The place of gliclazide MR in the evolving type 2 diabetes landscape: A comparison with other sulfonylureas and newer oral antihyperglycemic agents

diabetes research and clinical practice

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Contents available at ScienceDirect

Diabetes Research and Clinical Practice journal homepage: www.elsevier.com/locat e/dia bre s

Review

The place of gliclazide MR in the evolving type 2 diabetes landscape: A comparison with other sulfonylureas and newer oral antihyperglycemic agents Stephen Colagiuri a,*, David Matthews b, Lawrence A. Leiter c, Siew Pheng Chan d, Giorgio Sesti e, Michel Marre f a

Boden Institute of Obesity, Nutrition and Exercise, University of Sydney, Sydney, NSW, Australia Oxford Centre for Diabetes, Endocrinology and Metabolism, and Harris Manchester College, University of Oxford, Oxford, UK c Division of Endocrinology & Metabolism, Li Ka Shing Knowledge Institute of St. Michael’s Hospital, University of Toronto, Ontario, Canada d Department of Medicine, University of Malaya Medical Centre, Kuala Lumpur 50603, W.P., Malaysia e Department of Medical and Surgical Science, University Magna-Græcia of Catanzaro, 88100 Catanzaro, Italy f Diabetes Department, Hoˆpital Bichat-Claude Bernard, Assistance Publique des Hoˆpitaux de Paris, Universite´ Denis Diderot Paris 7, and INSERM U1138, Paris, France b

A R T I C L E I N F O

A B S T R A C T

Article history:

The sulfonylureas are effective oral glucose-lowering agents with a long history of clinical

Received 19 December 2017

use. While all have the same general mechanism of action, their pharmacokinetic proper-

Received in revised form

ties are influenced by factors such as dosage, rate of absorption, duration of action, route of

4 May 2018

elimination, tissue specificity, and binding affinity for pancreatic b-cell receptor. The result

Accepted 16 May 2018

is a class of agents with similar HbA1c-lowering efficacy, but well-documented differences

Available online 24 May 2018

in terms of effects on hypoglycemia, and cardiovascular and renal safety. This review examines the differences between currently available sulfonylureas with a focus on how

Keywords: Sulfonylureas Type 2 diabetes DPP4 inhibitors Gliclazide Glipizide Glibenclamide/glyburide Glimepiride SGLT2 inhibitors

gliclazide modified release (MR) differs from other members of this class and from newer oral antihyperglycemic agents in the form of dipeptidyl peptidase-4 (DPP4) and sodium– glucose cotransporter 2 (SGLT2) inhibitors. The first part focuses on major outcome trials that have been conducted with the sulfonylureas and new oral agents. Consideration is then given to factors important for day-to-day prescribing including efficacy and durability, weight changes, hypoglycemia, renal effects and cost. Based on current evidence, third-generation sulfonylureas such as gliclazide MR possess many of the properties desired of a type 2 diabetes drug including high glucose-lowering efficacy, once-daily oral administration, few side effects other than mild hypoglycemia, and cardiovascular safety. Ó 2018 Elsevier B.V. All rights reserved.

* Corresponding author. E-mail address: [email protected] (S. Colagiuri). https://doi.org/10.1016/j.diabres.2018.05.028 0168-8227/Ó 2018 Elsevier B.V. All rights reserved.

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Contents 1. 2. 3. 4. 5.

6. 7.

8. 9.

1.

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2 Physiological basis of sulfonylurea action and clinical implications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2 Major outcome trials using sulfonylureas . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3 Major outcome trials with other oral antihyperglycemic agents. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5 Other clinically relevant considerations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6 5.1. Efficacy and durability. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7 5.2. Weight changes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7 5.3. Hypoglycemia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8 5.4. Renal effects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9 5.5. Cost . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9 Place of sulfonylureas in current guidelines for the management of type 2 diabetes . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9 Specific clinical situations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10 7.1. Maturity onset diabetes of the young (MODY) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10 7.2. Ramadan . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10 7.3. Older people . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10 7.4. Renal impairment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10 Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10 Disclosures . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11 Acknowledgments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11 Appendix A. Supplementary material . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11

Introduction

Sulfonylureas were the first oral agents to be developed for the treatment of type 2 diabetes in the early 1950s and have a long history of clinical use. Since then our increased understanding of the pathophysiology of type 2 diabetes has led to the development of a number of new drug classes with novel mechanisms of action, yet the sulfonylureas and metformin remain the most widely prescribed antihyperglycemic agents worldwide [1–3]. Safely achieving and maintaining adequate glycemic control remains an important objective and a challenge in many people with type 2 diabetes. Type 2 diabetes is no longer a pandemic only of economically affluent countries, but is also a major problem in the developing world. More than ever, cost-effective and safe therapies to lower blood glucose levels are required. However, while new treatments for diabetes may offer certain advantages over their predecessors, they may also come with new side effects or restrictions for use and at higher costs. Since the first sulfonylureas became available, drugs in this class have undergone several stages of development and have different pharmacological properties. Emerging evidence indicates that clinical characteristics commonly associated with the use of sulfonylureas are often not a class effect. This review examines how gliclazide MR differs from other currently available sulfonylureas and newer oral antihyperglycemic agents. The first part focuses on major outcome trials and some observational studies. Consideration is then given to factors important for day-to-day prescribing including efficacy and durability, weight changes, hypoglycemia, renal effects and cost.

