How Low Is Safe? The Frontier of Very Low (<30 mg/dL) LDL Cholesterol

Angelos D. Karagiannis; Anurag Mehta; Devinder S. Dhindsa; Salim S. Virani; Carl E. Orringer; Roger S. Blumenthal; Neil J. Stone; Laurence S. Sperling


Eur Heart J. 2021;42(22):2154-2169. 

In This Article

Benefits of Achieving Very Low LDL-C

Lower LDL-C appears to be atheroprotective and reduces the incidence of cardiovascular events. However, it is important to assess if cardiovascular benefit extends below 30 mg/dL. The GLAGOV study[64] used intracoronary intravascular ultrasound to evaluate the effect of evolocumab on coronary atheroma volume when administered to statin-treated patients. Patients on evolocumab had lower LDL-C (36.6 vs. 93.0 mg/dL; difference −56.5 mg/dL [95% CI, −59.7 to −53.4]; P < 0.001), slightly decreased percent atheroma volume (PAV) [0.95% decrease vs. 0.05% increase, difference −1.0% (95% CI, −1.8% to −0.64%); P < 0.001], lower normalized total atheroma volume (TAV) [5.8 mm3 decrease vs. 0.9 mm3 decrease, difference −4.9 mm3 (95% CI, −7.3 to −2.5); P < 0.001], and modest atherosclerotic plaques regression [64.3% vs. 47.3%; difference 17.0% (95% CI, 10.4–23.6%); P < 0.001 for PAV and 61.5% vs. 48.9%; difference 12.5% (95% CI, 5.9–19.2%); P < 0.001 for TAV]. A linear relationship between achieved LDL-C and percent atheroma volume progression was found ranging from 110 mg/dL to as low as 20 mg/dL.[64]

Sub-studies focused on patients achieving very low LDL-C have demonstrated a statistically significant reduction in the composite of cardiovascular death, myocardial infarction, ischaemic stroke, coronary revascularization, and unstable angina compared to patients with LDL-C values >30 mg/dL.[15,16,19] It appears that cardiovascular clinical benefit is log linearly dependent on LDL-C, increases monotonically with lower LDL-C, is conferred even to patients who start a lipid-lowering agent with a baseline LDL-C < 70 mg/dL, and is similar whether achieved by any combination of a statin, ezetimibe, and PCSK9 inhibitor.[15,16,65] The FOURIER trial did not show a cardiovascular benefit plateau, even for LDL-C levels as low as 10 mg/dL.[16]

In a prespecified analysis of ODYSSEY OUTCOMES trial in patients eligible for ≥3 years follow-up, alirocumab reduced all-cause death [hazard ratio (HR), 0.78; 95% CI, 0.65–0.94; P = 0.01].[66] A post hoc spline analysis from the same trial showed that in the alirocumab group all-cause mortality declines with lower achieved LDL-C levels, down to an LDL-C level of ~30 mg/dL (adjusted P-value for model = 0.017 for linear trend).[66] Whether all-cause mortality continues to decrease for LDL-C below 30 mg/dL is still unclear.

A post hoc analysis of FOURIER showed that PCSK9 inhibition reduced venous thromboembolism (VTE) events by 46% (HR, 0.54; 95% CI, 0.33–0.88; P = 0.014) beyond 1 year,[67] a meta-analysis of FOURIER and ODYSSEY OUTCOMES demonstrated a 31% relative decrease in VTE with PCSK9 inhibition (HR, 0.69; 95% CI, 0.53–0.90; P = 0.007)[67] and a prespecified analysis of Odyssey OUTCOMES showed a nonsignificant trend of fewer VTE events (HR, 0.67; 95% CI, 0.44–1.01; P = 0.06) in the treatment group.[68] Even though none of the studies find any correlation between VTE events rate and baseline LDL-C or magnitude of LDL-C reduction, a dedicated RCT investigating the possible effect of lowering LDL-C [or other lipoproteins such as Lp(a)] on lowering VTE events might be warranted. Similarly, evolocumab was found to reduce aortic stenosis events (HR of 0.48; 95% CI, 0.25–0.93) after the first year of treatment in an exploratory analysis of the FOURIER trial; however, there was not found any significant correlation between events and baseline LDL-C levels and further investigation is also needed.[69]