = 8) in SLC47A2 have also been characterized for their effects on metformin pharmacodynamics in a diverse US population (n = 272) [114]. Likewise, coding variants 485 C > T (rs19556609) and 1177 G > A (19525563) had significantly lowered metformin uptake and reduced protein expression in vitro. Addition of the −130 G > A promoter polymorphism to SLC47A2 haplotypes increased luciferase activities and reduced binding to the transcriptional repressor myeloid zinc finger 1. Similarly, diabetic patients who were homozygous for the −130 G > A variant (rs19560590) had a significantly reduced relative change in hemoglobin A1c compared with homozygous wild type or heterozygous individuals.
A large study in diabetic patients (800 cases and 400 controls) of Pakistani descent evaluated the influence of SLC47A2/MATE2‐K (rs138244461) on the efficacy of metformin [115]. Efficacy of diabetes was reported through hemoglobin A1c, random blood glucose, and fasting blood glucose measurements. Efficacy of metformin on cholesterol (total, HDL, LDL) and triglyceride profiles were also assessed. Study results showed that subjects homozygous for the wild‐type genotype (C/C) had statistically significant improvements of their diabetes versus patients who were heterozygous or homozygous for T/T.
A study was conducted to determine the allelic frequencies of the SLC47A1 (816 G > A; rs2289669) and SLC47A2 (−130 G > A; rs12943590) polymorphism in a South Indian population (n = 102) and found highly different prevalence than Chinese, Nigerian, and Northern and Western European ancestry [116]. Subsequently, the authors conducted a study evaluating SLC47A1 (816 G > A; rs2289669) and SLC47A2 (−130 G > A; rs12943590) on changes in fasting blood glucose, hemoglobin A1c, dosage requirements, and toxicities in type 2 diabetes mellitus patients (n = 105) from South India receiving metformin monotherapy [117]. The differences in fasting blood glucose and hemoglobin A1c between the G/G and AG/AA genotype groups for both SLC47A1 and SLC47A2, while greater, were not considered significant. Metformin dosing requirements and adverse events were also similar across genotype groups. By comparison, another study conducted in a South Indian population of metformin‐naïve Type 2 diabetic patients (n = 221) [118]. SLC47A2 (rs12943590) across a codominant model was significantly associated with better hemoglobin A1c response. An interaction analysis between the SLC22A1 (rs622342; A > C) and SLC47A1 (rs2289669, rs8065082) polymorphisms and between SLC22A2 (rs316019) and SLC47A2 and metformin response demonstrated hemoglobin A1c changes were greatest for SLC22A2 G/G genotype and SLC47A2 G/A genotype. The results demonstrate the power of assessing genetics of several transporters in determining associations with metformin response.
Chinese patients (n = 53) who were recently diagnosed with Type 2 diabetes and treated with metformin monotherapy were evaluated for associations between SLC22A1 (rs594709; G > A) and SLC47A1 (rs2289669) polymorphisms and treatment effects (glucose, lipids, insulin sensitivity) [119]. While SLC22A1 rs594709 G/G patients had larger increases in fasting insulin and greater decreases in insulin sensitivity than A/A or A/G genotypes, patients with SLC47A1 rs2289669 A/A had decreased fasting blood glucose and post‐prandial insulin than A/G or G/G. SLC47A1 rs2289669 G/G patients had a greater decrease in total cholesterol and low‐density lipoprotein cholesterol than A/G or A/A genotypes. These data suggested the interplay between polymorphisms in SLC22A1 and SLC47A1 and beneficial metabolic responses to metformin. Another study in patients (n = 291) receiving monotherapy with metformin were assessed for changes in hemoglobin A1c and basal glucagon‐like peptide (GLP‐1) according to the rs2289669 genetic polymorphism in SLC47A1 [120]. Carriers of the variant A allele (G/A and A/A) exhibited better hemoglobin A1c reductions and had larger increases in basal GLP‐1. After adjustment for multiple confounding variables, a significant association between the polymorphism and changes in hemoglobin A1c was observed. The authors also concluded that differential responses (increases) in basal GLP‐1, while not directly associated with changes to hemoglobin A1c, may contribute to inter‐individual responses to metformin.
