Skip to main content
NCBI home page
Journal of the American Society of Nephrology : JASN logoLink to Journal of the American Society of Nephrology : JASN
. 2026 Jan 28;37(7):1497–1506. doi: 10.1681/ASN.0000001006

Inclisiran in Patients with CKD

Post Hoc Pooled Analysis of Three Phase 3 Trials

Ulf Landmesser 1,✉, Kausik K Ray 2, Frederick J Raal 3, Lorena Garcia Conde 4, Jackie Han 5, Wolfgang Koenig 6,7,8, Lawrence A Leiter 9, Gregory G Schwartz 10, R Scott Wright 11, on behalf of the ORION Investigators
PMCID: PMC13337159  PMID: 41604274

Visual Abstract

graphic file with name jasn-37-1497-g001.jpg

Open in a new tab

Keywords: atherosclerosis, atherosclerotic cardiovascular disease, CKD, eGFR, inclisiran, lipid therapy, low-density lipoprotein cholesterol, PCSK9 inhibitor

Abstract

Key Points

  • Inclisiran for LDL cholesterol reduction was analyzed post hoc in patients with CKD.

  • Mean percentage LDL cholesterol reduction from baseline was around 50% regardless of eGFR in phase 3 trials.

  • Inclisiran showed sustained and effective LDL cholesterol–lowering in patients across various levels of eGFR values, without new safety findings.

Background

Lowering LDL cholesterol reduces the risk of atherosclerotic cardiovascular disease in patients with CKD. The efficacy and safety of inclisiran versus placebo in patients without and with CKD were investigated in a post hoc pooled analysis of three phase 3 trials (ORION-9, ORION-10, and ORION-11).

Methods

Patients with heterozygous familial hypercholesterolemia, atherosclerotic cardiovascular disease or its risk equivalent, and elevated LDL cholesterol were randomized 1:1 to subcutaneous inclisiran or placebo on days 1 and 90 and every 6 months thereafter for 540 days. Patients were stratified based on baseline eGFR (by CKD Epidemiology Collaboration equation): ≥90, 60 to <90, 45 to <60, and 15 to <45 ml/min per 1.73 m2. Coprimary end points were percentage change in LDL cholesterol at day 510 and time-adjusted percentage change after day 90 and through day 540. Safety was also evaluated.

Results

Of 3660 patients, 1610 (44%) had eGFR ≥90, 1608 (44%) 60 to <90, 300 (8%) 45 to <60, and 142 (4%) 15 to <45 ml/min per 1.73 m2. The mean (95% confidence interval) placebo-corrected percentage changes in LDL cholesterol from baseline at day 510 in patients with eGFR ≥90, 60 to <90, 45 to <60, and 15 to <45 ml/min per 1.73 m2 were −49.9% (−53.2 to −46.6), −51.2% (−54.4 to −48.0), −54.7% (−62.5 to −47.0), and −44.7% (−57.6 to −31.8), respectively (P < 0.001); the corresponding mean (95% confidence interval) time-adjusted placebo-corrected percentage changes in LDL cholesterol from baseline after day 90 through day 540 were −48.4% (−50.8 to −46.1), −51.8% (−54.2 to −49.4), −55.6% (−61.0 to −50.2), and −50.4% (−59.3 to −41.5; each P < 0.001). Significant decreases in total cholesterol, apolipoprotein B, non-HDL cholesterol, and lipoprotein(a) occurred in all eGFR groups. Inclisiran was well tolerated without new safety findings.

Conclusions

Inclisiran demonstrated sustained and effective LDL cholesterol reduction in patients with or at risk of atherosclerotic cardiovascular disease, regardless of baseline eGFR as low as 15 ml/min per 1.73 m2, without new safety findings.

Clinical Trial registry name and registration number:

ClinicalTrials.gov, ORION-9 (NCT03397121), ORION-10 (NCT03399370), and ORION-11 (NCT03400800).

Introduction

Patients with CKD experience a significantly higher risk of atherosclerotic cardiovascular disease events.1,2 More severe CKD, as reflected by lower eGFR, is associated with greater incidence of cardiovascular events and death.3 Furthermore, patients with prevalent atherosclerotic cardiovascular disease and CKD are at even higher risk of cardiovascular events.4,5 Present guidelines consistently classify patients with advanced CKD at high risk, but recommendations for LDL cholesterol treatment goals differ. The Kidney Disease Improving Global Outcomes (KDIGO) guideline recommends statin therapy for patients with CKD and atherosclerotic cardiovascular disease without specifying LDL cholesterol goals.6 The European Society of Cardiology (ESC) recommends LDL cholesterol goals of <1.4 mmol/L (<55 mg/dl) or <1.8 mmol/L (<70 mg/dl), plus an LDL cholesterol reduction of >50% from baseline, respectively, for patients considered at high or very high risk on the basis of eGFR <60 ml/min per 1.73 m2.7 Both the American College of Cardiology/American Heart Association and the ESC guidelines recommend statin therapy for patients with atherosclerotic cardiovascular disease and non–dialysis-dependent stages 3-5 CKD, regardless of baseline LDL cholesterol levels.1,7 However, some patients with CKD experience myopathy or statin intolerance,8,9 necessitating the use of nonstatin lipid therapies. Consequently, KDIGO, ESC, and American College of Cardiology/American Heart Association guidelines each indicate that nonstatin therapies, such as ezetimibe or proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors, be considered for patients who do not achieve LDL cholesterol goals despite maximum-tolerated statin therapy.1,6,7 In fact, on a background of statin therapy, ezetimibe and anti-PCSK9 monoclonal antibodies have been shown to reduce the risk of cardiovascular events compared with placebo.10–12

Inclisiran, a first-in-class small interfering RNA agent, degrades PCSK9 mRNA in the liver to prevent PCSK9 production, resulting in increased LDL receptor concentration and reduced plasma LDL cholesterol levels.13 Pivotal phase 3 ORION-9 (NCT03397121), ORION-10 (NCT03399370), and ORION-11 (NCT03400800) trials demonstrated that twice-yearly (after initial and 3-month doses) inclisiran provides sustained and effective LDL cholesterol lowering and is well tolerated in patients with or at high risk of atherosclerotic cardiovascular disease.14–16 In addition, data from the phase 1 ORION-7 (N=31) and phase 2 ORION-1 (N=247) trials demonstrate that exposure to inclisiran sodium 300 mg reduced PCSK9 and LDL cholesterol levels consistently across CKD stages 1-4; patients requiring hemodialysis (stage 5) were excluded. Patients with more advanced CKD had higher initial maximum plasma concentrations of inclisiran after administration, but this heightened exposure did not affect LDL cholesterol reduction, and inclisiran was undetectable in plasma after 48 hours, suggesting that dose adjustments are not necessary across various stages of CKD.17 Studies ORION-7 and ORION-1 were able to provide follow-up to 210 days of evaluation. The post hoc pooled analysis of the ORION-9, ORION-10, and ORION-11 trials aimed to assess the efficacy and safety of inclisiran versus placebo in a large pool of patients, encompassing those without or with CKD, over an extended follow-up duration.

