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

Existing Cholesterol-lowering Agents: Why They May Not be Enough in Patients With CKD

Statins and ezetimibe are the main cholesterol-lowering drugs. Several post hoc analyses of large clinical trials showed the efficacy of statins in reducing CVD in the CKD subset;[4] the extent of the benefit is similar to or even greater than that observed in the general population, especially for heart-related events. These trials suffered from the biases that CKD patients were little represented and those with more advanced disease were excluded.[5]

The findings of randomized trials targeting CKD patients are less encouraging. The Deutsche Diabetes Dialysis Study found no benefit with atorvastatin in reducing the risk of the primary, CV, endpoint in diabetic haemodialysis (HD) patients;[6] a possible benefit was observed only if pre-treatment low-density lipoprotein]-cholesterol (LDL-C) was >145 mg/dL.[7] In A Study to Evaluate the Use of Rosuvastatin in Subjects on Regular HD, rosuvastatin did not reduce the risk of CV events;[8] neither LDL-C levels nor allocation to therapy predicted the outcome.[9] The Study of Heart and Renal Protection (SHARP) trial evaluated the effect of statin and ezetimibe in nearly 10 000 CKD patients (3023 on dialysis and 6247 not).[10] It showed a 17% reduction in the risk of CV events in the simvastatin plus ezetimibe-treated group compared with placebo in the whole cohort. The subgroup analysis showed a minor effect in HD patients, with non-significant 10% reduction of CV relative risk.

One possible explanation of the lower efficacy of statins in advanced CKD is that CKD patients often have low cholesterol levels due to competing risks like the protein-energy wasting syndrome, and are less able to tolerate intensive treatment (during the SHARP trial, one-third of the patients discontinued the combination of simvastatin plus ezetimibe[10]) leading to a reduced lowering effect on LDL-C. In this respect, if statin therapy is adjusted for the lower LDL-C reduction, the 10% CV relative risk increases up to 16%.[10] The concept that statins have lower efficacy as CKD progresses is also suggested by a large meta-analysis of 28 trials (n = 183 419),[11] which showed smaller relative effects of statin-based therapy on major vascular events as renal function declines.

Statins or ezetimibe may be less effective in reducing some non-high-density lipoprotein cholesterol (HDL-C) particles that are more prevalent at advanced stages of CKD;[12] indeed, the lipid profile of CKD is different from that of the general population. Finally, increased oxidative stress affects lipid metabolism as well.[13,14] Lipoprotein(a) [Lp(a)] and chylomicron remnants or altered lipoproteins are often found,[15,16] together with small, dense LDL (sd-LDL), which are considered highly atherogenic.[17] Unlike in the general population, HDL may be not protective in CKD. Indeed, at dialysis start, higher serum amyloid proteins contained in HDL particles are detected;[18] these proteins are related to inflammation and impair lipid metabolism. CKD also impairs extraction of cellular lipids by HDL.[19]

Statins have well-known cholesterol-independent effects on inflammation, oxidative stress, endothelial protection and plaque-stabilizing activity; it is unknown whether these pleiotropic effects are maintained also in CKD, given the paucity of dedicated studies and discordant data in the existing ones.[20,21]

In recent years, new cholesterol-lowering drugs have become available. They decrease serum cholesterol much more than statins and ezetimibe alone or in combination. It is unknown whether these powerful agents are more effective than traditional treatments in CKD patients.