Inclisiran Reduces LDL-C in Patients Intolerant to Statins, PCSK9 Inhibitors

The use of inclisiran (Leqvio; Novartis) in patients with a history of adverse events (AEs) from statins and/or proprotein convertase subtilisin/kexin type 9 (PCSK9) monoclonal antibodies (mAb) was associated with reductions in low-density lipoprotein cholesterol (LDL-C) at 3 and 9 months. However, these reductions were lower than those reported in placebo-controlled trials, driven by attenuated LDL-C reductions in patients with prior PCSK9 mAb AEs.¹

The data were presented at the American Heart Association 2025 Scientific Sessions, which took place November 7 to 10, 2025, in New Orleans, Louisiana.¹

Could Inclisiran Play a Role in Statin- and PCSK9-Intolerant Patients?

Inclisiran has been proven effective as an adjunct to statin therapy in patients with high cholesterol. Trial data, including those presented at AHA, demonstrate that patients with acute coronary syndrome have speedier LDL-C goal achievement when treated with inclisiran and usual care compared with usual care alone. In real-world practice, inclisiran has led to 50% reductions in LDL-C while being well tolerated among recipients, exhibiting similar results to placebo-controlled trials.^2,3

Despite the effectiveness and widespread use of statins as a background LLT, many patients report statin intolerance. Experts say it affects 5% to 10% of individuals who try statin therapy. Intolerance means the patient cannot tolerate the lowest dose of 2 or more different statin therapies due to effects on muscles, joints, or liver function. Adverse events to PCSK9 inhibitors are rare, but investigators report that patients with prior muscle-related intolerance to statins have a greater likelihood of developing muscle-related AEs to a PCSK9 inhibitor.^4,5

Inclisiran, as a small interfering RNA medication, could help fill treatment gaps for patients who cannot tolerate statins or PCSK9 inhibitors. It is especially pertinent to determine, given the limited therapeutic options available to patients who are intolerant to standard lipid-lowering therapies and who face suboptimal LDL-C control.¹

Inclisiran Lowers LDL-C in Patients With Intolerance to Standard Care

The current researchers conducted a retrospective analysis of electronic health records of patients 18 years and older at a tertiary US preventive cardiology clinic. Patients must have received 1 or more doses of inclisiran between January 2022 and February 2024, with LDL-C measured at 3 and 9 months. Median values were reported for LDL-C reductions, according to the investigators.¹

Across the analyzable population, 56 had available LDL-C data at 3 months, 57 received a second dose, and 44 had available data at 9 months. Demographic data indicated that 44.4% of patients were categorized as secondary prevention, 33.3% were receiving statins at baseline, and 41.3% were receiving ezetimibe (Zetia; Merck & Co.) at baseline. Eighty-nine percent of the cohort had a history of prior AEs from statins at baseline, whereas 27.4% had a history of prior PCSK9 mAb AEs at baseline.¹

At 3 months, the overall median reduction was 40.7% (IQR, 15.7-51.7). Notably, 19.6% of patients had less than 10% LDL-C reductions. In patients with statin AEs, median LDL-C reductions were 40.7% (IQR, 9.3-50.7), whereas in patients with PCSK9 AEs, LDL-C was reduced by 23.6% (IQR, 0.5-46.7). When the investigators excluded patients with prior PCSK9 mAb AEs, the median 3-month reduction was 46.4% (IQR, 25.4-54.54), demonstrating the attenuating effect of prior LDL-C reductions in this cohort.¹

At 9 months, the median LDL-C reduction was 33.2% (95% CI, 10.9-46.4), according to the study authors.¹

The data demonstrate the effectiveness of inclisiran at 3 and 9 months in reducing LDL-C in individuals with a history of statin or PCSK9 mAb intolerance. Although the reductions were more modest compared with those reported in placebo-controlled trials, removing patients with prior PCSK9 mAb AEs led to similar overall LDL-C lowering as observed in clinical trials. The authors noted that further investigation is necessary to determine how patients with past intolerance to these medications can achieve sustained, robust LDL-C reductions. However, inclisiran presents as a promising nonstatin, non-PCSK9 inhibitor option for these patients.¹

REFERENCES

1. Sarraju A, Al-Dalakta A, Gambino K, et al. Lipid-lowering effects of inclisiran in statin- or PCSK9i monoclonal antibody-intolerant patients. Presented at: American Heart Association 2025 Scientific Sessions; November 9, 2025; New Orleans, LA. Accessed on AHA’s Virtual Platform on November 11, 2025.

2. Ferruggia K. Inclisiran plus usual care enhances LDL-C control post-acute coronary syndrome. Pharmacy Times. November 10, 2025. Accessed November 11, 2025. https://www.pharmacytimes.com/view/inclisiran-plus-usual-care-enhances-ldl-c-control-post-acute-coronary-syndrome

3. Halpern L. Inclisiran is well-tolerated, shows substantial LDL-C reductions in real-world practice. Pharmacy Times. September 29, 2025. Accessed November 11, 2025. https://www.pharmacytimes.com/view/inclisiran-shows-good-toleration-and-substantial-ldl-c-reductions-in-real-world-practice

4. Statin intolerance: pearls for practice in the PCSK9 inhibitor era. Cleveland Clinic. March 18, 2019. Accessed November 11, 2025. https://consultqd.clevelandclinic.org/statin-intolerance-pearls-for-practice-in-the-pcsk9-inhibitor-era

5. Cencetti J, Abramowitz C, Spoonhower H. Muscle-related adverse events associated with PCSK9 inhibitors in a veteran population. Fed Pract. 2023;40(2):62-67. doi:10.12877/fp.0357