SGLT-2 inhibitors in diabetes: a focus on renoprotection

SUMMARY Type 2 diabetes mellitus is an important public health problem, with a significant impact on cardiovascular morbidity and mortality and an important risk factor for chronic kidney disease. Various hypoglycemic therapies have proved to be beneficial to clinical outcomes, while others have failed to provide an improvement in cardiovascular and renal failure, only reducing blood glucose levels. Recently, sodium-glucose cotransporter-2 (SGLT2) inhibitors, represented by the empagliflozin, dapagliflozin, and canagliflozin, have been showing satisfactory and strong results in several clinical trials, especially regarding the reduction of cardiovascular mortality, reduction of hospitalization due to heart failure, reduction of albuminuria, and long-term maintenance of the glomerular filtration rate. The benefit from SGLT2 inhibitors stems from its main mechanism of action, which occurs in the proximal tubule of the nephron, causing glycosuria, and a consequent increase in natriuresis. This leads to increased sodium intake by the juxtaglomerular apparatus, activating the tubule glomerular-feedback and, finally, reducing intraglomerular hypertension, a frequent physiopathological condition in kidney disease caused by diabetes. In addition, this class of medication presents an appropriate safety profile, and its most frequently reported complication is an increase in the incidence of genital infections. Thus, these hypoglycemic agents gained space in practical recommendations for the management of type 2 diabetes mellitus and should be part of the initial therapeutic approach to provide, in addition to glycemic control, cardiovascular outcomes, and the renoprotection in the long term.

Dapagliflozin versus saxagliptin as add-on therapy in patients with type 2 diabetes inadequately controlled with metformin

ABSTRACT Objective: This analysis compared the efficacy and safety of the sodium-glucose cotransporter-2 (SGLT2) inhibitor, dapagliflozin, and the dipeptidyl peptidase-4 (DPP4) inhibitor, saxagliptin, both added on to metformin. Materials and methods: This was a post-hoc analysis from a double-blind, randomized, 24-week clinical trial (NCT01606007) of patients with type 2 diabetes (T2D) inadequately controlled with metformin. We compared the dapagliflozin 10 mg (n = 179) and saxagliptin 5 mg (n = 176) treatment arms. Results: Dapagliflozin showed significantly greater mean reductions versus saxagliptin in HbA1c (difference versus saxagliptin [95% CI]: −0.32% [-0.54, −0.10]; p < 0.005), fasting plasma glucose (-0.98 [-1.42, −0.54] mmol/L; p < 0.0001), body weight (-2.39 [-3.08, −1.71] kg; p < 0.0001) and systolic blood pressure (SBP) (-3.89 [-6.15, −1.63] mmHg; p < 0.001). More dapagliflozintreated than saxagliptin-treated patients achieved the composite endpoint of HbA1c reduction ≥ 0.5%, weight loss ≥ 2 kg, SBP reduction ≥ 2 mmHg and no major/minor hypoglycemia (24% versus 7%). No major events of hypoglycemia were reported. More patients on dapagliflozin (6%) versus saxagliptin (0.6%) experienced genital infections. Conclusion: Dapagliflozin demonstrated greater glycemic efficacy than saxagliptin with additional benefits on weight and SBP, and the safety profile was consistent with previous studies.

Uso de la dapagliflozina en el tratamiento de la diabetes mellitus tipo 2 / Use of dapagliflozin in the treatment of type 2 diabetes mellitus

Introducción: la dapagliflozina es un inhibidor del cotransportador sodio-glucosa tipo 2, un nuevo grupo de fármacos que disminuyen la glucemia, con bajo riesgo de hipoglucemia y con discreta pérdida de peso. Objetivo: describir algunos aspectos de interés sobre el uso de la dapagliflozina en el tratamiento de los pacientes con diabetes mellitus tipo 2, para lo cual, se realizó una revisión de varios artículos publicados sobre el tema, a través de algunas bases de datos y de los buscadores habituales (PubMed, Cochrane, Google, y otros), teniendo en cuenta su calidad y actualidad, según criterio de los autores. Desarrollo: la dapagliflozina es administrada por vía oral, e inhibe la reabsorción de glucosa en el túbulo proximal renal y aumenta la excreción urinaria de glucosa (efecto glucosúrico). Se utiliza a una dosis de 10 mg diarios, sola o asociada a otros medicamentos normo o hipoglucemiantes. En ambos casos es capaz de disminuir los niveles de la hemoglobina glucosilada. Su efectividad es similar a las sulfonilureas. Los efectos adversos más frecuentes se relacionan con un incremento de las infecciones genitourinarias, cetoacidosis con glucemias no tan elevadas, y cáncer. Conclusiones: la dapagliflozina es efectiva en reducir los niveles de la hemoglobina glucosilada, el peso corporal y de la presión arterial en pacientes con diabetes mellitus tipo 2, sobre todo, cuando se adiciona a otros medicamentos como la metformina. Su uso debe ser considerado como un tratamiento coadyuvante, aunque su indicación se debe individualizar, debido a su costo y sus posibles efectos adversos(AU)

Introduction: dapagliflozin is a sodium-glucose cotransporter 2 inhibitor, a new group of pharmaceuticals that reduce glycemia, with low risk of hypoglycemia and modest loss of weight. Objective: to describe some aspects of interest on the use of dapagliflozin in the treatment of patients with type 2 diabetes mellitus for which several articles published on this topic were reviewed through some databases and the regular searchers (PubMed, Cochrane, Google and others), taking into account their quality and topicality, according to the authors' criteria. Development: dapagliflozin is orally administered and inhibits the re-absorption of glucose in the renal proximal tubule and increases the urinary glucose excretion (glycosuric effect). The dose is 10 mg daily, single or combined with other normoglycemic and hypoglycemic drugs. In both cases, it is able to diminish the levels of glycosylate hemoglobin. The effectiveness of this new drug is similar to that of the sulfonylureas. The most frequent effects are related to increase in genitourinary infections, ketoacidosis with not so high glycemia values and cancer. Conclusions: dapagliflozin is effective for the reduction of levels of glycosylate hemoglobin, body weight and blood pressure in patients with type 2 diabetes mellitus, mainly when added to other drugs like metformin. It should be considered as a coadjuvant treatment, although it should be prescribed on an individual footing due to its cost and possible adverse effects(AU)