Efficiency and safety of SGLT2 inhibitors

Abstract

Background According to statistical data of the International Diabetes Federation in 2015 the number of diabetes mellitus (DM) patients was 415 millions. By 2040, projected number of patients will be about 642 millions. Despite the large arsenal of antidiabetic drugs, hypoglycemic means search with maximum efficiency and minimal side effects such as weight gain and hypoglycemia level are continued. Purpose The study of the efficacy and safety of new classes of hypoglycemic drugs due to analysis of publications in medical databases. Results SGLT2 inhibitors are a group of oral hypoglycemic drugs which therapeutic target are kidneys. The mechanism of action is glucose and sodium symport blockage, which ensures reduction of glucose reabsorption and normalize glycaemia. Glucose toxicity reduction at the usage of these drugs is manifested in the recovery of the pancreas beta cells sensitivity, thus increasing insulin synthesis, and sensitization of peripheral tissues to insulin action. The usage of SGLT2 inhibitors not only leads to blood glucose lowering but also to shift the energy balance in a negative way that creates additional benefits in DM patients with obesity. Side effects of SGLT2 inhibitors therapy include urinary tract and genital infections. These drugs also have a diuretic effect, which can lead to the dehydration or hypotension. Some researches highlight the risks for bone fractures. SGLT2 inhibitors increase concentrations of phosphate in serum, probably via increased tubular reabsorption, which has the potential to adversely affect bone. Furthermore, SGLT2 inhibitors increase concentrations of parathyroid hormone, which enhance bone resorption. The question of carcinogenesis is still controversial. Studies have implied that the SGLT receptor may play a role in glucose uptake in many cancers. SGLT2 inhibitors increase the risk for urinary tract infections, which could increase the risk for bladder cancer. Human trials showed excess cases of female breast, male bladder cancer; but they did not reach statistical significance. New data for dapagliflozin suggested that these excess cancers may be due to early diagnosis rather than increased incidence. Canagliflozin rat studies suggested increased risk for renal, adrenal, and Leydig cell tumors, but phase 3 clinical trials do not support increased incidence of these cancers in humans. Evidence for the link between SGLT2 inhibitor use and cancer risk is not conclusive and remains a safety issue. Studies with larger sample size, longer exposure duration, and use of SGLT2 inhibitors in different ethnicities are needed. In May 2015, the FDA issued a warning that SGLT2 inhibitors may lead to ketoacidosis. The decline in circulating insulin levels results in a lowering of the antilipolytic activity of insulin and consequent stimulation of the production of free fatty acids, which are converted to ketone bodies by β-oxidation in the liver. Obviously, not all individuals who take SGLT2 inhibitors are at high-risk for euglycemic ketoacidosis. SGLT2 inhibitors have the potential to reduce cardiovascular risk in DM patients not only through effects on glycemic control, but also via beneficial effects on body weight, blood pressure, lipids. Large studies are underway to elucidate the effects of SGLT2 inhibitors on these outcomes, the results of which are eagerly awaited. Conclusions The resume of the data is ambiguous. On one side, this class of drugs offers new opportunities in the treatment of DM type 2: first of all, a new, insulin independent mechanism of action, absence of negative effect on body weight, favorable pharmacokinetic properties and overall good tolerance. On the other side, mechanism of action of SGLT2 inhibitors is directed to the clinical manifestations of diabetes and not to the cause. Listed, identified and investigated nephroprotective and cardioprotective effects, data on the effects on bone, lack of carcinogenic risk are required confirmation in the long-term. The results of new clinical and epidemiological studies should identify the benefit/risk ratio of a new class of antidiabetic agents in the long-term, and its place in the treatment of patients with DM type 2.