Inclisiran With LLT Reduces LDL-C in Hypercholesterolemia Without Inducing Muscle Pain

Data presented at the European Society of Cardiology (ESC) 2025 Congress from the phase 4, randomized, double-blind, placebo-controlled V-DIFFERENCE clinical trial (NCT05192941) show that inclisiran (Leqvio; Novartis), a small interfering RNA (siRNA) therapy, in addition to standard lipid-lowering therapy (LLT), helped patients with hypercholesterolemia achieve their low-density lipoprotein cholesterol (LDL-C) goals compared with placebo. Notably, there were no associated muscle-related adverse events (MRAEs). The top-line results were announced in a news release from Novartis.^1,2

Hypercholesterolemia, or high cholesterol, directly contributes to the development of cardiovascular disease. | Image Credit: © IndigoElf - stock.adobe.com

“These results highlight the potential of [inclisiran] to transform cardiovascular care by improving meaningful patient outcomes,” Ruchira Glaser, MD, global head of the cardiovascular, renal, and metabolic development unit at Novartis, said in the news release. “V-DIFFERENCE has provided evidence that early use of [inclisiran] is an effective way to help patients reach their LDL-C goals faster without the need to add other therapies or maximize statin doses.”¹

Established Efficacy of Inclisiran

Inclisiran is a safe and effective nonstatin treatment option to reduce LDL-C. It received initial approval by the FDA in 2021 as an adjunct injection with diet and maximally tolerated statin therapy for adults with heterozygous familial hypercholesterolemia (HeFH) or clinical atherosclerotic cardiovascular disease (ASCVD). In 2025, it received an expanded indication for individuals with hypercholesterolemia.^1,3,4

Designed as a 284-mg injection, inclisiran’s subcutaneous administration—with a second dose at 3 months and follow-up injections every 6 months afterwards—makes it a palatable and attractive option for patients to lower their LDL-C who have struggled to do so on standard statin therapy. In addition, inclisiran shows capabilities in lowering the risk of complications compared with standard statins, including a lower risk of new-onset diabetes.^1,3,4

The safety and efficacy of inclisiran across its numerous indications were affirmed in a series of clinical trials under the VictORION clinical trial program. Differently than most of these trials, the V-DIFFERENCE investigators—in addition to efficacy and safety parameters—sought to evaluate quality-of-life (QoL) outcomes compared with placebo in individuals with hypercholesterolemia at high and very high cardiovascular risk who had not yet achieved guideline-recommended LDL-C goals, a first-of-its-kind study in this setting. In this trial, 1770 patients were randomized 1:1 to receive inclisiran plus LLT (n = 898) or placebo plus LLT (n = 872).¹

Quality of Life—Including Muscle Health—Preserved With Inclisiran Treatment

The investigators sought to determine the proportion of patients achieving their individual LDL-C target—either < 55 mg/dL or < 70 mg/dL, depending on cardiovascular risk—following 90 days of inclisiran treatment. Other end points featured percentage change from baseline in mean LDL-C level and the proportion of individuals experiencing at least 1 MRAE following 1 year of treatment.¹

In V-DIFFERENCE, 85% of patients treated with inclisiran and LLT following 90 days achieved their guideline-recommended LDL-C target. This is compared with 31% of patients utilizing placebo and LLT who achieved their LDL-C target (P < .0001). Notably, there were clinically meaningful benefits observed as early as 30 days following treatment with inclisiran, with 81% of the cohort achieving their LDL-C targets, according to V-DIFFERENCE investigators.¹

Furthermore, patients who received inclisiran plus LLT had a 43% reduction in risk of MRAE compared with patients receiving placebo plus LLT (P < .0001). There were also modest numerical improvements in pain-related QoL scores reported by the investigators. In an important development, inclisiran continued to demonstrate its efficacy in lowering LDL-C, with treatment on top of LLT reducing LDL-C levels by an average of 59% following a year of treatment, a superior reduction compared with placebo plus LLT (35%; P < .0001). There were significant differences observed between the 2 treatment groups as early as 60 days into the study, demonstrating inclisiran’s speedy and robust effectiveness.¹

"V-DIFFERENCE is the largest LDL-C lowering study with [inclisiran] to read out to date and the first to focus on patient-centered outcomes," Ulf Landmesser, MD, chairman of the department of cardiology, angiology, and intensive care medicine at German Heart Center of Charité, said in the news release. "These findings are significant as they demonstrate effective options for lipid management improvement in patients at risk, a majority of whom continue to remain above recommended LDL-C levels."¹

With these results, pharmacists can be confident that patient QoL will be sustained—and improved—with use of inclisiran on top of prescribed LLT. Pharmacists play an important role in prescribing inclisiran and counseling patients on its dosage, administration, and possible AEs. In this vein, the continued clinical development and research into inclisiran will be of utmost importance to pay attention to as future updates are released.

REFERENCES

1. Novartis Leqvio® shows statistically significant and clinically meaningful early LDL-C goal achievement with less muscle pain. Novartis. News Release. Released August 30, 2025. Accessed September 8, 2025. https://www.novartis.com/news/media-releases/novartis-leqvio-shows-statistically-significant-and-clinically-meaningful-early-ldl-c-goal-achievement-less-muscle-pain

2. Study of Efficacy, Safety, Tolerability and Quality of Life of Inclisiran (KJX839) vs Placebo, on Top of Ongoing Individually Optimized Lipid-lowering Therapy, in Participants With Hypercholesterolemia (V-DIFFERENCE). ClinicalTrials.gov Identifier: NCT05192941. Last Updated June 11, 2025. Accessed September 8, 2025. https://www.clinicaltrials.gov/study/NCT05192941?term=NCT05192941&rank=1

3. Ferruggia K. Inclisiran Receives FDA Approval for New Indication to Treat Hypercholesterolemia. Pharmacy Times. Published August 1, 2025. Accessed September 8, 2025. https://www.pharmacytimes.com/view/inclisiran-receives-fda-approval-for-new-indication-to-treat-hypercholesterolemia

4. Halpern L. LDL-C–Lowering Inclisiran May Carry Lower Risk of Diabetes Than Atorvastatin. Pharmacy Times. Published August 6, 2025. Accessed September 8, 2025. https://www.pharmacytimes.com/view/ldl-c-lowering-inclisiran-may-carry-lower-risk-of-diabetes-than-atorvastatin