Should NICE Reconsider Inclisiran Recommendation?

blood test tube on the results
Researchers examined NICE’s conclusions on inclisiran’s clinical outcomes, safety, and cost, which they say warrant more transparent data.

The National Institute for Health and Care Excellence (NICE) should reconsider its recommendation of inclisiran, a new cholesterol-lowering drug, until more data on clinically meaningful cardiovascular outcomes, safety, and cost are available, according to an editorial published in the British Medical Journal.

NICE published draft guidance that recommended inclisiran for select patient groups. The injectable drug, which only requires administration biannually, has been found to lower low-density lipoprotein (LDL) cholesterol by approximately 50% in patients who are not responsive to other lipid-lowering treatments. Meindert Boysen, director of NICE’s Centre for Health Technology Evaluation, touted inclisiran as “a potential game-changer in preventing thousands of people from dying prematurely from heart attacks and strokes.”

The editorial authors, however, argue that it is unknown whether inclisiran will improve cardiovascular outcomes. They also deemed the safety data on long-term effects “inadequate,” given the lifelong intended use of the drug.  The small number of study participants was also highlighted as “insufficient” safety data. Moreover, NICE has not released publically available data on their cost analysis, so the committee strongly recommends this guidance be reviewed after mature outcome data are available.

Per the editorial authors’ review, the clinical effectiveness of inclisiran was approved by NICE based on 3 placebo-controlled, 18-month trials: Orion-9 (patients with familial hypercholesterolemia); and Orion-10 and Orion-11 (reported together, patients with cardiovascular disease (CVD) and at high risk for CVD). All 3 trials had a primary outcome of change from baseline in serum concentrations of LDL cholesterol. However, the authors noted that doubts remain whether improvements in this area are an accurate reflection of CVD benefit, as LDL cholesterol is considered a surrogate outcome for CVD.

Secondary outcomes included an exploratory composite cardiovascular endpoint (death, cardiac arrest, nonfatal myocardial infarction, and stroke). However, the number of events reported was too low to draw conclusions. The drug was well-tolerated with no adverse events that warranted further investigation, according to the authors. Future studies will evaluate safety, tolerability, and efficacy of LDL cholesterol lowering over 4 years. In 2026, the Orion-4 trial will report on cardiovascular outcomes.

Until then, the editorial authors challenge the assumption from NICE’s analysis that inclisiran may also reduce CVD events, since it lowers LDL cholesterol. The underlying data are not available, the authors noted, and the link between reduced LDL cholesterol and cardiovascular risk remains to be determined as clinically important. For example, the Accelerate trial reported that, despite lowering LDL cholesterol by 31% in high-risk adults, it did not reduce the risk for cardiovascular events. Likewise, a systematic review of proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors, ezetimibe, and statins found that, while study participants achieved their recommended LDL cholesterol concentrations, the data showed a “lack of consistent mortality and cardiovascular benefit.”

In addition, the efficacy outcomes of the Cholesterol Treatment Triallists, the meta-analysis that established uncertain association between LDL lowering and improved cardiovascular outcomes, relates to statins only. According to the authors, statins have antithrombotic and anti-inflammatory properties that may also contribute to reductions in cardiovascular events.

The editorial authors concluded, “The drug may prove to be a ‘game changer,’ or it may not. Clinicians and their patients need to be aware of the limitations in the evidence. NICE should reconsider its decision until patient-relevant outcomes are available, and these, and all cost data, should be released for independent analysis.”


Byrne P, Demasi M, Smith SM. NICE guidance on inclisiran should be reconsidered. BMJ. Published online October 12, 2021. doi:10.1136/bmj.n2462