2. Physiological basis of sulfonylurea action and clinical implications The sulfonylureas stimulate insulin secretion by binding to specific receptors on the pancreatic b-cells, resulting in closure of ATP-sensitive K-channels (KATP) in the b-cell plasma membrane and opening of voltage-gated calcium channels [4,5]. KATP channels are a complex of two proteins: a poreforming subunit (Kir6.2) and a drug-binding subunit (SUR); the latter functioning as the receptor for sulfonylureas (Fig. 1) [6]. Two genes for sulfonylurea receptors have been identified encoding the proteins SUR1 and SUR2 [7]. The predominant type of SUR varies between tissues: SUR1 is predominantly found in pancreatic b-cells, SUR2A in cardiac muscle, and SUR2B in smooth muscle (Fig. 1). The opening of cardiac KATP channels is thought to protect the heart during periods of ischemia. Sulfonylureas with affinity for cardiac KATP channels may inhibit the opening of KATP channels in the cardiovascular system, whereas those that act selectively on the pancreatic b-cell SUR receptors may pose less of a cardiovascular risk [8] and are preferred especially in individuals at high risk for myocardial ischemia. While ß-cell oxidative stress is related to chronic hyperglycemia, it has been suggested that certain sulfonylureas may directly increase generation of reactive oxygen species and cause oxidative stress related b-cell apoptosis [9]. Gliclazide is known to be a general free radical scavenger, mediated by the azabicyclooctyl ring on its sulfonylurea core [10], and a number of experimental and clinical studies suggest that gliclazide may protect pancreatic b-cells from apoptosis induced by oxidative stress [11]. Clinically this could manifest as differences amongst sulfonylureas in terms of secondary

diabetes research and clinical practice

treatment failure. In a study that assessed treatment failure in 248 people with type 2 diabetes, secondary failure at 5 years was lower with gliclazide (7%) compared with glibenclamide (glyburide) (18%) and glipizide (26%) [12]. A retrospective analysis also found that patients treated with gliclazide required the addition of insulin less frequently and had a longer time prior to initiation of insulin therapy than those treated with glibenclamide, suggesting that gliclazide may protect b-cells and thereby delay the development of secondary treatment failure [13].

β-Cell

3.

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3

Major outcome trials using sulfonylureas

Cardiovascular disease remains the most common cause of death among adults with diabetes, and the optimization of blood glucose levels to reduce the risk of microvascular and macrovascular complications remains a major focus of therapy. The sulfonylureas were developed before the 2008 FDA/ EMA registration requirement that excess cardiovascular risk associated with new antihyperglycemic drugs be ruled out [14]; nevertheless a number of randomized controlled trials

Cardiac cell

SUR1

Kir

SUR2A

6.2

S

B

S

(a)

Kir 6.2

B

(b)

Octameric SUR-Kir6.2 complex

Kir6.2/SUR1

1nA

S

S

B

B 10 μM gliclazide

SUR1

100 nM glibenclamide

Kir6.2/SUR2A

Kir6.2

B S

B

S

5nA

10 μM gliclazide

(c)

100 nM glibenclamide

(d)

Fig. 1 – (a) The transmembrane complex of the SUR1 sulfonylurea receptor and the ATP- sensitive Kir6.2 potassium efflux channel on the pancreatic b-cells. Each SUR1 has a cytosolic sulfonylurea (S) binding site and a benzamido (B) binding site. (b) SUR2A on cardiac muscle cells (and SUR2B on vascular smooth muscle cells) does not have a sulfonylurea binding site. While all sulfonylureas have the same general mechanism of action, they exhibit differences in tissue specificity, interacting to varying degrees with the different types of SUR. Using recombinant channels expressed in vitro and endogenous KATP channels in native tissues it has been shown that glimepiride and glibenclamide inhibit cardiac and smooth muscle KATP channels in addition to those in b-cells with similar affinity and are only slowly reversible [7,96–100]. In contrast, tolbutamide and gliclazide are more selective, blocking b-cell KATP channels with high affinity, but not the cardiac or smooth muscle types of KATP channel, and are reversible [7,96–99]. (c) The SUR1–Kir6.2 complex is a non-covalently bonded octamer comprising 4* SUR1 and 4*Kir6.2, illustrated from the cytosolic surface to show the sulfonylurea and benzamido binding sites. (d) Inhibition of cloned b-cell (Kir6.2/SUR1) and cardiac (Kir6.2/SUR2a) KATP channels illustrating specificity and reversibility of gliclazide for SUR1. Glibenclamide inhibited both b-cell and cardiac KATP channels and exhibited non-reversible SUR1 inhibition [100].

4

diabetes research and clinical practice

(RCT) had evaluated the effectiveness of individual sulfonylureas for the prevention of vascular complications in people with type 2 diabetes both newly diagnosed and those at high cardiovascular risk. The first was the University Group Diabetes Program (UGDP) that randomized 1027 people to one of four treatment arms, one of which was tolbutamide [15]. The study began in 1961, and the tolbutamide arm was discontinued in 1969 because of an apparent increased risk of cardiovascular mortality; however, subsequent studies could not substantiate this finding. UGDP was the first RCT ever performed in diabetes, and had a number of flaws in its design including a failure of effective randomization which led to an excess of baseline vascular disease in those allocated tolbutamide [16]. The UK Prospective Diabetes Study (UKPDS) set out to examine the effect of intensified glucose control on the subsequent development of diabetes complications in people with newly-diagnosed type 2 diabetes [17,18]. Individuals were randomized to conventional glucose control with diet, or to intensive glucose lowering with a sulfonylurea (chlorpropamide, glibenclamide, glipizide) or insulin. The sulfonylureas proved as effective as insulin in decreasing the risk of microvascular complications, although neither treatment had a statistically significant effect on macrovascular disease [17]. There was no evidence of excess cardiovascular mortality. The UKPDS long-term follow-up trial of the original UKPDS cohort found that those randomized to intensive glycemic control using sulfonylureas or insulin during the 10 years of the study had a significant 15% lowered risk for myocardial infarction, 24% lowered risk for microvascular disease and 13% reduction in death from any cause at the end of 10 years of post-trial follow-up (Fig. 2) [19]. The recent TOSCA-IT (Thiazolidinediones or Sulfonylureas Cardiovascular Accidents Intervention Trial) trial examined sulfonylurea or pioglitazone add-on therapy in patients with type 2 diabetes at low cardiovascular risk inadequately controlled on metformin monotherapy. A total of 3028 adults were randomly assigned to pioglitazone or a sulfonylurea (glibenclamide 2%, glimepiride 48%, gliclazide 50%) and the long-term effects of the dual therapy on cardiovascular events were compared over a planned 5 years of follow-up [20]. Although the study was underpowered as it had fewer study participants and events than anticipated, no significant difference in the primary composite outcome (first occurrence of all-cause death, non-fatal myocardial infarction, non-fatal stroke or urgent coronary revascularization) was observed between the two treatments. In addition to similar low rates of cardiovascular events, both pioglitazone and a sulfonylurea as add-on to metformin were associated with few clinically relevant side effects over a median follow up of 4 years and 9 months. The aim of the glucose arm of the Action in Diabetes and Vascular Disease: Preterax and Diamicron MR Controlled Evaluation (ADVANCE) trial [21] was to extend the information gathered by the UKPDS and to determine whether intensifying glucose control to achieve an HbA1c  6.5% would provide additional benefit in reducing the risk of both micro- and macrovascular disease in people with established type 2 diabetes. The trial randomized 11,140 subjects into one of two glucose treatment arms: intensive glucose lowering with

