View metadata, citation and similar papers at core.ac.uk brought to you by CORE State of the art paper provided by Institutional Research Information System University of Turin Sulfonylureas and their use in clinical practice Daniele Sola1, Luca Rossi1, Gian Piero Carnevale Schianca2, Pamela Maffioli3, Marcello Bigliocca1, Roberto Mella1, Francesca Corlianò1, Gian Paolo Fra2, Ettore Bartoli1, Giuseppe Derosa3,4 1Department of Translational Medicine, University “Piemonte Orientale Amedeo Corresponding author: Avogadro”, Novara, Italy Dott. Luca Rossi MD 2AOU “Maggiore della Carità” Novara, Italy Department 3Department of Internal Medicine and Therapeutics, University of Pavia, Fondazione of Translational Medicine IRCCS Policlinico S. Matteo, Pavia, Italy University “Piemonte 4Center for the Study of Endocrine-Metabolic Pathophysiology and Clinical Research, Orientale Amedeo Avogadro” University of Pavia, Pavia, Italy Novara, Italy Phone: +3903213733276 Submitted: 17 November 2012 Fax: +3903213733600 Accepted: 27 October 2013 E-mail: luca.rossi_1981@ yahoo.it Arch Med Sci 2015; 11, 4: 840–848 DOI: 10.5114/aoms.2015.53304 Copyright © 2015 Termedia & Banach Abstract Many anti-diabetic drugs with different mechanisms of action are now avail- able for treatment of type 2 diabetes mellitus. Sulfonylureas have been ex- tensively used for treatment of type 2 diabetes for nearly 50 years and, even in our times, are widely used for treatment of this devastating chronic illness. Here, we review some of the available data on sulfonylureas, eval- uating their mechanism of action and their effects on glycemic control. We can conclude that sulfonylureas are still the most used anti-diabetic agents: maybe this is due to their lower cost, to the possibility of mono-dosing and to the presence of an association with metformin in the same tablet. How- ever, sulfonylureas, especially the older ones, are linked to a greater prev- alence of hypoglycemia, and cardiovascular risk; newer prolonged-release preparations of sulfonylureas are undoubtedly safer, mainly due to reducing hypoglycemia, and for this reason should be preferred. Key words: glycemic control, hypoglycemia, sulfonylureas. Introduction Many anti-diabetic drugs with different mechanisms of action are now available to treat type 2 diabetes mellitus, including sulfonylureas, glinides, thiazolidinediones [1, 2], biguanides [3], and α-glucosidase in- hibitors [4, 5]. Recently, incretin-related drugs, such as dipeptidyl pep- tidase-4 (DPP-4) inhibitors [6, 7], and glucagon-like peptide-1 (GLP-1) receptor agonists [8, 9], have been developed. Despite the large number of anti-diabetic agents available, however, sulfonylureas remain the most widely used drugs for treating patients with type 2 diabetes [10]. Sulfonylureas were discovered in 1942, when Janbon et al. observed that some sulfonamides generated hypoglycemia in experimental ani- mals. From this observation carbutamide (1-butyl-3-sulfonylurea) was synthesized. Carbutamide was the first sulfonylurea used to treat dia- betes, but was subsequently withdrawn from the market because of its adverse effects on bone marrow. By the 1960s several sulfonylureas became available; they are tra- ditionally classified into 2 groups (or generations). Gliclazide, glipizide, glibenclamide and glimepiride are second-generation sulfonylureas, cur- Sulfonylureas and their use in clinical practice rently used, while first-generation drugs (such as levels of insulin and insulin response to glucose tolbutamide and chlorpropamide) are no longer rise rapidly, resulting in lowered blood glucose. used. Second-generation drugs are equally effec- After this period, baseline and stimulated insulin tive in lowering blood glucose concentrations, but levels become lower compared to those measured there are differences in absorption, metabolism at the beginning of treatment; however, blood and dosing (Table I). glucose values remain unchanged. The reason for Sulfonylureas should be considered for dia- this observation is not clear. With regard to the betic patients who are not overweight or those secretory activity of sulfonylureas, the mechanism for whom metformin is contraindicated or is not is now known. They act by binding to the specif- enough to achieve adequate glycemic control [11]. ic receptor for sulfonylureas on β-pancreatic cells, blocking the inflow of potassium (K+) through the Mechanism of action ATP-dependent channel: the flow of K+ within the The main effect of sulfonylureas is the rise in β-cell goes to zero, the cell membrane becomes plasma insulin concentrations; consequently they depolarized, thus removing the electric screen are effective only when residual pancreatic β-cells which prevents the diffusion of calcium into the are present. The rise in plasma insulin levels occurs cytosol. The increased flow of calcium into β-cells for two reasons. Firstly, there is stimulation of in- causes the contraction of the filaments of acto- sulin