Diabetologia (2012) 55:1971–1977 and the Rotterdam Study [13] from the Netherlands, and the multi-centre CARDS (Collaborative Atorvastatin Diabetes Study) Trial [14] from the UK. Data were analysed in the individual cohorts, separately and combined in a meta-analysis. Finally an additional meta-analysis was performed using these new cohorts combined with the previously described GoDARTS and UKPDS stage 2 replication cohorts [8]. Methods Study cohorts and participants Inclusion criteria for all cohorts were: white ethnicity; continuous metformin treatment for at least 6 months; a pretreatment HbA1c value measured within 6 months of the start of metformin and at least one measurement within the 18 months after; no other glucose-lowering medication prescription except stable sulfonylurea treatment before and during metformin treatment. Ethics approval was obtained from the Medical Ethics Committee of the VU Vrije Universiteit Medical Center for the DCS, the Erasmus Medical Center for the Rotterdam Study, and for CARDS each centre obtained local research ethics committee approval after approval from the Multi-centre Research Ethics Committee. All participants gave written informed consent. 1973 Diabetes Care System West-Friesland The DCS started in 1996 and is a diabetes management model which aims to improve diabetes care by coordinating the different types of diabetes care and to improve patient empowerment by pro- viding education. Patients from the West-Friesland region in the Netherlands visit a local DCS centre once a year for a medical examination; therefore longitudinal information on medical history, drug use and drug response is available for all patients (n 0 5,424) [12]. Metformin response could be defined in 929 white patients, and their characteristics are shown in Table 1. Patients were genotyped for rs11212617 with a Taqman assay (Assay ID C_1314213; Applied Biosystems, Nieuwerkerk a/d IJssel, the Netherlands) according to the man- ufacturer’s protocol. The call rate was 97.6%, and there was no deviation from Hardy–Weinberg equilibrium (HWE; p0 0.46). Rotterdam Study The Rotterdam Study is a prospective population-based cohort study of 10,994 whites aged 55 years and older in Rotterdam, the Netherlands. Patients were invited between 1990 and 1999 and have been fol- lowed since then. The aim of the study was to investigate determinants of chronic and disabling diseases [13]. Medi- cation prescription data were available for nearly all partici- pants. Metformin response could be defined in 182 patients, and their characteristics are shown in Table 1. Participants were genotyped for rs609261, which is in high LD with rs11212617 (r2 0 1.0, HAPMAP, CEU) using Table 1 Characteristics of the cohorts included in this study Characteristic n Age (years) Male (%) BMI Baseline HbA1c (%) Baseline HbA1c (mmol/mol) Adherence eGFR Responders (%) Metformin monotherapy (%) Genotype frequency rs11212617; AA/AC/CC (%) Qualitya (selection, comparability, exposure) DCS 929 63.4±10.0 56.4 30.1±4.9 6.7±1.0 50±11 91.8±36.1 67.1 58.8 32.5/47.1/20.4 ****, *b, *** Rotterdam Study 182 74.2±8.1 45.1 8.3±1.5 67±16 88.4±14.7 57.7 35.7 32.4/46.7/20.9 ****,*b, *** CARDS 254 61.4±8.8 69.0 8.7±1.4 72±15 52.0 31.0 32.3/44.4/23.2 ****,*b, *** Data are means±SD or n (%) a Quality of the studies assessed with the Newcastle–Ottawa Assessment Scale (www.ohri.ca/programs/clinical_epidemiology/oxford.asp); the maximum scores for selection, comparability and exposure are ****, ** and ***, respectively. GoDARTS and UKPS are not represented in this table and both scored the maximum of ****, ** and *** b The Rotterdam Study and CARDS lacked the covariates BMI and eGFR in the analysis, and the DCS lacked the covariate adherence in the analysis, therefore these studies only scored one star for comparability eGFR, estimated glomular filtration rate calculated with the Cockcroft–Gault formula; NA, not available