Lipoprotein (a) is a highly atherogenic variant of LDL and its elevated levels are independently associated with the risk of atherosclerosis, myocardial infarction, aortic valve calcification and death in CKD patients (6, 13). Lp(a) levels are mainly genetically determined, but since it is cleared by the kidney, among other clearance mechanisms, Lp(a) may increase in CKD and in response to statins (13). The measured LDL-cholesterol includes the cholesterol content of Lp(a), which can contribute approximately 30-45% to measured LDL-cholesterol levels as a percentage of its mass (14). In CKD patients, the lower the measured LDL-cholesterol, the higher the content of Lp(a), which may explain the limited efficacy of statin therapy on cholesterol-lowering in advanced CKD.
New advances in lipid-lowering therapies
Two monoclonal antibodies that inhibit PCSK9 and lower LDL-cholesterol are currently available – evolocumab and alirocumab. Both have been tested in randomized, double-blind, placebo-controlled trials on a background of medium to high-intensity statin therapy and were shown to effectively reduce LDL-cholesterol and Lp(a) levels, as well as the risk of cardiovascular events (11, 12). The FOURIER (Further Cardiovascular Outcomes Research with PCSK9 Inhibition in Subjects with Elevated Risk) trial compared outcomes with evolocumab and placebo according to the level of kidney function, concluding that absolute reduction in the composite of cardiovascular death, myocardial infarction, or stroke with evolocumab was numerically greater with more advanced CKD (15). However, the trial did not include end-stage renal disease patients, therefore the efficacy and safety of this therapeutic regimen in this patient group still need to be addressed.
There are currently no approved medications to specifically lower Lp(a). Pelacarsen, a hepatocyte-directed antisense oligonucleotide targeting the LPA gene mRNA, has been shown to lower Lp(a) levels in several very recent trials, but it has not yet been investigated on patients with glomerular filtration rate <60ml/min or urinary albumin:creatinine ratio >100mg/g (13, 16). Even more so, the upcoming phase 3 Lp(a) HORIZON trial also a priori excludes patients with significant kidney disease (17). Given the increased risk for dyslipidemia and related complications in CKD patients, novel efficient and safe lipid-lowering therapeutics are urgently needed for this population.