OBJECTIVEMetformin is a commonly used glucose-lowering drug. However, apart from glycemic measures, no biomarker for its presence or dose has been identified. RESEARCH DESIGN AND METHODSA total of 237 biomarkers were assayed in baseline serum from 8,401 participants (2,317 receiving metformin) in the Outcome Reduction with Initial Glargine Intervention (ORIGIN) trial. Regression models were used to identify biomarkers for metformin use. RESULTSGrowth differentiation factor 15 (GDF15) was strongly linked to metformin, such that the odds of metformin use per SD increase in level varied from 3.73 (95% CI 3.40, 4.09) to 3.94 (95% CI 3.59, 4.33) depending on the other included variables. For the remaining 25 linked biomarkers, the odds ranged from 0.71 to 1.24. A 1.64 ng/mL higher GDF15 level predicted a 188-mg higher metformin dose (P < 0.0001). CONCLUSIONSGDF15 levels are a biomarker for the use of metformin in people with dysglycemia, and its concentration reflects the dose of metformin.Metformin is currently the most widely used glucose-lowering agent in the world that effectively lowers glucose levels; reduces incident diabetes (1); modestly reduces weight; and may reduce the occurrence of ischemic heart disease, mortality, and some malignancies (2). Whereas its glucometabolic effects are partially due to activation of the AMP-activated protein kinase (3), some of its other effects may be mediated by novel pathways. To identify nonglycemic biomarkers for such pathways, we screened a large panel of 237 markers, covering major physiological pathways that were assayed in baseline serum samples collected in 8,401 participants (;28% of whom were receiving various doses of metformin) in the recently completed Outcome Reduction with Initial Glargine Intervention (ORIGIN) trial. RESEARCH DESIGN AND METHODSThe ORIGIN trial recruited 12,537 people with diabetes, impaired glucose tolerance, or impaired fasting glucose levels who had additional cardiovascular (CV) risk factors (4). Prior to randomization, 8,494 participants (68%) provided baseline blood samples that were spun, separated, aliquoted, frozen (within 2 h of collection), and transported to the Population Health Research Institute Biobank in Hamilton, Ontario, Canada, where they were stored in nitrogen vapor-cooled tanks at 2160°C. A

Background: Novel, effective, and safe drugs are warranted for treatment of ischemic stroke. Circulating protein biomarkers with causal genetic evidence represent promising drug targets, but no systematic screen of the proteome has been performed. Methods: First, using Mendelian randomization (MR) analyses, we assessed 653 circulating proteins as possible causal mediators for 3 different subtypes of ischemic stroke: large artery atherosclerosis, cardioembolic stroke, and small artery occlusion. Second, we used MR to assess whether identified biomarkers also affect risk for intracranial bleeding, specifically intracerebral and subarachnoid hemorrhages. Third, we expanded this analysis to 679 diseases to test a broad spectrum of side effects associated with hypothetical therapeutic agents for ischemic stroke that target the identified biomarkers. For all MR analyses, summary-level data from genome-wide association studies (GWAS) were used to ascertain genetic effects on circulating biomarker levels versus disease risk. Biomarker effects were derived by meta-analysis of 5 GWAS (N≤20 509). Disease effects were derived from large GWAS analyses, including MEGASTROKE (N≤322 150) and UK Biobank (N≤408 961) studies. Results: Several biomarkers emerged as causal mediators for ischemic stroke. Causal mediators for cardioembolic stroke included histo-blood group ABO system transferase, coagulation factor XI, scavenger receptor class A5 (SCARA5), and tumor necrosis factor–like weak inducer of apoptosis (TNFSF12). Causal mediators for large artery atherosclerosis included ABO, cluster of differentiation 40, apolipoprotein(a), and matrix metalloproteinase-12. SCARA5 (odds ratio [OR]=0.78; 95% CI, 0.70–0.88; P =1.46×10 −5 ) and TNFSF12 (OR=0.86; 95% CI, 0.81–0.91; P =7.69×10 −7 ) represent novel protective mediators of cardioembolic stroke. TNFSF12 also increased the risk of subarachnoid (OR=1.53; 95% CI, 1.31–1.78; P =3.32×10 −8 ) and intracerebral (OR=1.34; 95% CI, 1.14–1.58; P =4.05×10 −4 ) hemorrhages, whereas SCARA5 decreased the risk of subarachnoid hemorrhage (OR=0.61; 95% CI, 0.47–0.81; P =5.20×10 −4 ). Multiple side effects beyond stroke were identified for 6 of 7 biomarkers, most (75%) of which were beneficial. No adverse side effects were found for coagulation factor XI, apolipoprotein(a), and SCARA5. Conclusions: Through a systematic MR screen of the circulating proteome, causal roles for 5 established and 2 novel biomarkers for ischemic stroke were identified. Side-effect profiles were characterized to help inform drug target prioritization. In particular, SCARA5 represents a promising target for treatment of cardioembolic stroke, with no predicted adverse side effects.