Methods

Study Design and Participants

The analysis cohort included participants from the pivotal phase 3 ORION-9, ORION-10, and ORION-11 double-blind, placebo-controlled, parallel-group trials.14,15 Qualifying patients had heterozygous familial hypercholesterolemia, atherosclerotic cardiovascular disease or its risk equivalent, and elevated LDL cholesterol (≥100 mg/dl for heterozygous familial hypercholesterolemia and atherosclerotic cardiovascular disease risk equivalent; ≥70 mg/dl for atherosclerotic cardiovascular disease) at screening despite maximally tolerated statins with or without additional oral lipid-lowering therapy. The maximum tolerated statin dose was defined as the maximum dose that can be taken on a regular basis without intolerable adverse events. For patients who are intolerant to statins, it was necessary to provide documented evidence of intolerance to the lowest approved dose of at least two different statins. Patients receiving anti-PCSK9 monoclonal antibodies were excluded.

Detailed inclusion and exclusion criteria have been published previously.14,15 In all three trials, participants were initially required to have a screening eGFR >30 ml/min per 1.73 m2 by eGFR using local clinical methodology. In the ORION-10 trial, the protocol was later amended to remove the eGFR criterion and to instead require no current or planned dialysis or kidney transplantation, therefore allowing inclusion of some patients with severe kidney impairment as measured at the local study site.

For this post hoc pooled analysis, all results were based on eGFR values estimated by the 2021 CKD Epidemiology Collaboration equation18 applied to creatinine measurements as provided by the central laboratory. Patients were classified into four categories based on their baseline eGFR. These categories align with KDIGO GFR categories: ≥90 ml/min per 1.73 m2 (KDIGO GFR category G1); 60 to <90 ml/min per 1.73 m2 (KDIGO GFR category G2); 45 to <60 ml/min per 1.73 m2 (KDIGO GFR category G3A); and 15 to <45 ml/min per 1.73 m2 (KDIGO GFR category G3B–G4). None of the patients had eGFR <15 ml/min per 1.73 m2, which aligns with KDIGO GFR category G5.

In the pivotal phase 3 trials, patients were randomized 1:1 to receive 300 mg inclisiran sodium (equivalent to 284 mg inclisiran) or placebo on days 1, 90, 270, and 450, with maximum-tolerated background oral lipid-lowering therapy. Follow-up visits for laboratory and safety assessments were conducted on days 30, 150, 330, and 510 and the end-of-trial visit on day 540 (Supplemental Figure 1). In all three trials, randomization was stratified according to background statin use and additionally according to country in the ORION-9 and ORION-11 trials. ORION-9 included patients from Canada, Europe, South Africa, and the United States; ORION-10 from the United States; and ORION-11 from Czech Republic, Germany, Hungary, The Netherlands, Poland, South Africa, Ukraine, and the United Kingdom. The study protocols were approved by the relevant Institutional Review Board/independent ethics committee, and all participants provided informed consent.

Outcomes

The coprimary efficacy end points were the percentage change in LDL cholesterol from baseline at day 510 and time-adjusted percentage change in LDL cholesterol from baseline after day 90 up to day 540. The key secondary efficacy end points were the absolute change in LDL cholesterol from baseline at day 510 and time-adjusted absolute change in LDL cholesterol from baseline after day 90 up to day 540.

Other secondary end points included the percentage and absolute changes from baseline at day 510 in total cholesterol, non-HDL cholesterol, apolipoprotein B (ApoB), triglycerides, lipoprotein(a) (Lp(a) at day 540), and remnant cholesterol (this was derived post hoc for the analysis). Exploratory post hoc end points included the effects of inclisiran on eGFR outcomes such as the number of patients with a decline in eGFR by ≥30%, ≥40%, and ≥50% based on baseline eGFR status and the percentage change in eGFR over time. Safety end points included the proportion of patients with treatment-emergent adverse events (TEAEs), serious TEAEs, TEAEs leading to discontinuation, death, frequent TEAEs (reported in ≥5% of patients), and clinically significant laboratory values.

Statistical Analysis

Baseline characteristics and efficacy were evaluated in the intent-to-treat (ITT) population comprising all randomized patients in the three trials. The percentage and absolute changes in LDL cholesterol from baseline to day 510 were analyzed using an analysis of covariance model with a multiple imputation washout model for missing data. The time-adjusted percentage and absolute changes in LDL cholesterol from baseline after day 90 up to day 540 was analyzed using a mixed-effects model for repeated measures with a control-based pattern mixture model for missing data imputation. The time-adjusted percentage (or absolute) change was defined as the average percentage (or absolute) change in LDL cholesterol from baseline after day 90 up to day 540 and was calculated from the respective mixed-effects model for repeated measures as a linear combination of the estimated means of the corresponding time points. Details of the multiple imputation methods and handling of missing data due to early discontinuation, including patients lost to follow-up, are available in Supplemental Appendix 1.

The percentage and absolute changes in other atherogenic lipids from baseline to day 510 were analyzed using a mixed-effects model for repeated measures without imputation. For Lp(a), median-based analysis at day 540 was provided from a quantile regression model without imputation of missing data. Models were applied separately within each eGFR categories. Tests for the interaction of treatment with eGFR categories were conducted for the key efficacy end points. Analyses by eGFR categories were not prespecified and, therefore, were not adjusted for multiplicity. Nominal P values and 95% confidence intervals (CIs) were considered as measures for the strength of the association between treatment arms and end points and not formal criteria to claim statistical significance. Safety was analyzed in the safety population comprising all patients who received ≥1 dose of the study drug.

Results

Demographics and Baseline Characteristics

In this pooled analysis, all 3660 randomized patients had available baseline eGFR levels and were classified into four groups: 1610 (44%) had eGFR ≥90, 1608 (44%) had 60 to <90, 300 (8%) had 45 to <60, and 142 (4%) had 15 to <45 ml/min per 1.73 m2. There were 14 patients (0.4%) with baseline eGFR <30 ml/min per 1.73 m2, all but one from ORION-10. This trial allowed patients with severe kidney impairment at screening and those with screening eGFR >30 ml/min per 1.73 m2 but presenting a lower value at baseline. No patient had baseline eGFR <15 ml/min per 1.73 m2, which would qualify for kidney failure. Owing to the limited number of patients with baseline eGFR 15 to <30 ml/min per 1.73 m2 and the imbalance between treatment groups (inclisiran n=10; placebo, n=4), robust results could not be generated using the statistical modeling techniques applied. Therefore, this subset was analyzed together with patients having baseline eGFR of 15 to <45 ml/min per 1.73 m2.

Baseline demographic and clinical characteristics were balanced between the inclisiran and placebo groups across all eGFR categories (Table 1). Overall, 3107 patients (85%) had atherosclerotic cardiovascular disease and 553 (15%) were atherosclerotic cardiovascular disease risk equivalent. Patients with lower rate of eGFR were older, more likely to be women, and more likely to have clinical atherosclerotic cardiovascular disease, heart failure, and hypertension and had a less intensive use of a lipid-lowering therapy. The mean LDL cholesterol at baseline was lower in patients with eGFR 15 to <45 ml/min per 1.73 m2 compared with patients with higher eGFR, likely due to the use of higher intensity lipid-lowering therapy in the former groups.

