Effects of SGLT2 Inhibitors and GLP-1 Receptor Agonists on Renin-Angiotensin-Aldosterone System

Abstract

Sodium-glucose cotransporters inhibitors (SGLT2-i) and GLP-1 receptor agonists (GLP1-RA) are glucose-lowering drugs that are proved to reduce the cardiovascular (CV) risk in type 2 diabetes mellitus (T2DM). In this process, the renin-angiotensin-aldosterone system (RAAS) is assumed to play a role. The inhibition of SGLT2 improves hyperglycemia hampering urinary reabsorption of glucose and inducing glycosuria. This “hybrid” diuretic effect, which couples natriuresis with osmotic diuresis, potentially leads to systemic RAAS activation. However, the association between SGLT2-i and systemic RAAS activation is not straightforward. Available data indicate that SGLT2-i cause plasma renin activity (PRA) increase in the early phase of treatment, while PRA and aldosterone levels remain unchanged in chronic treated patients. Furthermore, emerging studies provide evidence that SGLT2-i might have an interfering effect on aldosterone/renin ratio (ARR) in patients with T2DM, due to their diuretic and sympathoinhibition effects. The cardio- and reno-protective effects of GLP-1-RA are at least in part related to the interaction with RAAS. In particular, GLP1-RA counteract the action of angiotensin II (ANG II) inhibiting its synthesis, increasing the inactivation of its circulating form and contrasting its action on target tissue like glomerular endothelial cells and cardiomyocytes. Furthermore, GLP1-RA stimulate natriuresis inhibiting Na+/H+ exchanger NHE-3, which is conversely activated by ANG II. Moreover, GLP1 infusion acutely reduces circulating aldosterone, but this effect does not seem to be chronically maintained in patients treated with GLP1-RA. In conclusion, both SGLT2-i and GLP1-RA seem to have several effects on RAAS, though additional studies are needed to clarify this relationship.

Empagliflozin inhibits angiotensin II-induced hypertrophy in H9c2 cardiomyoblasts through inhibition of NHE1 expression

“…Our results demonstrated that SGLT-1 protein expression is significantly increased in H9c2 cardiomyoblasts when treated with ANG and EMPA individually. This supports findings from a recent study which demonstrated that changes in the activity of the intrarenal RAAS are positively correlated with changes in endogenous SGLT-2 expression levels and that ANG dose-dependently increases SGLT-2 expression in vitro [25]. Heart failure has been demonstrated to activate both systemic and intrarenal RAAS [25] and human SGLT-1 mRNA expression has been shown to be significantly increased in ischemic cardiomyopathy [26].…”

An Overview of the Cardiorenal Protective Mechanisms of SGLT2 Inhibitors

“…The association between RAAS and AGLT2-inhibition is simple. Plasma renin activity increases in the first three to six months of treatment, but remains unchanged in the long-term therapy similar to aldosterone [ 175 ].…”

Safety and efficacy of the SGLT2 inhibitor dapagliflozin in patients with systemic lupus erythematosus: a phase I/II trial

“…Unfortunately, for patients with LN (n=17) in our trial, dapagliflozin add-on therapy did not help reduce the proteinuria level. One explanation is that <50% of our patients with LN were on RAASis, which has been postulated to be required for SGLT2is to enhance their action 15 34. The other possible reason might be attributed to the fact that the participants had a relatively long LN duration (2.7 years) and were resistant to multiple (average of 4) previous immunosuppressants.…”