Commentary on the highs and lows of cardiovascular disease prevention

2017 saw the culmination of a number of trials evaluating novel approaches to prevention of atherosclerotic cardiovascular disease (ASCVD). Here we overview some of the highlights from the year.

The pinnacle of the PCSK9 revolution?

FOURIER (Further Cardiovascular Outcomes Research with PCSK9 Inhibition in Subjects with Elevated Risk) provided definitive evidence of the outcomes benefits of lowering plasma levels of low-density lipoprotein cholesterol (LDL-C) beyond current goals. FOURIER included patients with clinically evident ASCVD, defined as a history of myocardial infarction (MI), nonhaemorrhagic stroke, or symptomatic peripheral artery disease (PAD), as well as additional characteristics that placed them at higher cardiovascular risk. In these patients, the addition of the PCSK9 (proprotein convertase subtilisin/kexin type 9) inhibitor evolocumab to intensive statin therapy lowered LDL-C levels by 59% and led to a 15% reduction in major cardiovascular events and 20% reduction in the secondary ‘hard outcomes’ endpoint, a composite of cardiovascular death, MI and stroke.1 Safety data were unremarkable with an adverse event profile for evolocumab comparable with that previously reported.1,2

Subsequent insights from FOURIER were also illuminating. First, there was evidence to indicate no lower LDL-C threshold for clinical benefit. In a pre-specified analysis using data from 25,982 patients with LDL C values at week 4, there was a strong linear relationship between attained plasma LDL-C concentration and the risk of major cardiovascular events, extending to levels <0.20 mmol/L, with no increase in safety events.Another FOURIER analysis showed that the benefit of evolocumab treatment was similar in patients with and without diabetes, and that treatment did not worsen diabetes or increase the risk of developing diabetes within 2 years.4 Added to this, post hoc analyses showed that evolocumab was equally effective in reducing cardiovascular events in ASCVD patients irrespective of baseline LDL-C level (<1.8 mmol/L or ≥1.8 mmol/L), or whether background statin therapy was of maximal or submaximal potency.5

Other important analyses from FOURIER highlighted the benefit of PCSK9 inhibition in very high risk groups, including patients with peripheral artery disease (PAD),6 – commonly underdiagnosed and undertreated – as well as those with high-risk MI characteristics, including recent or recurrent MI or multivessel disease.7 In the case of PAD patients who typically exhibit more extensive atheroma and a greater risk factor burden, the absolute clinical benefit with PCSK9 inhibition was more than double that attained in patients without PAD. Furthermore, not only did further lowering of LDL-C levels reduce cardiovascular events, but there was also significant reduction in major adverse limb events, defined as acute limb ischaemia, major amputation, or urgent peripheral revascularization for ischaemia. Incidentally, exploratory analyses showed a linear relationship between attained plasma LDL-C level and reduction in the risk of major adverse limb events extending to 0.26 mmol/L.6

It has, however, not been ‘all fine sailing’ for PCSK9 inhibition. Another PCSK9 inhibitor, bococizumab was terminated due to attenuation of LDL lowering effect as a result of anti-drug antibody development; an effect specific to this antibody.Despite this, insights from the SPIRE (Evaluation of Bococizumab in Reducing the Occurrence of Major Cardiovascular Events in High Risk Subjects) cardiovascular outcomes studies provided supplementary evidence to that of FOURIER. In the SPIRE-2 cardiovascular outcomes trial in higher-risk patients (mean baseline LDL-C 3.4 mmol/L) treatment with bococizumab led to a 21% reduction in major cardiovascular events over 12 months (the time of closure of the study).9 The SPIRE programme also offered important information in patients with familial hypercholesterolaemia (FH). In a cohort of more than 1,500 FH patients, diagnosed either clinically or by molecular analysis, there was similar cardiovascular benefit, in terms of hard cardiovascular outcomes, from PCSK9 inhibition as in patients without FH.10

FOURIER has undoubtedly provided definitive evidence for PCSK9 inhibition as a therapeutic strategy in high risk patients with residual LDL-C burden despite intensive statin therapy. From a practical perspective, however, access to these treatments remains the major issue. In an updated statement, a Task Force from the European Society of Cardiology and European Atherosclerosis Society provided practical guidance to aid clinicians considering treatment with a PCSK9 inhibitor in ASCVD patients or FH patients without clinical events, focusing on threshold LDL-C levels and other indices of cardiovascular risk.11 Ultimately, to ensure judicious use of these treatments in cost-conscious healthcare systems, a pragmatic approach targeting treatment to those at highest risk, likely to attain highest clinical benefit, will no doubt prevail.12

