Inclisiran in CKD

The evidence supporting aggressive LDL cholesterol lowering continues to grow rapidly. Recently, the Effect of Evolocumab in Patients at High Cardiovascular Risk Without Prior Myocardial Infarction or Stroke diabetes subgroup analysis showed that evolocumab lowered major adverse cardiovascular events by 31% in patients with diabetes and no prior myocardial infarction or stroke,¹ while the Korean Effects of Ezetimibe Combination Therapy for Patients With Atherosclerotic Cardiovascular Disease trial demonstrated that targeting LDL cholesterol below 55 mg/dl instead of 70 mg/dl reduced cardiovascular events by 33% in patients with established atherosclerotic disease.² These findings highlight a field-wide consensus: Lower is better, and the methods to reach that goal matter. Patients with CKD face a cardiovascular burden that surpasses what traditional risk factors alone can explain. As glomerular filtration declines, the rates of myocardial infarction, stroke, and cardiovascular death are gradually higher, and this relationship persists even after accounting for hypertension, diabetes, and dyslipidemia. Lowering LDL cholesterol remains a key strategy to reduce cardiovascular risk in this population. The Kidney Disease Improving Global Outcomes (KDIGO) 2024 guideline recommends statin therapy for patients with CKD and atherosclerotic cardiovascular disease, regardless of initial LDL cholesterol levels.³ However, in real-world practice, many patients with advanced kidney disease remain undertreated.⁴ Factors such as statin intolerance, polypharmacy, and clinical inertia amid declining kidney function all contribute to the ongoing gap between guideline recommendations and actual prescribing habits.

Nonstatin lipid-lowering therapies have expanded treatment options for clinicians, although the evidence base in CKD remains less robust than might be expected for such a common comorbidity. The monoclonal antibodies targeting proprotein convertase subtilisin/kexin type 9 (PCSK9), evolocumab and alirocumab, have shown effective LDL cholesterol reduction in patients with impaired kidney function, with post hoc analyses from the Further Cardiovascular Outcomes Research with PCSK9 Inhibition in Under-studied or Elevated Risk subjects and Evaluation of Cardiovascular Outcomes After an Acute Coronary Syndrome During Treatment With Alirocumab trials demonstrating consistent treatment effects across categories of eGFR.^5,6 Notably, the Further Cardiovascular Outcomes Research with PCSK9 Inhibition in Under-studied or Elevated Risk subjects CKD subgroup analysis demonstrated not only consistent LDL cholesterol reduction across eGFR categories but also a significant 21% reduction in the composite of cardiovascular death, myocardial infarction, or stroke in patients with stage 3 or greater CKD, with absolute risk reduction numerically greater in those with more advanced kidney disease.⁵ That finding provides the strongest existing evidence that a PCSK9-directed strategy can reduce cardiovascular events in CKD, and it sets the stage for evaluating whether inclisiran, which targets the same pathway through a different mechanism, can replicate those benefits. Bempedoic acid, which inhibits ATP-citrate lyase upstream of the statin pathway, has also demonstrated efficacy in patients with mild to moderate kidney disease, although data on advanced stages are limited. Each of these agents addresses a specific niche. None has become a comprehensive solution for patients with advanced kidney disease, statin intolerance, and persistently elevated LDL cholesterol.

Inclisiran provides a different mechanistic approach. A small interfering RNA conjugated to a hepatocyte-targeting ligand, inclisiran silences the mRNA that encodes PCSK9, which leads to increased LDL receptor density on hepatocyte surfaces and improved LDL cholesterol clearance from the blood. Its pharmacokinetic profile is notable: After an initial dose and a 3-month loading phase, the drug is administered through subcutaneous injection twice a year. This dosing schedule is fundamentally different from the daily oral regimens or biweekly to monthly injections required by other lipid-lowering medications, making it especially beneficial for populations where medication adherence is difficult because of a high pill burden. Patients with CKD, who often take ten or more medications daily, are a prime example.

