This review provides information on the overall incidence of D-DIs as a cause of adverse patient outcomes, although there is still uncertainty about the impact of D-DIs on adverse patient outcomes. Our results suggest that a limited number of drugs are involved in the majority of cases and that the number of reasons for admission as a consequence of D-DIs seems to be modest.

Chloroquine and hydroxychloroquine are now being widely used for treatment of COVID-19. Both medications prolong the QT interval and accordingly may put patients at increased risk for torsades de pointes and sudden death. Published guidance documents vary in their recommendations for monitoring and managing these potential adverse effects. Accordingly, we set out to conduct a systematic review of the arrhythmogenic effect of short courses of chloroquine or hydroxychloroquine. We searched on MEDLINE and Embase, as well as in the gray literature up to April 17, 2020, for the risk of QT prolongation, torsades, ventricular arrhythmia, and sudden death with short-term chloroquine and hydroxychloroquine usage. This search resulted in 390 unique records, of which 41 were ultimately selected for qualitative synthesis and which included data on 1515 COVID-19 patients. Approximately 10% of COVID-19 patients treated with these drugs developed QT prolongation. We found evidence of ventricular arrhythmia in 2 COVID-19 patients from a group of 28 treated with high-dose chloroquine. Limitations of these results are unclear follow-up and possible publication/reporting bias, but there is compelling evidence that chloroquine and hydroxychloroquine induce significant QT-interval prolongation and potentially increase the risk of arrhythmia. Daily electrocardiographic monitoring and other risk mitigation strategies should be considered in order to prevent possible harms from what is currently an unproven therapy.

1,5,6,7 OBJECTIVE-Metformin, an oral glucose-lowering drug, is taken up in hepatocytes by the organic cation transporter (OCT) 1 and in renal epithelium by OCT2. In these cells, the multidrug and toxin extrusion (MATE) 1 protein, encoded by the SLC47A1 gene, is responsible for the excretion of metformin into the bile and urine, respectively. We studied the effect of single nucleotide polymorphisms (SNPs) in the SLC47A1 gene on the A1C-lowering effect of metformin. RESEARCH DESIGN AND METHODS-We identified all incident metformin users in the Rotterdam Study, a populationbased cohort study. Associations between 12 tagging SNPs in the SLC47A1 gene and change in A1C level were analyzed. RESULTS-One hundred and sixteen incident metformin users were included in the study sample. The rs2289669 GϾA SNP was significantly associated with metformin response. For the other SNPs, no associations were found. For each minor A allele at rs2289669, the A1C reduction was 0.30% (95% CI Ϫ0.51 to Ϫ0.10; P ϭ 0.005) larger. After Bonferroni correction for multiple testing, the P value was 0.045. M etformin is an oral glucose-lowering drug, widely used for the treatment of type 2 diabetes (1). The molecular mechanism of the glucose-lowering effect is not fully understood, although it is known that inhibition of the hepatic gluconeogenesis has an important role (2). Metformin is mainly eliminated by tubular secretion, and hepatic metabolism has a minor role. CONCLUSIONS-TheSeveral drug transporters are involved in the distribution and excretion of metformin (3). The role of two organic cation transporters (OCTs), OCT1 and OCT2, is assumed. OCT1 and OCT2 are members of the solute carrier (SLC) 22 family and encoded by the SLC22A1 and SLC22A2 genes, respectively, with gene location 6q25.3. OCT1 is expressed in the basolateral membrane of hepatocytes, and the uptake of metformin in the hepatocytes by OCT1 is an essential step for the glucose-lowering effect (4 -6). In OCT1 gene knockout mice, the metformin liver concentrations were lower and the glucose-lowering effect impaired (4,7). Genetic variations in the SLC22A1 gene (R61C, G401S, M420del, and G465R) are associated with differences in metformin plasma levels and glucose concentrations after an oral glucose tolerance test in healthy volunteers (4,7). OCT2 is expressed in the basolateral membrane of the renal epithelium, and transportation of metformin over this membrane may be the first step to tubular secretion (8,9). Genetic variations in SLC22A2 (T199I, T201M, and A270S) are associated with decreased renal excretion and increased plasma concentrations of metformin (10,11).Recently, a multidrug and toxin extrusion (MATE) transporter protein family was identified, assigned as the SLC 47 family (12,13). The SLC47A1 gene, with gene location 17p11.2, encodes the MATE1 transporter. Metformin is one of the substrates of this transporter (14). MATE1 is located in the bile canalicular membrane in the hepatocyte and in the brush border of the renal epithelium and is responsible for the final...