Beyond LDL-C

Targeting inflammation

While FOURIER has shown that lowering plasma LDL-C levels beyond current goals reduces cardiovascular events, it is also evident that a proportion of high risk patients continue to experience events even at low LDL-C levels. Added to this, evidence from the GLobal Assessment of Plaque reGression With a PCSK9 antibOdy as Measured by intraVascular Ultrasound (GLAGOV) study showed that despite very low levels of LDL-C on evolocumab (added to intensive statin therapy), 35% of these patients still had atheroma progression over the 18-month treatment period.13 Taken together, these findings reinforce the concept that the development and progression of atherosclerosis is multifactorial; although LDL-C is a major modifiable cardiovascular risk factor, there are also other contributors to this risk.

Mechanistically, it is known that atherosclerosis results from chronic inflammation at the sites of cholesterol accumulation in the artery wall, with LDL and its contents acting as the driver of both innate and adaptive immunity mechanisms. Indeed, inflammation has long been recognized as a predictor of future cardiovascular events.14 The question posed by many has been whether targeting inflammation could reduce cardiovascular events in high-risk patients.

In 2017, this question was answered by CANTOS (Canakinumab Anti-inflammatory Thrombosis Outcomes Study), truly a landmark proof-of-concept study.15 CANTOS tested whether targeting interleukin-1β (IL-1β), a proinflammatory cytokine that has multiple roles in the atherothrombotic process, with the monoclonal IL-1β antibody canakinumab, could reduce cardiovascular events. In terms of design, CANTOS could be considered a dose-ranging study in over 10,000 patients with a previous MI and elevated levels of high-sensitivity C-reactive protein (hs-CRP, ≥2 mg/L; median at baseline ~4.2 mg/L). Importantly, these patients were stabilized with intensive statin therapy resulting in lower plasma LDL-C levels at baseline than observed in FOURIER (2.12 mmol/L vs. 2.38 mmol/L). Thus, the study was truly investigating the impact of treatment solely targeting inflammation.

While placebo and the lowest dose of canakinumab (50 mg) had no effect, treatment with the two higher doses (150 mg and 300 mg) showed a 15% reduction in the primary endpoint (a composite of non-fatal MI, non-fatal stroke, or cardiovascular death), as well as 17% reduction in the secondary endpoint, which also included hospitalization for unstable angina requiring urgent revascularization. This latter finding was largely driven by a 30% reduction in the need for revascularization. And, as shown for LDL-C in FOURIER, lower is also better for inflammation, as individuals in CANTOS who showed a greater response to canakinumab (as defined by the extent of reduction in hsCRP) also derived greater clinical benefit.16 From a practical viewpoint, therefore, the magnitude of hsCRP reduction following a single dose of canakinumab might provide a simple means to identify individuals most likely to derive the greatest benefit from this treatment.

Not surprisingly, given the mode of action of canakinumab, there was an increase in infection, notably fatal infection, compared to placebo, but also fewer reports of arthritis, gout and osteoarthritis. Canakinumab was also associated with reduction in cancer mortality, which may in part be explained by the role of inflammation in cancer.17

REVEAL: less than revealing?

Inhibition of cholesteryl ester transfer protein (CETP), which facilitates exchange of esterified cholesterol from high-density lipoprotein (HDL) to very low-density lipoprotein (VLDL) and LDL, has had a long and tortuous road as a potential therapeutic strategy. The first of the CETP inhibitors, torcetrapib, was terminated due to excess mortality and cardiovascular events, despite raising HDL cholesterol (HDL-C) by more than 60% and lowering LDL-C by 20% in statin-treated patients. These effects were subsequently attributed to off-target adverse effects of torcetrapib.18 Dalcetrapib, with only a modest effect in raising HDL-C and no effect on LDL-C, was terminated after lack of benefit in the dal-OUTCOMES study in patients with recent acute coronary syndrome (ACS).19 More recently, evacetrapib – which both raised HDL-C by more than 100% and lowered LDL-C by more than 30% – was also were terminated due to futility following an interim analysis of the ACCELERATE study in an ACS population.20

