Statins for Graves' orbitopathy (STAGO): a phase 2, open-label, adaptive, single centre, randomised clinical trial

Published on Sep 27, 2021in The Lancet Diabetes & Endocrinology32.069
· DOI :10.1016/S2213-8587(21)00238-2
Giulia Lanzolla7
Estimated H-index: 7
(UniPi: University of Pisa),
Elena Sabini8
Estimated H-index: 8
(UniPi: University of Pisa)
+ 7 AuthorsMichele Marinò35
Estimated H-index: 35
(UniPi: University of Pisa)
Sources
Abstract
Summary null null Background null A protective action of statins on development of Graves' orbitopathy suggests that statins might be used for treatment of the disease. We aimed to assess the efficacy of the addition of a statin, atorvastatin, to intravenous glucocorticoids (ivGCs) on Graves' orbitopathy outcomes in patients with hypercholesterolaemia. null null null Methods null We did a randomised, open-label, phase 2, adaptive, clinical trial at a single, tertiary, referral hospital in Pisa, Italy. Patients with moderate-to-severe, active Graves' orbitopathy, with a low-density lipoprotein cholesterol concentration between 2·97 and 4·88 mmol/L were eligible for inclusion. Patients were randomly assigned (1:1) in 11 blocks of eight, using a computer-based system, to the ST group or the NST group. The ST group received ivGCs (methylprednisolone 500 mg once a week for 6 weeks followed by 250 mg once a week for an additional six weeks) for 12 weeks and oral atorvastatin (20 mg once a day) for 24 weeks. The NST group only received the ivGC regimen. Patients were unmasked to group allocation; however, the ophthalmological investigator was masked to randomisation. The primary endpoint was the Graves' orbitopathy outcome (composite evaluation of exophthalmos, clinical activity score, eyelid aperture, and diplopia) at 24 weeks in the modified intention-to-treat (ITT) population (patients who attended the week 12 visit). Patients were considered responders when at least two of the following criteria were fulfilled in the most affected eye, without worsening in any of the same measures in both eyes: (1) reduction in exophthalmos of 2 mm or more, with no increase by 2 mm or more in the other eye; (2) reduction of clinical activity score by two or more points; (3) reduction in eyelid aperture by 2 mm or more, with no increase by 2 mm or more in the other eye; and (4) disappearance or improvement (change from constant to inconstant, intermittent, or absent, or from inconstant to intermittent or absent) of diplopia, and (5) improvement in visual acuity by 0·2 decimals or more. The trial is registered with EUDRACT, 2018-001317-33, and null ClinicalTrials.gov , null NCT03110848 . null null null Findings null Between June 1, 2020, and Nov 30, 2020, 119 patients were screened for inclusion, of whom 88 (74%) patients were enrolled and randomly assigned to one of the two treatment groups (44 [50%] to the ST group and 44 [50%] to the NST group). Eight (9%) patients did not attend the 12 week visit; 80 (91%) patients (18 [23%] men and 62 [78%] women) were included in the modified ITT population (41 [51%] in the ST group and 39 [49%] in the NST group]. The proportion of Graves' orbitopathy composite evaluation responders at 24 weeks was higher in the ST group (21 [51%] of 41 patients) than the NST group (11 [28%] of 39 patients; attributable risk 0·23 [95% CI 0·02–0·44]; p=0·042). 26 adverse events occurred in 21 (24%) of 88 patients in the safety population. One (2%) of 44 patients in each group required treatment discontinuation, with no serious adverse events and no difference between groups. null null null Interpretation null Addition of oral atorvastatin to an ivGC regimen improved Graves' orbitopathy outcomes in patients with moderate-to-severe, active eye disease who were hypercholesterolaemic. Future phase 3 studies, which could potentially recruit patients regardless of low-density lipoprotein cholesterol concentration, are required to confirm this association. null null null Funding null Associazione Allievi Endocrinologia Pisana.
References30
Newest
#1Michele Marinò (UniPi: University of Pisa)H-Index: 35
#2Giulia Lanzolla (UniPi: University of Pisa)H-Index: 7
Last. Claudio Marcocci (UniPi: University of Pisa)H-Index: 73
view all 3 authors...
Source
#1Anton Nilsson (Lund University)H-Index: 8
#2Kleoniki Tsoumani (Lund University)H-Index: 1
Last. Tereza Planck (Lund University)H-Index: 8
view all 3 authors...
AIM The aim of this study was to examine the effect of statins and other lipid-lowering agents on the development of Graves´ orbitopathy (GO) in patients with newly diagnosed Graves´ disease (GD). METHODS Our sample included the full adult population of individuals living in Sweden with newly diagnosed GD between 2005 and 2018 (n=34,894). We compared the GO incidence in statin users (n=5,574) and nonusers (n=34,409) by applying Cox regression with a time-varying exposure variable. We adjusted fo...
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#1Giovanna Rotondo Dottore (UniPi: University of Pisa)H-Index: 6
#2Ilaria Bucci (UniPi: University of Pisa)H-Index: 2
Last. Michele Marinò (UniPi: University of Pisa)H-Index: 35
view all 12 authors...
Context Graves' orbitopathy (GO) is an autoimmune disease persisting when immunosuppression is achieved. Orbital fibroblasts from GO patients display peculiar phenotypes even if not exposed to autoimmunity, possibly reflecting genetic or epigenetic mechanisms, which we investigated here. Design The design entailed the use of primary cultures of orbital fibroblasts from GO and control patients. Cell proliferation, hyaluronic acid (HA) secretion and HA synthases (HAS) were measured. Next Generatio...
