Objective: We studied in people with type 2 diabetes whether blood metabolomic measures are associated with insufficient glycemic control and if this association is influenced differentially by various diabetes drugs. We then tested whether the same metabolomic profiles associate with initiation of insulin therapy. Methods: One-hundred-and-sixty-two metabolomic measures were analyzed using a NMR-based method in people with type 2 diabetes from four cohort studies (n=2641) and one replication cohort (n=395). Linear and logistic regression with adjustment for potential confounders followed by meta-analyses was done to analyze associations with HbA1c levels, six glucose-lowering drug categories, and insulin initiation during seven year follow-up (n=698). Results: After Bonferroni correction twenty-six measures were associated with insufficient glycemic control (HbA1c>53 mmol/mol). The strongest association was with glutamine (OR=0.66 (95%CI 0.61;0.73), P=7.6x10-19). In addition when compared to treatment naïve patients thirty-one metabolomic measures were associated with glucose-lowering drugs use (representing various metabolite categories, all P≤3.1x10-4). In drug-stratified analyses, associations with insufficient glycemic control were only mildly affected by different glucose-lowering drugs. Five of the 26 metabolomic measures (ApoA1 and M-HDL subclasses) were also associated with insulin initiation during follow-up in both discovery and replication. With the strongest association observed for M-HDL-CE (OR=0.54 (95%CI=0.42;0.71); P=4.5x10-6). Conclusion: In conclusion blood metabolomic measures were associated with present and future glycemic control and may thus provide relevant cues to identify those at increased risk of treatment failure.