Does it matter how we lower LDL-cholesterol? Answers from Mendelian randomisation studies

Thursday, 14 Mar 2019

“Nature’s randomised trials” have the potential to settle uncertainty surrounding the impact of lowering risk factors such as LDL-cholesterol on the risk of future cardiovascular events, and whether it actually matters how we lower them.

Speaking at a recent meeting of cardiologists and endocrinologists in Melbourne, cardiologist and genetic epidemiologist Professor Brian Ference, currently the Director of Research in Translational Therapeutics, at the University of Cambridge UK, described how Mendelian randomised studies are helping address unanswered questions about cardiovascular risk factors.

Mendelian randomised studies have little to do with genetics

Mendelian randomised studies are increasingly used in cardiovascular research. Professor Ference pointed out that, somewhat ironically, these studies have little to do with genetics: they use genetic polymorphisms associated with a potential risk factor as an instrument to randomly allocate subjects to a higher or lower level of exposure to that risk factor to study the impact it has on the risk of disease.

“If you have inherited an allele associated with a lower LDL-cholesterol, it’s analogous to being randomly allocated to a LDL-lowering therapy at birth, while inheriting the other allele is analogous to being allocated to usual care,” Professor Ference explained. “If allocation is random, then the only difference between the two groups should be their level of LDL-cholesterol.” This effect allows researchers to make unconfounded causal estimates of the effect of LDL-cholesterol on the risk of cardiovascular disease, he told delegates.

LDL-cholesterol has both a causal and cumulative effect on CHD risk

According to Professor Ference, Mendelian randomisation studies evaluating people with a genetic polymorphism that mimics the effects of a PCSK9-inhibitor show that ‘there’s no question that lower LDL-cholesterol due to PCSK9 inhibition is clearly causally associated with a lower risk of cardiovascular disease.’

But Mendelian randomisation does have its limitations. “It cannot be used to directly estimate the effect of a particular therapy in a randomised trial,” he noted. For example, each unit of lower LDL-cholesterol is associated with a much greater reduction in cardiovascular risk over time, as compared to the same reduction of LDL-cholesterol during short-term treatment after atherosclerosis has already developed.1,2 This implies that not only is LDL-cholesterol causally related to cardiovascular disease, but that there is a cumulative risk over time. “We need to translate those lifelong benefits of lower exposure into the expected benefits in a clinical trial,” he explained.

Statins and PCSK9 inhibitors have similar impacts on CV risk reduction

The results of major outcomes trials for PCSK9 inhibitors, such as FOURIER3, SPIRE4 and ODYSSEY5, found a lower than expected risk reduction in cardiovascular events compared to the expected benefit of lowering LDL-cholesterol to the same extent with a statin. Professor Ference said he did not believe that this was the result of additional benefits of statins over PCSK9 inhibitors, but more the case of “an unfair comparison”.

Statin studies have shown that the magnitude in reduction of cardiovascular events per mmol/L reduction in LDL-cholesterol in the first year of treatment is only around half what it is in each subsequent year.6 However, the expected benefit from statin therapy for every year of therapy has been based on averaging out the observed risk reductions in clinical trials over around 5 years of treatment.6

The shorter duration follow-up of FOURIER and SPIRE (2.2 years and one year, respectively) means that it’s more appropriate to compare the drugs’ effects on risk reduction over the same total duration of therapy or during each year of treatment, said Professor Ference. “When analysed this way, the PCSK9 inhibitors and statins have similar effects on the risk of cardiovascular events for the same duration of therapy,”7 he noted.

Does mechanism of lowering LDL-cholesterol matter?

Professor Ference said that clinical trial data, together with findings from Mendelian randomisation studies, “Strongly implies that the causal effect of LDL-cholesterol is not determined by the cholesterol content of the particles, but by the number of circulating particles themselves.”

“Therefore if we reduce cholesterol by simply decreasing the concentration of cholesterol carried by the particles, we are probably not going to do much to reduce the risk of cardiovascular events in our patients. By contrast, if we reduce LDL-cholesterol by reducing particles through upregulating of the LDL receptor with a statin, PCSK9 inhibitor or ezetimibe, we should substantially reduce risk, proportional to the reduction in LDL-cholesterol or reduction in apo-B,” he added.


This article was sponsored by Amgen, which has no control over editorial content. The content is entirely independent and based on published studies and experts’ opinions, the views expressed are not necessarily those of Amgen.


  1. Ference BA et al. Variation in PCSK9 and HMGCR and Risk of Cardiovascular Disease and Diabetes. N Engl J Med 2016; 375:2144-2153
  2. Ference BA et al. Effect of long-term exposure to lower low-density lipoprotein cholesterol beginning early in life on the risk of coronary heart disease: a Mendelian randomization analysis. J Am Coll Cardiol 2012;60:2631-9.
  3. Sabatine MS, et al. Evolocumab and clinical outcomes in patients with cardiovascular disease. N Engl J Med 2017;376:1713–1722.
  4. Ridker PM et al. Cardiovascular efficacy and safety of bococizumab in high-risk patients. N Engl J Med 2017;376:1527–1539.
  5. Robinson JG, et al. ODYSSEY LONG TERM Investigators. Efficacy and safety of alirocumab in reducing lipids and cardiovascular events. N Engl J Med 2015;372:1489–1499.
  6. Cholesterol Treatment Trialists’ Collaboration, et al. Efficacy and safety of more intensive lowering of LDL cholesterol: a meta-analysis of data from 170,000 participants in 26 randomised trials. Lancet. 2010 376:1670-81.
  7. Ference BA et al. Reduction of low density lipoprotein-cholesterol and cardiovascular events with proprotein convertase subtilisin-kexin type 9 (PCSK9) inhibitors and statins: an analysis of FOURIER, SPIRE, and the Cholesterol Treatment Trialists Collaboration. Eur Heart J. 2018 Jul 14;39(27):2540-2545.

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