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Canadian Journal of Cardiology

New Hope for Lipid-Lowering Beyond Statins: Effect of IMPROVE-IT on Understanding and Implementation of Atherosclerosis Prevention

  • Todd J. Anderson
    Correspondence
    Corresponding author: Dr Todd J. Anderson, 1403-29th St NW, Calgary, Alberta T2N 2T9, Canada. Tel.: +1-403-944-1033; fax: +1-403-944-1592.
    Affiliations
    Libin Cardiovascular Institute of Alberta, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada
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Published:March 18, 2015DOI:https://doi.org/10.1016/j.cjca.2015.03.019
      HMG Co-A (3-hydroxy-3 methylglutaryl coenzyme A) reductase inhibitors, or statins, are the most successful class of medications in cardiovascular history. By blocking cholesterol synthesis, and upregulating low-density lipoprotein (LDL) receptors, these drugs decrease LDL-cholesterol (LDL-C) by up to 50%, significantly reducing cardiovascular events.
      • Cholesterol Treatment Trialists' (CTT) Collaborators
      • Mihaylova B.
      • Emberson J.
      • et al.
      The effects of lowering LDL cholesterol with statin therapy in people at low risk of vascular disease: meta-analysis of individual data from 27 randomised trials.
      More than 25 randomized placebo controlled studies have demonstrated their efficacy, establishing statins as the drug of choice for cardiovascular risk reduction in a primary and secondary prevention setting. All major national guidelines recommend statins as first-line therapy in subjects at appropriate risk for pharmaceutical intervention.
      • Anderson T.J.
      • Gregoire J.
      • Hegele R.A.
      • et al.
      2012 Update of the Canadian Cardiovascular Society guidelines for the diagnosis and treatment of dyslipidemia for the prevention of cardiovascular disease in the adult.
      • European Association for Cardiovascular Prevention & Rehabilitation
      • Reiner Z.
      • Catapano A.L.
      • et al.
      ESC/EAS guidelines for the management of dyslipidaemias: the task force for the management of dyslipidaemias of the European Society of Cardiology (ESC) and the European Atherosclerosis Society (EAS).
      • Stone N.J.
      • Robinson J.
      • Lichtenstein A.H.
      • et al.
      2013 American College of Cardiology/American Heart Association/AHA guideline on the treatment of blood cholesterol to reduce atherosclerotic cardiovascular risk in adults: a report of the American College of Cardiology/American Heart Association task force on practice guidelines.
      Despite these impressive results, significant residual risk remains for subjects at highest risk. In individuals who have established vascular disease, or present with an acute coronary syndrome (ACS), fully 75% of the events are not prevented by current therapy with statins.
      • Cannon C.P.
      • Braunwald E.
      • McCabe C.H.
      • et al.
      Intensive versus moderate lipid lowering with statins after acute coronary syndromes.
      Of course, this is statin therapy in addition to interventions including coronary revascularization, cardiac rehabilitation, antiplatelet drug(s), β-blockers, and inhibition of the renin-angiotensin-aldosterone axis. This residual risk has been the focus of a great deal of epidemiological and interventional research over the past decade.
      Statins predominantly lower LDL-C with minimal effects on other lipid targets such as triglycerides, high-density lipoprotein (HDL) cholesterol (HDL-C), or lipoprotein (a). All of these lipid moieties have been associated with adverse cardiovascular events in cohort studies.
      • Emerging Risk Factors Collaboration
      • Erqou S.
      • Kaptoge S.
      • et al.
      Lipoprotein(a) concentration and the risk of coronary heart disease, stroke, and nonvascular mortality.
      • Yuan G.
      • Al-Shali K.Z.
      • Hegele R.A.
      Hypertriglyceridemia: its etiology, effects and treatment.
      As such, it was natural to test the hypothesis that drugs that target these molecules would improve cardiovascular events. In addition, there was evidence from a number of sources that suggested that lowering LDL-C as aggressively as possible would be another strategy to reduce risk. The “lower is better” sentiment was very prevalent among researchers in this field.
      • Cholesterol Treatment Trialists' (CTT) Collaborators
      • Mihaylova B.
      • Emberson J.
      • et al.
      The effects of lowering LDL cholesterol with statin therapy in people at low risk of vascular disease: meta-analysis of individual data from 27 randomised trials.
      However, in the past few years we have repeatedly witnessed spectacularly disappointing results with combination lipid-lowering therapy. Fibrates and niacin demonstrated reductions in cardiovascular events as monotherapy in the era before statin usage.
      • Canner P.L.
      • Berge K.G.
      • Wenger N.K.
      • et al.
      Fifteen year mortality in coronary drug project patients: long-term benefit with niacin.
      • Frick M.H.
      • Elo O.
      • Haapa K.
      • et al.
      Helsinki heart study: primary-prevention trial with gemfibrozil in middle-aged men with dyslipidemia. Safety of treatment, changes in risk factors, and incidence of coronary heart disease.
      However, in combination with various statins neither class of drugs reduce events. This has been evident in trials that included subjects with diabetes.
      • ACCORD Study Group
      • Ginsberg H.N.
      • Elam M.B.
      • et al.
      Effects of combination lipid therapy in type 2 diabetes mellitus.
      This population would be expected to benefit because of the effect of insulin resistance on increasing triglycerides and lowering HDL-C. The Action to Control Cardiovascular Risk in Diabetes (ACCORD) study failed to show benefit of fenofibrate in combination with simvastatin. Two important secondary prevention studies of niacin were reported in the past few years and were negative.
      • AIM-HIGH Investigators
      • Boden W.E.
      • Probstfield J.L.
      • et al.
      Niacin in patients with low HDL cholesterol levels receiving intensive statin therapy.
      • HPS2-THRIVE Collaborative Group
      • Landray M.J.
      • Haynes R.
      • et al.
      Effects of extended-release niacin with laropiprant in high-risk patients.
      There has been great excitement around new classes of medications such as the inhibitors of cholesterol ester transfer protein (CETP). These agents increase HDL-C by up to 40% and some decrease LDL-C by the same magnitude. However, to date, 2 of these agents have failed to reach their primary targets in randomized trials. Torcetrapib studies were halted prematurely because of off-target blood pressure effects of the drug leading to an increase in mortality.
      • Barter P.J.
      • Caulfield M.
      • Eriksson M.
      • et al.
      Effects of torcetrapib in patients at high risk for coronary events.
      Dalcetrapib did not show benefit with respect to atherosclerosis regression or hard outcomes.
      • Luscher T.F.
      • Taddei S.
      • Kaski J.C.
      • et al.
      Vascular effects and safety of dalcetrapib in patients with or at risk of coronary heart disease: the dal-VESSEL randomized clinical trial.
      Interestingly, a very recent study demonstrated a genetic differential in the response to this agent, with subjects with the ADCY9 gene on chromosome 16 demonstrating reduced events.

