Effects of sodium‐glucose cotransporter‐2 inhibitors on the cardiovascular and renal complications of type 2 diabetes

Abstract

Sodium‐glucose cotransporter‐2 inhibitors (SGLT‐2is) have been shown to mitigate the risks of cardiovascular (CV) and renal complications in patients with type 2 diabetes (T2D) and CV risk factors or CV disease (CVD). In CV outcomes trials (CVOTs) of patients with T2D and established CVD or multiple CV risk factors, empagliflozin and canagliflozin were associated with significant reductions in the risks of major adverse CV events (MACE), hospitalization for heart failure (HF) and kidney disease progression. In the DECLARE–TIMI 58 study, in which the majority of patients did not have established CVD, dapagliflozin was associated with significant reductions in the composite end point of CV death or hospitalization for HF and was noninferior to placebo with regard to MACE; although patients had relatively good renal function, dapagliflozin also showed renal benefits similar to those seen with empagliflozin and canagliflozin. This article reviews the increased risk of CVD and renal disease in patients with T2D and discusses the potential mechanisms of the cardioprotective and renoprotective effects of SGLT‐2i therapy. The observed improvements in CV and renal outcomes with SGLT‐2is in CVOTs suggest a class effect in this patient population and have influenced treatment guidelines for the way add‐on therapy to metformin is initiated in patients with T2D and high CV risk. The overall cardioprotective and renoprotective effects of SGLT‐2is in patients with T2D and high CV risk are most likely attributable to multiple mechanisms, including cardiac, haemodynamic, metabolic, anti‐inflammatory and renal effects.

Sodium–glucose cotransporter type 2 inhibitors for the treatment of type 2 diabetes mellitus

“…In addition to their specific renal effect (Supplementary Box 1), SGLT2is have a range of actions that involve multiple metabolic, endocrine, biochemical and haemodynamic pathways 11,12 . All these effects could contribute to the beneficial cardiovascular and renal effects reported with SGLT2is [13][14][15] .…”

Mesa 3: Efectos cardiovasculares de fármacos antidiabéticos

“…Los SGLT-2 son transportadores de alta capacidad y baja afinidad; los SGLT-1 son de baja capacidad y alta afinidad. En los pacientes con DM2 la expresión y actividad del SGLT-2 en el TCP están incrementadas, lo cual resulta en un aumento de la reabsorción renal de glucosa que contribuye a la hiperglucemia 120,121 .…”

“…Dado que su mecanismo de acción es independiente de insulina, no presentan riesgo para hipoglucemia. Los iSGLT-2 disponibles mundialmente son canaglifozina, dapaglifozina, empaglifozina, eruglifozina, ipraglifozina, luseoglifozina, sotaglifozina, remoglifozina y tofoglifozina [120][121][122][123][124].…”

“…A nivel miocárdico directo se puede detallar mejoría del consumo energético cardíaco por incremento de oxidación de cuerpos cetónicos (combustible de alta energía y oxigenación más eficiente, utilizado por el cardiomiocito de forma insulino-independiente), ácidos grasos libres, aminoácidos de cadena ramificada y lactato, y reducción de oxidación de glucosa, de la formación de AGE y acumulación de triglicéridos y glucosa. También disminución de la masa y diámetro VI, mejoría de la función diastólica del VI, reducción de rigidez arterial y de fibrosis miocárdica, y de activación neurohormonal (péptidos natriuréticos circulantes y catecolaminas) 120,[125][126][127][128][129][130] . .…”

Dysplastic urothelial changes accompany empagliflozin administration in urinary bladder of experimental diabetes

“…Empagliflozin (EMPA) is one of the sodium-glucose cotransporter 2 inhibitors (SGLT2is) that have the advantage of not causing hypoglycaemia as they act distinctively by increasing urinary glucose excretion. 1,2 EMPA has pleiotropic effects in type 2 diabetes (T2D) including a reduction of major adverse cardiovascular events 3,4 and an improvement in the renal outcomes, 5 yet uncommon but serious safety issues were reported with SGLT2is use, such as urinary tract infection (UTI). 6 Another important safety concern is the increased incidence of renal and testicular tumours associated with highdose EMPA in male mice.…”