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gliclazide MR and any other additional therapy to achieve HbA1c  6.5%, or standard glucose lowering with treatment according to local guidelines (if a sulfonylurea was required it could be any agent except gliclazide). Median follow-up was 5 years and the primary outcome was a composite of macrovascular (myocardial infarction, stroke, or cardiovascular death) and microvascular (retinopathy or nephropathy) events. The ADVANCE trial demonstrated that an intensive strategy based on gliclazide MR to achieve mean HbA1c levels of 6.5% improved microvascular (especially renal) outcomes safely with no demonstrable increase in mortality. The primary outcome occurred in 18.1% of people in the intensive control group and 20.0% in the standard control group (Fig. 3) (P = 0.013). Intensive control had no significant effect in reducing macrovascular disease (HR 0.94, P = 0.32), and the difference was therefore primarily due to fewer microvascular events, in particular, diabetes nephropathy which was reduced by approximately 20%. ADVANCE suggested that there were no detrimental effects on cardiovascular risk with gliclazide MR, even when used in individuals at high-risk of cardiovascular disease [21]. A post-trial follow-up of patients 10 years after initiation of the intensive glucose control strategy indicated long-term cardiovascular safety of the intensive treatment regimen based on gliclazide MR and continued renal benefits (29 events vs 53 end-stage renal disease [ESRD] events (HR 0.54, P < 0.01) [22,23]. In another population at high cardiovascular risk, the Danish STENO-2 trial randomized 160 people with type 2 diabetes and microalbuminuria to conventional therapy managed by their physician or intensive multifactorial intervention including metformin or gliclazide to maintain HbA1c < 6.5% [24,25]. A total of 118 cardiovascular events occurred over the 8-year follow- up: 85 events among 35 subjects (44%) in the conventional-therapy group compared with 33 events among 19 subjects (24%) in the intensive-therapy group [25]. STENO-2 illustrated the benefits of a multiple risk factor intervention strategy and does not allow any conclusions to be drawn concerning which treatment component was the most beneficial in terms of reducing the incidence of diabetes-related complications. Nevertheless, it is noteworthy that metformin and gliclazide were the oral antihyperglycemic drugs of choice [26]. A systematic review and network meta-analysis of controlled trials that included at least two sulfonylureas has shown that all-cause and cardiovascular related mortality is lower with the pancreatic b-cell specific sulfonylureas gliclazide and glimepiride compared with glibenclamide [27]. Another recent review concluded that there is no definitive evidence of harm with second- and third-generation sulfonylureas [28]. Despite this reassuring RCT evidence, observational studies have provided conflicting associations between sulfonylurea use and cardiovascular events and mortality. A recent review highlighted some of the methodological limitations of observational studies which may contribute to these conflicting findings [29]. Of the 19 observational studies identified in this review, only 6 had no major design-related biases and in 5 there was an association between sulfonylureas and an increased relative risk of 1.16–1.55. Overall, the lowest predicted relative risk was for studies with no major bias,

diabetes research and clinical practice

comparator other than metformin, and cardiovascular outcome (1.06 [95% CI 0.92–1.23]), whereas the highest was for studies with bias, metformin comparator, and mortality outcome (1.53 [95% CI 1.43–1.65]). One of the 6 identified studies in the above review with no major bias examined the association of cardiovascular events and mortality between different sulfonylureas [30]. Compared with metformin, over a median follow-up of 3.3 years, glimepiride, glibenclamide (glyburide), glipizide and tolbutamide were associated with increased all-cause mortality in subjects

Myocardial Infarction 1.4

Hazard Ratio

1.0 0.8 0.6 0.4 12

14

16

18

20

Median follow up (years)

End of randomized trial

No. of Events Conventional therapy 186

212

239

271

296

319

Sulfonylurea-insulin

450

513

573

636

678

387

Microvascular Disease 1.4

P = 0.01

P = 0.001

Hazard Ratio

1.2 1.0 0.8 0.6 0.4 10

12

14

16

End of randomized trial

18

20

Median follow up (years)

No. of Events Conventional therapy 121

155

187

205

212

222

Sulfonylurea-insulin

277

338

378

406

429

225

P = 0.44

P = 0.006

Hazard Ratio

1.2 1.0 0.8 0.6 0.4 10

12

14

16

End of randomized trial

18

20

Median follow up (years)

