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

Abstract

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 For glucagon-like peptide-1 receptor agonists, a small early decrease in renal function persists for 2 years and is superseded by a small improvement in renal function, with no effect on renal outcomes.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decrease in glomerular filtration with sodium-glucose co-transporter-2 inhibitors persists for only 1 year and is superseded by a durable improvement in renal function and a reduced risk of serious adverse renal events.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.

Glucagon Receptor Antagonism Ameliorates Progression of Heart Failure

“…Several other diabetic therapies, including GLC-like peptide-1 agonists 37, 38, dipeptidyl peptidase 4 inhibition (39), and sodium glucose cotransporter 2 inhibitors 40, 41, have demonstrated various degrees of cardiovascular benefits along with ameliorated metabolic defects in glucose homeostasis. Yet, not all glucose-lowering therapies have such significant cardiovascular protective effects as sodium glucose cotransporter 2 inhibition 42, 43, 44, 45, 46. It is also unclear if these therapies will be efficacious for common forms of heart failure without the confounding metabolic disorders.…”

The New Era for Reno-Cardiovascular Treatment in Type 2 Diabetes

“…It has recently been described that treatment with empagliflozin decreases NHE3 expression in the kidneys of diabetic otsuka long-evans tokushima Fatty (OLETF) rats, as well as the expression of Na + -K + -2Cl − cotransporters and epithelial Na + channels, when compared to untreated littermates, suggesting that SGLT2 modulates the Na + reabsorption of several tubular transporters [47]. GLP-1RAs only seem to decrease NHE3 activity [48,49,50], a fact that would explain the difference in the natriuretic potential of these two drugs [51]. It is unclear whether GLP-1RAs inhibit NHE3 activity through interaction with the GLP-1 receptor or extrarenal mechanisms, such as the renin–angiotensin system or atrial natriuretic peptide modulation [52,53].…”

Acute kidney injury, renal impairment and renal failure associated with sodium glucose co‐transporter‐2 inhibitors in at‐risk groups: A systematic review

“…1,4 The literature on renal outcomes associated with SGLT-2is is conflicting. Some studies have indicated that SGLT-2is slow the progression of chronic kidney disease (CKD), 5,6 reduce the annual decline in estimated glomerular filtration rate (eGFR) 7,8 and reduce the development of AKI 9 ; however, others have shown a decline, or an initial decline followed by an improvement, in renal function. [10][11][12][13] This question is important, as with an ever-growing array of treatment options for type 2 diabetes, selecting the right medication and avoiding adverse events are important.…”

“…The literature on renal outcomes associated with SGLT‐2is is conflicting. Some studies have indicated that SGLT‐2is slow the progression of chronic kidney disease (CKD), 5,6 reduce the annual decline in estimated glomerular filtration rate (eGFR) 7,8 and reduce the development of AKI 9 ; however, others have shown a decline, or an initial decline followed by an improvement, in renal function 10–13 …”