Lipid lowering drugs and inflammatory changes: an impact on cardiovascular outcomes?

Abstract

Inflammatory changes are responsible for maintenance of the atherosclerotic process and may underlie some of the most feared vascular complications. Among the multiple mechanisms of inflammation, the arterial deposition of lipids and particularly of cholesterol crystals is the one responsible for the activation of inflammasome NLRP3, followed by the rise of circulating markers, mainly C-reactive protein (CRP). Elevation of lipoproteins, LDL but also VLDL and remnants, associates with increased inflammatory changes and coronary risk. Lipid lowering medications can reduce cholesterolemia and CRP: patients with elevations of both are at greatest cardiovascular (CV) risk and receive maximum benefit from therapy. Evaluation of the major drug series indicates that statins exert the largest LDL and CRP reduction, accompanied by reduced CV events. Other drugs, mainly active on the triglyceride/HDL axis, for example, PPAR agonists, may improve CRP and the lipid pattern, especially in patients with metabolic syndrome. PCSK9 antagonists, the newest most potent medications, do not induce significant changes in inflammatory markers, but patients with the highest baseline CRP levels show the best CV risk reduction. Parallel evaluation of lipids and inflammatory changes clearly indicates a significant link, both guiding to patients at highest risk, and to the best pharmacological approach. Key messages Lipid lowering agents with "pleiotropic" effects provide a more effective approach to CV prevention In CANTOS study, patients achieving on-treatment hsCRP concentrations ≤2 mg/L had a higher benefit in terms of reduction in major CV events The anti-inflammatory activity of PCSK9 antagonists appears to be of a minimal extent.

PCSK9 inhibition and inflammation: A narrative review

“…The two major variables resulting from lipid lowering medications, i.e. reduction of LDL-C and hs-CRP in ASCVD patients appear to be additive as independent predictors [135,136]. In major statin trials, e.g.…”

Novel strategies to target proprotein convertase subtilisin kexin 9: beyond monoclonal antibodies

“…113 Of note, anti-PCSK9 monoclonal antibodies reverse the pro-inflammatory profile of monocytes in familial hypercholesterolaemia 114 and improve vascular inflammation. 115 Moreover, the observation that lower levels of PCSK9 are associated with reduced inflammation, especially in patients with the highest level of the inflammatory marker high sensitivity C-reactive protein (hs-CRP), 116 will need to be properly validated in specific clinical trials on inflammationassociated pathologies, as was done with the mAb canakinumab targeting interleukin-1b in the CANTOS anti-inflammatory thrombosis outcome study. 117 A recent meta-analysis reported a lack of effect of anti-PCSK9 therapy with mAbs on circulating hs-CRP levels, at least for the shortterm treatment, 118 and an analysis of the FOURIER trial showed that changes in hs-CRP levels were similar between evolocumab and placebo, even in subjects with a higher baseline hs-CRP level.…”

Treatment With Gemfibrozil Prevents the Progression of Chronic Kidney Disease in Obese Dahl Salt-Sensitive Rats

“…Roman and colleagues reported that administration of fenofibrate decreased arterial pressure in SS rats fed high salt diet with established hypertension and renal disease (Wilson et al, 1998). The exact mechanism by which fibrates lower arterial pressure is not completely understood but involves various pathways such as anti-lipidemic (Jonkers et al, 2001;Kim and Kim, 2020), anti-inflammatory (Feingold and Grunfeld, 2000;Diep et al, 2004;Ruscica et al, 2018), nitric oxide (Newaz et al, 2005;Ibarra-Lara et al, 2010;Esenboga et al, 2019;Xu et al, 2019), and 20-HETE (Roman et al, 1993;Wilson et al, 1998). In the current study, we cannot exclude the impact of any of these pathways on reducing arterial pressure in response to gemfibrozil treatment.…”