Sodium-glucose co-transporter 2 (SGLT2) inhibitors are a new class of glucose-lowering drugs. They work by blocking the low-affinity, high-capacity SGLT2 protein located in the proximal convoluted tubule of the nephron. The SGLT2 protein is responsible for the resorption of approximately 90% of filtered glucose while the remainder is reabsorbed by SGLT1 proteins found on the distal part of the proximal convoluted tubule. SGLT2 inhibition results in glycosuria (and natriuresis as the protein is a co-transporter), thereby lowering plasma glucose concentrations. This mechanism is unique compared with all other glucose-lowering agents as it does not interfere with endogenous insulin or incretin pathways.
In
recent cardiovascular outcome trials, SGLT2 inhibitors are associated with
30%–35% lower risk of hospitalization for heart failure. Other glucose-lowering
agents appear to be more potent than SGLT2 inhibitors, but fail to reduce
cardiovascular risk, particularly with regard to heart failure outcomes.
Moreover, although the glucose-lowering efficacy of SGLT2-inhibitor therapy
declines at lower estimated glomerular filtration rates, its cardiovascular
benefits are remarkably preserved, even in patients with renal impairment. This
implies differing mechanisms of action in glycemic control and cardiovascular
risk reduction.
