© Borgis - Postępy Nauk Medycznych 3/2013, s. 229-232
Bernadetta Kałuża1, *Edward Franek1, 2
Inhibitory SGLT2 – nowe doustne leki przeciwcukrzycowe
SGLT2 inhibitors – new oral hypoglycemic drugs
1Department of Internal Diseases, Endocrinology and Diabetology, Central Clinical Hospital of the Ministry of Interior, Warszawa
Head of Department: prof. Edward Franek, MD, PhD
2Department of Human Epigenetics, Medical Research Center, Polish Academy of Sciences, Warszawa
Head of Department: prof. Monika Puzianowska-Kuźnicka, MD, PhD
Liczba chorych na cukrzycę na całym świecie wzrasta. Równocześnie glikemia u wielu chorych nie spełnia kryteriów wyrównania podawanych przez Amerykańskie lub Polskie Towarzystwa Diabetologiczne. Te dwa fakty przyczyniają się do burzliwego rozwoju nowych możliwości terapeutycznych w cukrzycy. Jedną z takich możliwości opisano w poniższym artykule. Są to leki hamujące transport glukozy i sodu w nerkach. Z jednej strony nasilają one wydalanie glukozy z moczem (naśladując naturalny mechanizm obronny organizmu), powodując zmniejszenie glikemii i ujemny bilans energetyczny, sprzyjający zmniejszeniu masy ciała, z drugiej wzmożone wydalanie sodu z moczem powoduje spadek ciśnienia tętniczego. Ceną za te efekty lecznicze jest jednak zwiększona częstość zakażeń układu moczowego i dróg rodnych. Pierwszym lekiem z tej grupy dopuszczonym na rynek jest dapagliflozyna.
The prevalence of diabetes increases worldwide and glycemia in many patients Dos not meet the targets precised by American or Polish Diabetes Association. These two fact stimulate development of new treatment possibilities in diabetes. One of them, described below, are kidney sodium and glucose transporter inhibitors. From the one side they increase urinary glucose excretion (mimicking the natural defense mechanism of the organism) resulting in decrease of glycemia and in negative energy balance, favoring decrease of weight, from the other icreased sodium excretion decreases blood pressure. The price for that effects is however increased frequency of genitourinary tract infections. The first marketed drug belonging to this group is dapagliflosine.
The kidney is one of important players regulating the homeostasis of glucose and carbohydrates. One of the involved mechanisms is glucose excretion and reabsorption, mediated by sodium-glucose cotransporters, mainly type 2 (SGLT2), located in the S1 segment of the proximal tubule. This transporter is encoded by SLC5 (specifically SCL5A2) gene (1). It is characterized by high capacity, but low affinity for glucose, and is responsible for about 90% of the reabsorption of glucose from the tubuli (2, 3) (the remaining 10% of glucose is in the physiological conditions reabsorbed by type 1 transporter, SGLT1, located in the S2/S3 segment of proximal tubule (4). The molar ratio of transferred glucose to transferred to sodium is 1:1 for the SGLT2 transporter (1:2 for SGLT1) (2, 5). Sodium-glucose transporter type 2 is sodium-dependent, one-way co-transporter, expressed on the luminal side of the nephron proximal tubule cells (5, 6). It is responsible for active glucose transport from the lumen of renal proximal tubule to renal epithelial cells, against the concentration gradient. Transported to epithelial cells glucose produces gradient between the cell and interstitial fluid, which is then used by GLUT transporters (7, 8).
The mechanism of action of SGLT inhibitors
SGLT2 inhibitors are structurally similar to fenyloglukozide called phlorizin, a non-selective blocker that blocks both type 1 and 2 receptor (9). There is evidence that it acts on SGLT in a double manner: by carbohydrate group and by sugar-free part of the aromatic ring. It seems that glucose-free parts of of SGLT proteins, having a polar structures located on a large transmembranous loop, with the help of which they can interact with glucose-free parts of the inhibitors, play a key role in the mechanism of blocking. On this basis phlorizine binds to nonspecific hydrophobic pocket formed in the last part of the loop (9-11). It should be noted that the SGLT 2 is a protein composed of 672 amino acids which form fourteen transmembranous segments arranged in loops (12, 13).