Anacetrapib, the most recent in the line of CETP inhibitors to be tested in clinical development, had a similar lipid modifying profile to evacetrapib. Culmination of REVEAL (Randomized EValuation of the Effects of Anacetrapib Through Lipid-modification study) in more than 30,000 patients with stable ASCVD (predominantly coronary heart disease) and very well controlled LDL-C levels (mean 1.58 mmol/L at baseline) on intensive statin therapy, revealed a modest albeit significant benefit on the primary outcome (major coronary events) with a relative risk reduction of 9% with anacetrapib versus placebo (statin alone); this only emerged after 2 years of treatment.21 Safety findings indicated no adverse effect of anacetrapib on cancer, liver, muscle, cognitive function, or other adverse events, and a lower incidence of new-onset diabetes than placebo (5.3% versus 6.0%, p=0.05), although there was higher blood pressure on anacetrapib (by 0.7 mmHg for systolic blood pressure, and 0.3 mmHg for diastolic blood pressure versus placebo).21  However, the writing was on the wall for anacetrapib with evidence of accumulation in adipose tissue, and uncertainty regarding the long-term consequences of this effect.22 So, 2017 draws to a close for now for this potential therapeutic strategy for reducing residual cardiovascular risk. 

Back to basics: can we do better with primary prevention?

Global risk scores provide a guide to clinicians in primary prevention efforts. Yet these tools are far from infallible, and in some individuals, fail to detect risk until the consequences are irreversible. Indeed, the prospective PESA (Progression of Early Subclinical Atherosclerosis) study has shown that subclinical atherosclerosis is prevalent in low-risk middle-aged adults.23 Even among individuals with LDL-C levels considered normal (mean ~3.1 mmol/L) and without other established cardiovascular risk factors (i.e. non-smoking, untreated blood pressure <140/90 mm Hg, fasting glucose <126 mg/dL, and HDL-C ≥1.03 mmol/L), half had subclinical atherosclerosis, with multiple vascular sites affected in nearly 30%.24 The critical role of LDL in early human atherogenesis was reaffirmed by evidence of an independent association between plasma LDL-C level and the presence and extent of atherosclerosis.24 These important findings from the PESA study underline the need for new approaches to primary prevention, potentially involving a combination of imaging, biomarkers and genetics, to allow clinicians to instigate management earlier and thus prevent the disabling consequences of ASCVD.

Looking to 2018

2017 was a rollercoaster for lipid and cardiovascular research; what will 2018 offer? In brief, we look forward to results of the ODYSSEY OUTCOMES study with alirocumab in patients with a recent ACS. With a longer treatment duration, this study may offer insights into the impact of PCSK9 inhibition on cardiovascular mortality. Beyond the PCSK9 monoclonal antibodies, there is also the promise of inclisiran, a long-acting RNA interference therapeutic agent that inhibits the synthesis of PCSK9, with further data awaited in high risk patient groups, including those with FH. There is also likely to be novel insights from studies with bempedoic acid (previously known as ETC-1002), an inhibitor of adenosine triphosphate-citrate lyase, an enzyme involved in fatty acid and cholesterol synthesis. Animal and in vitro studies have shown that bempedoic acid decreases LDL-C levels and attenuates atherosclerosis.25
And beyond LDL-C, there is also likely to be news from studies evaluating novel therapeutic approaches for the management of high triglycerides and elevated lipoprotein(a). 2018 offers more blockbusters in the areas of lipid research and ASCVD prevention, so hold on to your hats!!


1. Sabatine MS, Giugliano RP, Keech AC et al. Evolocumab and clinical outcomes in patients with cardiovascular disease. N Engl J Med 2017;376:1713-1722.

2. Roth EM. A safety evaluation of evolocumab. Expert Opin Drug Saf 2018;17:99-106.

3. Giugliano RP, Pedersen TR, 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;390:1962-1971.

4. Sabatine MS, Leiter LA, Wiviott SD et al. Cardiovascular safety and efficacy of the PCSK9 inhibitor evolocumab in patients with and without diabetes and the effect of evolocumab on glycaemia and risk of new-onset diabetes: a prespecified analysis of the FOURIER randomised controlled trial. Lancet Diabetes Endocrinol 2017;5:941-950.

5. Giugliano RP, Keech A, Murphy SA et al. Clinical efficacy and safety of evolocumab in high-risk patients receiving a statin: secondary analysis of patients with low LDL cholesterol levels and in those already receiving a maximal-potency statin in a randomized clinical trial. JAMA Cardiol 2017;2:1385-1391.

6. Bonaca MP, Nault P, Giugliano RP et al. Low-density lipoprotein cCholesterol lowering with evolocumab and outcomes in patients with peripheral artery disease. Insights from the FOURIER Trial (Further Cardiovascular Outcomes Research With PCSK9 Inhibition in Subjects With Elevated Risk). Circulation 2017; doi: 10.1161/CIRCULATIONAHA.117.032235. [Epub ahead of print]

7. Sabatine MS, De Ferrari GM, Giugliano RP et al. Clinical benefit of evolocumab in patients with a history of MI: an analysis of FOURIER. American Heart Association Annual Scientific Sessions. Late-Breaking Science in Prevention. November 13, 2017.