secretion by pancreatic β-cells, and secondly, myosin responsible for the exocytosis of insulin, there is a decrease in hepatic clearance of insulin. which is therefore promptly secreted in large In particular, this second effect appears mainly amounts (Figure 1). after the increase of insulin secretion has taken In particular, the sulfonylureas receptor (SUR1), place. In fact, in the first month of treatment, the a 1581-amino acid protein, has high affinity for Table I. Various generations of sulfonylureas Molecules Gen. Dose [mg] Duration of Activity of Elimination Structure action* T1/2 metabolites T1/2 Tolbutamide I 500–2000 Short Inactive Urine ≈ 100% O O O 4.5 to 6.5 h S N N CH H H 3 H3C O Glibenclamide II 2.5–15 Intermediate Active Bile ≈ 50% O S O to long 10 h O Cl NH 5 to 7 h NH NH O CH3 Glimepiride II 1–6 Intermediate Active Urine ≈ 80% O H H N N 5 to 8 h 3 to 6 h O S O O O N N H Glipizide II 2.5–20 Short to Inactive Urine ≈ 70% O O O N intermediate NH S NH 2 to 4 h H3C N O N H Gliclazide II 40–320 Intermediate Inactive Urine ≈ 65% O O O 10 h S N N N H H H3C Gliquidone II 15–180 Short to Inactive Bile ≈ 95% intermediate 3 to 4 h O NH O NH S O O O N O *Short duration of activity means < 12 h, intermediate 12–24 h, long over 24 h. Arch Med Sci 4, August / 2015 841 D. Sola, L. Rossi, G.P.C. Schianca, P. Maffioli, M. Bigliocca, R. Mella, F. Corlianò, G.P. Fra, E. Bartoli, G. Derosa K+ β-cell Glucose ADP K+ Glycolysis SU ATP Inhibition Activation ADP ATP Mitochondria Ca2+ Insulin released from granules Figure 1. Mechanism of action of sulfonylureas On the top right corner is represented the SUR, while octagon is sulfonylurea (SU). When the SU binds SUR, the flow of K (arrows) stopped, so the cell membrane is depolarized. An increased flow of calcium cause the contraction of the filaments of actomyosin responsible for the exocytosis of insulin. glibenclamide. SUR1 is a member of the ATP-bind- been proposed for the interaction between sulfo- ing cassette (ABC) super-family that has two nu- nylureas, glinides and SUR. The A site is located on cleotide binding folds (NBF-1 and NBF-2). Each the eighth (between TM segments 15 and 16) cy- nucleotide binding fold contains the Walker A and tosolic loop, which is specific for SUR1. Instead the B motifs and the SGGQ ABC signature, and it is B site involves the third (between TM segments important in nucleotide regulation of the func- 5 and 6) cytosolic loop, which is very similar in all tional activities of ABC proteins. SUR1 has three SURs. According to these different sites of inter- transmembrane domains (TMD), TMD0, TMD1 action, sulfonylureas and glinides can be divided and TMD2, which consist respectively of 5, 6 and into three groups. The first of these includes nate- 6 transmembrane (TM) segments that are numerat- glinide, tolbutamide and gliclazide, which are mol- ed progressively. TMD0 contains the TM segments ecules that bind specifically the A site of SUR1, from 1 to 5, TMD1 contains the TM segments from while the second group, which includes glimepiri- 6 to 11, and TMD2 contains the TM segments de and glibenclamide, binds non-specifically the B from 12 to 17. SUR1 is expressed at higher lev- sites of both SUR1 and SUR2A as well as the A site els in pancreatic islets. SUR1 is also present in the of SUR1; finally, the third group (which includes brain. Also a second type of sulfonylureas receptor meglitinide and repaglinide) binds to the B site of exists; it is named SUR2A (formerly called SUR2), SUR1 and SUR2A. and it is an isoform of SUR1. SUR2A is a protein of Beside the “first phase”, sulfonylureas also 1545 amino acids sharing 68% amino acid iden- increase the “second phase” of insulin secretion tity with SUR1. SUR2A has a low affinity for glib- that begins 10 min later as insulin granules are enclamide. Several variants of SUR2A have also translocated to the membrane of the β-cell. This been identified. One of them, SUR2B, differs from second phase involves the progressive formation SUR2A by 42 amino acids in the C-terminus, where of new insulin granules, and it is possible only if it is, instead, similar to SUR1. Although SUR2A is β-cell function is preserved. It is important to un- expressed predominantly in heart and skeletal derline that the release of insulin induced by sul- muscle, SUR2B is expressed widely in other tissues. fonylureas is independent of glucose levels, and In the past a two-site model (A site and B site) had this can increase the risk of hypoglycemia. 842 Arch Med Sci 4, August / 2015 Sulfonylureas and their use in clinical practice The impairment of the effect on insulin secre- of rate of amino acid incorporation into protein; tion that occurs during chronic administration inhibition of transaminase activity; inhibition of of sulfonylureas is due to the down-regulation the ratio of bound to free insulin; reduction of of the receptor for sulfonylureas on the surface intestinal glucose absorption; inhibition in insu- of β-cells.