Safety and efficacy of inclisiran in South African patients at high cardiovascular risk: A subanalysis of the ORION phase III clinical trials
Open accessAbstract
Background. Inclisiran significantly reduced low-density lipoprotein cholesterol (LDL-C) in individuals with heterozygous familial hypercholesterolaemia, established atherosclerotic cardiovascular disease (ASCVD) or ASCVD risk equivalents (type 2 diabetes, familial hypercholesterolaemia or a 10-year risk of a cardiovascular event ≥20%) in the ORION phase III clinical trials. Infrequent dosing at days 1, 90, 270 and 450 resulted in a mean LDL-C reduction of ~50%. A total of 298 participants from South Africa (SA) were enrolled. Local data are needed to support the use of inclisiran in the SA population, potentially addressing an unmet need for additional LDL-C-lowering therapies. Objectives. To analyse the ORION phase III trial data to assess the efficacy and safety of inclisiran in SA participants. Methods. ORION-9, 10 and 11 were randomised, double-blind, phase III trials. Participants were receiving maximally tolerated statins with or without other lipid-lowering therapies (excluding protein convertase subtilisin/kexin type 9 (PCSK9) inhibitors). Participants were randomised 1:1 to inclisiran sodium 300 mg/284 mg (free acid) or placebo administered at days 1, 90, 270 and 450. The co-primary endpoints were the LDL-C percentage change from baseline to day 510 and the time-averaged percentage change in LDL-C from baseline after day 90 up to day 540. Key secondary endpoints included the absolute change in LDL-C from baseline to day 510, the time-averaged absolute change from baseline after day 90 up to day 540, and changes in other lipids and lipoproteins. Results. The mean age of the participants was 58.6 years (56% male). The mean LDL-C level at baseline was 3.6 mmol/L. At day 510, inclisiran reduced LDL-C levels by 54.2% compared with placebo (95% confidence interval (CI) –61.3 - –47.2; p<0.0001). The corresponding time-averaged reduction in LDL-C was 52.8% (95% CI –57.9 - –47.8; p<0.0001). Treatment-emergent adverse events at the injection site were more common with inclisiran compared with placebo (10.1% v. 0.7%); however, all were mild or moderate in nature and none were persistent. Conclusion. Inclisiran, given in addition to maximally tolerated standard lipid-lowering therapy, is effective and safe and results in robust reductions in LDL-C in SA patients at high cardiovascular risk.
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The reduction of LDL-C levels reached 54.2% in South African patients participating in ORION-10 and ORION-11.
“The reduction of LDL-C levels reached 54.2% in South African patients participating in ORION-10 and ORION-11 [41].”
From Inclisiran SiRNA therapy for durable LDL-C reduction: a systematic review and meta-analysis highlighting a breakthrough in long-term cardiovascular risk management (2026) · cites this paper as [41]
The Co-primary endpoints section reports a 54.2% LDL-C difference between the inclisiran and placebo groups in the South African cohort, not a 54.2% reduction from baseline in treated patients; that reduction was 46.5%. The Trial design and oversight section also says ORION-10 included only US sites, so South African participants could not have participated in ORION-10. Page numbers are unavailable in our copy. (LLM, conf=0.90)
Experimental — accuracy not yet measuredThe analysis of 11 RCTs for quantitative synthesis included more than 13,000 participants and showed inclisiran produces significant LDL-C reduction versus placebo treatment.
“The analysis of 11 RCTs for quantitative synthesis included more than 13,000 participants showed inclisiran produces significant LDL-C reduction versus placebo treatment [24, 25, 38–44, 46, 49].”
From Inclisiran SiRNA therapy for durable LDL-C reduction: a systematic review and meta-analysis highlighting a breakthrough in long-term cardiovascular risk management (2026) · cites this paper as [41]
The Co-primary endpoints section reports a significant LDL-C reduction with inclisiran versus placebo (p<0.0001). However, the Trial population section describes 298 South African participants, and the Trial design and oversight section identifies three ORION trials; this paper does not report a quantitative synthesis of 11 RCTs involving more than 13,000 participants. (LLM, conf=0.88)
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- Authors
- Carbohydrate and Lipid Metabolism Research Unit, F. O. H. S., Raal, F., Ableson, M., Vergelegen Mediclinic, S. W., Blignaut, S., Paarl Research Centre, P., Burgess, L., Tread Research, C. U., Coetzer, S., Accelerated Enrollment Solutions, H. C. R. C., Ebrahim, I., Netcare Unitas Hospital, C., Gibbon, A., Medical Affairs, N., Jansen van Rensburg, D., Park Medical Centre, E., Jaros, M., Summit Analytical, D., Lombard, L., Kuilsriver Netcare Hospital, C. T., van Nieuwenhuizen, E., Accelerated Enrollment Solutions, W. C. R. C., Pretorius, M., Tiervlei Trial Centre, C. T., van Tonder, A., Medical Affairs, N., Urbach, D., & Accelerated Enrollment Solutions, H. C. R. C.
- Affiliations
- University of the Witwatersrand (ZA)
- Stellenbosch University (ZA)
- Netcare Unitas Hospital (ZA)
- Novartis (Switzerland) (CH)
- ORCID
- Venue
- South African Medical Journal
- Published
- 2022-06-01
- Volume
- 112
- Issue
- 6
- Pages
- 426-432
- ISSN
- 0256-9574 (ISSN-L)
- 2078-5135
- OpenAlex
- W4281731690
- Cited by
- 14
- References
- 23
- Citations by year
- 2026: 2 · 2025: 4 · 2024: 2 · 2023: 6
- FWCI
- 2.88
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- cc-by-nc
- Locations
- South African Medical Journal (publishedVersion, cc-by-nc)
- PubMed (publishedVersion)
- Funders
- Novartis Pharma
- Topics
- Health Sciences › Medicine › Surgery › Lipoproteins and Cardiovascular Health
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Lipid metabolism and disorders
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Blood Pressure and Hypertension Studies
- Keywords
- inclisiran, LDL cholesterol lowering, high cardiovascular risk, South African patients, PCSK9 inhibition, statin intolerance, lipid-lowering therapy, safety, efficacy, heterozygous familial hypercholesterolemia, atherosclerotic cardiovascular disease, type 2 diabetes, South Africa, sub-Saharan Africa
- MeSH terms
- Proprotein Convertase 9, Heart Disease Risk Factors, Cardiovascular Diseases, Diabetes Mellitus, Type 2, Female, Humans, Hyperlipoproteinemia Type II, Cholesterol, LDL, Male, Middle Aged, Risk Factors, Sodium, South Africa, Subtilisins, Treatment Outcome, Hydroxymethylglutaryl-CoA Reductase Inhibitors, RNA, Small Interfering, Atherosclerosis
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