R3i Editorials

April 2023
Residual risk in 2023: where to?
Prof. Jean-Charles Fruchart, Prof. Michel Hermans, Prof. Pierre Amarenco

Residual cardiovascular risk has evolved from a concept 1 to become an established target in cardiovascular disease research. Recent studies, particularly those focused on lipids, have shown that targeting a lower level of low-density lipoprotein cholesterol (LDL-C) reduces the residual risk of major cardiovascular events including stroke 2,3. The potential of targeting other lipid parameters, notably triglyceride-rich lipoproteins (for which plasma triglycerides are a surrogate in clinical practice) 4 and lipoprotein(a) 5, has been the focus of much interest. In the case of the former, there has been one positive study, REDUCE-IT with high-dose icosapent ethyl 6, the results of which led to changes in guideline recommendations for managing elevated TG in high-risk patients. However, it is pertinent that the observed relative risk reductions in cardiovascular events in REDUCE-IT did not relate to the extent of TG lowering with icosapent ethyl 6. Moreover, given the complexity of regulation of triglyceride-rich lipoprotein levels 4, it is perhaps not surprising that other studies did not show significant reduction in residual cardiovascular risk 7,8. The development of novel therapeutic approaches to target elevated TG, largely driven by findings from Mendelian randomization studies 9, offer opportunities to test this further. Additionally, targeting elevated lipoprotein(a) as an approach to reduce residual cardiovascular risk awaits results from the ongoing Lp(a) HORIZON trial (10).

Given the multifactorial nature of residual cardiovascular risk, other targets warrant evaluation. CANTOS (Canakinumab Anti-inflammatory Thrombosis Outcomes Study) was a landmark study providing proof of the concept that targeting inflammation with canakinumab, a fully human monoclonal antibody targeted to interleukin (IL)-1β, reduced residual cardiovascular risk, against a background of best evidence-based treatment including well controlled LDL-C levels 11. Once again as for studies targeting TG, not all studies were positive. For example, the CIRT (Cardiovascular Inflammation Trial) 12 with methotrexate in 3,000 patients with a previous myocardial infarction or multivessel coronary artery disease and type 2 diabetes mellitus or metabolic syndrome, did not significantly impact cardiovascular events or all-cause mortality, largely due to lack of effect of methotrexate on high-sensitivity C-reactive protein, IL-6, or IL-1β. How the therapy reduces inflammatory risk, as well as baseline patient selection criteria may explain the difference in success of these studies 13.

The advent of newer antiglycaemic therapies, notably the glucagon-like peptide 1 (GLP-1) receptor agonists and sodium-glucose cotransporter 2 (SGLT2) inhibitors has heralded new changes to diabetes care, with evidence of cardiovascular benefit from major prospective studies. The first of these in 2015, EMPA-REG OUTCOME (Empagliflozin, Cardiovascular Outcomes, and Mortality in Type 2 Diabetes trial) 14 demonstrated a 14% relative risk reduction of the primary outcome (a composite of cardiovascular death, non-fatal MI, or non-fatal stroke), as well as 38% relative risk reduction for cardiovascular death. Importantly, these reductions in cardiovascular events and death were observed in patients receiving best evidence-based treatment: 81% were on angiotensin-converting enzyme inhibitors or angiotensin receptor blockers, 77% were on a statin, and 82% were on aspirin 14.

Other studies have corroborated the cardiovascular benefit from both classes of antiglycaemic therapy, and helped to differentiate their effects (15-19). SGLT2 inhibitors showed benefit predominantly in heart failure hospitalization and in slowing progression of renal impairment. The most recent study with this agent, EMPA-KIDNEY, demonstrated benefit in terms of reduced risk of progression of renal disease or cardiovascular death in a wide range of patients with chronic kidney disease with and without diabetes (20). In contrast, GLP-1 receptor agonists impact atherosclerotic outcomes and do not appear to have a significant impact on heart failure endpoints. The underlying mechanisms for these effects with both agents are still under investigation. Additionally, there is interest in finerenone, a novel, nonsteroidal, selective mineralocorticoid receptor antagonist indicated for the treatment of diabetic kidney disease. In the FIGARO-DKD trial in patients with type 2 diabetes and CKD, finerenone was shown to reduce cardiovascular outcomes (death from cardiovascular causes, nonfatal myocardial infarction, nonfatal stroke, or hospitalization for heart failure) by 13% (p=0.03). This benefit was driven mainly by reduction in hospitalization for heart failure 21.

2023 heralds another active year in the search for therapeutic agents effective in reducing residual cardiovascular risk. Importantly, clinical trial design is also evolving to consider wider patient selection criteria, to ensure that patients included in these trials are representative of those seen in routine clinical practice. The Residual Risk Reduction Initiative looks forward to another exciting year in the search to reduce residual cardiovascular risk.

References

  1. Fruchart JC, Sacks F, Hermans MP, et al. The Residual Risk Reduction Initiative: a call to action to reduce residual vascular risk in patients with dyslipidemia. Am J Cardiol 2008;102(10 Suppl):1K-34K.
    2. Sabatine MS, Giugliano RP, Keech AC, et al. Evolocumab and clinical outcomes in patients with cardiovascular disease. N Engl J Med 2017; 376:1713–22.
    3. Schwartz GG, Steg PG, Szarek M, et al. Alirocumab and cardiovascular outcomes after acute coronary syndrome. N Engl J Med 2018;379:2097–107.
    4. Ginsberg HN, Packard CJ, Chapman MJ, et al. Triglyceride-rich lipoproteins and their remnants: metabolic insights, role in atherosclerotic cardiovascular disease, and emerging therapeutic strategies-a consensus statement from the European Atherosclerosis Society. Eur Heart J 2021;42:4791-806.
    5. Kronenberg F, Mora S, Stroes ESG, et al. Lipoprotein(a) in atherosclerotic cardiovascular disease and aortic stenosis: a European Atherosclerosis Society consensus statement. Eur Heart J 2022;43:3925-46.
    6. Bhatt DL, Steg PG, Miller M, et al. Cardiovascular risk reduction with icosapent ethyl for hypertriglyceridemia. N Engl J Med 2019;380:11-22.