Pharmacokinetics of SGLT2 inhibitors
All SGLT2 inhibitors are administered orally. Pharmacokinetical parameters such as rate of absorption, time to maximal serum concentration after exposure, time of dissociation from the receptor are different in different drugs of the class. For example, dapagliflozine and ipragliflozine are rapidly absorbed. Peak serum dapagliflozine concentration is achieved after about 1 hour of exposure (12). Ipragliflozin is similarly absorbed and its half-time is about 12 hours (13, 14). The relationship between the dose, plasma concentration and time is linear. Ipragliflozine has several inactive metabolites, called M1, M2, M3, M4 and M6, the main metabolite is M2 (13). Seragliflozine is rapidly absorbed and also rapidly metabolized, maximum concentration is achieved after 30-45 minutes after exposure. The half-life is approximately 0.5 hours to 1 hour (15). Pharmacokinetic of canagliflozine is dose dependent, but much longer than in case of previously mentiod SGLT2 inhibitors. The half-life is approximately 12-15 hours, and time peak concentration after exposure is achieved after similar time (16).
Therapeutic effect of SGLT2 inhibitors
It has been proven that patients with type 2 diabetes have a higher expression of SGLT2 receptors compared to healthy subjects (11, 17, 18). Blocking of these transporters leads to increased urinary excretion of glucose and reduction of both fasting and postprandial plasma glucose concentration. It is estimated that SGLT2 inhibitors may block the reabsorption of glucose at about 60%. Therefore, these compounds may be used in the treatment of diabetes-especially type 2 diabetes mellitus. Indeed, dapagliflozine is the first drug of the calss which is accepted by European Medicine Agency and may be marketed in the European Union.
SGLT2 inhibitors reduce blood glucose not influencing insulin levels, however they may also improve insulin sensitivity and reduce gluconeogenesis in the liver (18). They seem not only to improve glucose control (percentage of glycated hemoglobin, fasting and postprandial plasma glucose) but also body weight as well systolic blood pressure (18). The two latter effects seem to be dependent on the diuretic effect of these medications. This effect, in turn, is probably dependent on the osmotic effect exerted by glucosuria, however it may also result from natriuresis. Sodium excretion occurs in the last parts of nephrons as a rebound after the sodium reabsorption in the proximal parts. There is no evidence up to date that SGLT2 inhibitors may increase natriuresis directly (17, 18).
There is a tendency to the use of selective SGLT2 inhibitors. Non-selective inhibitor of SGLT, such as phlorizine hydrolyzes in the intestine to the aglycone called phloretin, which potently blocks not only SGLT1 transporters, but also GLUT proteins, which causes undesirable adverse effects such as exacerbation of insulin resistance and hypoglycemia in the CNS (17-19).
Possible side effects
Selective SGLT2 inhibitors appear to be safe. The risk of hypoglycemia is low. They may, however, increase the risk of urogenital infections. In women the infections are rather bacterial and fungal, in men fungal balanitis is probably most important. In some patients these diuretic drugs may cause an increase in hematocrite value, but they rather do not increase a frequency of hypovolemia. It also appears that they do not result in impairment of renal function, although they may lead to an increase of serum urea concentration (18, 19). It is not entirely clear yet whether there is a higher incidence of cancer in subjects using these drugs. Because of slightly higher incidence of breast and bladder cancer FDA has not yet approved dapaglifozine, although the European Medicines Agency (EMA), however, approved the drug judging that it is probably safe and the difference in cancer incidence between dapagliflozin and placebo treated subjects is non significant.
Dapagliflozine as model representative of SGLT2 inhibitors
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