ISIS 388626 is an antisense sodium-glucose cotransporter 2 (SGLT2) inhibitor designed to treat type 2 diabetes mellitus by induction of glucosuria. ISIS 388626 was demonstrated to be safe and effective in preclinical trails in several species. We undertook the present study to evaluate the safety and efficacy of 13 weekly doses of 50, 100, and 200 mg of ISIS 388626 in humans. ISIS 388626 increased 24-hour urinary glucose excretion dose dependently with 508.9 ± 781.45 mg/day in the 100-mg and 1299.8 ± 1833.4 mg/day in the 200-mg cohort, versus 88.7 ± 259.29 mg/day in the placebo group. ISIS 388626 induced a reversible increase in serum creatinine, with the largest effect after eight doses of ISIS 388626 (200 mg; 0.38 ± 0.089 mg/dl; 44% increase over baseline). Three subjects were discontinued as a result of creatinine increases. The renal clearance test revealed no indications for impairment of glomerular filtration or renal perfusion. The creatinine increases were accompanied by a rise in the levels of urinary renal damage markers [β-2-microglobulin (B2M), total protein, kidney injury molecule (KIM1), α-glutathione S-transferase (aGST), N-acetyl-β-(d)-glucosaminidase (NAG)]. Other treatment-related adverse events included mild injection site reactions occurring in 8-19% of the subjects. In conclusion, ISIS 388626 treatment induced glucosuria at a dose level of 200 mg/week. This intended pharmacological effect was small, amounting to approximately 1% of the total amount of filtered glucose. Changes in serum and urinary markers were indicative of transient renal dysfunction, most probably of tubular origin. Whether the glucosuria is caused by specific SGLT2 inhibition or general tubular dysfunction or a combination remains uncertain.