News & Perspective

New analysis suggests that very low LDL-C levels are still better

2 years ago, OP Editor

An aggressive reduction of low-density lipoprotein cholesterol (LDL-C) levels is now achievable with monoclonal antibodies that inhibit proprotein convertase subtilisin/kexin type 9 (PCSK9),1 but a lower threshold of LDL-C remains unknown. Nonetheless, a new analysis of the FOURIER trial was presented in the 2017 European Society of Cardiology (ESC) Congress, demonstrating that a very aggressive reduction of LDL-C levels with evolocumab does not seem to pose additional safety concerns.2

This secondary analysis of the FOURIER trial examined the efficacy and safety endpoints of patients with an LDL-C assessment at week 4, who did not experience a primary efficacy or prespecified safety event prior to the week 4 visit.2 Approximately 26,000 patients were stratified post-randomization into five prespecified groups irrespective of treatment allocation, based on achieved LDL-C at week 4 from baseline.2,3

Initial results from the primary analysis of the trial has demonstrated a strong relationship between on-treatment LDL-C levels and major cardiovascular outcomes, without a significant association between LDL-C levels and prespecified adverse events in patients followed up for a median of 2.2 years.1 Based on the secondary analysis of the trial, such findings can now be extended to unprecedented low levels of LDL-C, with the lowest prespecified group (2,669 patients) achieving LDL-C less than 0.5mmol/L (median 0.36mmol/L) (Figure 1).2,4 At week 4, these patients had the lowest rate for cardiovascular death, myocardial infarction, or stroke (adjusted hazard ratio 0.69, 95% CI: 0.56-0.85, p=0.0001) as compared to the group with highest LDL-C levels (≥2.6mmol/L).2,4 No meaningful difference in the safety profile across the five groups was reported.2-4


“With this analysis, we’ve further demonstrated the safety and efficacy of achieving an LDL-C well below current targets,” said the lead author, Dr. Robert P. Giugliano of Brigham and Women’s Hospital and Harvard Medical School. “These findings from the first analysis of a large cohort of patients to achieve such ultra-low LDL-C levels support the use of intensive lipid-lowering therapies, such as the combination of evolocumab and statin therapy, in high-risk patients to safely reduce the risk of another cardiovascular event.”3

Moreover, an exploratory subgroup of 504 patients with an ultra-low LDL-C (less than 0.2mmol/L) showed even further reduction in the previously mentioned cardiovascular endpoints (adjusted hazard ratio 0.59, 95% CI: 0.37-0.92, p=0.0001; in comparison to those with LDL-C ≥2.6mmol/L), with no increase in safety events.2,4

“Although longer-term follow-up will be important, the totality of evidence to date from trials of intensive lipid lowering supports reduction of LDL-C in high-risk patients to levels below those currently recommended in cholesterol guidelines,” said Dr. Giugliano.2

Dr. Ian Graham, one of the chairs of the expert panel who drafted the 2016 European Society of Cardiology/European Atherosclerosis Society clinical guidelines for the management of dyslipidemia, also commented to the FOURIER event curve showing clinical benefit at very low levels of LDL-C. “We haven’t gotten to the point where [the benefit] stops, even at those extraordinary low levels of LDL cholesterol. It hasn’t levelled out and it hasn’t gone up. In most things in medicine, except for smoking, there’s a J-shape association with drugs if you really push it. It hasn’t happened.”5

These clinical findings are also supported by the results from an exploratory visual histology sub-study of evolocumab in the GLAGOV trial.6 Although the study did not detect a statistically significant difference in normalized dense calcium volume between treatment arms (evolocumab or placebo; in addition to statin), the observed directional trend in increased dense calcium with corresponding reduction in LDL-C is consistent with findings from previous statin studies.6,7

“Plaque instability has been linked to rupture and subsequent blood clots associated with atherosclerotic cardiovascular disease and cardiovascular events such as stroke and heart attack,” said Dr. Sean E. Harper, executive vice president of Research and Development at Amgen. “The directional data in this Repatha (evolocumab) sub-study supports the hypothesis that lowering LDL-C may play a role in changing the composition of the coronary artery plaque.”6

  1. Sabatine MS, Giugliano RP, Keech AC, et al. Evolocumab and Clinical Outcomes in Patients with Cardiovascular Disease. N Engl J Med. 2017;376(18):1713-1722.
  2. FOURIER – New analysis examines how low cholesterol can safely go. ESC Press Office. 2017 (Accessed August 31 2017, at
  3. New Repatha (evolocumab) Analysis Demonstrates Cardiovascular Outcomes Efficacy And Safety Of Achieving Very Low LDL-C Levels. Amgen News Releases. 2017 (Accessed August 31 2017, at
  4. Giugliano RP, Pedersen TP, Park JG, et al. Clinical efficacy and safety of achieving very low LDL-cholesterol concentrations with the PCSK9 inhibitor evolocumab: a prespecified secondary analysis of the FOURIER trial. Lancet. 2017 [Epub ahead of print].
  5. Ultra-Low LDL Levels? FOURIER Suggests Efficacy of Evolocumab. TCTMD. 2017 (Accessed September 1 2017, at
  6. New Virtual Histology Sub-Study Evaluates Impact of Repatha (Evolocumab) On Coronary Artery Plaque Composition. Amgen News Releases. 2017 (Accessed September 1 2017, at
  7. Global Assessment of Plaque Regression With a PCSK9 Antibody as Measured by Intravascular Ultrasound – GLAGOV. ACC Latest in Cardiology. 2017 (Accessed September 1 2017, at


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