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Efficacy and Safety of Diacerein in Patients with Inadequately 1356 Diabetes Care Volume 40, October 2017 Efficacy and Safety of Diacerein Claudia R.L. Cardoso, Nathalie C. Leite, Fernanda O. Carlos, Andreia´ A. Loureiro, in Patients With Inadequately Bianca B. Viegas, and Gil F. Salles Controlled Type 2 Diabetes: A Randomized Controlled Trial Diabetes Care 2017;40:1356–1363 | https://doi.org/10.2337/dc17-0374 OBJECTIVE To assess, in a randomized, double-blind, and placebo-controlled trial, the efficacy and safety of diacerein, an immune modulator anti-inflammatory drug, in improving glycemic control of patients with type 2 diabetes. RESEARCH DESIGN AND METHODS Eighty-four patients with HbA1c between 7.5 and 9.5% (58–80 mmol/mol) were randomized to 48-week treatment with placebo (n = 41) or diacerein 100 mg/day (n = 43). The primary outcome was the difference in mean HbA1c changes during treatment. Secondary outcomes were other efficacy and safety measurements. A gen- eral linear regression with repeated measures, adjusted for age, sex, diabetes duration, and each baseline value, was used to estimate differences in mean changes. Both intention-to-treat (ITT) analysis and per-protocol analysis (excluding 10 patients who interrupted treatment) were performed. RESULTS Diacerein reduced HbA1c compared with placebo by 0.35% (3.8 mmol/mol; P =0.038) EMERGING TECHNOLOGIES AND THERAPEUTICS in the ITT analysis and by 0.41% (4.5 mmol/mol; P = 0.023) in the per-protocol analysis. The peak of effect occurred at the 24th week of treatment (20.61% [6.7 mmol/mol; P =0.014]and20.78% [8.5 mmol/mol; P = 0.005], respectively), but it attenuated fi fi toward nonsigni cant differences at the 48th week. No signi cant effect of diacerein Department of Internal Medicine, University Hospi- was observed in other efficacy and safety measures. Diarrhea occurred in 65% of tal Clementino Fraga Filho, and School of Medicine, patients receiving diacerein and caused treatment interruption in 16%. Seven pa- Universidade Federal do Rio de Janeiro, Rio de tients in the diacerein group reduced insulin dosage, whereas 10 in the placebo group Janeiro, Brazil increased it; however, mild hypoglycemic events were equally observed. Corresponding author: Gil F. Salles, gilsalles@ hucff.ufrj.br. CONCLUSIONS Received 20 February 2017 and accepted 11 May 2017. Diacerein reduced mean HbA1c levels, with peak of effect at the 24th week of treat- ment. The drug was well tolerated and may be indicated as adjunct treatment in Clinical trial reg. no. NCT02242149, clinicaltrials .gov. patients with type 2 diabetes, particularly in those with osteoarthritis. This article contains Supplementary Data online at http://care.diabetesjournals.org/lookup/ The pivotal role of inflammatory pathways in the pathogenesis of type 2 diabetes and suppl/doi:10.2337/dc17-0374/-/DC1. its associated long-term complications currently is well accepted (1). The two main © 2017 by the American Diabetes Association. physiopathological mechanisms underlying type 2 diabetes development and Readers may use this article as long as the work is properly cited, the use is educational and not progression, namely defective pancreatic b-cell insulin secretion and peripheral for profit, and the work is not altered. More infor- insulin resistance, both have immunoinflammatory-mediated bases, particularly those mation is available at http://www.diabetesjournals involving the proinflammatory cytokine interleukin-1b (IL-1b) pathways (1,2). This .org/content/license. care.diabetesjournals.org Cardoso and Associates 1357 evidence has led to proposals to target RIO-T2D cohort conducted at a ter- specific with virtually no interference inflammatory pathways as potential tiary care university hospital to assess from common hemoglobin variants. treatment for type 2 diabetes (3,4). whether diacerein was superior to pla- No interference with diacerein is re- Diacerein (1,8-diacetoxy-9,10-dioxo- cebo in improving glycemic control of ported. A 24-h sterile urine sample dihydroanthracene-3-carboxylic acid), an patients with poorly controlled type 2 was collected to assess 24-h albumin- anthraquinone derivative found in Cassia diabetes. All participants gave written uria. Glomerular filtration rate was esti- gender plants, has been indicated mainly informed consent, and the local ethics mated by the Chronic Kidney Disease for the symptomatic treatment of osteo- committee had previously approved the Epidemiology Collaboration equation arthritis (5,6). Although its specific mech- study protocol (Rio de Janeiro, Brazil). (23). Clinical blood pressure (BP) was anism of action is still unclear, diacerein is Participants were randomly assigned measured twice on two occasions (at believed to act by its metabolite rhein as after trial registration between Octo- screening and at the end of the run-in an immune modulator by mainly inhibit- ber 2014 and January 2016, and the period) in the sitting position with a di- ing the synthesis and activity of proin- last patient visit occurred in January gital BP monitor (HEM-907XL; Omron flammatory cytokines, such as tumor 