Cardiovascular safety of romosozumab warrants ‘rigorous assessment’
medwireNews: Romosozumab and other sclerostin inhibitors may increase cardiovascular risk, suggests evidence from a meta-analysis of randomized trials and a study of genetic variants that mimic pharmacologic inhibition of sclerostin.
“Our findings support the U.S. FDA and EMA’s addition of a warning for cardiovascular risk to romosozumab’s label,” write the researchers in Science Translational Medicine.
They note that three sclerostin inhibitors are or have been in clinical development; romosozumab is approved for osteoporosis, blosozumab was under investigation for osteoporosis but development was halted due to injection site reactions, and setrusumab is currently in phase 2 trials for osteogenesis imperfecta.
In the first part of their study, Jonas Bovijn (University of Oxford, UK) carried out a meta-analysis of data from two randomized phase 3 trials of romosozumab in people with osteoporosis – BRIDGE and ARCH – with published data on cardiovascular events.
Analysis of 25 events from 4298 people indicated that treatment with romosozumab at a dose of 210 mg once monthly was associated with a significant threefold increased risk for cardiac ischemic events relative to alendronate or placebo treatment (odds ratio [OR]=2.98).
This risk was attenuated, but remained statistically significant, when unpublished data from the FRAME trial of romosozumab versus placebo was added to the analysis, with an OR of 1.54 based on 57 events in 11,455 individuals.
“Thus, data from clinical trials support a probable but not unambiguous excess risk of cardiac disease arising from treatment with romosozumab,” say Bovijn et al.
Next, the researchers used biobank data to evaluate two genetic variants in SOST – the gene encoding sclerostin – that were shown to be associated with bone mineral density (BMD) in a genome-wide association study.
“Naturally occurring human genetic variation can serve as a proxy for therapeutic stimulation or inhibition of a drug target, presenting a valuable opportunity to assess the likely consequences of modifying a therapeutic target on both the intended therapeutic effects and target-mediated adverse drug reactions,” they explain.
When scaled to the increase in BMD seen with 1 year of romosozumab treatment (210 mg/month; 0.09 g/cm2 of higher BMD), carriage of the two SOST variants (rs7209826 and rs188810925) was associated with a significant reduction in the risk for osteoporosis (OR=0.43) and fracture (OR=0.59), but a significant increase in the risk for myocardial infarction and/or coronary revascularization (OR=1.18) and major adverse cardiovascular events (OR=1.12).
The team also identified significant associations between the two genetic variants and an elevated risk for hypertension and type 2 diabetes, suggesting “that the excess risk of coronary events related to inhibition of sclerostin is driven, at least in part, by an increase in cardiovascular risk factors with an established etiological role in [coronary heart disease].”
Taken together, “our results warrant a rigorous assessment of the effect of romosozumab (and other sclerostin inhibitors in clinical development) on cardiovascular disease and cardiometabolic risk factors,” conclude Bovijn and colleagues.
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