New Agents to Reduce Cholesterol Levels: Implications for Nephrologists

Lucia Del Vecchio; Ivano Baragetti; Francesco Locatelli


Nephrol Dial Transplant. 2020;35(2):213-218. 

In This Article

The Experience in Patients With CKD

There are several reasons why PCSK9 inhibitors may be useful in CKD patients. PCSK9 inhibitors cause a dramatic fall of LDL-C. The marked decrease of serum cholesterol may be more effective than the milder one obtained with statins in CKD patients. Indeed, the extent of LDL-C lowering may modulate coronary vascular calcifications. According to a longitudinal study of 120 subjects, the annual log-transformed score of progression of coronary artery calcification was lower when PCSK9 inhibitor was added to statin.[59]

CKD patients tolerate less statin therapy compared with the general population; suboptimal treatment is a possible reason for statin failure in advanced CKD.

At present, limited data are available for the CKD population. The majority of clinical trials with PCSK9 inhibitors excluded CKD patients at advanced stages or not considered CKD among exclusion criteria. The FOURIER trial enroled patients with eGFR ≥20 mL/min/1.73 m2; however, no information is given on the mean GFR of the enroled patients.[46] The ODYSSEY OUTCOME trial included patients with slightly higher eGFR (>30 mL/min/1.73 m2); the percentage of patients with eGFR <60 mL/min/1.73 m2 ranged between 12 and 25% (depending on whether they have had an event or not).[48] Unfortunately, no trials foresaw pre-specified analyses for the CKD population. Recently, Toth et al.[60] reported a post hoc, pooled analyses of eight Phase III ODYSSEY trials enroling 4629 patients treated either with alirocumab 150 mg or placebo or ezetimibe on top of statin therapy. The treatment period ranged between 24 and 104 weeks. Overall, 10.1% of the subjects had CKD (eGFR of 30–59 mL/min/1.73 m2). Compared with those without CKD, they were slightly older, and had a higher incidence of diabetes, lower levels of LDL-C, non-HDL-C and apoB, and higher levels of triglycerides and Lp(a). Significant reductions of LDL-C with alirocumab versus control treatment were observed regardless of CKD diagnosis and baseline proteinuria. Significant changes in apoB, non-HDL-C, Lp(a) and HDL-C were also observed independently of CKD status. No safety issues were raised in CKD patients compared with the overall trial population.

PCSK9 inhibitors have pleiotropic effects other than LDL-C lowering.[61] Interestingly, serum PCSK9 levels are linearly associated with the fraction and amount of necrotic core tissue in coronary atherosclerosis, independently of serum LDL-C levels and statin use.[62]

Finally, PCSK9 inhibitors significantly decreased small LDL and Very Low Density Lipoprotein (VLDL) subclasses and increased LDL particle size independently of triglyceride levels.[63] This is of interest, given that alterations in LDL and HDL subclass distribution towards smaller particles are often observed in CKD patients. PCSK9 inhibition also decreases Lp(a).[64] The concentration of this particle is increased in CKD patients, but published data on the relationship between Lp(a) and CVD outcomes in CKD are limited and variable in their conclusions.

The association between nephrotic syndrome and dyslipidaemia is well known. PCSK9 is increased in mice with acute nephrotic syndrome.[65] The observation was confirmed in 50 patients with nephrotic syndrome.[65] Recently, one patient with steroid-resistant nephrotic syndrome was treated with evolocumab and obtained partial remission.[66]