LDL-C & heart disease – definitive proof?

October 2, 2023 news

Professor Tim Noakes received an email from a supporter of the diet-heart hypothesis questioning his stance on the significance of LDL cholesterol in atherosclerotic cardiovascular disease (ASCVD). Tim asked me to take a look at the paper attached to the email. The paper was titled "Association between achieved Low-Density Lipoprotein cholesterol levels and long-term cardiovascular and safety outcomes: An analysis of FOURIER-OLE" by Gaba et al. This study focused on PCSK9 inhibitors, a topic that we have reviewed previously in Monday notes.

The FOURIER (Further cardiovascular OUtcomes Research with PCSK9 Inhibition in subjects with Elevated Risk) trial involved 27,564 participants with cardiovascular disease, LDL cholesterol (LDL-C) ≥70 mg/dL, and who were taking statins. Patients received either evolocumab (a PCSK9 inhibitor) or a placebo injection, with an average follow-up of 2.2 years. The study claimed that evolocumab reduced the risk of major cardiovascular events. I raised concerns about subgroup analysis and the drug's effectiveness at specific LDL-C levels. The Telegraph, a UK national newspaper, covered my findings.

FOURIER-OLE (FOURIER-Open Label Extension) followed up on 6,559 patients from the original trial for an average of 5 years. This study aimed to determine the optimal LDL-C levels in terms of efficacy and safety. Patients were grouped based on their achieved LDL-C levels after 12 and 24 weeks of evolocumab treatment, and cardiovascular incidents were compared.

Gaba et al reported that lower LDL-C levels correlated with a reduced risk of cardiovascular events and no greater adverse effects. However, there are some concerns about the claims:

Patient Characteristics: Significant differences existed between those with the lowest and highest LDL-C levels. Adjustments were made, but the impact of these differences remains unclear.
Endpoints: Subjective endpoints like hospital admissions and coronary revascularisations can skew results. In this study, differences in subjective endpoints influenced the overall outcome, despite no significant differences in objective events.
Deaths: The study reported no significant difference in cardiovascular deaths, but a difference in all-cause mortality. Another team of researchers published a paper questioning the death figures.
Serious Adverse Events: Approximately one in eight patients experienced serious adverse events, irrespective of LDL-C levels.
Lp(a): Differences in lipoprotein(a) levels were substantial between groups, and PCSK9 inhibitors are known to impact Lp(a). Lp(a) may be a confounding factor in the results.
Limitations: The study had limitations, including the use of LDL-C measurements at 12-24 weeks, baseline imbalances, and potential selection bias.

In response to the question about LDL cholesterol's role in ASCVD, Professor Noakes emphasised the need to consider metabolic syndrome and type 2 diabetes as primary causes. Hopefully, my deeper review has provided the prof with more points to go back with. Not least, the (drug company) conflicts of interest behind the Gaba et al paper were vast.