Table 1.

Baseline demographic and clinical characteristics by baseline eGFR (intent-to-treat population)

Characteristic eGFR ≥90 ml/min per 1.73 m2 eGFR 60 to <90 ml/min per 1.73 m2 eGFR 45 to <60 ml/min per 1.73 m2 eGFR 15 to <45 ml/min per 1.73 m2
Inclisiran (n=822) Placebo (n=788) Inclisiran (n=790) Placebo (n=818) Inclisiran (n=155) Placebo (n=145) Inclisiran (n=66) Placebo (n=76)
Age, yr, mean±SD 60±10 59±10 67±8 67±9 69±8 71±7 72±7 69±7
Male, n (%) 557 (68) 548 (70) 529 (67) 564 (69) 96 (62) 93 (64) 44 (67) 39 (51)
eGFR, ml/min per 1.73 m2, median (Q1–Q3) 93 (85–103) 93 (86–102) 71 (65–76) 70 (64–76) 51 (46–53) 50 (46–53) 37 (32–39) 37 (34–40)
LDL cholesterol, mg/dl, mean±SD 116±47 115±45 108±40 108±44 111±53 105±35 103±40 104±35
Atherosclerotic cardiovascular disease status, n (%)
 Atherosclerotic cardiovascular disease 637 (77) 629 (80) 706 (89) 721 (88) 148 (95) 135 (93) 61 (92) 70 (92)
 Atherosclerotic cardiovascular disease risk equivalent 185 (23) 159 (20) 84 (11) 97 (12) 7 (5) 10 (7) 5 (8) 6 (8)
Cardiovascular risk factors, n (%)
 Congestive heart failure 74 (9) 62 (8) 99 (13) 114 (14) 27 (17) 32 (22) 13 (20) 19 (25)
 Hypertension 595 (72) 602 (76) 661 (84) 655 (80) 141 (91) 136 (94) 59 (89) 70 (92)
 Diabetes mellitus 279 (34) 252 (32) 287 (36) 269 (33) 76 (49) 67 (46) 45 (68) 43 (57)
 Hyperlipidemia 796 (97) 760 (96) 752 (95) 773 (94) 151 (97) 136 (94) 64 (97) 73 (96)
 Familial hypercholesterolemia 205 (25) 193 (24) 113 (14) 133 (16) 14 (9) 14 (10) 8 (12) 12 (16)
Lipid-lowering therapy, n (%)
 Statins 764 (93) 732 (93) 727 (92) 749 (92) 136 (88) 126 (87) 59 (89) 68 (89)
 High-intensity statin 626 (76) 629 (80) 578 (73) 570 (70) 104 (67) 95 (66) 48 (73) 51 (67)
 Ezetimibe 146 (18) 136 (17) 82 (10) 111 (14) 20 (13) 12 (8) 3 (5) 11 (14)
Open in a new tab

Patients were classified into four categories based on their baseline eGFR. These categories align with Kidney Disease Improving Global Outcomes (KDIGO) GFR categories: ≥90 ml/min per 1.73 m2 (KDIGO GFR category G1); 60 to <90 ml/min per 1.73 m2 (KDIGO GFR category G2); 45 to <60 ml/min per 1.73 m2 (KDIGO GFR category G3A); and 15 to <45 ml/min per 1.73 m2 (KDIGO GFR category G3B–G4). None of the patients had GFR <15 ml/min per 1.73 m2, which aligns with KDIGO GFR category G5. Q1, lower quartile; Q3, upper quartile.

Overall, 237 (6%) patients discontinued the trials before the day 540 visit, including 46 (1%) patients considered lost to follow-up.

Efficacy

Primary End Points

The mean percentage change in LDL cholesterol from baseline at day 510 and the corresponding time-adjusted percentage change from baseline after day 90 up to day 540 were significantly greater with inclisiran versus placebo (P < 0.001), irrespective of baseline eGFR category (Figure 1A). In patients with eGFR ≥90, 60 to <90, 45 to <60, and 15 to <45 ml/min per 1.73 m2, the mean (95% CI) placebo-corrected percentage changes in LDL cholesterol from baseline at day 510 were −49.9% (−53.2 to −46.6), −51.2% (−54.4 to −48.0), −54.7% (−62.5 to −47.0), and −44.7% (−57.6 to −31.8), respectively (P < 0.001, Figure 1A; treatment by eGFR subgroup interaction effect P = 0.42; Supplemental Table 1). The corresponding mean (95% CI) time-adjusted placebo-corrected percentage changes in LDL cholesterol from baseline after day 90 up to day 540 were −48.4% (−50.8 to −46.1), −51.8% (−54.2 to −49.4), −55.6% (−61.0 to −50.2), and −50.4% (−59.3 to −41.5) (each P < 0.001, Figure 1A; treatment by eGFR subgroup interaction effect P = 0.11; Supplemental Table 1).

Figure 1.

Figure 1

Open in a new tab

Placebo-corrected LDL cholesterol change from baseline at day 510 and corresponding time-adjusted change from baseline after day 90 and up to day 540 by baseline eGFR (ITT population). (A) Percentage change in LDL cholesterol and (B) absolute change in LDL cholesterol. Note: the percentage and absolute changes in LDL cholesterol from baseline to day 510 were analyzed using an ANCOVA model with a multiple imputation washout model for missing data. The time-adjusted percentage and absolute changes in LDL cholesterol from baseline after day 90 and up to day 540 was analyzed using a mixed-effects model for repeated measures with control-based pattern mixture model for missing data imputation. The displayed mean percentage (%) and absolute (mg/dl) changes over time are least squares mean values derived from mixed-effects model for repeated measures without imputation. All models were adjusted for baseline LDL cholesterol value and study and applied separately within each eGFR category. Treatment differences are presented for inclisiran − placebo. Patients were classified into four categories based on their baseline eGFR. These categories align with KDIGO GFR categories: ≥90 ml/min per 1.73 m2 (KDIGO GFR category G1); 60 to <90 ml/min per 1.73 m2 (KDIGO GFR category G2); 45 to <60 ml/min per 1.73 m2 (KDIGO GFR category G3A); and 15 to <45 ml/min per 1.73 m2 (KDIGO GFR category G3B–G4). None of the patients had GFR <15 ml/min per 1.73 m2, which aligns with KDIGO GFR category G5. Δ, treatment difference; ANCOVA, analysis of covariance; CI, confidence interval; ITT, intent-to-treat; KDIGO, Kidney Disease Improving Global Outcomes.

