Abstract
Sodium-Glucose Cotransporter 2 inhibitors (SGLT2i), or gliflozins, are a group of antidiabetic drugs that have shown improvement in renal and cardiovascular outcomes in patients with kidney disease, with and without diabetes. In this review, we will describe the different proposed mechanisms of action of SGLT2i. Gliflozins inhibit renal glucose reabsorption by blocking the SGLT2 cotransporters in the proximal tubules and causing glucosuria. This reduces glycemia and lowers HbA1c by ~1.0%. The accompanying sodium excretion reverts the tubuloglomerular feedback and reduces intraglomerular pressure, which is central to the nephroprotective effects of SGLT2i. The caloric loss reduces weight, increases insulin sensitivity, lipid metabolism, and likely reduces lipotoxicity. Metabolism shifts toward gluconeogenesis and ketogenesis, thought to be protective for the heart and kidneys. Additionally, there is evidence of a reduction in tubular cell glucotoxicity through reduced mitochondrial dysfunction and inflammation. SGLT2i likely reduce kidney hypoxia by reducing tubular energy and oxygen demand. SGLT2i improve blood pressure through a negative sodium and water balance and possibly by inhibiting the sympathetic nervous system. These changes contribute to the improvement of cardiovascular function and are thought to be central in the cardiovascular benefits of SGLT2i. Gliflozins also reduce hepcidin levels, improving erythropoiesis and anemia. Finally, other possible mechanisms include a reduction in inflammatory markers, fibrosis, podocyte injury, and other related mechanisms. SGLT2i have shown significant and highly consistent benefits in renal and cardiovascular protection. The complexity and interconnectedness of the primary and secondary mechanisms of action make them a most interesting and exciting pharmacologic group.
Highlights
Sodium Glucose Cotransporter 2 inhibitors (SGLT2i), known as gliflozins, are an exciting and highly interesting group of “relatively new drugs” that have shown consistent positive results in renal and cardiovascular protection
They inhibit the action of the Sodium Glucose Cotransporter 2 (SGLT2) in the kidney and cause glucosuria. They were thought of and developed as glucose lowering therapies, yet large clinical trials in a very short time have demonstrated clinical benefits that far exceeded what was expected. In this short review we describe the physiologic effects of SGLT2 inhibitors and discuss the clinical benefits demonstrated to date
SGLT2 cotransporters are almost exclusively found in renal tissue, whereas SGLT1 are mostly found in the small intestine, heart, and skeletal muscle, aside from the kidney (Table 1) [3,4,5]
Summary
Received: 15 September 2021 Accepted: 22 November 2021 Published: 20 December 2021. Citation: Fonseca-Correa JI and Correa-Rotter R (2021) Sodium-Glucose Cotransporter 2 Inhibitors Mechanisms of Action: A Review. Sodium-Glucose Cotransporter 2 inhibitors (SGLT2i), or gliflozins, are a group of antidiabetic drugs that have shown improvement in renal and cardiovascular outcomes in patients with kidney disease, with and without diabetes. Gliflozins inhibit renal glucose reabsorption by blocking the SGLT2 cotransporters in the proximal tubules and causing glucosuria. This reduces glycemia and lowers HbA1c by ∼1.0%. SGLT2i improve blood pressure through a negative sodium and water balance and possibly by inhibiting the sympathetic nervous system. These changes contribute to the improvement of cardiovascular function and are thought to be central in the cardiovascular benefits of SGLT2i. The complexity and interconnectedness of the primary and secondary mechanisms of action make them a most interesting and exciting pharmacologic group
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