      Tardif JC, Rheaume E, Lemieux Perreault LP, et al. Pharmacogenomic determinants of the cardiovascular effects of dalcetrapib. Circ Cardiovasc Genet http://dx.doi.org/10.1161/CIRCGENETICS.114.000663, accessed Jan 15, 2015.

      This will likely lead to further studies with this agent. The results of phase III studies with other CETP inhibitors will be available in the next few years. The recent trial data certainly had people questioning whether there was any utility in trying to modulate cardiovascular risk through a lipid pathway other than with statins.
      The long awaited results of the Improved Reduction of Outcomes: Vytorin Efficacy International Trial (IMPROVE-IT) study were recently presented at the 2014 American Heart Association. This was a randomized trial of simvastatin 40 mg (n = 9077) or simvastatin 40 mg and ezetemibe 10 mg (n = 9067) in subjects who presented with an ACS and low-average cholesterol values (1.3-3.2 mmol/L; mean, 2.46 mmol/L). Subjects were randomized within 10 days after the event and then followed and treated for a median of 6.0 years (n = 5314 primary end points). Despite relatively low LDL-C values, the event rate was high at 4%-5% per year. The LDL-C values achieved in the trial were well below current guidelines (1.8 vs 1.4 mmol/L in the statin vs combination groups). There was no increase in adverse events with the combination therapy. Importantly there was a statistically significant reduction in the primary end point of cardiovascular death, myocardial infarction, stroke, revascularization, and ACS requiring hospitalization. The reduction in the primary end point was 6.4% (P = 0.016). The reduction in the hard events of cardiovascular death, myocardial infarction, and stroke was 10.0% (P = 0.003). When the study was put into the context of the regression analysis that compared percentage reduction in events and the absolute reduction in LDL-C between the 2 groups, it fell within the confidence interval of this previously established relationship (20% reduction per 1 mmol/L decrease in LDL-C).
      In my mind, despite the relatively small magnitude of event reduction (number needed to treat = 50), this study should be considered a landmark trial in lipid research. It is the first trial to demonstrate that lipid modulation beyond statin therapy has a favourable effect on hard end points. This creates great excitement for those who work on existing trials of combination therapy and for those about to begin those studies.
      • Mikhailidis D.P.
      • Athyros V.G.
      Dyslipidaemia in 2013: new statin guidelines and promising novel therapeutics.
      The study validates the already widespread use of ezetemibe in subjects at risk. One previous study had demonstrated that the combination of simvastatin and ezetemibe reduced events compared with placebo in subjects with chronic kidney disease (Study of Heart and Renal Protection). However, there was no statin-only comparison arm in that study.
      • Baigent C.
      • Landray M.J.
      • Reith C.
      • et al.
      The effects of lowering LDL cholesterol with simvastatin plus ezetimibe in patients with chronic kidney disease (study of heart and renal protection): a randomised placebo-controlled trial.
      In addition, there were several studies with surrogate end points that showed no benefit of ezetemibe therapy. Further strength for the benefits of ezetemibe come specifically from recently published studies that used a Mendelian randomization approach. Ezetemibe decreases cholesterol by blocking intestinal absorption via the Niemann Pick C1-like 1 protein receptor. Individuals born with inactivating mutations of the Niemann Pick C1-like 1 gene had lifelong lower LDL-C levels (0.31 mmol/L) and an impressive 53% reduction in coronary heart disease events.
      • Myocardial Infarction Genetics Consortium Investigators
      • Stitziel N.O.
      • Won H.H.
      • et al.
      Inactivating mutations in NPC1L1 and protection from coronary heart disease.
      The IMPROVE-IT study provided further evidence that lower LDL-C levels are beneficial in higher-risk individuals. It does not establish whether a specific target should be advocated but does reassure guideline committees such as the Canadian Cardiovascular Society (CCS) Dyslipidemia committee that the current recommendations, which include targets, are reasonable. There was much debate about this point after the introduction of the 2013 American College of Cardiology/American Heart Association guidelines in which statin therapy was recommended for certain risk individuals without the need for a threshold LDL-C or subsequent target after therapy was initiated.
