Treat-to-Target ULT Associated With Reduced Cardiovascular Risk in Gout, With Abhishek Abhishek, MD, PhD

Achieving serum urate targets with urate-lowering therapy (ULT) in gout is associated not only with fewer disease flares but with a statistically significant reduction in major adverse cardiovascular events (MACE), according to a recent study published in JAMA Internal Medicine.

RheumatologyLive spoke with investigator Abhishek Abhishek, MD, PhD, professor of rheumatology at the University of Nottingham and a practicing rheumatologist in the United Kingdom, who says that the findings should equip clinicians with a new evidence-based rationale for persuading patients to commit to treat-to-target therapy.

The analysis used an emulated target trial framework applied to primary care data from the Clinical Practice Research Datalink Aurum, linked to hospitalization and mortality records, covering January 1, 2007, to March 29, 2021. The study enrolled 109,504 patients aged 18 years or older with gout and a pretreatment serum urate level above 6 mg/dL who were newly prescribed ULT, with a mean age of 62.9 years (SD, 15.2), 22.2% female, and mean disease duration of 2.5 years (SD, 3.6). Patients were classified into a treat-to-target (T2T) arm — those who achieved a serum urate level below 6 mg/dL within 12 months of their first ULT prescription (27.3% of the cohort, predominantly on allopurinol) — or a non-T2T arm. Follow-up extended up to 5 years.

Patients in the T2T ULT arm had a significantly lower risk of MACE over 5 years than those in the non-T2T arm, with a weighted hazard ratio of 0.91 (95% CI, 0.89–0.92), corresponding to a 9% relative risk reduction. The weighted 5-year survival difference was 1.0% (95% CI, 0.5–1.6), representing a modest absolute risk reduction — meaning roughly 1 cardiovascular event prevented per 100 patients treated to target. Abhishek noted this modest absolute effect should be understood in the context of the global burden of gout, with an estimated 55.8 million people affected in 2020 and projections reaching 95.8 million by 2050, making even small absolute risk reductions consequential at population scale. Patients at high or very high baseline cardiovascular risk derived significantly greater benefit than those at moderate risk, supporting a precision counseling approach that prioritizes treat-to-target ULT most urgently in those with the highest preexisting cardiovascular burden.

The cardiovascular risk reduction was more pronounced in patients who achieved serum urate levels below 5 mg/dL — the threshold recommended by major guidelines for patients with tophi, frequent flares, or other gout complications. In this subgroup, the weighted hazard ratio was 0.77 (95% CI, 0.72–0.81), representing a 23% relative risk reduction, with a weighted event-free survival difference of 2.6% (95% CI, 0.9–3.6). Abhishek characterized this as a sensitivity analysis that warrants formal investigation as a primary endpoint in future work. Treat-to-target ULT was also associated with significantly fewer gout flares, with a weighted incidence rate ratio of 0.97 (95% CI, 0.95–0.99). Negative control outcomes — including cataract, acute bronchitis, and acute appendicitis — showed no association with T2T ULT, supporting the internal validity of the findings. The benefit in cardiovascular outcomes accrued progressively over time rather than emerging immediately: in the first year of follow-up, event rates were comparable between arms, with separation developing over the subsequent 2 to 5 years.

“This is not a topic on which we are going to get a randomized control trial, because treat-to-target ULT is recommended as good practice… But I hope that they will be looked at by by guideline writing groups who would consider and make a recommendation,” Abhishek said.

Abhishek’s disclosures include UpToDate, SOBI, Novartis, and Eli Lilly.

References

1. Cipolletta E, Sandström TZ, Rozza D, et al. Treat-to-target urate-lowering treatment and cardiovascular outcomes in patients with gout. JAMA Intern Med. Published online January 26, 2026. doi:10.1001/jamainternmed.2025.7453

2. University of Nottingham. Gout medication can reduce the risk of heart attack and stroke, finds new study. News release. January 26, 2026. https://www.eurekalert.org/news-releases/1113714