Inclisiran in individuals with diabetes or obesity: Post hoc pooled analyses of the ORION ‐9, ORION ‐10 and ORION ‐11 Phase 3 randomized trials
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Aims: To conduct a pooled analysis of Phase 3 trials investigating the efficacy and safety of inclisiran across glycaemic and body mass index (BMI) strata. Materials and Methods: Participants were randomized 1:1 to receive 300 mg inclisiran sodium or placebo twice yearly, after initial and 3‐month doses up to 18 months, with background oral lipid‐lowering therapy. Analyses were stratified by glycaemic status (normoglycaemia, prediabetes, and diabetes) or BMI (<25, ≥25 to <30, ≥30 to <35, and ≥35 kg/m 2 ). Co‐primary endpoints were percentage and time‐adjusted percentage change in low‐density lipoprotein (LDL) cholesterol from baseline. Safety was also assessed. Results: Baseline characteristics were balanced between treatment arms and across strata. Percent LDL cholesterol change (placebo‐corrected) with inclisiran from baseline to Day 510 ranged from −47.6% to −51.9% and from −48.8% to −54.4% across glycaemic/BMI strata, respectively. Similarly, time‐adjusted percentage changes after Day 90 and up to Day 540 ranged from −46.8% to −52.0% and from −48.6% to −53.3% across glycaemic/BMI strata, respectively. Inclisiran led to significant reductions in proprotein convertase subtilisin/kexin type 9 and other atherogenic lipids and lipoproteins versus placebo across the glycaemic/BMI strata. The proportions of individuals achieving LDL cholesterol thresholds of <1.8 mmol/L and <1.4 mmol/L with inclisiran increased with increasing glycaemic and BMI strata. Across the glycaemic/BMI strata, a higher proportion of individuals had mild/moderate treatment‐emergent adverse events (TEAEs) at the injection site with inclisiran (2.8%–7.7%) versus placebo (0.2%–2.1%). Conclusion: Inclisiran provided substantial and sustained LDL cholesterol lowering across glycaemic/BMI strata, with a modest excess of transient mild‐to‐moderate TEAEs at the injection site.
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ORION-9, −10 and −11 combined in a pooled analysis (n = 3,658) demonstrated LDL-C reductions of 47.6% to 51.9% between different glycemic groups and 48.8% to 54.4% between different BMI groups.
“ORION-9, −10 and − 11 combined in a pooled analysis (n = 3,658) demonstrated LDL-C reductions of 47.6% to 51.9% between different glycemic groups including normoglycemia, prediabetes and diabetes and 48.8% to 54.4% between different BMI groups from underweight (< 25 kg/m²) to obesity (≥ 35 kg/m²) [40].”
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 [40]
The Study population section reports a pooled sample of 3,658, and Figure 1 reports the cited Day 510 LDL-C reduction ranges across glycaemic and BMI groups. However, the citing sentence calls the <25 kg/m² BMI group “underweight”; the paper classifies it as “normal” (Population section). (LLM, conf=0.88)
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 [40]
The Key secondary endpoints section reports lower LDL cholesterol with inclisiran than placebo, with p < 0.001 across the reported glycaemic and BMI strata. But the Methods and Discussion identify this paper as a pooled analysis of three Phase 3 trials, not an analysis of 11 RCTs involving more than 13,000 participants. Page numbers are not available in our copy. (LLM, conf=0.88)
Experimental — accuracy not yet measuredAnalysis of ORION-1, ORION-9, ORION-10, and ORION-11 revealed that apoB concentrations decreased by 36%-48%.
“Analysis of ORION-1 and ORION-9 and ORION-10 and ORION-11 revealed that non–HDL-C levels decreased by 38%–50% while apoB concentrations decreased by 36%–48% [40].”
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 [40]
Section 3.2.2 reports that apoB percentage changes were significantly greater with inclisiran than placebo across the analysed subgroups. But the Population section specifies that the pooled analysis included ORION-9, ORION-10 and ORION-11, not ORION-1, and the retrieved text does not establish the claimed 36%–48% apoB range. (LLM, conf=0.83)
Experimental — accuracy not yet measuredAnalysis of ORION-1, ORION-9, ORION-10, and ORION-11 revealed that non-HDL-C levels decreased by 38%-50%.
“Analysis of ORION-1 and ORION-9 and ORION-10 and ORION-11 revealed that non–HDL-C levels decreased by 38%–50% while apoB concentrations decreased by 36%–48% [40].”
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 [40]
Section 3.2.2 (page unavailable) reports significantly greater reductions in non-HDL cholesterol with inclisiran than with placebo. But the Population section (2.1; page unavailable) identifies only ORION-9, ORION-10 and ORION-11 as included trials, not ORION-1, and the retrieved passages do not establish the stated 38%–50% range. (LLM, conf=0.87)
Experimental — accuracy not yet measured
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2026 ACC/AHA/AACVPR/ABC/ACPM/ADA/AGS/APhA/ASPC/NLA/PCNA Guideline on the Management of Dyslipidemia
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“Analysis of ORION-1 and ORION-9 and ORION-10 and ORION-11 revealed that non–HDL-C levels decreased by 38%–50% while apoB concentrations decreased by 36%–48% [40].”
- Authors
- Leiter, L. A., Raal, F. J., Schwartz, G. G., Koenig, W., Ray, K. K., Landmesser, U., Han, J., Conde, L. G., & Wright, R. S.
- Affiliations
- St. Michael's Hospital (CA)
- University of the Witwatersrand (ZA)
- University of Colorado Anschutz (US)
- Deutsches Herzzentrum München Technische Universität München Munich Germany
- Imperial College London (GB)
- Deutsches Herzzentrum der Charité (DE)
- Novartis Pharmaceuticals Corporation East Hanover New Jersey USA
- Novartis (Switzerland) (CH)
- Mayo Clinic (US)
- Corresponding author
- Leiter, Lawrence A.
- ORCID
- Venue
- Diabetes, Obesity and Metabolism
- Publisher
- Wiley
- Published
- 2024-05-17
- Volume
- 26
- Issue
- 8
- Pages
- 3223-3237
- ISSN
- 1462-8902 (ISSN-L)
- 1463-1326
- OpenAlex
- W4397002346
- Cited by
- 27
- References
- 8
- Citations by year
- 2026: 10 · 2025: 16 · 2024: 1
- FWCI
- 11.37
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Diabetes Obesity and Metabolism (publishedVersion, cc-by-nc)
- PubMed (publishedVersion)
- mediaTUM – the media and publications repository of the Technical University Munich (Technical University Munich) (submittedVersion)
- Funders
- National Institute for Health and Care Research
- Imperial College London
- Novartis Pharma
- NIHR Imperial Biomedical Research Centre
- Topics
- Health Sciences › Medicine › Surgery › Lipoproteins and Cardiovascular Health
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Lipid metabolism and disorders
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes, Cardiovascular Risks, and Lipoproteins
- Keywords
- inclisiran, PCSK9 inhibition, LDL cholesterol lowering, diabetes mellitus, obesity, body mass index, prediabetes, glycemic status, treatment-emergent adverse events, injection site reactions, atherogenic lipoproteins
- MeSH terms
- Adult, Aged, Blood Glucose, Diabetes Mellitus, Type 2, Double-Blind Method, Female, Glycated Hemoglobin, Humans, Hypoglycemic Agents, Cholesterol, LDL, Male, Middle Aged, Obesity, Body Mass Index, Treatment Outcome, Clinical Trials, Phase III as Topic, RNA, Small Interfering
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