Background: Inclisiran is a small interfering RNA that prevents PCSK9 (proprotein convertase subtilisin/kexin type 9) synthesis, lowering low-density lipoprotein cholesterol. In ORION trials, efficacy and safety outcomes of inclisiran were similar among different renal impairment degrees, but no data are available in peritoneal dialysis (PD). Case Summary: We present the case of a 47-year-old woman with severe and recurrent cardiovascular disease and end-stage renal disease on PD. Following inclisiran injection, low-density lipoprotein cholesterol levels significantly decreased by 56.2% at 3 months. Reductions in apolipoprotein B, lipoprotein(a), and PCSK9 concentration were observed. No side effects were reported. Discussion: This report suggests, for the first time, that inclisiran may represent a potential treatment option for lipid control in patients undergoing PD, with results comparable to those reported in clinical trials and a good tolerability profile. Take-Home Message: Inclisiran is a potential lipid-lowering therapy in patients on peritoneal dialysis

Ferri N.

Giachetti G.

Lupo M. G.

Molinaroli E.

Orlandi E.

Rinaldi E.

Sani E.

Zoppini G.

English

Archivio istituzionale della ricerca - Università di Padova

J A C C : C A S E R E P O R T S V O L . 3 0 , N O . 1 8 , 2 0 2 5ª 2 0 2 5 T H E A U T H O R S . P U B L I S H E D B Y E L S E V I E R O N B E H A L F O F T H E AM E R I C A NC O L L E G E O F C A R D I O L O G Y F OU N D A T I O N . T H I S I S A N O P E N A C C E S S A R T I C L E U N D E RT H E C C B Y - N C - N D L I C E N S E ( h t t p : / / c r e a t i v e c o mm o n s . o r g / l i c e n s e s / b y - n c - n d / 4 . 0 / ) .CARDIOMETABOLICCLINICAL CASETreatment With Inclisiran DuringPeritoneal DialysisElena Sani, MD,a Elisabetta Rinaldi, MD, PHD,a Maria Giovanna Lupo, MSC, PHD,b Elena Orlandi, MD,aElisa Molinaroli, MD,a Gabriele Giachetti, MD,a Nicola Ferri, PHD,b Giacomo Zoppini, MD, PHDaABSTRACTISSFroMeThinsvisMaBACKGROUND Inclisiran is a small interfering RNA that prevents PCSK9 (proprotein convertase subtilisin/kexin type 9)synthesis, lowering low-density lipoprotein cholesterol. In ORION trials, efficacy and safety outcomes of inclisiran weresimilar among different renal impairment degrees, but no data are available in peritoneal dialysis (PD).CASE SUMMARY We present the case of a 47-year-old woman with severe and recurrent cardiovascular disease andend-stage renal disease on PD. Following inclisiran injection, low-density lipoprotein cholesterol levels significantlydecreased by 56.2% at 3 months. Reductions in apolipoprotein B, lipoprotein(a), and PCSK9 concentration wereobserved. No side effects were reported.DISCUSSION This report suggests, for the first time, that inclisiran may represent a potential treatment option for lipidcontrol in patients undergoing PD, with results comparable to those reported in clinical trials and a good tolerabilityprofile.TAKE-HOMEMESSAGE Inclisiran is a potential lipid-lowering therapy in patients on peritoneal dialysis. (JACCCaseRep.2025;30:103897) © 2025 The Authors. Published by Elsevier on behalf of the American College of Cardiology Foundation.This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).TAKE-HOME MESSAGES Patients on peritoneal dialysis exhibit aunique atherogenic lipid profile and faceunmet needs in the management ofdyslipidemia. Inclisiran is a small interfering RNA targetingPCSK9 that could represent a potentialtreatment option for lipid control in patientson peritoneal dialysis.HISTORY OF PRESENTATIONA 47-year-old woman was referred by her nephrolo-gist to the metabolism clinic to discuss lipidmanagement.PAST MEDICAL HISTORYThe patient has a known diagnosis of nonfamilialmixed dyslipidemia and elevated lipoprotein(a)[Lp(a)], complicated by severe and recurrent cardio-vascular