2017. Healthcare, Kyoto, Japan) and suitably necrosis factor-a (TNF-a), IL-6, and espe- sized cuffs. Body weight and height cially IL-1b, in several experimental mod- Eligibility were also measured at screening and els of osteoarthritis (7–10). In animal Eligible participants were current adult the end of the run-in period. models of obesity and diabetes, diacerein RIO-T2D patients (#75 years of age) with has been demonstrated to downregulate type 2 diabetes, with screening HbA Randomization and Intervention 1c At the end of the run-in period, 84 pa- IL-1b, IL-6, and TNF-a and their down- levels between 7.5% (58 mmol/mol) tients were considered adherent to anti- ward signaling in liver, adipose tissue, and 9.5% (80 mmol/mol), and on ei- diabetic treatment, persisted with HbA pancreatic islets, and muscle (11,12); to ther stable oral or insulin treatment. 1c levels between 7.5% (58 mmol/mol) and increase b-cell mass and insulin secretion The characteristics of the RIO-T2D co- 9.5% (80 mmol/mol), and were random- by protecting b-cells from apoptosis hort, its inclusion criteria, and its proce- ized to placebo (n = 41) or diacerein (13,14); and to reduce peripheral insulin dures and diagnostic definitions have 100 mg/day add-on treatment as a single resistance, particularly in the liver and ad- been described previously (20–22). morning dosage (n = 43) for 48 weeks. ipose tissue (12), resulting in improve- Exclusion criteria were pregnancy, con- One specialized nurse, who used sealed ments in glucose tolerance and lower comitant life-threatening diseases, signif- opaque envelopes in blocks of four, per- fasting glycemia levels (11–14). More- icant cognitive impairment, advanced formed the randomization, which was over, rhein has been shown to have ben- renal failure (serum creatinine $177 stratified by sex, age (#60, .60 years), eficial effects in experimental diabetic mmol/L), chronic hepatic disorders (ex- and baseline HbA level (7.5–8.4%, 8.5– nephropathy (15,16) and in diabetes- cept nonalcoholic fatty liver disease), 1c 9.5%). This nurse distributed the al- related nonalcoholic fatty liver disease and major cardiovascular events in the located medications but had no other (17,18). Despite this experimental evi- previous 6 months. All eligible partici- contact with the participants. All other dence, only one previous clinical study pants (n = 142) entered an 8-week researchers, the attending physicians, (19) to our knowledge has assessed the run-in period where adherence to antidi- and the participants were blind to allo- effect of diacerein in patients with type 2 abetic treatment was assessed by pill cated treatment. diabetes. The study was a randomized counting and direct observation of insulin controlled trial (RCT) that showed poten- administration. Follow-up and Outcomes tial beneficial effects of diacerein on im- Participants were followed by their attend- proving glycemic control, reducing Baseline Procedure ing physicians with a recommendation serum inflammatory biomarkers, and At the end of the 8-week run-in period, to keep antidiabetic, antihypertensive, increasing insulin secretion. However, before randomization, all patients had and antilipidemic treatments unchanged the study evaluated only a small sample fasting blood samples collected to assess throughout the 48-week period, except of 40 drug-naive patients with recent- HbA1c, glycemia, serum lipids, creatinine, in case of hyperglycemic or hypoglycemic onset type 2 diabetes over a 60-day treat- uric acid, liver function (alanine and as- warnings. Participants were seen at the ment period. Therefore, we conducted a partate aminotransferases, g-glutamyl 4th, 8th, 12th, 24th, 36th, and 48th weeks nested RCT of patients with poorly con- transferase, alkaline phosphatase, and al- by another specialized nurse who used a trolled type 2 diabetes and high cardio- bumin), and hematological/inflammatory standard questionnaire to assess adher- vascular risk in an ongoing cohortdthe indices (hematocrit, leukocyte and plate- ence to treatment by pill counting and ad- Rio de Janeiro Type 2 Diabetes (RIO- let counts, serum ferritin, and C-reactive verse event occurrence and at the 12th, T2D) cohort studydto assess the efficacy protein). HbA1c was measured by boro- 24th, 36th, and 48th weeks by their at- and safety of 1-year diacerein add-on nate affinity high-performance liquid tending physicians who repeated the treatment in improving glycemic control. chromatography (Premier Hb9210; Trin- same laboratory examinations except for ity Biotech, São Paulo, Brazil) certified 24-h albuminuria, which was repeated RESEARCH DESIGN AND METHODS by the National Glycohemoglobin Stan- only at the 24th and 48th weeks. In case Design Overview dardization Program. This assay has an of gastrointestinal intolerance, partici- The study was a single-center, randomized intra- and interassay coefficient of varia- pants were instructed to change their (1:1), double-blind, parallel, placebo- tion ,2% and a linear range of measure- morning medication to the evening after controlled clinical trial nested within the ment from 3.8 to 18.5% and is highly dinner.
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