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In July 2017, The Pharmaceutical Journal published an opinion article, ‘The cholesterol and calorie hypotheses are both dead — it is time to focus on the real culprit: insulin resistance‘, which makes the case that there is little evidence of a link between cardiovascular disease and low-density lipoprotein cholesterol (LDL-C).
As a result, the following headline — ‘Injectable treatment recommended by NICE for patients with high cholesterol‘ — published in The Pharmaceutical Journal on 1 September 2021, piqued my interest.
This news article quotes Meindert Boysen, deputy chief executive at the National Institute of Health and Care Excellent (NICE), saying that inclisiran (Leqvio; Novartis) “represents a potential game-changer in preventing thousands of people from dying prematurely from heart attacks and strokes”. So what is the evidence that supports these extravagant life-saving claims?
First, there is no long-term data on effectiveness or safety. To date, the trials of inclisiran are short term (only 18 months) — NICE even acknowledges this as an issue.
Second, the NICE recommendation is based solely on a surrogate marker (LDL-C). Inclisiran is undoubtedly effective at lowering LDL-C; however, as noted above, LDL-C is a weak surrogate marker of cardiovascular disease. There is conflicting evidence that LDL-C is actually a causal factor in heart disease at all. For example, a study published in December 2020 by Danish researchers demonstrated that the lowest risk of all-cause mortality was found at an LDL-C concentration of 3.6 mmol/L (140 mg/dL). In comparison, the highest association with all-cause mortality was at LDL-C levels of less than 1.8mmol (70mg/dL).
Third, there is a lack of transparency. The push to lower cholesterol with statins (also now with PCSK9 inhibitors) to prevent heart disease has been hugely influenced over decades by meta-analyses performed by the Cholesterol Treatment Trialists’ Collaboration at the University of Oxford (CTT). The CTT asserts there to be a linear relationship between LDL-C reduction (by statins) and a concomitant reduction in cardiovascular disease. However, the individual patient data — upon which they make these claims — is not accessible to third parties for independent scrutiny.
NICE justifies its decision to be guided by the CTT opinion on the basis that “the clinical experts stated that the CTT meta-analyses were appropriate and that a similar relationship between LDL-C lowering and a reduction in cardiovascular event risk as seen with statin use could be expected with inclisiran”. But statins have multiple pleiotropic effects — anti-inflammatory, antithrombotic and on the microbiome — any or all of which may be responsible for the (meagre) benefits seen in secondary prevention patients.
Lastly, there is no evidence of cardiovascular benefit with inclisiran. An analysis by the European Medicines Agency, published in October 2020, found there was a “lack of cardiovascular outcome data” in the regulatory documents sent to the drug agency. My pharmacist colleagues may, like me, find this astonishing. It also found that “the number and percentage of deaths was comparable between the placebo and the inclisiran group, but numbers are too small for clear conclusions”.
Of course, inclisiran is not the first PCSK9 inhibitor to be licensed. Yet, to the best of my understanding, none of the existing drugs have been demonstrated to actually prolong life. Now, there are ongoing studies (such as Orion-4) examining the effect of inclisiran on major cardiovascular events and, crucially, life expectancy, but these are not due to report until December 2024.
There are many more points I could make but my main one is this: as pharmacists, our profession is uniquely at the interface between patients, prescribers and therapeutics. Very few of us will have the time (or inclination) to review the literature and reach independent conclusions. It is, therefore, essential that when advising patients and medical colleagues, we can rely upon genuine evidence, based in science and transparently provided, not hyperbolic statements based upon industry-sponsored trials.
Perhaps The Pharmaceutical Journal will commission an independent review of its own?
Graham Phillips, St Albans, Hertfordshire
Novartis was contacted, but declined to provide a response to this letter.