disease (CVD). Cardiovascular historyincluded acute myocardial infarction with cardiacarrest at 35 years of age treated with percutaneousN 2666-0849m the aDivision of Endocrinology, Diabetes and Metabolism, Universitydicine, University of Padova, Padova, Italy.e authors attest they are in compliance with human studies committetitutions and Food and Drug Administration guidelines, including patienit the Author Center.nuscript received December 9, 2024; revised manuscript received Februatransluminal angioplasty on left anterior descendingartery. She further underwent quadruple coronaryartery bypass grafting surgery 10 years later forhttps://doi.org/10.1016/j.jaccas.2025.103897of Verona, Verona, Italy; and the bDepartment ofes and animal welfare regulations of the authors’t consent where appropriate. For more information,ry 21, 2025, accepted March 6, 2025.ABBR EV I A T I ON SAND ACRONYMSapo B = apolipoprotein BCKD = chronic kidney diseaseCVD = cardiovascular diseaseHD = hemodialysisLDL-C = low-densitylipoprotein cholesterolLDL-R = low-densitylipoprotein receptorLLT = lipid-lowering therapyLp(a) = lipoprotein(a)PCSK9 = proproteinconvertase subtilisin/kexintype 9PD = peritoneal dialysissiRNA = small interfering RNATC = total cholesterolTG = triglyceridesSani et al J A C C : C A S E R E P O R T S , V O L . 3 0 , N O . 1 8 , 2 0 2 5Treatment With Inclisiran During Peritoneal Dialysis J U L Y 9 , 2 0 2 5 : 1 0 3 8 9 72critical stenosis of left anterior descendingartery, right coronary artery, and first andsecond obtuse marginal arteries. Subse-quently, the following year she experiencedcoronary artery bypass grafting failureinvolving 3 grafts, which was treated withmedical therapy only. Renal history consistedin end-stage renal disease secondary to anepisode of acute renal failure 5 years beforepresentation, on a background of post-streptococcal glomerulonephritis. Since then,she has been on peritoneal dialysis (PD) andis currently a candidate for kidney trans-plantation. Additional cardiovascular riskfactors were a history of radiation and hor-monal therapy for left-sided breast cancer,arterial hypertension, impaired fastingglucose, overweight, and former smokingstatus.DIFFERENTIAL DIAGNOSISSecondary causes (hypothyroidism, nephrotic syn-drome, diabetes mellitus, cholestatic liver disease)and familial forms of dyslipidemia were excludedbased on clinical and biochemical evaluation, as wellas based on family and personal medical history.INVESTIGATIONWhen she came to our attention, lipid-loweringtherapy (LLT) included atorvastatin (80 mg), ezeti-mibe (10 mg), and omega-3 fatty acids (3 g). Duringthe last year, mean low-density lipoprotein choles-terol (LDL-C) concentration was 76 mg/dL, totalcholesterol (TC) was 149 mg/dL, triglycerides (TG)were 113 mg/dL, and Lp(a)was 102 mg/dL. At baseline,body weight was 71 kg, height was 1.60 m, and bodymass index was 27.7 kg/m2. A recent echocardiogramshowed a preserved left ventricular ejection fraction(57%), while carotid doppler ultrasonography docu-mented bilateral bulb plaques determining mild ste-nosis (15%).MANAGEMENTConsidering the very high cardiovascular risk of ourpatient and the nonachievement of LDL-C target(<55 mg/dL) despite maximal background LLT, wedecided to start inclisiran therapy, according toprescription criteria. We preferred inclisiran overalirocumab or evolocumab due to its convenientbiannual administration, to promote patient’sadherence and satisfaction with therapy. Inclisiran284 mg subcutaneous injection was administered by amedical doctor early in the morning after completionof nocturnal PD session. The subsequent PD sessionwas initiated at least 12 hours after inclisiran injec-tion. Venous blood samples for a complete biochem-ical evaluation were collected after an overnight fastat baseline and at 3-month