Key Secondary End Points

The mean absolute change in LDL cholesterol from baseline at day 510 and the corresponding time-adjusted absolute change from baseline after day 90 up to day 540 were significantly greater with inclisiran versus placebo (P < 0.001), irrespective of baseline eGFR category (Figure 1B). In patients with eGFR ≥90, 60 to <90, 45 to <60, and 15 to <45 ml/min per 1.73 m2, the mean (95% CI) placebo-corrected absolute changes in LDL cholesterol (mg/dl) from baseline at day 510 were −53.7 (−57.5 to −50.0), −52.8 (−56.1 to −49.5), −55.7 (−62.9 to −48.4), and−46.6 (−59.1 to −34.2), respectively (each P < 0.001, Figure 1B; treatment by eGFR subgroup interaction effect P = 0.55; Supplemental Table 1). The corresponding mean (95% CI) time-adjusted placebo-corrected absolute changes in LDL cholesterol (mg/dl) from baseline after day 90 and up to day 540 was −52.0 (−54.7 to −49.2), −53.0 (−55.5 to −50.5), −56.3 (−61.7 to −50.9), and −50.5 (−58.5 to −42.6) mg/dl, respectively (each P < 0.001, Figure 1B; treatment by eGFR subgroup interaction effect P = 0.71; Supplemental Table 1).

Other Secondary End Points

The placebo-corrected percentage changes in total cholesterol, ApoB, non–HDL cholesterol, triglycerides, Lp(a), and remnant cholesterol from baseline to day 510 (day 540 for Lp[a]) were significantly greater with inclisiran than with placebo, regardless of eGFR category. The placebo-corrected absolute changes correlated with their respective percentage changes (Table 2). The interactions of treatment and eGFR subgroups were not statistically significant for most atherogenic lipids with the exception of triglycerides and remnant cholesterol (Supplemental Table 1).

Table 2.

Placebo-corrected percentage and absolute changes in other atherogenic lipids at day 510

Parameters Percentage Change, %, LS Mean (95% CI)a Absolute Change, mg/dl, LS Mean (95% CI)a
eGFR ≥90 ml/min per 1.73 m2 eGFR 60 to <90 ml/min per 1.73 m2 eGFR 45 to <60 ml/min per 1.73 m2 eGFR 15 to <45 ml/min per 1.73 m2 eGFR ≥90 ml/min per 1.73 m2 eGFR 60 to <90 ml/min per 1.73 m2 eGFR 45 to <60 ml/min per 1.73 m2 eGFR 15 to <45 ml/min per 1.73 m2
Total cholesterol −31.9 (−34.0 to −29.9) −32.2 (−34.2 to −30.3) −36.2 (−40.6 to −31.8) −32.7 (−41.4 to −24.1) −59.4 (−63.5 to −55.3) −59.3 (−62.9 to −55.7) −66.3 (−74.2 to −58.4) −62.7 (−77.8 to −47.6)
ApoB −40.5 (−42.8 to −38.3) −42.5 (−44.7 to −40.3) −44.9 (−49.9 to −39.9) −42.1 (−51.1 to −33.0) −39.7 (−42.0 to −37.4) −40.1 (−42.3 to −38.0) −42.3 (−47.0 to −37.7) −40.3 (−48.8 to −31.7)
Non–HDL cholesterol −45.1 (−47.8 to −42.3) −46.8 (−49.4 to −44.2) −49.8 (−55.8 to −43.8) −47.3 (−58.4 to −36.2) −61.8 (−65.9 to −57.8) −62.4 (−65.9 to −58.9) −66.4 (−74.0 to −58.9) −65.7 (−80.7 to −50.7)
Triglycerides −6.7 (−11.2 to −2.3) −11.6 (−15.6 to −7.6) −7.6 (−15.6 to 0.5) −30.3 (−48.1 to −12.6) −9.1 (−15.9 to −2.2) −18.1 (−24.6 to −11.5) −10.3 (−23.5 to 2.8) −39.5 (−73.0 to −6.0)
Lp(a),a nmol/L −20.3 (−22.9 to −17.7) −20.0 (−22.4 to −17.6) −28.6 (−37.6 to −19.7) −22.3 (−33.2 to −11.5) −8.2 (−9.7 to −6.8) −8.2 (−9.6 to −6.9) −12.0 (−15.4 to −8.7) −6.4 (−12.4 to −0.5)
Remnant cholesterol −16.5 (−20.5 to −12.4) −20.7 (−24.5 to −16.9) −17.8 (−25.6 to −10.0) −40.9 (−59.8 to −22.0) −4.9 (−6.1 to −3.7) −6.3 (−7.5 to −5.1) −5.4 (−7.8 to −3.0) −11.9 (−18.6 to −5.2)
Open in a new tab

Patients were classified into four categories based on their baseline eGFR. These categories align with Kidney Disease Improving Global Outcomes (KDIGO) GFR categories: ≥90 ml/min per 1.73 m2 (KDIGO GFR category G1); 60 to <90 ml/min per 1.73 m2 (KDIGO GFR category G2); 45 to <60 ml/min per 1.73 m2 (KDIGO GFR category G3A); and 15 to <45 ml/min per 1.73 m2 (KDIGO GFR category G3B–G4). None of the patients had GFR <15 ml/min per 1.73 m2, which aligns with KDIGO GFR category G5. ApoB, apolipoprotein B; CI, confidence interval; Lp(a), lipoprotein(a); LS, least squares.

a

The percentage and absolute changes (least square mean [95% confidence interval]) in other atherogenic lipids except lipoprotein(a) from baseline to day 510 were analyzed using mixed-effects model for repeated measures without imputation, including fixed effects for treatment, visit, study, and treatment-by-visit interaction, and baseline value as a covariate. For lipoprotein(a), median (95% confidence interval) values at day 540 was provided from quantile regression models without imputation, with treatment and study as factors and baseline value as a covariate. All models were applied separately within each eGFR category. Treatment differences are presented for inclisiran − placebo.

Exploratory End Points

The proportions of patients experiencing reduction in eGFR by ≥30%, ≥40%, and ≥50% were not significantly different between inclisiran and placebo groups, regardless of eGFR category (P > 0.05 for all; Supplemental Table 2). The percentage change in eGFR over time showed no effect of inclisiran compared with placebo (Supplemental Figure 1).

Safety

The safety population comprised 3655 patients classified by baseline eGFR. Inclisiran was well tolerated, with a safety profile similar to placebo, except for a higher proportion of patients with clinically relevant mild or moderate TEAEs at the injection site with inclisiran, regardless of baseline eGFR categories (Table 3 and Supplemental Tables 2 and 3). The most common TEAEs (≥5%) in both treatment arms were diabetes mellitus, nasopharyngitis, upper respiratory tract infection, and hypertension. TEAEs and treatment-emergent serious adverse events were more frequent in patients with low eGFR at baseline (Table 3). Frequent TEAEs with inclisiran were generally similar to placebo and consistent across the eGFR categories. Clinically relevant laboratory abnormalities were low and similar for inclisiran and placebo, independent of baseline eGFR category (Supplemental Table 3).

Table 3.

