R3i Editorials

May 2024
Reducing residual risk: lower cholesterol and inflammation is better
Prof Jean-Charles Fruchart, Prof. Michel Hermans, Prof. Pierre Amarenco

Within the lipid focus, there has been considerable effort to address non-LDL-lipids implicated in this risk. Following disappointment with HDL-targeted therapies, attention was re-directed to elevated triglycerides (TG, a marker for TG-rich lipoproteins and their remnants) as a potential therapeutic target 4. A growing body of evidence from epidemiologic and genetic studies supported this approach 5. Results from recent outcomes studies have, however, been less conclusive, engendering much debate. Perhaps the key take home message from these trials is that unlike LDL, the regulation of TG levels is complex. Novel TG-lowering approaches may offer new insights into this conundrum.

Beyond lipids, attention has increasingly focused on inflammation. Residual inflammatory risk may affect patient outcome by adversely impacting local inflammatory processes after a myocardial infarction, and inflammatory activity influencing atherosclerotic plaque progression 6. Large-scale clinical trials have added to our understanding of the role of inflammation in residual cardiovascular risk. Both CANTOS (Canakinumab Anti-Inflammatory Thrombosis Outcomes Study) with canakinumab (interleukin-1β inhibition) 7, and COLCOT (Colchicine Cardiovascular Outcomes Trial) and LoDoCo2 (Low Dose Colchicine 2) with colchicine 8, showed that suppressing inflammation, as measured by high-sensitivity C-reactive protein (hsCRP), can improve cardiovascular outcomes among high-risk patients with well-managed LDL-C levels.

As inflammation and hyperlipidaemia act synergistically to drive atherosclerotic progression 9, it is anticipated that targeting both of these residual risk components would yield additional benefit. Indeed, that is the conclusion of the report featured in this month’s Focus. In a previous analysis, the investigators showed the value of hsCRP as a predictor of cardiovascular risk in an analysis of more than 30,000 patients with atherosclerosis who received guideline-directed medical care, including statin therapy (10). In a follow-up study, the relative effect of inflammation and hyperlipidaemia as predictors of cardiovascular risk was investigated using the CLEAR-Outcomes trial (Cholesterol Lowering via Bempedoic Acid, an ACL-Inhibiting Regimen Outcomes Trial) database in over 13,000 patients with statin-intolerance 11. The key finding was that inflammation detected by hsCRP was at least as strong a predictor of cardiovascular events as hyperlipidaemia (detected as either LDL-C or non-HDL-C). Thus, not only is “lower is better” the maxim for LDL-C, but also for hsCRP.

Cumulative insights from recent trials underline the multifactorial nature of residual cardiovascular risk. Targeting inflammation alongside optimal lipid lowering is likely to be central to future therapeutic strategies to reduce residual cardiovascular risk.

References

  1. References
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    2. Timmis A, Vardas P, Townsend N, et al. European Society of Cardiology: cardiovascular disease statistics 2021. Eur Heart J 2022;43:716-99.
    3. Visseren FLJ, Mach F, Smulders YM, et al. 2021 ESC Guidelines on cardiovascular disease prevention in clinical practice. Eur Heart J 2021;42:3227-337.
    4. Libby P. Triglycerides on the rise: should we swap seats on the seesaw? Eur Heart J 2015;36:774-6.
    5. Nordestgaard BG. Triglyceride-rich lipoproteins and atherosclerotic cardiovascular disease: new insights from epidemiology, genetics, and biology. Circ Res 2016;118:547-63.
    6. Matter MA, Paneni F, Libby P, et al. Inflammation in acute myocardial infarction: the good, the bad and the ugly. Eur Heart J 2024;45:89–103.
    7. Ridker PM, Everett BM, Thuren T, et al; CANTOS Trial Group. Antiinflammatory therapy with canakinumab for atherosclerotic disease. N Engl J Med 2017;377:1119–1131.
    8. Tardif JC, Kouz S, Waters DD, et al. Efficacy and safety of low-dose colchicine after myocardial infarction. N Engl J Med 2019;381:2497–505.
    9. Ridker PM. Targeting residual inflammatory risk: The next frontier for atherosclerosis treatment and prevention. Vascul Pharmacol 2023:153:107238.
    10. Ridker PM, Bhatt DL, Pradhan AD, et al. Inflammation and cholesterol as predictors of cardiovascular events among patients receiving statin therapy: a collaborative analysis of three randomized trials. Lancet 2023;401:1293–301.
    11. Ridker PM, Lei L, Louie MJ, et al. Inflammation and cholesterol as predictors of cardiovascular events among 13970 contemporary high-risk patients with statin intolerance. Circulation 2024;149:28–35.