Treatment of Graves’ orbitopathy with statins in combination with glucocorticoids shows benefits among people with — and even without — high cholesterol, results from a new randomized clinical trial show.
“Our results [indicate] that adding atorvastatin to intravenous glucocorticoids seems to potentiate the effects of glucocorticoids,” senior author Michelle Marino, MD, an associate professor of endocrinology in the Department of Clinical and Experimental Medicine at the University of Pisa, Italy, told Medscape Medical News.
“At least in hypercholesterolemic patients with moderate-to-severe and active Graves’ orbitopathy, atorvastatin should be considered in addition to intravenous glucocorticoids,” Marino said.
The study was presented by first author Giulia Lanzolla, MD, also of the University of Pisa and University Hospital of Pisa, at the virtual 90th Annual Meeting of the American Thyroid Association (ATA).
Hypercholesterolemia, well known to promote systemic inflammation, has been previously linked to Graves’ orbitopathy, and the use of statins has also been shown to possibly provide a protective effect in the risk of developing the thyroid eye disease.
Furthermore, patients with Graves’ orbitopathy and high cholesterol levels, compared with those with normal cholesterol, have been shown to have poorer responses to treatment with glucocorticoids, which have long been the first line of treatment.
Asked for comment on the findings, Marius Stan, MD, a consultant in the Division of Endocrinology, Diabetes, Metabolism and Nutrition, Mayo Clinic, Rochester, Minnesota, said he didn’t think the outcome measure used — a composite of a variety of measures of thyroid eye disease — was best to truly understand the benefits.
Statins for Graves‘ Orbitopathy (STAGO) Study Details
For a better understanding of the effects with and without the addition of statins in a randomized trial, Lanzolla and colleagues enrolled 88 patients with high cholesterol and moderate-to-severe active Graves’ orbitopathy in the phase 2 STAGO trial.
Patients were randomized to two groups of 44 patients each to receive treatment either with intravenous (IV) methylprednisolone at 500 mg per week for 6 weeks, followed by 250 mg per week for another 6 weeks, in combination with atorvastatin 20 mg daily for 12 weeks, or methylprednisolone alone for 12 weeks.
The primary endpoint was a composite of Graves orbitopathy outcomes and included measures of exophthalmos, clinical activity score, eyelid aperture, diplopia, and visual acuity, as assessed in the modified intention-to-treat population.
The trial met the primary composite endpoint, with 51.2% of those treated with statins achieving the outcome (21 of 41) versus 28.2% (11 of 39) of those treated with glucocorticoids alone (odds ratio [OR], 2.76; P = .03).
The study also achieved secondary outcomes, with 43.9% in the statin group having a response to treatment at 12 weeks versus 23% in the glucocorticoid group (OR 2.60; P = .05). The statin group also had a greater improvement in quality of life measures (P = .03).
The glucocorticoid-only group meanwhile had a significantly greater rate of Graves orbitopathy relapse at 24 weeks, with six relapses versus none in the statin group (15.3% vs 0.0%; OR 0.06; P = .01).
Interestingly, there were no significant differences in low-density lipoprotein (LDL) cholesterol between those who did and did not respond to treatment in the statin group.
The most likely explanation for those findings is that “atorvastatin acts through its pleiotropic action, resulting in an anti-inflammatory effect,” Marino said.
“In addition, the effect may be related to the capability of statins to inhibit fibroblast proliferation,” Marino added.
“Total cholesterol had a behavior similar to LDL cholesterol, [while] HDL cholesterol did not change across the study.”
There were no major adverse events related to atorvastatin, with one patient in each group requiring treatment discontinuation.
In the rapidly evolving landscape of treatments for Graves’ orbitopathy, including the recent US Food and Drug Administration approval for teprotumumab in thyroid eye disease, the potential role of statins remains to be seen, Marino noted.
“Graves’ orbitopathy is a rather complex disease, and in its mild-to-moderate forms it is very rare for a patient to require only a single treatment,” Marino explained. “Rehabilitative surgery is needed quite often once the disease is inactive.”
The authors note that a composite overall Graves’ orbitopathy outcome was used as the primary endpoint because the alternative of a change in single eye features may not reflect a true modification of Graves’ orbitopathy and could be affected by a number of unrelated factors.
“By contrast, the composite evaluation offers a more realistic picture,” the authors write in the article, which was also published in The Lancet Diabetes and Endocrinology.
Composite Outcome Not Best Way of Assessing Effects of Statins
Stan extrapolated on his criticism of the trial.
“The study has interesting results but fails to show that any particular eye feature is benefited by the combination therapy, showing only the composite outcome to be improved,” he told Medscape Medical News.
“Unfortunately, that is hard to extrapolate to patient care, where one or another of Graves’ orbitopathy features are present and are the intended target of therapy,” he said.
Stan added that IV glucocorticoids are meanwhile also changing the landscape of treatment of thyroid eye disease.
“This…current plan is to recommend a more individualized approach, depending on what is the main problem for that thyroid eye disease case,” he explained.
Marino noted that the authors are currently planning a double-blind, placebo-controlled phase 3 clinical trial of the statin/glucocorticoid combination to include patients regardless of their cholesterol levels.
The study received funding from Associazione Allievi Endocrinologia Pisana. The authors have reported no relevant financial relationships. Stan is on the advisory board for Horizon Pharma/Immunovant and provides general consulting for VasaraGen/Septerna and ValenzaBio/Medicxi.
90th Annual Meeting of the ATA. Abstract #3. Presented September 30, 2021.
Lancet Diabetes Endocrinol. Published online September 27, 2021. Abstract
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