In this issue of JASN, Landmesser and colleagues present a post hoc pooled analysis of three pivotal phase 3 trials, A Randomized Trial Assessing the Effects of Inclisiran on Clinical Outcomes Among People With Cardiovascular Disease (ORION)-9, ORION-10, and ORION-11, examining the effectiveness and safety of inclisiran across different baseline eGFR categories.⁷ The analysis included 3660 randomized patients divided into four groups aligned with KDIGO GFR categories: eGFR of 90 or greater (G1), 60 to <90 (G2), 45 to <60 (G3A), and 15 to <45 (G3B through G4). The primary end points were percentage and absolute changes in LDL cholesterol from baseline. The results are encouraging. Placebo-corrected LDL cholesterol reductions at day 510 were approximately 50%, 52%, 55%, and 45% across the four eGFR categories, respectively, and the time-adjusted reductions from day 90 through day 540 were similarly consistent. No statistically significant treatment-by-eGFR subgroup interaction was observed for the primary end point. Reductions in secondary atherogenic lipid parameters, including non-HDL cholesterol, apo B, lipoprotein(a), and remnant cholesterol, followed a similar trend. The safety profile was comparable across all eGFR groups, with no new signals or adverse effects on eGFR trajectories over the follow-up period.

The strengths of this analysis are notable. The pooled dataset includes data from three well-designed, double-blind, placebo-controlled trials with follow-up extending more than 540 days. The consistent reduction of LDL cholesterol across various eGFR categories is clinically important, especially because efficacy was sustained even in patients with eGFR 15 to <45 ml/min per 1.73 m². The secondary lipid end points add value because reductions in apo B, non-HDL cholesterol, and remnant cholesterol target atherogenic lipoprotein fractions that are often disproportionately high in kidney disease. The absence of safety concerns for the kidney, including no difference in the proportion of patients experiencing eGFR declines of 30% or more, provides a crucial baseline for future research.

Several limitations temper the conclusions. This was a post hoc analysis, and the original trials were neither designed nor powered to evaluate outcomes on the basis of kidney function. The number of patients with advanced CKD was small: Only 142 had an eGFR of 15 to <45, 14 had an eGFR below 30, and none had an eGFR below 15 ml/min per 1.73 m². Data on urinary albumin-to-creatinine ratio or protein-to-creatinine ratio were not collected, which limits the ability to characterize kidney damage beyond eGFR and to determine whether inclisiran affects proteinuria. Because KDIGO classifies CKD severity using both eGFR and albuminuria category, patients in this analysis were incompletely staged, and meaningful differences in cardiovascular risk within each eGFR stratum may have gone undetected. Baseline LDL cholesterol was lower in the most advanced eGFR group, reflecting more aggressive background lipid-lowering therapy, suggesting that the slightly lower percentage decrease in this subgroup may be due to a floor effect rather than reduced drug efficacy. Most importantly, cardiovascular outcomes were not recorded in these trials. We can now demonstrate that inclisiran lowers LDL cholesterol in patients with CKD. However, whether this reduction leads to fewer myocardial infarctions, strokes, or cardiovascular deaths remains unconfirmed.

That question will be addressed by ongoing cardiovascular outcomes trials. ORION-4, a randomized trial evaluating the effects of inclisiran on clinical outcomes in patients with cardiovascular disease, along with the A Study of Inclisiran to Prevent Cardiovascular Events in High-risk Primary Prevention Patients and Study of Inclisiran to Prevent Cardiovascular Events in Participants With Established Cardiovascular Disease trials in primary and secondary prevention populations, will provide the event-driven data needed to complete the evidence chain.^8–10 Until those results are available, the Landmesser analysis offers the best available evidence on how inclisiran behaves pharmacologically across different levels of kidney function. For nephrologists and cardiologists managing lipids in patients with CKD, the key takeaway is that inclisiran significantly lowers LDL cholesterol without requiring dose adjustments or apparent kidney toxicity, even in patients with stage 3B and 4 disease. The twice-yearly dosing schedule addresses one of the most persistent barriers to effective lipid management in this population: the challenge of daily medication adherence, especially given complex, multidrug regimens.

The convergence of a high-risk population, an undertreated risk factor, and a well-tolerated therapy with a favorable dosing profile provides a strong clinical rationale for inclisiran in CKD. What remains is the essential evidence of clinical outcomes. Until those data are available, inclisiran in CKD holds an important place in cardiovascular therapeutics: biologically compelling, pharmacologically promising, and possibly just one well-designed trial away from potentially changing practice.

Disclosures

Disclosure forms, as provided by each author, are available with the online version of the article at http://links.lww.com/JSN/F818.

Author Contributions

Conceptualization: Sascha N. Goonewardena, Robert S. Rosenson.

Project administration: Sascha N. Goonewardena.

Writing – original draft: Sascha N. Goonewardena, Robert S. Rosenson.

Writing – review & editing: Sascha N. Goonewardena, Robert S. Rosenson.

Funding

None.