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.
Highlights
Cardiovascular disease (CVD) is the main cause of morbidity and mortality in patients with type 2 diabetes (T2DM), with a relevant impact on the economic costs for health care systems and on the quality of life for many patients [1, 2]
Among patients with type 2 diabetes mellitus (T2DM) and established cardiovascular disease, some trials reported the additional benefit of a lower rate of major adverse cardiac events (MACE) in patients treated with sodium–glucose cotransporter-2 inhibitors (SGLT2-i) [7, 10]
There is a growing body of evidence suggesting a significant beneficial class effect associated with SGLT2 inhibition, resulting in MACE, cardiovascular death and hospitalization for heart failure (HHF) reduction, despite some variabilities in the findings provided by individual CVOTs [40]
Summary
Cardiovascular disease (CVD) is the main cause of morbidity and mortality in patients with type 2 diabetes (T2DM), with a relevant impact on the economic costs for health care systems and on the quality of life for many patients [1, 2]. The ANGIV/AT4/IRAP cascade: ANG IV (derived from the metabolization of ANG II through aminopeptidases A and N) binds the AT4 receptor, which has been identified as the insulin-regulated aminopeptidase (IRAP), but the role of this pathway in the blood pressure and renal regulation is still uncertain [22] These new axes have raised great interest because their targeting could provide novel therapeutic strategies for hypertension, cardiovascular and kidney diseases. Mochel et al postulated that the optimal efficacy of drug affecting RAAS (for example ACE inhibitors) should be expected with bedtime dosing [29] This hypothesis has been confirmed in clinical trials including hypertensive patients that demonstrated an improved blood pressure control [30, 31] and reduction of cardiovascular events [31] when anti-hypertensive drugs have been administered at bedtime
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