No. of Events Conventional therapy 213

267

330

400

460

537

Sulfonylurea-insulin

610

737

868

1028

1163

489

other

oral

To date three cardiovascular outcome trials with the dipeptidyl peptidase-4 (DPP4) inhibitors and two with a sodium– glucose cotransporter 2 (SGLT2) inhibitor have been published. For saxagliptin (SAVOR-TIMI), sitagliptin (TECOS), and alogliptin (EXAMINE) [32–34], the occurrence of the primary major adverse cardiovascular events (MACE) did not differ from placebo groups, confirming the non-inferiority of the new treatments for cardiovascular safety. A separate analysis of hospitalization for heart failure as a stand-alone exploratory endpoint demonstrated a potential concern for saxagliptin, and a less evident trend for alogliptin and no signal of harm with sitagliptin. On the basis of these findings, the FDA recommended a label warning regarding the risk of heart failure and further heart failure safety monitoring for saxagliptin and alogliptin. In contrast, the SGLT2 inhibitors empagliflozin and canagliflozin demonstrated non-inferiority as well as superiority on MACE compared with placebo in the EMPA-REG OUTCOME and CANVAS trials, respectively [35,36], albeit with an increased risk of amputation with canagliflozin. In all of the above trials a high proportion of patients were using concomitant metformin (66.2–81.6%) and/or sulfonylureas (40.2–46.5%), which were continued throughout the trial, demonstrating that the beneficial cardiovascular outcomes observed also occur with a high proportion of background sulfonylurea use. The ongoing CAROLINA study will

3

Death from Any Cause 1.4

with

P = 0.01

1.2

10

with and without previous myocardial infarction whereas gliclazide and repaglinide were not statistically different from metformin in both subjects without and with previous myocardial infarction. Another observational study compared pancreas nonspecific, long-acting sulfonylureas (glibenclamide [glyburide]/glimepiride) with pancreas-specific, short-acting sulfonylureas (gliclazide/glipizide/tolbutamide) [31]. Over a relatively short mean follow-up of 1.2 years, there was a similar association between the 2 groups and risk of cardiovascular events and mortality, but an increased risk of severe hypoglycemia with long-acting sulfonylureas.

4. Major outcome trials antihyperglycemic agents

P = 0.052

5

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Fig. 2 – Hazard ratios for patients in the United Kingdom Prospective Diabetes Study who had myocardial infarction, microvascular disease or who died from any cause are shown for the sulfonylurea–insulin group versus the conventional-therapy group. The overall values at the end of the randomized study in 1997 are shown (red squares), along with the annual values during the 10-year post-trial monitoring period (blue diamonds). Hazard ratios below unity indicate a favorable outcome for sulfonylurea-insulin therapy. Numbers of first events in an aggregate outcome that accumulated in each group are shown at 2-year intervals. The vertical bars represent 95% confidence intervals [19]. Reproduced with permission from Holman RR, et al. N Engl J Med 2008;359:1577–1589, Copyright Massachusetts Medical Society.

6

diabetes research and clinical practice

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Fig. 3 – Cumulative incidences of events, according to glucose-control strategy. The hazard ratios for intensive glucose control as compared with standard glucose control were as follows: for combined major macrovascular or microvascular events, 0.90 (95% confidence interval [CI], 0.82–0.98) (Panel A); for major macrovascular events, 0.94 (95% CI, 0.84–1.06) (Panel B); for major microvascular events, 0.86 (95% CI, 0.77–0.97) (Panel C); and for death from any cause, 0.93 (95% CI, 0.83–1.06) (Panel D). The vertical dashed lines indicate the 24-month and 48-month study visits, at which additional data on microvascular events were collected, specifically the ratio of urinary albumin to creatinine and results of a retinal examination. For events relating to these data, the event time was recorded as the date of the visit. The curves were truncated at month 66, by which time 99% of the events had occurred. The effects of treatment (hazard ratios and P values) were estimated from unadjusted Cox proportional-hazard models that used all the available data [21]. Reproduced with permission from ADVANCE Collaborative Group. N Engl J Med 2008;358:2560–2572, Copyright Massachusetts Medical Society.

provide cardiovascular outcome data from a head-to-head comparison of a sulfonylurea (glimepiride) and a DPP4inhibitor (linagliptin) and is due to complete in 2019 [37]. In a network meta-analysis of 73 RCTs that reported the risk of all-cause mortality or adverse cardiovascular outcomes for oral antihyperglycemic agents, SGLT2 inhibitors were associated with significant benefits in terms of all-cause and cardiovascular-related mortality and morbidity in patients with type 2 diabetes, compared with both placebo and other oral agents [38]. Although this analysis compared the difference between classes of oral agents, and not individual drugs, there was no difference in all-cause or cardiovascu-

lar mortality and risk of myocardial infarction between metformin and placebo or other oral agents including the sulfonylureas, thiazolidinediones (TZD) and DPP4 inhibitors. A subgroup analysis which stratified for age, cardiovascular risk, baseline HbA1c and duration of diabetes did not change the findings.

5.

Other clinically relevant considerations

With the availability of new oral antihyperglycemic agents, the task of choosing the most appropriate therapy has become more complex. In addition to efficacy and cardiovas-

diabetes research and clinical practice

cular safety, important factors to consider are drug effects on weight change, hypoglycemia, renal effects, and associated cost.

5.1.

