After a preliminary examination of multiple databases with the relevant keywords, we retrieved 182 articles. Amongst these, 151 articles were from PubMed, 27 from Google scholar, and four from Cochrane. Duplicates were removed, after the second screening. We excluded 123 articles based on the titles, abstracts,language selection and availability of full-text articles. Twenty-eight articles were found to be possibly eligible. Twenty one studies were excluded as they did not match the review's inclusion criteria with non relevance and unmatched end points. Finally seven studies are included based on the studies eligibility criteria.The majority of the research found to be done in Asian people. The duration of the research studies ranged from 24 h for single dosage studies on healthy volunteers to 6 months for patients who had been taking Metformin. The average participants age in the study ranged between 18 and 80 years.
The participants in the study were either healthy volunteers or diagnosed with T2DM on Metformin monotherapy. The Metformin's pharmacodynamic parameters were assessed through HbA1c, fasting blood glucose, postprandial blood glucose, or oral glucose tolerance test. Metformin's pharmacokinetics were evaluated by Peak Concentration (C max), Area Under the Curve (AUC), Maximum Time to achieve Cmax (Tmax), Elimination Rate Constant (K or kel), Metformin Uptake Extent and Half-Life (t1/2).
The genetic variants of the OCT2 polymorphism
A total of 13 SNPs were found from the included studies. The SNPs observed were rs7757336, rs316019, rs201919876, rs17588242, rs10755577, rs17589858, rs3127573, rs2928035, rs316024, rs316026, rs316025, rs662301, rs533452. The effects of the observed SNPs on metformin response were quite diverse and appeared to be either positive, negative, or both.
A study in a healthy volunteer Chinese population reported one SNP, 808G > T (Ala270Ser), with a Minor allele frequency of 13.3%. This study further substantiated the nonsynonymous SNP 808G > T polymorphism in the OCT2 gene with amino acid change: alanine to serine is linked with a decreased Metformin CLr (renal clearance) and Metformin CLr and Tubular Clearance (CLt) were found to be significantly reduced in homozygous TT carriers (homozygous for 808G > T). Initially, the GT and TT groups seemed to have a higher total plasma concentration (AUC) of Metformin than the GG group, although this difference did not achieve statistical significance. However, it was discovered that there were significant differences in the CLr and CLt of Metformin between the three genotype groups (P = 0.024 and 0.037, one-way ANOVA). Additionally, the mean Metformin CLr and CLt values were 26.1% (P = 0.022) and 28.0% (P = 0.036) less in TT carriers than in GG carriers respectively .
The SNP rs316019 (808G/T) was genotyped in European Americans (94) andAfrican Americans (66). The study was conducted only in healthy participants who are homozygous reference and heterozygous 808G/T gene as there were no homozygotes 808T/T found in the study. There is no significant difference in the mean Tmax and Cmax between the two genotype groups. The CLR, Serum renal clearance (SrCLR), and total clearance of Metformin were considerably higher in heterozygous variant allele (808G/T) of OCT2 compared to those reference allele (808G/G) homozygous. Statistically, significant difference was not found with the total clearance, presumably because of the diversity in the bioavailability of the subjects. The following variables (race, gender, OCT2 genotype, creatinine clearance (CLCR) and age) were evaluated using multi-variant analysis as Metformin CLR predictors. Merely, genotype and CLCR were found to be good measures of Metformin CLR among these variables. With genotype alone accounting for 28% versus 22% of the total variance in Metformin CLR and CLCR, respectively concluding OCT2 genotype as the only predictor of Metformin SrCLR) which is significant .
A study included fifty healthy Caucasian volunteers and were genotyped for c.808G > T. Both peak plasma concentration (Cmax) and area under the curve of plasma concentration–time to infinity (AUC0-∞) were lesser in the homozygous variant group compared to homozygous and heterozygous and wild types. The apparent (CL/F = Dose/AUC0-∞)) total clearance, CLrenal, secretory clearance CLsec, and volume of distribution (Apparent Vd/F) appeared to be higher in variant homozygous group compared to both the homozygous and heterozygous wild types. For all pharmacokinetic parameters, there were no statistically significant variations among the various c.808G > T genotype groups. On average, the GFR contributed for 22% of the variation in the CLrenal, and the addition of the OCT2 c.808 (G > T) genotype elevated this to 24% .
The study involved 212 Denmark healthy population in total, and it determined that OCT2 c.808 (G > T) genotypes have no affect on the Clrenal .
The study established the frequencies of the SNP rs201919874 in Pakistani diabetes patients. The distributional properties of SNPs SLC22A2 rs201919874 in T2DM patients receiving Metformin monotherapy and in combination with sulfonylureas were compared to those of healthy individuals. There was a statistical difference between groups in terms of HbA1c, fasting, and random glucose levels. This study discovered an association between the SLC22A2 gene's allele A and the therapeutic effectiveness of Metformin. The Metformin response was associated with the heterozygous genotype GA of SLC22A2 rs201919874 in both patient groups (p < 0.05). As Group A patients failed to achieve normal levels of HbA1c as well as fasting and random blood glucose levels, GA and AA genotypes were associated with therapeutic efficacy of Metformin in these population (p < 0.05). Significant associations were observed in Metformin T2DM patients in terms of random blood glucose, fasting glucose, and HbA1c, however, no strong correlation were detected in combination T2DM patients. Patients treated with combination treatment versus metformin showed a significant variation in genotypes with regard to HbA1c levels .
The study was conducted in Latvia and Slovakia population and reported that the minor alleles of the SNP rs7757336 of OCT2 is strongly linked with Metformin inefficiency in newly diagnosed T2DM patients (n = 233). 25 healthy, non-diabetic volunteers participated in a pharmacokinetic study to understand the influence of the identified SNPs on Metformin. The findings of a pharmacokinetic study on 25 healthy volunteers supported the finding that SNP rs7757336 in the 5′ flanking regions of the genes coding for organic cation transporter 2 was associated with the absence of Metformin response and the minor alleles of rs775336 consistently related with lower concentrations of Metformin and AUC∞ of plasma. According to the results, allele probabilities for the major and minor alleles remained at 0.118 and 0.132, respectively. The study subjects were divided into a reference group (n = 12) and a risk group (n = 13) with at least one risk allele. Metformin's AUC∞ in plasma was considerably lower (P = 0.009) in the risk group (4.62 ± 1.29 µg/h/mL) compared with reference group (6.30 ± 1.51 µg/h/mL). In the reference group, there was indeed a significant rise in Cmax (0.84 ± 0.25 g/mL compared to 0.60 ± 0.18 g/mL, P = 0.022); meanwhile, the apparent clearance had grown significantly in the risk group (59.64 ± 18.11 g/h compared to 42.47 ± 9.50 g/h, P = 0.01). The genetic variant rs7757336 was strongly related to lower Metformin response .
rs17588242, rs2928035, rs316024, rs316026 rs662301, rs10755577, rs17589858, rs3127573, rs316025, rs533452
A study by Al-Eitan et al., 212 Jordanians population were screened for 10 OCT2 polymorphisms, and they found nil significant association of glycemic control in T2DM patients on Metformin. The Study showed that there was no discernible correlation between renal Metformin clearance and these specific SLC22A2 SNPs (rs2928035, rs17588242, rs316024, rs316026 rs662301, rs10755577, rs17589858, rs3127573, rs316025 and rs533452.). Furthermore, no statistically significant evidence was found in the present investigation to support any of these examined SLC22A2 SNPs having effect on glycemic control. Polymorphisms found in this study had a p value greater than 0.05, indicating no statistical significance .