8. Ridker PM, Tardif JC, Amarenco P et al. Lipid reduction variability and antidrug-antibody formation with bococizumab. N Engl J Med 2017;376:1517-1526.

9. Ridker PM, Revkin J, Amarenco P et al. Cardiovascular efficacy and safety of bococizumab in high-risk patients. N Engl J Med 2017;376:1527-15.39

10. Ridker PM on behalf of the Studies of PCSK9 Inhibition and the Reduction of vascular Events (SPIRE) Investigators. Cardiovascular Efficacy of PCSK9 Inhibition Among 1,578 Patients With Familial Hypercholesterolemia: The SPIRE Clinical Trials FH Analysis. Abstract M2006. AHA Scientific Sessions, Presented 13 November, 2017.

11. Landmesser U, Chapman MJ, Stock JK et al. 2017 Update of ESC/EAS Task Force on practical clinical guidance for proprotein convertase subtilisin/kexin type 9 inhibition in patients with atherosclerotic cardiovascular disease or in familial hypercholesterolaemia. Eur Heart J 2017;doi: 10.1093/eurheartj/ehx549. [Epub ahead of print]

12. Annemans L, Packard CJ, Briggs A, Ray KK. ‘Highest risk-highest benefit’ strategy: a pragmatic, cost-effective approach to targeting use of PCSK9 inhibitor therapies. Eur Heart J 2017;doi: 10.1093/eurheartj/ehx710. [Epub ahead of print].

13. Nicholls SJ, Puri R, Anderson T et al. Effect of evolocumab on progression of coronary disease in statin-treated patients: the GLAGOV randomized clinical trial. JAMA 2016;316:2373-2384.

14. Liuzzo G, Biasucci LM, Gallimore JR et al. The prognostic value of C-reactive protein and serum amyloid A in severe unstable angina. N Engl J Med 1994;331:417–424.

15. Ridker PM, Everett BM, Thuren T et al. Antiinflammatory therapy with canakinumab for atherosclerotic disease. N Engl J Med 2017;377:1119-1131.

16. Ridker PM, MacFadyen JG, Everett BM et al. Relationship of C-reactive protein reduction to cardiovascular event reduction following treatment with canakinumab: a secondary analysis from the CANTOS randomised controlled trial. Lancet 2017; doi: 10.1016/S0140-6736(17)32814-3. [Epub ahead of print]

17. Ridker PM, MacFadyen JG, Thuren T et al. Effect of interleukin-1β inhibition with canakinumab on incident lung cancer in patients with atherosclerosis: exploratory results from a randomised, double-blind, placebo-controlled trial. Lancet 2017;390:1833-1842.

18. Barter PJ, Caulfield M, Eriksson M, et al. ILLUMINATE Investigators Effects of torcetrapib in patients at high risk for coronary events. N Engl J Med 2007;357:2109–2122.

19. Schwartz GG, Olsson AG, Abt M et al. Effects of dalcetrapib in patients with a recent acute coronary syndrome. N Engl J Med 2012;367:2089-2099.

20. Lincoff AM, Nicholls SJ, Riesmeyer JS et al. Evacetrapib and cardiovascular outcomes in high-risk vascular disease. N Engl J Med 2017;376:1933-1942.

21. HPS3/TIMI55–REVEAL Collaborative Group, Bowman L, Hopewell JC et al. Effects of anacetrapib in patients with atherosclerotic vascular disease. N Engl J Med 2017;377:1217-1227.

22. Krishna R, Gheyas F, Liu Y et al. Chronic administration of anacetrapib is associated with accumulation in adipose and slow elimination. Clin Pharmacol Ther 2017;102:832-840.

23. Fernández-Friera L, Peñalvo JL, Fernández-Ortiz A et al. Prevalence, vascular distribution, and multiterritorial extent of subclinical atherosclerosis in a middle-aged cohort: the PESA (Progression of Early Subclinical Atherosclerosis) Study. Circulation 2015;131:2104-2113.

24. Fernández-Friera L, Fuster V2, López-Melgar B et al. Normal LDL-cholesterol levels are associated with subclinical atherosclerosis in the absence of risk factors. J Am Coll Cardiol 2017;70:2979-2991.

25. Pinkosky SL, Newton RS, Day EA et al. Liver-specific ATP-citrate lyase inhibition by bempedoic acid decreases LDL-C and attenuates atherosclerosis. Nat Commun 2016;7:13457.