Contrasting effects on the risk of macrovascular and microvascular events of antihyperglycemic drugs that enhance sodium excretion and lower blood pressure

Three classes of anti‐hyperglycaemic medications are distinguished by their urinary sodium excretion‐enhancing and blood pressure‐lowering actions: long‐acting glucagon‐like peptide‐1 receptor agonists, dipeptidyl peptidase‐4 inhibitors and sodium‐glucose co‐transporter‐2 inhibitors. Yet, these drugs exert different effects on macrovascular risk. Glucagon‐like peptide‐1 receptor agonists reduce atherosclerotic thromboembolic events, but have little effect on heart failure; sodium‐glucose co‐transporter‐2 inhibitors decrease the occurrence of heart failure, but have minimal effect on myocardial infarction and stroke; and dipeptidyl peptidase‐4 inhibitors do not ameliorate either atherosclerotic thromboembolic events or heart failure. Similarly, the three classes of drugs differ in their early effects on renal function. Dipeptidyl peptidase‐4 inhibitors produce a small decrease in renal function that persists for the duration of treatment, and they do not prevent serious adverse renal events. For glucagon‐like peptide‐1 receptor agonists, a small early decrease in renal function persists for 2 years and is superseded by a small improvement in renal function, with no effect on renal outcomes. In contrast, an initial decrease in glomerular filtration with sodium‐glucose co‐transporter‐2 inhibitors persists for only 1 year and is superseded by a durable improvement in renal function and a reduced risk of serious adverse renal events. These differences may be related to different actions on the proximal tubular reabsorption of sodium, and thereby, on glomerular hyperfiltration. Anti‐hyperglycaemic drugs that have natriuretic actions differ markedly in their ability to modulate macrovascular and microvascular risk. These contrasting profiles cannot be predicted by their effects on blood glucose or blood pressure.