Pfizer Confirms: Leading JAK Inhibitor Often Comes With Weight Gain

Inflammation and autoimmune patients taking tofacitinib (Xeljanz) in the drug's late-stage and post-marketing studies were more likely than those on placebo to gain weight and body mass index (BMI) points, pooled data from more than 5,000 rheumatoid arthritis (RA) patients showed.

After 6 months, placebo was associated with a mean weight gain of 0.4 kg (o.88 lb), compared with 1.2-1.9 kg (2.6-4.2 lb) with tofacitinib (all P<0.01), depending on the dose, according to Jose L. Rivas, MD, of Pfizer's facility in Madrid, Spain, and colleagues.

Some 55% of placebo group members gained weight to some degree, while this occurred in 65%-70% of those on tofacitinib after 6 months, the researchers reported in ACR Open Rheumatologyopens in a new tab or window. Weight gain ≥5% was even more lopsided: this was seen in 11% of the placebo patients, versus 16%-28% of patients on tofacitinib.

And, both the mean absolute weight gains and the proportions with gains ≥5% were greater still in patients who took tofacitinib for 12 months: 2.0-2.6 kg (4.5-5.6 lb) and 33%-37%. (No 12-month data were given for those on placebo.)

BMI changes in 6 months were consistently less than 1 point with the Janus kinase (JAK) inhibitor, irrespective of dose, although still greater than with placebo. Average increases at 6 months were 0.4-0.7 points with the different drug doses, versus 0.1 points with placebo.

Rivas and colleagues drew on data from eight phase III/IV studies of tofacitinib, the pioneering JAK inhibitor for RA, with a total of 5,335 patients. Three dosing regimens were tested in these trials: 5 mg twice daily (n=2,349), 10 mg twice daily (n=1,611), 11 mg once daily (n=694), and placebo (n=681). The first two tofacitinib doses were administered for up to 12 months, while placebo and the 11-mg dose through 6 months.

Some 77%-84% of patients were women with mean ages of 52-57, depending on the dosing group. Approximately two-thirds were white. Weight at baseline averaged around 72 kg (158 lb), and mean BMI was about 27.

Change in weight was positively, if weakly, correlated with the 28-joint Disease Activity Score as modified by erythrocyte sedimentation rate (DAS28-ESR), a key measure of RA symptom severity. Correlation coefficients at 6 months ranged from 0.04 to 0.142, none of which indicated a strong relationship; moreover, the highest value was seen in the placebo group.

Results were similar when Rivas's group examined change in BMI against DAS28-ESR. In both cases, because obesity is associated with systemic inflammation, which is in turn an exacerbating factor in RA, these findings weren't surprising.

Still, patients with significant weight gain did show substantial increases in total cholesterol levels, by roughly 30-40 mg/dL at 6 months.

"Weight and BMI continued to increase through 12 months of observation in the studies, so a new equilibrium had not yet been reached," the researchers wrote. "Longer term observations are warranted to establish whether there is sustained weight gain, if this varies by tofacitinib dose, and if there are any health implications of continued weight gain."


Indeed, it's not clear what those might be. Although weight gain is generally considered unhealthy, Rivas and colleagues pointed out that, among RA patients, previous research had suggested that high BMI is protective against cardiovascular and overall mortality, while being underweight was detrimental.

"Further research is warranted on the relationship between disease activity and changes in weight and BMI with tofacitinib in RA, and whether these changes are associated with increased risk of other comorbidities with known associations with weight," the researchers concluded.

Limitations included that an examination of tofacitinib's effects on body weight had not been part of the trials' original protocols. Rivas and colleagues noted, too, that eligibility criteria varied among the eight trials; some patients were on tofacitinib monotherapy while others were taking corticosteroids and/or other medications for RA.

Disclosures

The study was funded by Pfizer, maker of tofacitinib. Several authors were Pfizer employees, including Rivas. Several c0-authors reported relationships with Pfizer and/or other commercial entities.

Primary Source

ACR Open Rheumatology

Source Reference: opens in a new tab or windowWollenhaupt J, et al "Analysis of the impact of tofacitinib treatment on weight and body mass index in patients with rheumatoid arthritis" ACR Open Rheumatol 2025; DOI: 10.1002/acr2.70040.

https://www.medpagetoday.com/rheumatology/generalrheumatology/115558