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#1Yi-Hsuan Wei (NTU: National Taiwan University)H-Index: 1
#2Shu-Lang Liao (NTU: National Taiwan University)H-Index: 24
Last. Chang-Hao Yang (NTU: National Taiwan University)H-Index: 29
view all 5 authors...
Transforming growth factor-β (TGF-β)-induced differentiation of orbital fibroblasts into myofibroblasts is an important pathogenesis of Graves’ ophthalmopathy (GO) and leads to orbital tissue fibrosis. In the present study, we explored the antifibrotic effects of simvastatin and ROCK inhibitor Y-27632 in primary cultured GO orbital fibroblasts and tried to explain the molecular mechanisms behind these effects. Both simvastatin and Y-27632 inhibited TGF-β-induced α-smooth muscle actin (α-SMA) exp...
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#1Adriano Naselli (University of Catania)H-Index: 2
#2Diletta Moretti (University of Catania)H-Index: 1
Last. Rosario Le Moli (University of Catania)H-Index: 7
view all 8 authors...
Background: High dose intravenous glucocorticoid (ivGC) therapy is the first line treatment in moderate to severe Graves’ ophthalmopathy (GO) and is associated with a clinical response rate ranging from 50% to 80%. Recently, a positive correlation between total cholesterol and low-density lipoproteins cholesterol (LDLc) with GO presentation and activity has been described. Objective: We aimed at evaluating whether, in patients with moderate to severe active GO treated with ivGC therapy, choleste...
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Standardization of treatment outcomes in randomized clinical trials (RCTs) for active, moderate-to-severe Graves' orbitopathy (GO) is needed to make results of different RCTs comparable and to draw sound conclusions on the efficacy of a given treatment. Both subjective patient-reported outcome (PRO) and objective clinician-reported outcome (CRO) are important in this regard. In this paper, it is proposed that primary PRO should be the evaluation of treatment-related changes in the quality of lif...
Source
#1Giulia Lanzolla (UniPi: University of Pisa)H-Index: 7
#2Guia VannucchiH-Index: 24
Last. Michele Marinò (UniPi: University of Pisa)H-Index: 35
view all 7 authors...
Graves' Orbitopathy (GO) is the most frequent extrathyroidal manifestation of Graves' disease (GD). Its ultimate cause remains unclear, but it is commonly considered an autoimmune disorder due to self recognition of autoantigens constitutively expressed by orbital fibroblasts (OFs), and thyroid epithelial cells. High dose intravenous glucocorticoids (ivGC) are the most commonly used treatment for moderately severe and active GO. However, based on the complex pathogenesis of GO, a number of facto...
Source
#1Bushra Shahida (Lund University)H-Index: 5
Last. Tereza Planck (Lund University)H-Index: 8
view all 7 authors...
Background: Smoking is a strong risk factor for the development of Graves’ ophthalmopathy (GO). Immediate early genes (IEGs) are overexpressed in patients with active GO compared to healthy controls. The aim of this study was to study the effects of tobacco smoking and simvastatin on preadipocytes and orbital fibroblasts (OFs) in the adipogenic process. Methods: Cigarette smoke extract (CSE) was generated by a validated pump system. Mouse 3T3-L1 preadipocytes or OFs were exposed to 10% CSE with ...
Source
#1Giulia Lanzolla (UniPi: University of Pisa)H-Index: 7
#2E. Sabini (UniPi: University of Pisa)H-Index: 4
Last. Michele Marinò (UniPi: University of Pisa)H-Index: 35
view all 12 authors...
Background It has been suggested that high cholesterol represents a risk factor for Graves’ orbitopathy (GO). In a recent cross-sectional study, a correlation between cholesterol and the presence of GO was found in patients with a Graves’ disease (GD) of recent onset. To confirm this observation, we conducted a retrospective investigation in consecutive patients with GD. The primary outcome was the relationship between the presence of GO and low-density lipoprotein (LDL)-cholesterol.
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#1Elena Sabini (UniPi: University of Pisa)H-Index: 8
#2Barbara Mazzi (UniPi: University of Pisa)H-Index: 18
Last. Michele Marinò (UniPi: University of Pisa)H-Index: 35
view all 13 authors...
Background: Limited data suggest that treatment with statins is associated with a reduced risk of Graves' orbitopathy (GO) in patients with Graves' disease (GD), attributed to the anti-inflammatory rather than to the hypolipemic effects of these medications. The aim of the present study was to investigate whether there is an association between high cholesterol and GO. The primary outcome was the relation between GO and low-density lipoprotein (LDL)-cholesterol. The secondary outcomes were the r...
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Cited By0
Newest
#1Daniel J. Toft (UIC: University of Illinois at Chicago)H-Index: 1
Source
#1G. Rotondo Dottore (UniPi: University of Pisa)H-Index: 4
#2Liborio Torregrossa (UniPi: University of Pisa)H-Index: 22
Last. Michele Marinò (UniPi: University of Pisa)H-Index: 35
view all 15 authors...
The extent to which mononuclear cells and TSH-receptor autoantibodies (TRAb) contribute to Graves’ orbitopathy (GO) is not completely defined. Here we investigated the relationship between the immunohistochemical phenotype of orbital infiltrating cells and GO features in a large number of patients. We conducted an observational cohort study in 76 consecutive patients with GO (16 men and 60 women) who underwent orbital decompression over a period of 18 consecutive months. An ophthalmological eval...
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#1Luigi Bartalena (University of Insubria)H-Index: 75
#2Eliana Piantanida (University of Insubria)H-Index: 21
Last. Maria Laura Tanda (University of Insubria)H-Index: 29
view all 3 authors...
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