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

Sub-studies/Secondary Analyses of Patients Achieving Very Low LDL-C

HMG-CoA reductase inhibitors (statins), NPC1L1 inhibitor (ezetimibe), and PCSK9 inhibitors (evolocumab, alirocumab) are lipid-lowering drugs that significantly reduce LDL-C and the incidence of cardiovascular events.[62] In several trials (JUPITER, PROVE-IT TIMI-22, IMPROVE-IT, FOURIER, ODYSSEY trials) with lipid-lowering agents (high-intensity statin, statin/ezetimibe combination, statin/PCSK9 inhibitor combination, PCSK9 monotherapy) ~10–25% of patients in the treatment groups achieved very low (<30 mg/dL) LDL-C.[3,4,6,7,63] The combination of a PCSK9 inhibitor with a statin ± ezetimibe results in the greatest LDL-C reduction.

Published sub-studies of the aforementioned trials focused specifically on patients achieving very low LDL-C values, analysing possible benefits and adverse effects between treatment groups based on attained LDL-C levels (Table 1).[15–19] The largest reported experience with LDL-C < 30 mg/dL is with evolocumab in the FOURIER trial.[16] In that trial, the median LDL-C at 4 weeks was 19.4 mg/dL (<0.5 mmol/L) and trended slightly higher over the next 168 weeks. The longest exposure, though, was seen in IMPROVE-IT trial of over 6 years.[15]

The profile of patients attaining very low LDL-C is most frequently characterized by lower baseline LDL-C and Lp(a) levels, higher baseline triglycerides, male gender, older age, non-smokers, history of diabetes, higher haemoglobin A1c, and higher dose of lipid-lowering medications.[15,16,18,19]