      • Stone N.J.
      • Robinson J.
      • Lichtenstein A.H.
      • et al.
      2013 American College of Cardiology/American Heart Association/AHA guideline on the treatment of blood cholesterol to reduce atherosclerotic cardiovascular risk in adults: a report of the American College of Cardiology/American Heart Association task force on practice guidelines.
      It is appreciated that the magnitude of LDL-C-lowering is modest with ezetemibe. There will now be great anticipation of the ongoing Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9) trials in which LDL-C reductions of 50%-60% can be demonstrated in subjects already treated with statins.
      • Robinson J.G.
      • Nedergaard B.S.
      • Rogers W.J.
      • et al.
      Effect of evolocumab or ezetimibe added to moderate- or high-intensity statin therapy on LDL-C lowering in patients with hypercholesterolemia: the LAPLACE-2 randomized clinical trial.
      • Stein E.A.
      • Mellis S.
      • Yancopoulos G.D.
      • et al.
      Effect of a monoclonal antibody to PCSK9 on LDL cholesterol.
      • Cannon C.P.
      • Shah S.
      • Dansky H.M.
      • et al.
      Safety of anacetrapib in patients with or at high risk for coronary heart disease.
      The IMPROVE-IT trial has created the expectation that significant attenuation of cardiovascular end points could be seen in these trials. Similarly, some CETP inhibitors significantly decrease LDL-C while they increase HDL-C. The LDL-C effect alone should result in event reduction if there are no off-label effects as was seen with torcetrapib. This would appear to be the case for the newer agents.
      • Cannon C.P.
      • Shah S.
      • Dansky H.M.
      • et al.
      Safety of anacetrapib in patients with or at high risk for coronary heart disease.
      Like any good clinical trial, IMPROVE-IT poses a number of questions. Was the benefit seen related to the specific mechanism of action of ezetemibe, or was it simply an LDL-C-lowering effect? Although the ‘lower is better’ hypothesis remains alive and well, what is our new target for subjects with established atherosclerosis and ongoing risk? A randomized trial with specific targets will be required to answer that question and will be important in light of the new and effective drugs that will likely find their way to the marketplace in the next few years. The level of LDL-C in IMPROVE-IT was well below current guidelines for countries with targets. Will similar event reductions be realized in subjects with stable coronary disease or in primary prevention where optimal levels are not achieved because of genetic factors, statin intolerance, or diminished effect? It is not likely that clinical trial evidence will ever become available to answer that question.
      Finally, what should guidelines committees do in light of the present information? This will not only apply to routine combination therapy with statin and ezetemibe in an ACS population, but whether targets should continue to be used and if yes then at what level? The current CCS guideline recommends levels of < 2.0 mmol/L in high-risk subjects. The last version of the European Society Cardiology guideline advocated for < 1.8 mmol/L in those at very high risk. Without a specific trial this will be an interesting discussion as the CCS guidelines are updated in 2015.
      In summary, this landmark study provides a reality check for health care providers who treat subjects with atherosclerotic risk. Statins should not be considered the only pharmacological therapy any more based on the present trial. There is life beyond statins for new agents and certainly for ezetemibe in certain patient populations. Good news indeed for our patients.

      Disclosures

      T.J.A. participates in studies funded by Merck and AMGEN.

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        Effect of evolocumab or ezetimibe added to moderate- or high-intensity statin therapy on LDL-C lowering in patients with hypercholesterolemia: the LAPLACE-2 randomized clinical trial.
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