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13 April 2015
Hint of outcomes benefit with PCSK9 inhibition
Two reports indicate potential for long-term cardiovascular benefit with proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibition. Treatment with either agent (evolocumab or alirocumab) also appeared to be well tolerated.
Sabatine M, Giugliano R, Wiviott S, et al. Efficacy and safety of evolocumab in reducing lipids and cardiovascular events. New Engl J Med 2015; published online 15 March, DOI:10.1056/NEJMoa1500858
Robinson J, Farnier M, Krempf M et al; Efficacy and safety of alirocumab in reducing lipids and cardiovascular events. New Engl J Med 2015; published online 15 March, DOI: 10.1056/MEJMoa1501031
STUDY SUMMARY      Sabatine et al.
Objective: To evaluate the long-term safety and efficacy [low-density lipoprotein cholesterol (LDL-C) reduction] with evolocumab in high cardiovascular risk patients. There was also a pre-specified exploratory analysis on adjudicated cardiovascular outcomes.  
Study design: Open-label, randomised, controlled longer-term extensions of the OSLER trial. OSLER-1 enrolled patients who completed phase II trials, and OSLER-2 enrolled patients who completed phase III trials.
Study population: A total of 4,465 patients (mean age 58 years, 80% with ≥1 cardiovascular risk factor) were included representing 74% of patients in the parent studies. A total of 3,128 (70%) patients were receiving statin therapy at the start of the OSLER trials.
Primary variable: ·       Incidence of adverse events.
Secondary variables:
  • LDL-C reduction
  • Reduction in cardiovascular outcomes (a composite of death, myocardial infarction, unstable angina requiring hospitalisation, coronary revascularisation, stroke, transient ischaemic attack and heart failure requiring hospitalisation)
Methods: Patients were randomised 2:1 to evolocumab (OSLER-1, 420 mg once a month; OSLER-2, 140 mg every 2 weeks or 420 mg once a month) plus standard therapy or standard therapy alone. Lipids, creatinine kinase levels, liver function tests, and the development of binding and neutralising antibodies against evolocumab were assayed. Cardiovascular events were adjudicated by a central clinical events committee for exploratory analysis. Data from both trials were combined into a single analysis set.
Main results:
  • Most adverse events occurred with the same frequency in both groups, although neurocognitive events (including delirium, cognitive and attention disorders, dementia and mental impairment) were more frequent in the evolocumab group (Table). Adverse event reporting rates did not vary significantly with the achieved level of LDL-C.
  • Evolocumab reduced LDL-C levels by 61% compared with standard therapy alone, from a median of 120 mg/dL (3.1 mmol/L) to 48 mg/dL (1.2 mmol/L) at 12 weeks, P<0.001. LDL-C lowering was sustained over the 11.1 month follow-up period.
  • The rate of cardiovascular events at 1 year was significantly lower in the evolocumab group (0.95% vs 2.18% with standard therapy alone; hazard ratio 0.47, 95% CI 0.28 to 0.78, P=0.003).


Table. Selected adverse events in the OSLER-1 and -2 trials.

Adverse event

Evolocumab (n=2,976)

n (%)

Standard therapy (n=1,489)

n (%)


2060 (69.2)

965 (64.8)


222 (7.5)

111 (7.5)


190 (6.4)

90 (6.0)

Neurocognitive events

27 (0.9)

4 (0.3)

Authors’ conclusion: During approximately 1 year of therapy, the use of evolocumab plus standard therapy, as compared with standard therapy alone, significantly reduced LDL-C levels and the incidence of cardiovascular events in a pre-specified exploratory analysis.


STUDY SUMMARY     Robinson et al.
Objective: To evaluate the long-term efficacy and safety of alirocumab. There was also a post hoc exploratory analysis of major adverse cardiovascular outcomes.
Study design: Phase III randomised double-blind placebo-controlled study conducted at 320 sites in 27 countries throughout Africa, Europe, and North and South America.
Study population: A total of 2,341 high cardiovascular risk patients (mean age 60 years, 62% male, LDL-C level >1.8 mmol/L) were randomised (1,553 to alirocumab 150 mg every 2 weeks and 788 to placebo). All were receiving statin therapy before screening.  
Primary variable: ·       Percentage change in LDL-C from baseline to week 24
Secondary variables:
  • Adverse events
  • Major adverse cardiovascular outcomes (coronary heart disease death, non-fatal MI, ischaemic stroke and unstable angina requiring hospitalisation)
Methods: Patients were randomised to double-blind treatment with alirocumab (150 mg every 2 weeks, n=1,553) or placebo (n=788), in addition to standard treatment, every 2 weeks for up to 78 weeks. Post hoc analysis compared the rate of major cardiovascular events between the two study groups.
Main results:
  • The mean percentage change in LDL-C from baseline to week 24 was -61.0% with alirocumab vs 0.8% with placebo (difference of -61.9%, P<0.001). For other efficacy end points see Table.
  • The alirocumab group had higher rates of injection-site reactions than standard therapy (5.9% vs 4.2%), myalgia (5.4% vs 2.9%), neurocognitive events (1.2% vs 0.5%) and ophthalmological events (2.9% vs 1.9%).
  • The rate of major adverse cardiovascular events was lower with alirocumab than with placebo (1.7% vs 3.3%, hazard ratio 0.52, 95% CI 0.31 to 0.90, nominal P=0.02).