Efficacy and durability

A number of systematic reviews and meta-analyses have been conducted to assess the comparative efficacy of the different classes of antihyperglycemic therapies in patients inadequately controlled on metformin monotherapy to try to inform decision making concerning choice of second-line therapy. A consistent finding has been that there are no statistically significant differences between drug classes in terms of HbA1c-lowering efficacy [39,40]. Despite similar reductions in HbA1c, a systematic review of 218 RCTs in nearly 79,000 patients has found considerable variability with regard to attainment of an HbA1c goal <7% among the different classes of antihyperglycemic agents [41]. Among the oral agents with published trial data available at the time of the review, the proportion of patients achieving the goal was highest with the sulfonylureas and metformin (48% and 42%, respectively). Both the DPP4 inhibitors and glinides achieved the goal in 39% of patients, followed by the TZDs (33%) and alpha glucosidase inhibitors (26%). When members of the sulfonylurea class are considered individually, all agents result in a statistically significant reduction in HbA1c relative to placebo, with no statistically significant differences between individual agents [39,42]. A meta-analysis of RCTs performing head-to- head comparisons of DPP4 inhibitors with sulfonylureas reported significantly greater HbA1c reductions with the sulfonylureas [43]. Type 2 diabetes is a progressive disease and long-term durable glycemic control is a difficult goal, particularly in newlydiagnosed patients who present with a high baseline HbA1c and in whom long-term exposure to hyperglycemia is likely. In ADOPT (A Diabetes Outcome Progression Trial), rosiglitazone, metformin, and glibenclamide were evaluated as initial monotherapy treatment for recently diagnosed type 2 diabetes in a double-blind, randomized, controlled clinical trial involving 4360 patients [44]. There was a cumulative incidence of secondary failure of 21% with metformin, 34% with glibenclamide, and 15% with rosiglitazone at 5 years. On the other hand, there is evidence that longer-term glycemic control over 5 years can be maintained with a sulfonylurea-based treatment regimen. In ADVANCE, mean HbA1c was lowered to a target of 6.5% using an intensive gliclazide MR-based strategy. Four out of five patients attained an HbA1c  7% with no deterioration for a mean of 5 years [21]. A recent meta-analysis to compare glycemic durability of sulfonylureas and DPP4 inhibitors assessed changes in HbA1c levels from an intermediate time point (26 or 52 weeks) to 104 weeks of treatment in eight RCTs [45]. Compared with sulfonylureas, DPP4 inhibitors were associated with smaller increases in HbA1c level from 24 to 28 weeks to 104 weeks (mean difference 0.16%, 95% CI: 0.21 to 0.11; P < 0.001) and from 52 weeks to 104 weeks ( 0.06%, 95% CI 0.10 to 0.02; P = 0.001). A separate systematic review and meta-analysis of 12 long-term RCTS of DPP4 inhibitors with durations of up to 108 weeks found that their

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7

effect on HbA1c decreased during the second year of treatment [46]. The 2-year period used in most of these trials for assessing glycemic durability is relatively short. The ongoing GRADE (Glycemia Reduction Approaches in Diabetes: a comparative Effectiveness) study will compare glycemic control with four drug classes (sulfonylurea, DPP4 inhibitor, GLP-1 receptor agonist, and basal insulin) when added to metformin therapy over 4 years in patients with recent-onset type 2 diabetes [47], though unfortunately an SGLT2 inhibitor arm is not included. Two trials have assessed glycemic durability of the SGLT2 inhibitors versus a sulfonylurea as add-on therapy to metformin. In the first, 1549 patients were randomized to empagliflozin or glimepiride [48]. At 2 years, the mean difference in change from baseline HbA1c was 0
11% (95% CI 0
19 to 0
02; P = 0.0153 in favor of empagliflozin); 4-year data for this trial have not yet been published. In the second trial, dapagliflozin was compared with glipizide in 814 patients [49]. Sustained reductions in HbA1c of 0.30% (95% CI 0.51 to 0.09) were observed in favor of dapagliflozin after 4 years of treatment, with a significantly lower HbA1c coefficient of failure for dapagliflozin than for glipizide: 0.19 (95% CI 0.12–0.25) versus 0.61 (95% CI 0.49–0.72, difference 0.42; P = 0.0001). No trials have compared an SGLT2 inhibitor with gliclazide. Two trials have compared sulfonylurea and TZDs added to metformin as dual therapy and reported that the rate of increase of HbA1c is slightly, but significantly, greater with sulfonylurea compared with a TZD [20,50].

5.2.

Weight changes

When considered as a class, sulfonylurea monotherapy is reported to induce an approximately 1.5–2.5 kg increase in weight [51]. In the UKPDS, people on sulfonylurea monotherapy gained more weight compared to those receiving dietary intervention (chlorpropamide + 2.6 kg, glibenclamide + 1.7 kg) [17]. Most of the weight gain occurred in the first year of therapy and levelled off thereafter. In the UKPDS, the sulfonylurea-induced weight gain stabilized after the first 3 or 4 years [52]. In the ADOPT study, glyburide monotherapy was associated with weight gain during the first year (+1.6 kg), after which it remained stable [43]. In the ADVANCE study, mean body weight during the follow-up period was 0.7 kg greater in the intensive control group than in the standard-control group (P < 0.001) [21], but overall weight gain was negligible with gliclazide MR intensive therapy (0.1 kg over 5 years of follow-up) [53]. When analyzed by baseline BMI subgroup, a small mean weight loss of 0.5 kg was observed in obese people (BMI  30 kg/m2) [53]. Data from the active control group of the RECORD trial showed that weight was not increased in patients randomized to dual therapy with metformin and a sulfonylurea [50]. Over 5 years of follow-up, weight gain was neutral in patients with background metformin randomized to a sulfonylurea and there was a mean weight loss of 1.5 kg in patients on background sulfonylurea randomized to metformin. A similar pattern of weight change was also observed with dual metformin and sulfonylurea therapy in the TOSCA study with an initial small weight gain in the first year returning to baseline weight over 5 years [20].

8

diabetes research and clinical practice

16,000 50 nmol/L 6–12 30–120

>24

No

Urine 65%

0.8 mmol/L

1.35 – 7.3 nmol/L – 5.4 nmol/L – Urine 60% Urine 70% Yes No 24 >24 2–3 1–6

Third generation sulfonylureas Glimepiride Glipizide GTS (gastrointestinal therapeutic system) Gliclazide MR (modified release)

16,000 50 nmol/L 4–6

10–24

No

Urine 65%

0.8 mmol/L

6.4 – 27 nmol/L – 4.2 nmol/L – Bile > 50% Urine 70% Yes No 16–24 12–24 2–4 1–3

2.5–15 2.5–15 divided into 1–2 doses 80–320 Gliclazide (regular)

Chlorpropamide

Second generation sulfonylureas Glibenclamide (glyburide) Glipizide (regular)

– – – Yes 2–4

24

Urine 80 to 90%

314.8 1.7 mmol/L

SUR 2A SUR 1

5.4 lmol/L Urine 100% No Short 3–4

500–2000 in 2 or 3 divided doses 100–500 single daily dose First generation sulfonylureas Tolbutamide

Peak plasma levels (h) Daily dose (mg) Product

Table 1 – Pharmacokinetic properties of available sulfonylureas.