Safety summary by baseline eGFR categories (safety population)

Parameter eGFR ≥90 ml/min per 1.73 m2 eGFR 60 to <90 ml/min per 1.73 m2 eGFR 45 to <60 ml/min per 1.73 m2 eGFR 15 to <45 ml/min per 1.73 m2
Inclisiran (n=820), n (%) Placebo (n=787), n (%) RR (95% CI) Inclisiran (n=793), n (%) Placebo (n=814), n (%) RR (95% CI) Inclisiran (n=154), n (%) Placebo (n=145), n (%) RR (95% CI) Inclisiran (n=66), n (%) Placebo (n=76), n (%) RR (95% CI)
Patients with ≥1 TEAE 630 (77) 574 (73) 1.1 (1.0 to 1.1) 614 (77) 647 (79) 1.0 (0.9 to 1.0) 131 (85) 127 (88) 1.0 (0.9 to 1.1) 55 (83) 61 (80) 1.0 (0.9 to 1.2)
Patients with ≥1 TESAE 146 (18) 152 (19) 0.9 (0.8 to 1.1) 159 (20) 193 (24) 0.8 (0.7 to 1.0) 46 (30) 40 (28) 1.1 (0.8 to 1.5) 23 (35) 34 (45) 0.8 (0.5 to 1.2)
Patients with ≥1 event leading to study discontinuation 18 (2) 14 (2) 1.2 (0.6 to 2.5) 24 (3) 11 (1) 2.2 (1.1 to 4.5) 2 (1) 6 (4) 0.3 (0.1 to 1.5) 1 (2) 4 (5) 0.3 (0.0 to 2.5)
Patients with ≥1 clinically relevant TEAE at the injection site 17 (2) 1 (0.1) 16.3 (2.2 to 122.3) 19 (2) 2 (0.2) 9.8 (2.3 to 41.7) 1 (0.6) 0 NA 1 (2) 1 (1) 1.2 (0.1 to 18.1)
 Mild 11 (1) 1 (0.1) 10.6 (1.4 to 81.6) 12 (2) 1 (0.1) 12.3 (1.6 to 94.5) 0 0 NA 0 1 (1) NA
 Moderate 6 (0.7) 0 NA 7 (0.9) 1 (0.1) 7.2 (0.9 to 58.3) 1 (0.6) 0 NA 1 (2) 0 NA
 Severe 0 0 NA 0 0 NA 0 0 NA 0 0 NA
Open in a new tab

Patients were classified into four categories based on their baseline eGFR ≥90 ml/min per 1.73 m2 (Kidney Disease Improving Global Outcomes [KDIGO] GFR category G1); 60 to <90 ml/min per 1.73 m2 (KDIGO GFR category G2); 45 to <60 ml/min per 1.73 m2 (KDIGO GFR category G3A); and 15 to <45 ml/min per 1.73 m2 (KDIGO GFR category G3B–G4). None of the patients had GFR <15 ml/min per 1.73 m2, which aligns with KDIGO GFR category G5. Risk ratio of inclisiran/placebo within each baseline eGFR subgroup. CI, confidence interval; NA, not available; RR, risk ratio; TEAE, treatment-emergent adverse event; TESAE, treatment-emergent serious adverse event.

Discussion

This post hoc pooled analysis of 3660 patients from the pivotal phase 3 ORION-9, ORION-10, and ORION-11 trials demonstrated that inclisiran, compared with placebo, reduced LDL cholesterol significantly and consistently with a favorable safety profile, across categories of kidney function spanning CKD stages 1-4. Inclisiran, administered twice yearly (after initial and 3-month doses) for up to 18 months provided sustained and effective LDL cholesterol reductions after the second dose until the end of the study (placebo-corrected time-adjusted percentage change) of 48.4%, 51.8%, 55.6%, and 50.4% among patients with eGFR ≥90, 60 to <90, 45 to <60, and 15 to <45 ml/min per 1.73 m2, respectively. These findings align with the overall pooled population results, where the time-adjusted percentage reduction in LDL cholesterol was 50.5%.16

Compared with individuals with normal kidney function, patients with CKD typically exhibit distinct differences in their lipid profiles, including elevated triglycerides, increased levels of Lp(a), and reduced HDL cholesterol.19–21 In individuals with impaired kidney function, triglycerides, Lp(a), and non–HDL cholesterol may correlate with cardiovascular risk.4,22 Our analysis showed significant reductions in each of these atherogenic lipoproteins with inclisiran across all eGFR categories.

Non–HDL cholesterol, a comprehensive measure of cholesterol content in ApoB-containing particles, was reduced by >45% with inclisiran. ApoB, which represents the total number of atherogenic particles, was reduced by >42% with inclisiran versus placebo. Moreover, remnant cholesterol, which is a proatherogenic risk factor in individuals with CKD,8 was reduced by >16% (up to >40% in eGFR 15 to <45 ml/min per 1.73 m2 group) with inclisiran versus placebo. These changes are important in a population where cardiovascular risk reduction can be challenging.

Assignment to inclisiran versus placebo did not affect the trajectory of kidney function, with no difference in the numbers of patients with reductions in eGFR ≥30%, ≥40%, or ≥50% (Supplemental Table 4).

A prior analysis showed transient greater plasma inclisiran concentration in patients with kidney dysfunction versus patients with normal kidney function,17 but in the current analysis, CKD severity did not affect the reduction of LDL cholesterol with inclisiran. A meta-analysis found that high-intensity statins significantly reduced the decline in eGFR compared with placebo, usual care or no-statin treatment. However, this effect was not observed with moderate-intensity or low-intensity statins.23 Nonetheless, the KDIGO guidelines endorse moderate-intensity or high-intensity statin in patients with CKD.6 Analyses of the Further Cardiovascular Outcomes Research With PCSK9 Inhibition in Subjects With Elevated Risk and ODYSSEY OUTCOMES trials corroborate a lower usage of high-intensity statins in populations with advanced CKD,10,11 which aligns with the present study patients (Table 1 and Supplemental Table 5). Anti-PCSK9 monoclonal antibodies have shown effective LDL cholesterol reduction in combination with statin in hypercholesterolemia patients, regardless of impaired kidney function,4,10 similar to inclisiran results in patients with CKD.

