Il-6 Levels, CKD Status Could Identify Patients Needing Anti-Inflammatory Treatment

Interleukin 6 (IL-6) and chronic kidney disease (CKD) stage may help identify patients with chronic coronary syndrome in need of anti-inflammatory treatment, according to new research published in JAMA Cardiology.

Past research has shown increased levels of IL-6 are associated with cardiovascular events, while CKD is also linked with cardiovascular disease (CVD). “The underlying mechanism connecting CKD and CVD remains not fully understood, with inflammation proposed as a potential link,” researchers explained. “Still, it is unknown whether inflammatory activity as reflected by biomarkers are associated with cardiovascular outcomes across the range of kidney function.”

In an effort to better understand the associations between IL-6, CKD, and the risk of major cardiovascular outcomes in patients with chronic coronary syndrome, investigators conducted a sub study analysis of the Stabilization of Atherosclerotic Plaque by Initiation of Darapladib Therapy (STABILITY) trial.

The multicenter cohort study included patients from 663 centers across 39 countries who were enrolled in the trial between December 2008 and April 2010. Individuals were followed-up with for a median of 3.7 years.

As part of STABILITY, 15,828 patients with chronic coronary syndrome were randomized to darapladib (inhibitor of lipoprotein-associated phospholipase A2) treatment or placebo—added to optimal medical therapy—while IL-6 and estimated glomerular filtration rate (eGFR) were considered exposures for this sub study.

“CKD was categorized into CKD stages, normal (eGFR ≥90 mL/min/1.73 m2), mildly decreased (eGFR 60-90mL/min/1.73 m2), and moderately to severely decreased (eGFR <60 mL/min/1.73 m2),” authors wrote. “For categorical analysis, IL-6 was categorized into less than 2.0 ng/L or 2.0 ng/L or more because this level was close to the study median of 2.1 ng/L.”

Of the 14,611 individuals with available IL-6 levels at baseline, median (interquartile range [IQR]) age was 65 (59-71) years, and the majority were male. Those with CKD tended to be older, female, and have more comorbidities compared with individuals without CKD.

Analyses revealed:

• During follow-up, major adverse cardiovascular events (MACE) occurred in 1459 individuals (10%)
• Higher levels of IL-6 were in continuous models independently associated with risk of MACE (P < .001) in all CKD strata
• Using predefined strata, elevated IL-6 level (≥2.0 vs <2.0 ng/L) was associated with increased risk of MACE at normal kidney function (2.9% vs 1.9% events/y [hazard ratio (HR), 1.35; 95% CI, 1.02-1.78]), mild CKD (3.3% vs 1.9% [HR 1.57; 95% CI, 1.35-1.83]), and moderate to severe CKD (5.0% vs 2.9% [HR, 1.60; 95% CI, 1.28-1.99]

Overall, data showed “higher levels of IL-6 in patients with chronic coronary syndrome were independently associated with increased risk of MACE across the range of eGFR and within commonly used CKD strata. Also, the magnitude of net risk with elevated levels of IL-6 increased with higher CKD burden.”

Although several drugs have been shown to reduce the risk of cardiovascular events in patients with acute and chronic coronary syndrome, no anti-inflammatory drug is routinely used in this population.

The observational nature of the current analysis, in addition to the fact patients were included in a randomized clinical trial mark limitations to this study. As patients with eGFR level less than 30 mL/min/1.73 m2 were excluded from STABILITY trial, findings cannot be generalized to those with severe CKD.

“IL-6 level and CKD status should be useful as decision support for selection of patients with chronic coronary syndrome who may derive benefit from anti-inflammatory treatment with general and specific IL-6 inhibition,” researchers concluded.

Reference:

Batra G, Lakic TG, Lindbäck J, et al. Interleukin 6 and cardiovascular outcomes in patients with chronic kidney disease and chronic coronary syndrome. JAMA Cardiol. Published online August 25, 2021. doi:10.1001/jamacardio.2021.3079