Duration of action (h)

Active metabolites

Excretion

SUR subtype affinity (concentration of half maximal inhibition [Ki])

Relative affinity SUR1/SUR2A

5.3.

1 4 3 ( 2 0 1 8 ) 1 –1 4

Hypoglycemia

Differences have been observed in hypoglycemic risk among the different sulfonylureas which may be explained by variations in their pharmacological profiles related to the selectivity and reversibility of the individual sulfonylurea for SUR1 on the b-cell and the route of drug elimination (Table 1) [54-56]. Glibenclamide and glimepiride are long-acting and the formation of active metabolites increases the risk for prolonged and severe hypoglycemia, particularly in the elderly [57,58]. The risk is significantly less with glipizide and gliclazide partly due to metabolism to inactive metabolites. Moreover, a gradual increase in drug concentrations with the modified release formulations of these drugs further reduces the risk for hypoglycemia when compared with the sharp increase in drug plasma concentrations observed with glibenclamide and glimepiride. Several meta-analyses have compared the risk of hypoglycemia among the different sulfonylureas. A comparison of glibenclamide with other sulfonylureas, found glibenclamide was associated with a 1.4 times relative risk increase in overall hypoglycemic events and 4.7 increased risk for severe hypoglycemia [55]. A meta-analysis of RCTs with a duration of 12–52 weeks compared the relative risk of hypoglycemia with newer generation sulfonylureas when added to metformin monotherapy [59]. With comparable reductions in HbA1c of 0.66 to 0.84%, gliclazide conferred the lowest risk of hypoglycemia of any severity compared with glimepiride (OR 0.40; 95% CI, 0.13–1.27), glibenclamide (OR 0.21; 95% CI 0.03–1.48) and glipizide (OR 0.22, 95% CI, 0.05–0.96), although only the risk associated with glipizide was statistically higher than the risk with gliclazide. A meta-analysis of hypoglycemia incidence in RCTs of sulfonylureas found that hypoglycemia with glucose 3.1 mmol/L was experienced by 10.1% (95% CI 7.3–13.8%) of patients with any sulfonylurea, but only 1.4% (95% CI 0.8–2.4%) of patients treated with gliclazide [56]. Severe hypoglycemia was experienced by 0.8% (95% CI 0.5–1.3%) on any sulfonylurea and 0.1% (95% CI 0–0.7%) on gliclazide. A systematic review and metaanalysis of RCTs including gliclazide has also reported a significantly lower risk of hypoglycemia with gliclazide compared with other sulfonylureas (RR 0.47; 95% CI 0.77–0.70, P = 0.004) [42]. In the GUIDE study, gliclazide MR and glimepiride were similarly effective in improving blood glucose control, but for gliclazide MR this was achieved with approximately 50% fewer hypoglycemic episodes in comparison with glimepiride [60]. In the ADVANCE study, the intensive strategy based on gliclazide MR was associated with a low risk of severe hypoglycemia: only 2.7% of subjects (vs 1.5% in the standard control group) had at least one severe hypoglycemic episode [21]. In comparison, in the ACCORD and VADT studies, the rates of severe hypoglycemic events in the intensive arm were 16.2% and 21.2%, respectively [61,62]. While a direct causal relationship between hypoglycemia and death or vascular outcomes has not been demonstrated [63], severe hypoglycemia is known to result in a cascade of physiological effects that may increase cardiovascular disease risk.

diabetes research and clinical practice

A meta-analysis of 41 RCTs of the DPP4 inhibitors reported that compared with placebo, the DPP4 inhibitors have a very low risk of hypoglycemia [64]. A separate meta-analysis of head- to-head comparisons of DPP4 inhibitors and sulfonylureas, which included 12 RCTs and nearly 11,000 patients found the DPP4 inhibitors were less likely to achieve an HbA1c <7%, but had a lower risk of hypoglycemia (OR, 0.13; 95% CI 0.11–0.16) [43]. In a meta-analysis of clinical trials comparing SGLT2 inhibitors with placebo in 45 studies (n = 11 232) and with active comparators in 13 studies (n = 5175), hypoglycemic risk was similar to that of the active comparators (metformin, sitagliptin, sulfonylurea) [65]. An analysis of US claims data for people with type 2 diabetes has reported that despite the introduction of newer antidiabetes agents, achievement of target HbA1c goals and overall rate of severe hypoglycemia have remained the same [1].

5.4.

Renal effects

The variation in sulfonylurea pharmacokinetic properties also affects their clinical suitability for individuals with impaired renal function. The use of sulfonylureas in individuals with impaired renal function is dependent on the level of renal impairment and risk of hypoglycemia. For sulfonylureas with active metabolites there is an increased risk of hypoglycemia as estimated glomerular filtration rate (eGFR) declines. For this reason, use of glibenclamide should be limited to those with normal renal function or with moderate kidney disease (eGFR 60–90 mL/min) and avoided when eGFR is <60 mL/min [66]. Glimepiride may be used when eGFR is >60 mL/min, but w14ith reduced dose at 30–60 mL/min [66]. Both gliclazide and glipizide have only inactive metabolites and their risk of increased hypoglycemia with renal insufficiency is low and they may be safely used at eGFR levels >30 mL/min, and at reduced dose below this level with careful monitoring [66]. The ADVANCE trial provided important information on the role of gliclazide MR throughout the clinical course of renal disease from microalbuminuria to ESRD. Intensive glucose lowering based on gliclazide MR reduced the risk of newonset microalbuminuria by 9% (P = 0.01), macroalbuminuria by 30% (P < 0.001), new or worsening nephropathy by 21% (P = 0.006), and ESRD by 65% (P = 0.02) [67]. In addition, intensive glucose-lowering based on gliclazide MR led to regression of albuminuria by one stage in 62% of those with albuminuria at baseline, with the majority achieving normoalbuminuria. A persistent benefit of gliclazide MR intensive glucose control with respect to ESRD was observed for 10 years after initiation of therapy [22]. The use of antihyperglycemic agents in individuals with renal impairment is discussed further in section 7.4 (renal impairment).