Inclisiran was generally well tolerated regardless of CKD severity, with similar proportions of TEAEs and treatment-emergent serious adverse events reported between treatment arms and across eGFR subgroups. The safety profile was consistent with the overall pooled population.16 TEAEs at the injection site were more common with inclisiran but were mild to moderate, with none being severe. A pooled analysis of seven clinical trials with 3576 patients showed that long-term inclisiran treatment for up to 6 years was well tolerated without new safety findings.24 Furthermore, ORION-8 demonstrated a favorable long-term safety and tolerability profile with up to 6.8 years of inclisiran exposure.25

There are limitations to this pooled analysis. There were very few patients with severe form of the disease, with only 142 patients having a baseline eGFR 15 to <45 ml/min per 1.73 m2. Furthermore, there were only 14 patients with eGFR of 15 to <30 ml/min per 1.73 m2, and none had an eGFR <15 ml/min per 1.73 m2. Hence, estimates of efficacy, safety, and tolerability of inclisiran are imprecise in CKD stages 3B and 4 and unknown in CKD stage 5. Furthermore, data on urinary albumin-to-creatinine ratio or urinary protein-to-creatinine ratio were not collected in the original ORION-9, ORION-10, and ORION-11 studies and are therefore unavailable for this post hoc analysis. This limits our ability to evaluate kidney damage markers and their relationship to LDL cholesterol lowering. To ensure accurate kidney function classification despite this limitation, eGFR was calculated using the 2021 CKD Epidemiology Collaboration equation. In addition, cardiovascular outcome data were not captured in these trials, which restricts conclusions regarding long-term cardiorenal benefit. Ongoing placebo-controlled cardiovascular outcomes trials, including ORION-4,26 VICTORION-1 Prevent,27 and VICTORION-2 Prevent,28 will provide further insights into efficacy, safety, and tolerability of inclisiran in high-risk populations.

Inclisiran, administered twice-yearly (after initial and 3-month doses) with maximum-tolerated statins or other oral lipid-lowering therapies, provides sustained and effective LDL cholesterol lowering with favorable safety for a broad range of patients with atherosclerotic cardiovascular disease, including those with advanced CKD. However, given the limited sample size in advanced CKD stages, these findings should be interpreted with caution.

Acknowledgments

The authors thank all the investigators, trial site staff, and patient volunteers who participated in the trials. The authors thank Shreekant Sharma and Ritika Paul (Novartis Healthcare Pvt Ltd., India) for providing medical writing support and assistance, which was funded by Novartis Pharma AG, Basel, Switzerland, in accordance with Good Publication Practice guidelines (http://www.ismpp.org/gpp3), and Klaus Molle, PhD (Novartis Pharma AG), for critical review of the manuscript. The data in this article were presented in part at the American College of Cardiology 70th Annual Scientific Session, Atlanta, Georgia; May 15-17, 2021.

Footnotes

*

The list of nonauthor contributors is extensive and has been provided in the Supplemental Summary 1.

See related editorial, “Inclisiran in CKD: A Therapeutic Answer to a Persistent Treatment Gap,” on pages 1376–1378.

Contributor Information

Collaborators: John Homan, Traci Turner, Linda Hemphill, Chad Wadell, John Pullman, Robert Fishberg, Joshua Knowles, Seth Baum, Leslie Forgosh, Anthony Captain, Atoya Adams, Alexis Baass, Robert Dufour, Jean Bergeron, Daniel Gaudet, Lesley Burgess, Nyda Fourie, Soritha Coetzer, Mark Abelson, Elane Van Nieuwenhuizen, Iftikhar Ebrahim, Maria Pretorius, Dirkie Jansen van Rensburg, Frederick Raal, Gerben Mol, Eric Stroes, Gerard Hovingh, Frank Visseren, Henricus van Kesteren, Paul van Bergen, Luis Masana, Fernando Civeira Murillo, Jose Luis Diaz, Francisco Fuentes Jimenez, Daniel Zambon Rados, Xavier Pinto Sala, Erik Schmidt, Lars Juel Andersen, Pernille Corell, Morten Bottcher, Kristian Korsgaard Thomsen, Ib Christian Klausen, Jens Dahlgaard Hove, Åke Olsson, Stefano Romeo, Mats Eriksson, Vera Adamkova, Lucie Solcova, Jan Zeman, James Kopp, Michael Adams, Linda Murray, Charles Michieli, Jeffery DeGrauw, William Ellison, Leslie Tharenos, Stephen Halpern, Michele Reynolds, Michael Noss, Gary Korff, Stephen Canowitz, Randall Severance, Douglas Schumacher, William Kirby, Jeffrey Klein, Rickie Conrady, Tami Wahlin, Robert Lending, Michael Harper, Jennifer Kay, Mehrdad Ariani, John Scott, Ahmed Arif, Mohammad Shoukfeh, Bogdan Gheorghiu, Matthew Teltser, Timothy Crater, David Ramstad, Sara Llerena, Anwar Ahmad, Krishnamoorthy Vivekananthan, Jeffrey Wayne, Neil Fraser, Dennis Levinson, Jeffrey Geohas, Barry McLean, Sady Alpizar, John Evans, Robert Buynak, Michael Seep, Sashi Makam, Ramachandra Patak, Matthew Budoff, Ahmad Aslam, Stephen Jones, Seth Baum, Alvaro Murcia, Hessam Aazami, Jalal Abbas, Jeffrey Anderson, David Bouda, Robert Busch, Robert Falcone, Leslie Forgosh, Randal Jacks, John LeDoux, Steven Lupovitch, Sharan Mahal, Joe Pouzar, Priyavadan Shah, Thomas Stuckey, Suhail Zavaro, Jose Cardona, Mahesh Changlani, Winston Gandy, Bernard Garcia, William Jennings, Norman Lepor, James Lovell, Ronald Mayfield, Howard Rubenstein, Gerald Shockey, Stuart Stoller, Joseph Szcytowski, Antonio Terrelonge, Jorge Venereo, Phillip Toth, Laura Akright, Mahesh Amin, Nabil Andrawis, Anthony Captain, Anurekha Chadha, Ankur Doshi, Jonathan Fialkow, Ferris George, Timberly Gilford, Ashwini Gore, Tariq Haddad, Aaron Hartman, Sandeep Khurana, Michael Koren, Srikanth Malempati, Joaquin Martinez-Arraras, Mark Napoli, Brien Peirpont, Drew Purdy, Erich Schramm, Alfred Tan, Charles Treasure, Kishor Vora, Jonathan Waltman, Andrew Waxler, James Wild, Jonathan Bornfreund, Atoya Adams, Saadat Ansari, Sabrina Benjamin, Kenneth Blaze, Cristian Breton, Thomas Carlson, Evelyne Davidson, William Davila, Philip Diller, Frank Eder, Mahfouz El-Shahawy, Roger Estevez, Neil Farris, David Henderson, James Holler, Mumtazuddin Zubair Jafar, Curtis Jantzi, Vicki Kalen, Daniel Koontz, Padma Mangu, Brock Merritt, Alan Miller, Nidal Morrar, Edward Pereira, Jorge Posada, William Randall, Lilia Rodriguez Ables, Saihari Sadanandan, Satinder Saini, Bruce Seaton, Charles Sharpe, Pamela Stearns, Sanjay Vora, Michelle Welch, Mohamed El-Shahawy, Robert Lipetz, Traci Turner, Jorge Navas, George Kichura, Phyllis Marx, Jan Malecha, Antonin Dufka, Katrin Arelin, Suresh Yadav, Christel Contzen, Liana Vismane, Manuela Licka, Károly Nagy, Csaba Hajdú, Karoly Wittmann, Csilla Nemeti, Malgorzata Duszynska, Anna Sidorowicz-Bialynicka, Piotr Rozpondek, Malgorzata Jagielska-Plata, Jolanta Krzykowska, Dorota Knychas, Elzbieta Blach, Robert Glowka, Jerzy Pregowski, Donald Drozdz, Renata Bijata-Bronisz, Danuta Wronska, Rafal Sztembis, Jaroslaw Trebacz, Boguslaw Derlaga, Marek Styczkiewicz, Bozena Zieba, Teresa Rusicka, Janusz Spyra, Lesley Burgess, Nyda Fourie, Dorothea Urbach, Thomas Coetzer, Elane Nieuwenhuizen, Landman Lombard, Yacoob Vahed, Suzanne Blignaut, Inna Sorokina, Oleksandra Donets, Halyna Myshanych, Oleksandr Kovalov, Anna Kulyk, Myroslava Vayda, Orest Abrahamovych, Vira Tseluyko, Roman Stets, Imrozia Arif, Nicoletta Sulli, Devina Weeraratne, Yieng Huong, Madhu Venkate Gowda, Christina Kyriakidou, Hawys Thomas, Nicoletta Sulli, Adrian Renouf Adrian, Mark Blagden, Rehan Symonds, Mahadev Ramjee, Timothy Hall, Ian Collyer, Philip Stratford-Smith, Paul Jackson, Grainne Breen, Keith Richardson, Stephen Tomkinson, Simon De Vial, Samina Ashraf, Peter Wilson, and Damian Allcock

