A novel lipid-lowering therapy, administered twice yearly, showed a significant reduction of elevated low-density lipoprotein cholesterol (LDL-C), a key modifiable risk factor for atherosclerotic cardiovascular disease, according to a new study.

Inclisiran, a small interfering RNA targeting hepatic proprotein convertase subtilisin/kexin type 9, led to greater LDL receptor expression and substantial LDL-C reduction, explained the study’s corresponding author, Fellipe Batista, MD, of Centro Edson Bueno-Rede Total Care in Rio de Janeiro, Brazil.

The study, published in JACC: Advances, could be relevant to the estimated 25.5% of US adults who have high levels of LDL-C (≥ 130 mg/dL).

Inclisiran produced major reductions in LDL-C among a variety of patient populations during clinical trials, Batista said. In addition to its potent and sustained LDL-lowering effect, the main advantages of inclisiran are its distinct mechanism of action and infrequent dosing schedule, he said. Inclisiran is administered by subcutaneous injection initially, again at 3 months, and then every 6 months.

“This is particularly useful for patients who have difficulty adhering to daily oral therapy or whose LDL-C levels remain above their target level despite maximally tolerated statin treatment,” he said.

Two Key Trials

Batista and the study team conducted a systematic review and meta-analysis consisting of nine randomized controlled trials involving 6355 individuals. The data from the trials included patients from around the globe who have never used lipid-lowering drugs, had several cardiovascular risk factors or at very high risk receiving maximum dosages of lipid-lowering drugs prior to inclisiran, and healthy control participants.

They observed inclisiran was associated with about 49% greater reduction in LDL-C than placebo. Its positive effect was found across populations receiving different intensities of background lipid-lowering therapy, including statins.

Some recent evidence suggests an inclisiran-based strategy may produce greater LDL-C lowering than usual care statin strategies in some populations, Batista explained. “However, statins have much more established evidence for reducing cardiovascular events, and long-term cardiovascular outcome data for inclisiran are still being collected,” he said.

Compared with prior literature, this analysis integrates, for the first time, data from both the ORION and VICTORION trial programs, offering the most comprehensive synthesis of inclisiran’s efficacy to date, the researchers said. Previous pooled analyses, they noted, concentrated on subsets of trials and did not include the latest evidence from the VICTORION studies.

“Statins remain the foundational cornerstone of lipid-lowering therapy due to decades of robust clinical trial evidence demonstrating significant reductions in major adverse cardiovascular events, widespread availability, and cost-effectiveness,” said Jaideep Patel, MD, a cardiologist at Johns Hopkins Medicine in Baltimore.

“However, statins require daily adherence, which frequently drops below 50% within the first year of prescription,” he pointed out. “In addition, a subset of patients reported statin-associated muscular symptoms that limit optimal dosing and therefore overall lipid reduction.”

Patel, who was not involved with the study, agreed with Batista that the dosing schedule is a primary advantage of inclisiran.

Minimizing Disparities

Patients most likely to benefit from inclisiran are at high cardiovascular risk but remain above guideline-recommended LDL-C targets despite maximally tolerated lipid-lowering therapy, Batista said.

“In addition to those having difficulty maintaining adherence to daily medications, this includes patients with established atherosclerotic cardiovascular disease, previous myocardial infarction or stroke, persistently elevated LDL-C, or statin intolerance,” he said.

Going forward, Batista noted, “the most important unanswered question is whether the substantial reduction in LDL-C translates into a definitive reduction in cardiovascular disease and mortality.”

Patel would like to see future trials evaluate the efficacy, safety, and adherence profiles of combined low-dose statins, ezetimibe, and inclisiran simultaneously.

“Rather than viewing inclisiran as a replacement for statins, it is best utilized as complementary or sequential therapy to help achieve LDL-lowering goals, without adding to the daily pill burden,” he said.

Patel suggested focusing on plaque stabilization and regression using CT angiography, comparing statins with inclisiran.

Future research, he added, should also concentrate on minimizing geographic and socioeconomic disparities, ensuring that high-risk and underrepresented populations gain equal access to these lipid-lowering innovations.

Ongoing cardiovascular outcome trials, including ORION-4 and VICTORION-2P, will be essential, Batista noted.

“Researchers should evaluate long-term safety, real-world adherence, and cost-effectiveness,” he said. “Individual patient-level analyses would help identify patients most likely to benefit. In addition, computational and in silico approaches may complement traditional clinical trials by estimating long-term cardiovascular outcomes and identifying optimal treatment strategies.”

Batista and Patel reported no relevant financial relationships.

Martta Kelly is a medical journalist who lives in the New York metropolitan area.