5.5.

Cost

With its increasing prevalence and high cost of treatment, diabetes places an enormous demand on economic resources. In 2015/16 the Net Ingredient Cost (NIC, cost of the drug without any dispensing costs, fees or discount) for managing diabetes in England was £956.7, representing 10.6% of the total cost of all primary care prescribing [68]. The average NIC/item of the newer agents such as the DPP4 inhibitors and SGLT2

1 4 3 ( 2 0 1 8 ) 1 –1 4

9

inhibitors was approximately eight and tenfold more expensive, respectively, than that of the sulfonylureas. While not as high, similar cost trends have been observed in other countries. A US claims database study analyzed the data of over 37,000 people with type 2 diabetes aged over 40 years and diagnosed between 1995 and 2010 to develop a model for the benefits and harms of four commonly used second-line antihyperglycemic treatment regimens: sulfonylurea, DPP4 inhibitor, GLP-1 receptor agonist, or insulin. Outcomes considered were clinical effectiveness, quality of life, and cost [69]. They found that the use of a sulfonylurea after metformin for the treatment of type 2 diabetes had as much of an effect in terms of life-years and quality-adjusted life years as newer medications such as DPP4 inhibitors, but with far lower costs (monthly medication cost (USD) of metformin 81.75, sulfonylurea 54.85, GLP-1 receptor agonist 325.97, DPP4 inhibitor 232.84). An analysis of the cost of antihyperglycemic drugs in Germany in 2015 reported that metformin and the sulfonylureas (adjusted cost difference in Euros 71 and 49, respectively) were associated with lower annual medication costs compared with the DPP4 inhibitors (+51), GLP-1 receptor agonists (+104), SGLT2 inhibitors (+27) and insulin (+19) [70].

6. Place of sulfonylureas in current guidelines for the management of type 2 diabetes The antihyperglycemic efficacy of the sulfonylureas is recognized in guidelines such as those of the American Diabetes Association (ADA) where efficacy of metformin, sulfonylureas, TZDs and GLP-1 receptor agonists is listed as high, compared with intermediate for the DPP4 and SGLT2 inhibitors [71]. The current approach to the management of type 2 diabetes generally involves individualization of treatment and is centered on achieving glycemic control while minimizing the risk of hypoglycemia and diabetes complications. In recent updates to international guidelines such as the ADA Standards of Care 2018, sulfonylureas are an option as addon to metformin in patients with known CVD after agents with proven cardiovascular benefit have been tried, and remain a second-line add-on to metformin in those without known CVD [72–74]. There are several national and international guidelines that go further in differentiating within the sulfonylurea class based on intra-class differences, and tend to highlight gliclazide as having, compared to other sulfonylureas, a lower risk of cardiovascular disease, a lower risk of hypoglycemia and weight neutrality (2013 Dutch type 2 diabetes guidelines from the Dutch College of General Practitioners [75], 2016 Royal Australian College of General Practitioners and Diabetes Australia [76], Italian Society of Diabetes guidelines [77], and 2017 Society for Endocrinology, Metabolism and Diabetes of South Africa guidelines [78]). Gliclazide MR 60 mg is considered a preferred sulfonylurea in individuals with chronic kidney disease (CKD) in the guidelines from the National Kidney Foundation Kidney Disease Outcomes Quality Initiative [79]. The World Health Organization (WHO) advocates the use of metformin and gliclazide, as an example of a third-generation sulfonylurea, in patients with type 2 diabetes in their model list of essential medicines [80].

10

diabetes research and clinical practice

The South Asian Federation of Endocrine Societies continue to recommend sulfonylureas as preferred second-line agents after metformin [81]. A lack of differentiation between second- line treatments in the AACE/ACE guidelines may be explained by the fact that gliclazide is not registered in the USA [74]. In the 2013 Canadian Diabetes Association guidelines, gliclazide is listed as the sulfonylurea with the lowest incidence of hypoglycemia [82].

7.

Specific clinical situations

7.1.

Maturity onset diabetes of the young (MODY)

MODY is a group of disorders characterized by b-cell dysfunction that result from a single gene mutation, the most common of which encodes the nuclear transcription factor 1 homeobox A (HNF1A). Individuals with this subtype are characterized by high sensitivity to the effects of sulfonylurea treatment [83]. In a randomized, cross-over trial, glycemic responses to gliclazide and metformin were compared between people with HNF1A mutations and those with type 2 diabetes matched for fasting blood glucose and body mass index [84]. The group with HNF1A MODY had a 5.2-fold greater response to gliclazide than to metformin (P = 0.0007), while in the group with type 2 diabetes the effects of gliclazide and metformin were similar. The International Society for Pediatric and Adolescent Diabetes (ISPAD) guidelines recommend sulfonylureas as first-line treatment in individuals with HNF1A MODY and, as long as there are no issues with hypoglycemia, patients can be maintained on low-dose sulfonylureas for decades [85] before they progress to insulin.

7.2.