follow-up, before eachinclisiran administration, with an additional timepoint after 1 month to assess early efficacy and safety.TC, high-density lipoprotein cholesterol, and TG weredetermined by colorimetric assay (Cobas 8000 c 702module, Roche Diagnostics). LDL-C was calculatedusing the Martin-Hopkins equation. Apolipoprotein B(apo B) and Lp(a) were determined by immuno-turbidimetry (Atellica CH, Siemens Healthineers).Plasma proprotein convertase subtilisin/kexin type 9(PCSK9) concentrations were measured by a com-mercial enzyme-linked immunosorbent assay kit(DPC900, R&D Systems) onto a microplate precoatedwith a monoclonal antibody specific for humanPCSK9.OUTCOME AND FOLLOW-UPFollowing a single inclisiran injection, LDL-C levelssignificantly decreased from 64 mg/dL to 43 mg/dL(32.8%) at 1 month and 28 mg/dL (56.2%) at3 months. As expected, concomitant reductions inapo B concentrations were observed at 1 month(18.8%) and at 3 months (42.0%). Lp(a) levels werealso reduced from 84 to 62 mg/dL (26.2%) at3 months, but no difference was noticed at 1 month(Figure 1). PCSK9 levels at baseline were more thandouble the typical reference values1 and markedlydropped by 64.6% at 1 month and 71.3% at 3 months(Figure 2). No significant changes in glucose, creati-nine, uric acid, liver enzyme, and creatine kinaselevels were observed (Table 1). Despite the shortfollow-up, no side effects or CVD events wereencountered. Background LLT was maintained duringfollow-up and the patient self-reported generalsatisfaction with inclisiran dosing regimen.DISCUSSIONDyslipidemia is a common metabolic complication ofchronic kidney disease (CKD). Dyslipidemia observedin PD patients tends to be more atherogenic than thatobserved in nondialysis CKD and hemodialysis (HD)populations, due to PD-specific mechanisms, likeperitoneal dialysate glucose uptake and protein los-ses. These patients show increased levels of TC, LDL-C, TG, apo B–containing lipoproteins such as verylow-density lipoproteins and intermediate-densitylipoproteins, and small dense low-density lipopro-tein and Lp(a), with low levels of high-densityFIGURE 1 Effect of Inclisiran on LipidsTotal cholesterol, low-density lipoprotein (LDL) cholesterol, apolipoprotein B (apo B), and lipoprotein(a) [Lp(a)] plasma levels at baseline and1 month and 3 months after first inclisiran administration.J A C C : C A S E R E P O R T S , V O L . 3 0 , N O . 1 8 , 2 0 2 5 Sani et alJ U L Y 9 , 2 0 2 5 : 1 0 3 8 9 7 Treatment With Inclisiran During Peritoneal Dialysis3lipoprotein.2 CVD is the major cause of morbidity andmortality in CKD, particularly end-stage renal dis-ease. Accordingly, international guidelines classifypatients with CKD as being at high (stage G3 CKD) orvery high risk (stage G4 or G5 CKD or on dialysis) ofCVD, in relation to their glomerular filtration rate.3 PDpatients have higher PCSK9 levels compared with HDFIGURE 2 Effect of Inclisiran on PCSK9 LevelsProprotein convertase subtilisin/kexin type 9 (PCSK9) plasma concentraadministration.and renal transplant patients as well as comparedwith general population.4 In this context, PCSK9might be a promising therapeutic target. Inclisiran is asmall interfering RNA that prevents the synthesis ofPCSK9, increasing the expression of low-densitylipoprotein receptors (LDL-Rs), thus lowering LDL-Clevels. In randomized controlled phase 3 trialstions at baseline and 1 month and 3 months after inclisiranTABLE 1 Glucose, Creatinine, Uric Acid, AST, ALT, GGT, and CKplasma levels at baseline and 1 Month and 3 Months After FirstInclisiran AdministrationBaseline 1-mo Follow-Up 3-mo Follow-UpGlucose, mg/dL 99 108 100Creatinine, mg/dL 14.2 14.3 13.1Uric acid, mg/dL 5.6 5.1 4.2AST, mg/dL 18 29 21ALT, mg/dL 36 38 23GGT, mg/dL 16 17 9CK, mg/dL 124 121 116ALT ¼ alanine aminotransferase; AST ¼ aspartate aminotransferase; CK ¼ creatinekinase; GGT ¼ gamma-glutamyltransferase.Sani et al J A C C : C A S E R E P O R T S , V O L . 