Lipid Profiles in Patients With Ulcerative Colitis Receiving Tofacitinib-Implications for Cardiovascular Risk and Patient Management

Abstract

Background: Patients with ulcerative colitis (UC) are at elevated risk of cardiovascular disease vs the general population, despite a lower prevalence of traditional risk factors, including hyperlipidemia. Mechanistic studies in patients with rheumatoid arthritis and psoriasis suggest that tofacitinib restores serum lipids to preinflammation levels by reversing inflammation-induced cholesterol metabolism changes. We reviewed data on lipid levels and cardiovascular events, alongside recommendations for managing lipid levels during tofacitinib treatment in patients with UC, based on up-to-date expert guidelines.

Methods: Data were identified from a phase 3/open-label, long-term extension (OLE) tofacitinib UC clinical program (cutoff May 27, 2019). Literature was identified from PubMed (search terms "lipid," "cholesterol," "lipoprotein," "cardiovascular," "inflammation," "atherosclerosis," "tofacitinib," "rheumatoid arthritis," "psoriasis," "inflammatory bowel disease," "ulcerative colitis," "hyperlipidemia," and "guidelines") and author knowledge. Data were available from 4 phase 3 clinical trials of 1124 patients with moderately to severely active UC who received ≥1 dose of tofacitinib 5 or 10 mg twice daily in induction (two identical trials), maintenance, and OLE studies (treatment duration ≤6.8 years; 2576.4 patient-years of drug exposure).

Results: In the OLE study, tofacitinib treatment was not associated with major changes from baseline in total cholesterol, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, triglycerides, total cholesterol/high-density lipoprotein cholesterol, and low-density lipoprotein cholesterol/high-density lipoprotein cholesterol, with lipid levels and ratios generally remaining stable over time. The major adverse cardiovascular events incidence rate was 0.26/100 patient-years (95% confidence interval, 0.11-0.54).

Conclusions: Lipid levels and ratios remained generally unchanged from baseline in the OLE study after tofacitinib treatment, and major adverse cardiovascular events were infrequent. Long-term studies are ongoing.

Clinicaltrials.gov identifiers: NCT01465763, NCT01458951, NCT01458574, NCT01470612.

Keywords: clinical trials; lipids; tofacitinib.

FIGURE 1.

Mean change from baseline in lipid levels to month 48 in the OLE study. A, Total-c. B, HDL-c. C, LDL-c. D, Triglycerides. E, Ratio of total-c/HDL-c. F, Ratio of LDL-c/HDL-c. Error bars represent standard error. Abbreviations: BID, twice daily; HDL-c, high-density lipoprotein cholesterol; LDL-c, low-density lipoprotein cholesterol; OLE, open-label, long-term extension; total-c, total cholesterol; SE, standard error.

FIGURE 2.

Reverse cholesterol transport pathway (reproduced with permission from Charles-Schoeman et al). Abbreviations: ApoA-1, apolipoprotein A-1; ApoB-100, apolipoprotein B-100; CE, cholesterol ester; CETP, cholesterol ester transfer protein; FC, free cholesterol; HDL-c, high-density lipoprotein cholesterol; LCAT, lecithin-cholesterol acyltransferase; LDL-c, low-density lipoprotein cholesterol; LDL-cr, LDL-c receptor; SR-B1, scavenger receptor class B type 1.

FIGURE 3.

Algorithm for management of lipids in patients receiving tofacitinib. Risk assessment, stratification of patient, and monitoring of lipids should be based on clinical practice guidelines for hyperlipidemia (European Society of Cardiology, European Atherosclerosis Society, American College of Cardiology, American Heart Association). Abbreviations: LDL-c, low-density lipoprotein cholesterol.