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WASHINGTON -- Patients taking Janus kinase (JAK) inhibitors for rheumatoid arthritis (RA) may not have to worry so much about increased cardiovascular risk -- if they're taking statins, research presented here suggested.

Among participants in the landmark ORAL Surveillance study assigned to the JAK inhibitor tofacitinib (Xeljanz) and also using statins, major adverse cardiovascular events (MACE) were no more common than among those randomized to tumor necrosis factor (TNF) inhibitors, according to Jon Giles, MD, MPH, of Cedars-Sinai Medical Center in Los Angeles.

Whereas the trial's original primary analysis showed roughly double the MACE risk with tofacitinib as compared with TNF blockers, when the JAK inhibitor group was stratified according to statin use, MACE rates were numerically lower when the tofacitinib dose was 5 mg twice daily (HR 0.84, 95% CI 0.34-2.07), Giles reported at the American College of Rheumatology's annual meeting.

Tofacitinib at 10 mg twice daily still showed a potential for increased risk (HR 1.83) even with statins, but it fell short of statistical significance. When patients on both doses were lumped together, statin use dropped the overall MACE hazard ratio to 1.32 (95% CI 0.64-2.72).

When the session moderator asked whether the findings meant cardiovascular risk was no longer a worry with JAK inhibitors when combined with statins, Giles wasn't willing to go that far. He did say the study "provides a lot of reassurance for me."

Before tofacitinib was first approved for RA in 2014, its trial data had shown signals for increased risk for MACE and also for certain cancers. The FDA ordered the drug's manufacturer, Pfizer, to conduct a major postmarketing study to evaluate these risks more fully. ORAL Surveillance started in 2014 and primary results were published in 2022, leading to boxed warnings that the agency applied to all JAK inhibitors.

In the three-arm, open-label study, 4,632 patients were randomized 1:1:1 to the two tofacitinib doses or to a TNF inhibitor (either adalimumab [Humira] or etanercept [Enbrel]).

Patients in the combined tofacitinib groups developed MACE at a rate of 3.4% and new cancers were seen in 4.2% during a median 4 years of follow-up; for those treated with either adalimumab or etanercept, the corresponding rates were 2.5% and 2.99%, respectively. The MACE rate was slightly higher with 10 mg versus 5 mg twice daily (3.5% vs 3.2%), Giles noted.

However, statins are well recognized to lower MACE rates. Since it was likely that many ORAL Surveillance participants would use them -- they were not prohibited, and the trial was actually enriched for preexisting atherosclerotic cardiovascular disease (ASCVD) that would typically involve statin treatment -- Giles's group (with support from Pfizer) thought a post-hoc analysis would be worthwhile to see whether statins mitigated the risk associated with tofacitinib.

Statin use at baseline actually was lower than might be expected. Of the 4,632 patients in the trial, 23.4% were on a statin at enrollment. Even among patients with preexisting ASCVD, barely half were users, and this was the case for only 27% of those considered at high risk for ASCVD.

The number of statin users rose during the trial, however, as about 12% of those in the tofacitinib groups started on them, as did 7% of the TNF inhibitor group. In total, 33% of the tofacitinib groups and 27% of those assigned to TNF inhibitors used statins during the study.

As one would expect, baseline statin users across all three study arms had lower LDL cholesterol levels than nonusers. Tofacitinib generally raises LDL levels, more than occurs with TNF blockers, but the increase was lower with statin use. LDL levels on treatment in the 5-mg tofacitinib group were nearly the same as in the TNF inhibitor arm, although they averaged almost 10 mg/dL higher in the 10-mg group.

Limitations to the study were numerous, Giles cautioned. It was a post-hoc analysis (i.e., not prespecified) and the trial was not powered to examine these questions about statins. As well, statin treatment was not randomized, raising the likelihood of confounding by indication. (On the other hand, Giles pointed out that statins are generally given to patients at increased ASCVD risk, which would actually bias the results toward a lesser benefit from statins.) Too, the study period was too short to assess long-term MACE rates.

And perhaps the biggest limitation was that the study didn't look at whether statins affect cancer risk from JAK inhibitors. Giles had opened his talk by joking that this might be the last analysis to come out of ORAL Surveillance. But after his presentation, Josef Smolen, MD, of the Medical University of Vienna, came to the microphone to ask about the cancer issue.

Giles responded that no, this study didn't address it, but it's an important question that warrants yet another look at the data.

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