Disclosures

Disclosure forms, as provided by each author, are available with the online version of the article at http://links.lww.com/JSN/F677.

Author Contributions

Conceptualization: Lorena Garcia Conde, Jackie Han, Wolfgang Koenig, Ulf Landmesser, Lawrence A. Leiter, Frederick J. Raal, Kausik K. Ray, Gregory G. Schwartz, R. Scott Wright.

Data curation: Lorena Garcia Conde, Jackie Han, Wolfgang Koenig, Ulf Landmesser, Lawrence A. Leiter, Frederick J. Raal, Kausik K. Ray, Gregory G. Schwartz, R. Scott Wright.

Formal analysis: Jackie Han.

Funding acquisition: Wolfgang Koenig, Ulf Landmesser, Lawrence A. Leiter, Frederick J. Raal, Kausik K. Ray, Gregory G. Schwartz, R. Scott Wright.

Investigation: Lorena Garcia Conde, Jackie Han, Wolfgang Koenig, Ulf Landmesser, Lawrence A. Leiter, Frederick J. Raal, Kausik K. Ray, Gregory G. Schwartz, R. Scott Wright.

Methodology: Lorena Garcia Conde, Jackie Han, Wolfgang Koenig, Ulf Landmesser, Lawrence A. Leiter, Frederick J. Raal, Kausik K. Ray, Gregory G. Schwartz, R. Scott Wright.

Project administration: Lorena Garcia Conde, Jackie Han.

Resources: Lorena Garcia Conde, Jackie Han.

Software: Lorena Garcia Conde, Jackie Han.

Supervision: Lorena Garcia Conde, Jackie Han, Wolfgang Koenig, Ulf Landmesser, Lawrence A. Leiter, Frederick J. Raal, Kausik K. Ray, Gregory G. Schwartz, R. Scott Wright.

Validation: Lorena Garcia Conde, Jackie Han.

Writing – original draft: Ulf Landmesser.

Writing – review & editing: Lorena Garcia Conde, Jackie Han, Wolfgang Koenig, Ulf Landmesser, Lawrence A. Leiter, Frederick J. Raal, Kausik K. Ray, Gregory G. Schwartz, R. Scott Wright.

Funding

This work was supported by Novartis Pharma AG, Basel, Switzerland.

Declarative Statements

This study includes clinical experimentation and received Institutional Review Board or Ethics Committee approval. All patients provided written informed consent. This study includes clinical experimentation and complies with the Declaration of Helsinki.

Data Availability Statements

Data Type: Clinical Trial Data. Reason for Restricted Access: Requests for patient-level data and supporting clinical documents will be considered by an independent review panel based on scientific merit. All data provided are anonymized to respect the privacy of patients who have participated in the trial in line with applicable laws and regulations. This availability of these trial data is according to the criteria and process described on www.clinicalstudydatarequest.com.

Supplemental Material

This article contains the following supplemental material online at http://links.lww.com/JSN/F678.

Supplemental Summary 1. List of investigators and study sites.

Supplemental Appendix 1. Details of multiple imputation methods and missing data.

Supplemental Table 1. Treatment-by-eGFR subgroup interaction effects (ITT population).

Supplemental Table 2. Frequent TEAEs (≥5% in any treatment group) by baseline eGFR (safety population).

Supplemental Table 3. Clinically relevant laboratory measurements by baseline eGFR (safety population).

Supplemental Table 4. Proportion of patients achieving exploratory eGFR thresholds at any visit by baseline eGFR (ITT population).

Supplemental Table 5. Statin use at baseline with dose by baseline eGFR (ITT population).

Supplemental Figure 1. Percent change in eGFR from baseline (ITT population).