Ramadan

It has been estimated that 80–90% of Muslims with diabetes fast during Ramadan, which has been shown to increase the risk of severe hypoglycemia by 7.5-fold [86,87]. A comparison of the incidence of hypoglycemia with glibenclamide, glimepiride, and gliclazide MR and the DPP4 inhibitor sitagliptin in 1024 people with type 2 diabetes fasting during Ramadan reported that the proportion with one or more symptomatic hypoglycemic events was 19.7%, 12.4%, 6.6% and 6.7% in the glibenclamide, glimepiride, gliclazide and sitagliptin groups, respectively [88]. A number of other studies that have assessed the risk of hypoglycemia with oral antihyperglycemic agents in Muslims fasting during Ramadan have also demonstrated similar low rates for gliclazide and DPP4 inhibitors [89,90]. A sulfonylurea with a low risk of hypoglycemia can therefore be safely continued during Ramadan under physician supervision and with Ramadan-focused advice [87,88,90].

7.3.

Older people

In older people with type 2 diabetes the choice of antihyperglycemic agent should focus on drug safety, and in particular protecting against hypoglycemia. In a small trial that compared the effect of glibenclamide and gliclazide on the frequency of hypoglycemic events and glycemic control in the

1 4 3 ( 2 0 1 8 ) 1 –1 4

elderly, results revealed that while both were similar for glycemic control after 6 months of treatment, the incidence of hypoglycemic episodes was significantly greater with glibenclamide when compared with gliclazide [54]. The majority of the hypoglycemic episodes occurred within one month of initiating treatment with either agent. A subgroup analysis of participants over the age of 75 (n = 53) from a head-to-head comparison of gliclazide MR versus glimepiride also found that most hypoglycemic episodes in people >75 years old occurred at the lowest treatment doses (15 on 30–60 mg gliclazide MR out of 22 episodes, and 48 on glimepiride 1–2 mg out of 56 episodes) [60].

7.4.

Renal impairment

A significant number of people with diabetes will develop impaired renal function [91]. Once eGFR falls below 60 mL/ min, the pharmacokinetics of antihyperglycemic drugs may be altered and all antihyperglycemic treatments with the exception of pioglitazone and insulin must be reduced or withdrawn as eGFR declines. With the sulfonylureas (and in some cases their active metabolites) there may be inadequate clearance. This increases the risk of both symptomatic and severe hypoglycemia by approximately twofold compared with people without renal impairment [92]. Sulfonylureas with no active metabolites may be used in those with renal impairment with appropriate monitoring. This is the case with gliclazide, which like the DPP4 inhibitors may be used in CKD stages 1–3 (eGFR > 30 mL/min) and at a reduced dose in patients with severe CKD [93,94]. In terms of the newer antihyperglycemic agents, all the DPP4 inhibitors can be used in patients with CKD, but require downward dose adjustments with falling eGFR; linagliptin can be administered without dose reduction at all CKD stages as it is predominantly eliminated by a hepatobiliary route [94]. In contrast, the SGLT2 inhibitors are generally contraindicated in patients with eGFR < 60 mL/min, mainly because their ability to block glucose reabsorption is dependent on adequate renal function; the efficacy of these agents therefore decreases along with the stages of renal impairment. Furthermore, in June 2016 the US FDA warned about the risk of acute kidney injury for drug products containing canagliflozin and dapagliflozin, but not empagliflozin [95].

8.

Conclusions

Controlling elevated blood glucose, maintaining this control over the long term, and preventing the development of microvascular and macrovascular complications are the main challenges in the management of type 2 diabetes. When deciding on a treatment strategy it is essential to consider both patient- and drug-specific characteristics. The recent approvals of a number of new treatment options for type 2 diabetes have led to revised treatment algorithms from major diabetes organizations. However, despite the availability of these newer agents, all treatment guidelines still recommend metformin as first-line therapy in most people, with sulfonylureas in general remaining an important second- and thirdline treatment choice based on documented efficacy and

diabetes research and clinical practice

safety, extensive clinical experience, ease of use, ability to use in combination with all other antihyperglycemic agents, and low cost. In patients with type 2 diabetes and known cardiovascular disease, agents with evidence of beneficial effects on cardiovascular endpoints may be preferred. While HbA1c-lowering efficacy is consistent across the sulfonylureas, their side-effect profiles are unique displaying clinically relevant within-class differences which are acknowledged by several guidelines.

9.

Disclosures

SC has received speaker/consulting honoraria from AstraZeneca, Merck, Novartis, Novo Nordisk, Sanofi, Servier, and Takeda. DM reports receiving research support from Janssen; serving on advisory boards and as a consultant for Novo Nordisk, Novartis, Sanofi-Aventis, Janssen, and Servier; and giving lectures for Novo Nordisk, Servier, Sanofi-Aventis, Novartis, Janssen, Mitsubishi Tanabe, and Ache´ Laboratories. LAL has received research grant support and/or speaker/ consulting honoraria from AstraZeneca, Boehringer Ingelheim, Eli Lilly, GlaxoSmithKline, Janssen, Merck, Novo Nordisk, Sanofi, and Servier. GS has received speaker/consulting honoraria from Novo Nordisk, Eli Lilly, AstraZeneca, Boehringer Ingelheim, Merck, Sanofi, Pfizer, Abbott, and Servier. SPC has received speaker/consulting honoraria from AstraZeneca, Boehringer Ingelheim, Eli Lilly, Janssen, Merck, Novartis, Novo Nordisk, Sanofi, and Servier. MM has received research grant support and/or speaker/consulting honoraria from Abbott, Astra-Zeneca, Boehringer-Ingelheim, Eli Lilly, Merck, Novo-Nordisk, Sanofi, and Servier.

Acknowledgments Editorial assistance for this paper was provided by Jenny Grice and funded by Servier Affaires Me´dicales.

Appendix A. Supplementary material Supplementary data associated with this article can be found, in the online version, at https://doi.org/10.1016/j.diabres.2018. 05.028.

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