3 0 , N O . 1 8 , 2 0 2 5Treatment With Inclisiran During Peritoneal Dialysis J U L Y 9 , 2 0 2 5 : 1 0 3 8 9 74(ORION-10 and ORION-11), inclisiran significantlyreduced LDL-C levels by approximately 50% vs pla-cebo in high-cardiovascular- risk populations.5 In arecent analysis, Wright et al6 evaluated the pharma-cokinetics of inclisiran in patients with normal renalfunction and mild, moderate, and severe renalimpairment from phase 1 and 2 trials (ORION-7 andORION-1) and revealed that exposure to inclisiranincreased with greater degrees of renal impairment.Nevertheless, inclisiran had a short plasma half-life(5-10 hours) and was undetectable in plasma after48 hours of administration, regardless of the degreeof renal impairment. Increased plasma exposure toinclisiran did not influence its pharmacodynamicprofile, as both the magnitude and the duration of theeffect on LDL-C and PCSK9 levels were similar inpatients with normal or altered renal function, withconsistent safety results. Collectively, these findingsunderscore the potential therapeutic value of incli-siran for individuals with hypercholesterolemia andrenal impairment without the necessity for doseadjustments.6 However, the effect of PD on inclisiranpharmacokinetics has not been studied, and no dataare available regarding the use of inclisiran inpatients undergoing PD.In our patient, we observed a significant reductionin LDL-C plasma concentrations at 3 months(56.2%), similar to that reported in the ORION-10and ORION-11 trials.5 Apo B levels concomitantlyreduced by 42.0% at 3 months, in line with whatnoticed in ORION-10 and ORION-11 trials.5 A remark-able reduction in Lp(a) plasma concentrations wasalso reported at 3 months (26.2%), comparable towhat observed in a prespecified analysis of theORION-11 trial.7 Moreover, PCSK9 levels markedlydropped by 64.6% at 1 month and 71.3% at 3 months,similarly to what was reported in the ORION-1 trial.6In our patient, however, baseline PCSK9 plasmaconcentrations were higher than those of ORION-1population, and generally more than double thetypical reference values.1 This finding is consistentwith what reported in a small cross-sectional studyin PD patients by Jin et al.4 Finally, our patientreached and maintained at 3 months both the pri-mary LDL-C target of <55 mg/dL and the secondaryapo B goals of <65 mg/dL, according to 2019 Euro-pean Society of Cardiology/European AtherosclerosisSociety guidelines for the management of dyslipi-demia.3 Our patient was already on a high dose ofstatin therapy, which could have influenced incli-siran efficacy. It is well known that statin and PCSK9inhibitor therapies have a synergistic effect due thestatin-induced expression of SREBP-2 (sterol-bindingregulatory protein-2), leading to increased tran-scription of LDL-R and PCSK9 messenger RNA.Inclisiran works by inhibiting PCSK9 synthesis,resulting in unopposed LDL-R expression at the cellsurface and consequently enhanced clearance ofcirculating LDL-C.8This case may be of particular interest becausethere are no studies reported in the literatureregarding the use of inclisiran in patients on renalreplacement therapy (PD or HD). To our knowledge,there are only few case reports published in literatureregarding the use of PCSK9 monoclonal antibodies(alirocumab and evolocumab) in patients undergoingPD.9,10 Inclisiran therapy may exert certain advan-tages compared with PCSK9 monoclonal antibodies inPD patients. For example, the infrequent dosing ofinclisiran may represent an attractive option toovercome the burden of polypharmacotherapy in thispopulation and to facilitate scheduling of injectionbetween dialysis sessions. Furthermore, thesevulnerable patients can be closely monitored by