Effect of treatment on lipid profiles in patients with inflammatory bowel disease a systematic review and meta-analysis

Lead Investigator: Janneke van der Woude, Erasmus Medical Center
Title of Proposed Research: Effect of treatment on lipid profiles in patients with inflammatory bowel disease a systematic review and meta-analysis
Vivli Data Request: 4043
Funding Source: None
Potential Conflicts of Interest: None

Summary of the Proposed Research:

Inflammatory bowel disease (IBD) is a chronic inflammatory disorder of the gastrointestinal tract with a complex, multifactorial etiology. IBD consists of two separate diagnoses: ulcerative colitis (UC) and Crohn’s disease (CD), who differ in extent due to differences in the affected segment, extend, fashion, histology, complications and extra-intestinal manifestations. UC is characterized by superficial mucosal inflammation of the rectum and to a variable extent the colon in a continuous fashion, usually without granulomas in the biopsies. CD is characterized by skip lesions of, most frequently, the ileum and colon. Potentially, also the proximal gastrointestinal tract is affected in CD. The inflammation is transmural leading to structuring disease with ileus-like symptoms due to stenosis and penetrating disease characterized by fistula, micro perforations and abscesses. Also, extra-intestinal manifestations can occur in patients with inflammatory bowel disease, including arthritis, dermatological (erythema nodosum, pyoderma gangrenosum), oral (aphthous ulcera) and ocular (uveitis) lesions.

Chronic systemic inflammation is an independent risk factor for atherosclerosis due to stimulation of plaque formation, leading to endothelial dysfunction and platelet activation and aggregation. IBD is associated with venous thromboembolism, particularly during disease flares (Grainge et al. 2010). A meta-analysis of 9 cohort and case control studies, suggested that IBD is associated with a higher risk on cerebrovascular accidents (CVA, OR 1.18) and ischemic heart disease (IHD, OR 1.19). Predictive factors were the female gender and a younger age (<40-50 years), with no difference between UC and CD. There was no association with peripheral arterial disease (Singh et al. 2014). In addition, conflicting results were reported with regard to cardiovascular disease (CVD) mortality. Moreover, patients with IBD show an increase in intima thickness as measurement of atherosclerotic disease burden (Papa et al. 2005). Most interestingly, studies conclude that IBD is one of the disorders where changes in lipid profiles are observed, namely a hypercholesterolemia without evident increase in traditional cardiovascular risk factors including obesity, diabetes, hypertension or familiar hypercholesterolemia. IBD patients tend to have lower levels of total cholesterol and low density lipoprotein cholesterol (LDL-C) during disease activity whereas decrease in inflammation due to medical therapy increases those variables (Aris et al. 2011). Previous studies have found that treatment with infliximab (Koutroubakis et al. 2009) and tofacitinib (Sands et al. 2018) alter the lipid profile comparably. Although this increase in ‘bad’ cholesterol is unwanted, the increase in high density lipoprotein cholesterol (HDL-C) can be beneficial due to cardioprotective functioning. Therefore, we will conduct a literature review and meta-analysis to assess the metabolic actions of IBD treatment on the lipid profile.

Statistical Analysis Plan:

Statistical analysis of lipid levels before and after treatment was performed by comprehensive meta-analysis. The continuous data of the absolute lipid levels will be expressed as means with standard deviations (SD). Since TG is not normally distributed in general in contrast to TC, HDL and LDL and this distribution varies across studies, a 2-log transformation will be performed on all data. Our effect measure of interest is the absolute mean change of lipid levels after drug therapy (mg/dL or mmol/L) as compared to baseline (week 0 – week X). The individual studies were weighted by their inverse variances. The weighted mean (WM) will be calculated for groups before and after the intervention and the weighted mean difference (WMD) calculated as the sum of the differences in the individual studies. Forest plots will be generated to illustrate the study-specific effect sizes along with the 95% CI. This, together with I squared statistics, will be used to check for heterogeneity between studies. When high levels of heterogeneity will be found, a sensitivity analysis will be performed by removing each study one at a time to evaluate the stability of the results. In case of sufficient data, a subgroup meta-analysis will be performed on the considered outcome per IBD diagnosis (CD or UC), treatment duration (short-term, mid-term and late-term), drugs class (corticosteroids, TNFα antagonist, janus kinase inhibitors and calcineurin inhibitors), origin of population (Europe, United States, Asia, Australia with Oceania, Africa) and lipid variable (e.g. TC, HDL-C, LDL-C, TG). Separate sensitivity analyses will be performed on studies with the presence of a control group (either placebo-controlled or healthy controls) and by excluding abstracts with lack of full text publication. A random effects analysis will be performed assuming to control for expected and potentially unobserved heterogeneity due to complexity of our main data (IBD, drugs and lipids). Funnel plot will be used to check for publication bias. Eventually, an Egger’s regression test will be performed to form an objective judgement on publication bias. In case of missing data at some time-point or absence of the exact p-values, a multivariate linear mixed model will secondarily be used and the results obtained by the two methods will be compared.

Requested Studies:

A Randomized, Placebo Controlled, Double Blind, Parallel Group Multi-Center Study In Order To Investigate Safety And Efficacy Of CP- 690 550 In Subjects With Moderate To Severe Ulcerative Colitis
Data Contributor: Pfizer Inc.
Study ID: NCT00787202
Sponsor ID: NCT00787202

Multicentre, Randomized, Double-blind, Placebo-controlled, Parallel-group Study Of Oral Cp-690,550 As An Induction Therapy In Subjects With Moderate To Severe Ulcerative Colitis
Data Contributor: Pfizer Inc.
Study ID: NCT01465763
Sponsor ID: NCT01465763

A Multicentre, Randomized, Double-blind, Placebo-controlled, Parallel-group Study Of Oral Cp-690,550 As An Induction Therapy In Subjects With Moderate To Severe Ulcerative Colitis
Data Contributor: Pfizer Inc.
Study ID: NCT01458951
Sponsor ID: NCT01458951

Public Disclosures:

J A M Sleutjes, J E Roeters van Lennep, E Boersma, A C de Vries, C J van der Woude, P292 Effect of drug therapy on the lipid profiles of patient with Inflammatory Bowel Disease: a systematic review and meta-analysis, Journal of Crohn’s and Colitis, Volume 15, Issue Supplement_1, May 2021, Pages S322–S323, doi.org/10.1093/ecco-jcc/jjab076.416
Sleutjes, JAM, Roeters van Lennep, JE, Boersma, E, et al. Systematic review with meta-analysis: effect of inflammatory bowel disease therapy on lipid levels. Aliment Pharmacol Ther. 2021; 00: 1– 14. doi.org/10.1111/apt.16580