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The antisense compound ISIS 388626 selectively inhibits renal glucose reabsorption by inhibiting the sodium–glucose cotransporter‐2 (SGLT2) mRNA expression. It is developed as an insulin‐independent treatment approach for type 2 diabetes mellitus (T2DM). The safety, tolerability, pharmacokinetics, and pharmacodynamics after subcutaneous administration of the drug were planned to be evaluated in healthy volunteers in a single‐ascending‐dose study (50–400 mg) and a multiple‐ascending‐dose study (6 weeks; weekly doses of 50–400 mg with loading dose regimen of three doses during the first week). The study was halted early because increases in serum creatinine occurred in the subjects participating in the 100 mg multiple‐dose cohort. The pronounced changes in serum creatinine were accompanied by increased urinary excretion of beta‐2‐microglobulin and KIM1. The possible mechanisms for these findings remain elusive and are in contrast to preclinical findings as comparable treatment with ISIS 388626 of animals did not reveal similar changes. Although exposure was limited, there was an indication that glucosuria increased upon active treatment. Before the concept of antisense‐mediated blocking of SGLT2 with ISIS 388626 can be explored further, more preclinical data are needed to justify further investigations.