theirphysicians, as only health care professionals areauthorized to administer inclisiran during biannualfollow-up visits. This minimizes both the risks of pooradherence and improper drug administration by thepatients. However, the benefits of inclisiran on car-diovascular morbidity and mortality have not yetbeen established and data from the ORION-4 trial willprovide more insight.CONCLUSIONSOur case report suggests, for the first time, thatinclisiran may represent a potential lipid-loweringtreatment in patients undergoing PD, allowing ourJ A C C : C A S E R E P O R T S , V O L . 3 0 , N O . 1 8 , 2 0 2 5 Sani et alJ U L Y 9 , 2 0 2 5 : 1 0 3 8 9 7 Treatment With Inclisiran During Peritoneal Dialysis5patient to reach the recommended lipid target levelswith no associated complications over short-termfollow-up. Overall, inclisiran provides a novel prom-ising way to handle the huge burden of dyslipidemiaand to reduce cardiovascular risk in patients withCKD. Further investigation in larger studies withlonger follow-up are needed in patients on PD, notonly to assess efficacy and safety, but also in terms ofcardiovascular morbidity and mortality.FUNDING SUPPORT AND AUTHOR DISCLOSURESThe authors have reported that they have no relationships relevant tothe contents of this paper to disclose.ADDRESS FOR CORRESPONDENCE: Dr Elena Sani,Division of Endocrinology, Diabetes and Metabolism,University of Verona, Piazzale Stefani, 1, 37126 Ver-ona, Italy. E-mail: elena.sani@univr.it.RE F E RENCE S1. Ferri N, Ruscica M, Coggi D, et al. Sex-specificpredictors of PCSK9 levels in a European popula-tion: the IMPROVE study. Atherosclerosis.2020;309:39–46.2. Mikolasevic I, Zutelija M, Mavrinac V, Orlic L.Dyslipidemia in patients with chronic kidney dis-ease: etiology and management. Int J NephrolRenov Dis. 2017;10:35–45.3. Mach F, Baigent C, Catapano AL, et al. 2019ESC/EAS guidelines for the management ofdyslipidaemias: lipid modification to reducecardiovascular risk. Eur Heart J. 2020;41(1):111–188.4. Jin K, Park BS, Kim YW, Vaziri ND. PlasmaPCSK9 in nephrotic syndrome and in peritonealdialysis: a cross-sectional study. Am J Kidney Dis.2014;63(4):584–589.5. Ray KK, Wright RS, Kallend D, et al. Two phase 3trials of inclisiran in patients with elevated LDLcholesterol. N Engl J Med. 2020;382(16):1507–1519.6. Wright RS, Collins MG, Stoekenbroek RM, et al.Effects of renal impairment on the pharmacoki-netics, efficacy, and safety of inclisiran: an analysisof the ORION-7 and ORION-1 studies. Mayo ClinProc. 2020;95(1):77–89.7. Ray KK, Kallend D, Leiter LA, et al. Effect ofinclisiran on lipids in primary prevention: theORION-11 trial. Eur Heart J. 2022;43(48):5047–5057.8. Sahebkar A, Simental-Mendía LE, Guerrero-Romero F, Golledge J, Watts GF. Effect of statintherapy on plasma proprotein convertase subtilisinkexin 9 (PCSK9) concentrations: a systematic re-view and meta-analysis of clinical trials. DiabetesObes Metab. 2015;17(11):1042–1055.9. González Sanchidrián S, Labrador Gómez PJ,Aguilar Aguilar JC, Davin Carrero E, GallegoDomínguez S, Gómez-Martino Arroyo JR. Evolocu-mab for the treatment of heterozygous familialhypercholesterolemia in end-stage chronic kidneydisease anddialysis.Nefrologia. 2019;39(2):218–220.10. Rivas Oural A, Astudillo Cortés E, BandeFernández JJ, Rodríguez Suárez MDC, DíazCorte MDC. Treatment with alirocumab in a pa-tient on peritoneal dialysis with statin intolerance.Nefrologia. 2021;41(1):76–79.KEY WORDS atherosclerosis,dyslipidemias, hypercholesterolemia, lipidmetabolism disorders, secondary prevention

Treatment With Inclisiran During Peritoneal Dialysis

https://www.research.unipd.it/bitstream/11577/3557561/1/Sani%202025%20JACC%20Inclisiran%20and%20peritoneal%20dialysis.pdf

Treatment With Inclisiran During Peritoneal Dialysis

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