Table. Selected efficacy endpoints in intention-to-treat population.

LDL cholesterol endpoint

Alirocumab (mmol/L)

Placebo (mmol/L)

Mean baseline level



Absolute level at week 24



Absolute change from baseline to week 24



Authors’ conclusion: Over a period of 78 weeks, alirocumab when added to statin therapy at the maximally tolerated dose, significantly reduced LDL-C levels. In a post hoc analysis, there was evidence of a reduction in cardiovascular events with alirocumab.


Despite best evidence-based treatment including statins, patients remain at high residual cardiovascular risk. The optimal strategy for reducing this residual risk has been the focus of numerous trials, targeting both LDL-C (as in IMPROVE-IT with ezetimibe1), as well as other atherogenic apolipoprotein B-containing lipids (ACCORD and FIELD with fenofibrate)2,3. While both fenofibrate trials were neutral for the total study population, meta-analysis of fibrate outcomes trials did indicate benefit in the subgroup of patients with atherogenic dyslipidaemia, the combination of elevated triglycerides and low high-density lipoprotein cholesterol.4 In ACCORD, for example, 17% of the total study population had this dyslipidaemia, although other studies suggest that up to 25% of moderate to high risk patients may exhibit this lipid phenotype.2,5,6

However, an alternative strategy has been to focus on LDL-C. As shown by IMPROVE-IT, lowering LDL-C levels by a further 16.7 mg/dL (0.4 mmol/L) with the combination of ezetimibe plus simvastatin compared with simvastatin alone, reduced the incidence of major cardiovascular events by 6% at the end of the trial, indicating the benefit of non-statin LDL-lowering therapeutic approaches. Thus, it has been suggested that further lowering of LDL-C levels, as with the PCSK9 inhibitors, may offer added benefit. In both of these reports, monoclonal antibody therapy targeting PCSK9 reduced LDL-C levels by about 60% compared with best-evidence-based treatment alone, and this translated to about 50% reduction in major cardiovascular events in exploratory analyses. However, it is pertinent to note that PCSK9 inhibition has effects beyond LDL-C lowering, including reduction of lipoprotein(a), a recognised cardiovascular risk factor and potential contributor to residual cardiovascular risk.7

Ultimately, we need to await the final results of ongoing outcomes studies with the PCSK9 inhibitors to evaluate whether this strategy does indeed reduce the high residual cardiovascular risk in patients receiving best evidence-based treatment.


1. Cannon CP, IMPROVE-IT Investigators. IMProved Reduction of Outcomes: Vytorin Efficacy International Trial. A multicenter, double-blind, randomized study to establish the clinical benefit and safety of Vytorin (ezetimibe/simvastatin tablet) vs simvastatin monotherapy in high-risk subjects presenting with acute coronary syndrome.

2. ACCORD Study Group, Ginsberg HN, Elam MB et al. Effects of combination lipid therapy in type 2 diabetes mellitus. N Engl J Med 2010;362:1563-74

3. Keech A, Simes RJ, Barter P et al; FIELD study investigators. Effects of long-term fenofibrate therapy on cardiovascular events in 9795 people with type 2 diabetes mellitus (the FIELD study): randomised controlled trial. Lancet 2005;366:1849-61.

4. Sacks FM, Carey VJ, Fruchart JC. Combination lipid therapy in type 2 diabetes. N Engl J Med 2010;363:692-4.

5. Plana N, Ibarretxe D, Cabré A et al. Prevalence of atherogenic dyslipidemia in primary care patients at moderate-very high risk of cardiovascular disease. Cardiovascular risk perception. Clin Investig Arterioscler 2014;26:274-84.

6. Bestehorn K, Smolka W, Pittrow D et al. Atherogenic dyslipidemia as evidenced by the lipid triad: prevalence and associated risk in statin-treated patients in ambulatory care. Curr Med Res Opin 2010;26:2833-9.

7. Khera AV, Everett BM, Caulfield MP et al. Lipoprotein(a) concentrations, rosuvastatin therapy, and residual vascular risk: an analysis from the JUPITER Trial (Justification for the Use of Statins in Prevention: an Intervention Trial Evaluating Rosuvastatin). Circulation 2014;129:635-42.

Key words PCSK9; cardiovascular outcomes; efficacy; safety; residual cardiovascular risk