The SLC47A1 variant (rs2289669; 816 G > A) can also impact metformin responses in Iranian subjects (n = 71) [121] and Chinese subjects [122]. After 6 months of therapy with metformin, patients who were heterozygous (A/G) for the noncoding polymorphism showed the greatest reduction in hemoglobin A1c. The study genetic demographics reported only 10 patients with the A/A genotype, which may have limited the ability to detect the full homozygous effect of the variant. An additional Chinese study studied the influence of SLC47A1 (rs2289669) on metformin pharmacokinetics and pharmacologic effects [122]. Newly diagnosed Type 2 diabetes patients (n = 220) were divided into SLC47A1 genotype groups (G/G, G/A, A/A). A subgroup of patients (10 per group) was evaluated for metformin pharmacokinetics. HbA1c level decrease was significantly greater in A/A (−2.32% vs G/A −1.16% vs G/G −1.07%, P < 0.05). Associations existed after adjustments for age, sex, body mass index, baseline HbA1c, and diabetes duration (P < 0.05). Patients with SLC47A1 A/A had higher metformin exposures (17,312 μg h/l vs 11,731 μg h/l vs 10,962 μg h/l) and lower renal secretory clearance (25.80 l/h vs 51.43 l/h vs 42.52 l/h) than other genotype groups. The results from metformin pharmacokinetics and hemoglobin A1c outcomes and alignment with the incorporation of the SCL47A1 genetics data suggest strong evidence for the effects of the polymorphism in the clinical environment in Chinese patients.
3.7.2.2 Nondiabetes Indications
The impact of SLC22A1/OCT1 and SLC47A1/MATE1 polymorphisms on clinical response to metformin in patients with castration‐resistant prostate cancer was evaluated [123]. Patients (n = 36) received metformin until disease progression or toxicity (diarrhea, bloating, anorexia, nausea, fatigue). Disease progression was greater in the C/C genotype for SLC22A1 (80%, rs622342) vs. carriers of the A allele (28.6%) and for carriers of the SLC47A1 A allele (44%, rs2289669) as compared with G/G wild‐type genotype (12.5%). Patients who were carriers of at least one A allele for SLC22A1 (41.9%) versus C/C genotype exhibited increased metformin levels. The authors concluded that polymorphisms in drug transporters may be viable biomarkers to predict progression and toxicity to metformin in clinical studies for castration‐resistant prostate cancer.
3.7.3 Cisplatin Toxicity
Cisplatin is a cancer therapeutic known to cause ototoxicity and nephrotoxicity in patients. A study in Canada enrolled patients (n = 206; predominantly Caucasian) receiving cisplatin and radiation for locally advanced head and neck squamous cell carcinoma and prospectively assessed for ototoxicity (defined as grade 2 or above from baseline, CTCAE v4.02) [124]. Pharmacogenetics of various transporters, including SLC47A1/MATE1, were assessed as covariates. Protective factors for ototoxicity risk were weekly vs. high‐dose cisplatin and SLC47A1/MATE1 (rs2289669) A/A carriers. Survival outcomes were not found to be statistically or clinically impacted by genetic variation in SLC47A1. A study in Chinese non‐small‐cell lung cancer patients (n = 403) also evaluated transporter genotype and toxicity response to platinum chemotherapy (83% cisplatin, 17% carboplatin) [125]. The SLC22A2 variant (rs316019; 808 G > T) was associated with hepatotoxicity and hematological toxicity. By comparison, SLC47A1 (rs2289669) was associated with hematological toxicity. Notably, the study did not appear to assess for renal toxicities secondary to platinum compounds.
While serum creatinine has been a traditional biomarker for kidney injury, limitations have garnered interest in urinary proteins that are secreted from anatomic locations in the nephron and can represent sites of injury to drugs and toxins. A recent study evaluated pharmacogenetics of transport pathways in cisplatin‐treated patients (n = 57) and traditional and novel biomarkers of acute kidney injury [99]. Notably,