References

  • 1.Grundy SM Stone NJ Bailey AL, et al. 2018 AHA/ACC/AACVPR/AAPA/ABC/ACPM/ADA/AGS/APhA/ASPC/NLA/PCNA guideline on the management of blood cholesterol: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. Circulation. 2019;139(25):e1082–e1143. doi: 10.1161/CIR.0000000000000625 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 2.Jankowski J, Floege J, Fliser D, Böhm M, Marx N. Cardiovascular disease in chronic kidney disease. Circulation. 2021;143(11):1157–1172. doi: 10.1161/CIRCULATIONAHA.120.050686 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 3.Wright RS Reeder GS Herzog CA, et al. Acute myocardial infarction and renal dysfunction: a high-risk combination. Ann Intern Med. 2002;137(7):563–570. doi: 10.7326/0003-4819-137-7-200210010-00007 [DOI] [PubMed] [Google Scholar]
  • 4.Toth PP Dwyer JP Cannon CP, et al. Efficacy and safety of lipid lowering by alirocumab in chronic kidney disease. Kidney Int. 2018;93(6):1397–1408. doi: 10.1016/j.kint.2017.12.011 [DOI] [PubMed] [Google Scholar]
  • 5.Cannon CP Blazing MA Giugliano RP, et al. Ezetimibe added to statin therapy after acute coronary syndromes. N Engl J Med. 2015;372(25):2387–2397. doi: 10.1056/nejmoa1410489 [DOI] [PubMed] [Google Scholar]
  • 6.Levin A Ahmed SB Carrero JJ, et al. Executive summary of the KDIGO 2024 clinical practice guideline for the evaluation and management of chronic kidney disease: known knowns and known unknowns. Kidney Int. 2024;105(4):684–701. doi: 10.1016/j.kint.2023.10.016 [DOI] [PubMed] [Google Scholar]
  • 7.Visseren FLJ Mach F Smulders YM, et al. 2021 ESC guidelines on cardiovascular disease prevention in clinical practice: developed by the task force for cardiovascular disease prevention in clinical practice with representatives of the European Society of Cardiology and 12 medical societies with the special contribution of the European Association of Preventive Cardiology (EAPC). Eur Heart J. 2021;42(34):3227–3337. doi: 10.1093/eurheartj/ehab484 [DOI] [PubMed] [Google Scholar]
  • 8.Pontremoli R Bellizzi V Bianchi S, et al. Management of dyslipidaemia in patients with chronic kidney disease: a position paper endorsed by the Italian Society of Nephrology. J Nephrol. 2020;33(3):417–430. doi: 10.1007/s40620-020-00707-2 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 9.Bitzur R, Cohen H, Kamari Y, Harats D. Intolerance to statins: mechanisms and management. Diabetes Care. 2013;36(suppl 2):S325–S330. doi: 10.2337/dcS13-2038 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 10.Charytan DM Sabatine MS Pedersen TR, et al. Efficacy and safety of evolocumab in chronic kidney disease in the FOURIER trial. J Am Coll Cardiol. 2019;73(23):2961–2970. doi: 10.1016/j.jacc.2019.03.513 [DOI] [PubMed] [Google Scholar]
  • 11.Tuñón J Steg PG Bhatt DL, et al. Effect of alirocumab on major adverse cardiovascular events according to renal function in patients with a recent acute coronary syndrome: prespecified analysis from the ODYSSEY OUTCOMES randomized clinical trial. Eur Heart J. 2020;41(42):4114–4123. doi: 10.1093/eurheartj/ehaa498 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 12.Stanifer JW Charytan DM White J, et al. Benefit of ezetimibe added to simvastatin in reduced kidney function. J Am Soc Nephrol. 2017;28(10):3034–3043. doi: 10.1681/ASN.2016090957 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 13.Nishikido T. Clinical potential of inclisiran for patients with a high risk of atherosclerotic cardiovascular disease. Cardiovasc Diabetol. 2023;22(1):20. doi: 10.1186/s12933-023-01752-4 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 14.Raal FJ Kallend D Ray KK, et al. Inclisiran for the treatment of heterozygous familial hypercholesterolemia. New Engl J Med. 2020;382(16):1520–1530. doi: 10.1056/NEJMoa1913805 [DOI] [PubMed] [Google Scholar]
  • 15.Ray KK Wright RS Kallend D, et al. Two phase 3 trials of inclisiran in patients with elevated LDL cholesterol. New Engl J Med. 2020;382(16):1507–1519. doi: 10.1056/NEJMoa1912387 [DOI] [PubMed] [Google Scholar]
  • 16.Wright RS Ray KK Raal FJ, et al. Pooled patient-level analysis of inclisiran trials in patients with familial hypercholesterolemia or atherosclerosis. J Am Coll Cardiol. 2021;77(9):1182–1193. doi: 10.1016/j.jacc.2020.12.058 [DOI] [PubMed] [Google Scholar]
  • 17.Wright RS Collins MG Stoekenbroek RM, et al. Effects of renal impairment on the pharmacokinetics, efficacy, and safety of inclisiran: an analysis of the ORION-7 and ORION-1 studies. Mayo Clin Proc. 2020;95(1):77–89. doi: 10.1016/j.mayocp.2019.08.021 [DOI] [PubMed] [Google Scholar]
  • 18.Inker LA Eneanya ND Coresh J, et al. New Creatinine- and cystatin C–based equations to estimate GFR without race. New Engl J Med. 2021;385(19):1737–1749. doi: 10.1056/NEJMoa2102953 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 19.Elsadany M, Yang Y, Gupta S, Mattana J. Emerging therapies for cardiovascular disease: PCSK9 inhibitors and their potential role in patients with CKD. Kidney News. 2020;12(6):18. https://www.kidneynews.org/view/journals/kidney-news/12/6/article-p18_11.xml. [Google Scholar]
  • 20.Mach F Baigent C Catapano AL, et al. 2019 ESC/EAS guidelines for the management of dyslipidaemias: lipid modification to reduce cardiovascular risk: the task force for the management of dyslipidaemias of the European Society of Cardiology (ESC) and European Atherosclerosis Society (EAS). Eur Heart J. 2019;41(1):111–188. doi: 10.1093/eurheartj/ehz455 [DOI] [PubMed] [Google Scholar]
  • 21.Hopewell JC, Haynes R, Baigent C. The role of lipoprotein (a) in chronic kidney disease. J Lipid Res. 2018;59(4):577–585. doi: 10.1194/jlr.R083626 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 22.Harper CR, Jacobson TA. Managing dyslipidemia in chronic kidney disease. J Am Coll Cardiol. 2008;51(25):2375–2384. doi: 10.1016/j.jacc.2008.03.025 [DOI] [PubMed] [Google Scholar]
  • 23.Sanguankeo A, Upala S, Cheungpasitporn W, Ungprasert P, Knight EL. Effects of statins on renal outcome in chronic kidney disease patients: a systematic review and meta-analysis. PLoS One. 2015;10(7):e0132970. doi: 10.1371/journal.pone.0132970 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 24.Wright RS Koenig W Landmesser U, et al. Safety and tolerability of inclisiran for treatment of hypercholesterolemia in 7 clinical trials. J Am Coll Cardiol. 2023;82(24):2251–2261. doi: 10.1016/j.jacc.2023.10.007 [DOI] [PubMed] [Google Scholar]
  • 25.Wright RS Raal FJ Koenig W, et al. Inclisiran administration potently and durably lowers LDL-C over an extended-term follow-up: the ORION-8 trial. Cardiovasc Res. 2024;120(12):1400–1410. doi: 10.1093/cvr/cvae109 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 26.ClinicalTrials.gov. A Randomized Trial Assessing the Effects of Inclisiran on Clinical Outcomes Among People with Cardiovascular Disease (ORION-4). ClinicalTrials.gov Identifier: NCT03705234; 2023. Accessed November 29, 2023. https://clinicaltrials.gov/study/NCT03705234 [Google Scholar]
  • 27.ClinicalTrials.gov. A Study of Inclisiran to Prevent Cardiovascular Events in High-risk Primary Prevention Patients. ClinicalTrials.gov Identifier: NCT05739383; 2023. Accessed November 29, 2023. https://clinicaltrials.gov/study/NCT05739383 [Google Scholar]
  • 28.ClinicalTri.als.gov. A Study of Inclisiran to Prevent Cardiovascular (CV) Events in Participants with Established Cardiovascular Disease (VICTORION-2P). ClinicalTrials.gov Identifier: NCT05030428; 2023. Accessed November 29, 2023. https://clinicaltrials.gov/study/NCT05030428 [Google Scholar]

Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Data Availability Statement

Data Type: Clinical Trial Data. Reason for Restricted Access: Requests for patient-level data and supporting clinical documents will be considered by an independent review panel based on scientific merit. All data provided are anonymized to respect the privacy of patients who have participated in the trial in line with applicable laws and regulations. This availability of these trial data is according to the criteria and process described on www.clinicalstudydatarequest.com.

Articles from Journal of the American Society of Nephrology : JASN are provided here courtesy of American Society of Nephrology

RESOURCES