The so-called LDL hypothesis is the concept that excess low-density lipoprotein (LDL) cholesterol is a causal factor in the development of atherosclerotic vascular disease. By extension, this hypothesis also assumes that reducing LDL cholesterol levels, regardless of the means, should produce a corresponding reduction in cardiovascular events. Considerable evidence supports the LDL hypothesis, including animal studies and epidemiologic studies involving humans, as well as clinical trials of both statins and nonstatin lipid-modifying agents. In a meta-analysis that included more than 90,000 participants in 14 randomized trials of statins, the Cholesterol Treatment Trialists’ (CTT) collaborators found that, on average, a reduction of 1 mmol per liter (38.7 mg per deciliter) in LDL cholesterol levels yields a consistent 23% reduction in the risk of major coronary events over 5 years

Jarcho, John A.

Keaney, John F., Jr.

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University of Massachusetts Medical School eScholarship@UMMS Cardiovascular Medicine Publications and Presentations Cardiovascular Medicine 2015-06-18 Proof That Lower Is Better--LDL Cholesterol and IMPROVE-IT John A. Jarcho Brigham and Women's Hospital Et al. Let us know how access to this document benefits you. Follow this and additional works at: https://escholarship.umassmed.edu/cardio_pp  Part of the Cardiology Commons, Cardiovascular Diseases Commons, and the Lipids Commons Repository Citation Jarcho JA, Keaney JF. (2015). Proof That Lower Is Better--LDL Cholesterol and IMPROVE-IT. Cardiovascular Medicine Publications and Presentations. https://doi.org/10.1056/NEJMe1507041. Retrieved from https://escholarship.umassmed.edu/cardio_pp/93 This material is brought to you by eScholarship@UMMS. It has been accepted for inclusion in Cardiovascular Medicine Publications and Presentations by an authorized administrator of eScholarship@UMMS. For more information, please contact Lisa.Palmer@umassmed.edu. E d i t o r i a lT h e  n e w  e ngl a nd  j o u r na l  o f  m e dic i n en engl j med 372;25 nejm.org June 18, 20152448Proof That Lower Is Better — LDL Cholesterol and IMPROVE-ITJohn A. Jarcho, M.D., and John F. Keaney, Jr., M.D.The so-called LDL hypothesis is the concept that excess low-density lipoprotein (LDL) cholesterol is a causal factor in the development of athero-sclerotic vascular disease. By extension, this hypothesis also assumes that reducing LDL cho-lesterol levels, regardless of the means, should produce a corresponding reduction in cardiovas-cular events. Considerable evidence supports the LDL hypothesis, including animal studies and epidemiologic studies involving humans, as well as clinical trials of both statins and nonstatin lipid-modifying agents. In a meta-analysis that included more than 90,000 participants in 14 ran-domized trials of statins, the Cholesterol Treat-ment Trialists’ (CTT) collaborators found that, on average, a reduction of 1 mmol per liter (38.7 mg per deciliter) in LDL cholesterol levels yields a consistent 23% reduction in the risk of major coronary events over 5 years.1Despite this body of evidence, there has been a long-standing argument that the beneficial ef-fects of statins are not adequately explained by their effects on LDL cholesterol. Statins have a complex array of biologic effects — including amelioration of endothelial dysfunction, increased nitric oxide bioavailability, antioxidant properties, and inhibition of inflammation — that are un-related to their lipid-lowering effect and that are sometimes called “pleiotropic effects.”2 It has been argued that such effects may account for at least some of the benefit of statin therapy in preventing cardiovascular events. This alterna-tive theory is sometimes referred to as the “statin hypothesis” — the idea that statins have a unique efficacy in atherosclerotic vascular dis-ease that is not shared by other lipid-modifying agents and that reduction in LDL cholesterol levels is not the only basis for the beneficial ef-fect of statins (Fig. 1).Several recent negative clinical trials have seemed to offer support for the statin hypothe-sis. In each of these trials, the addition of a nonstatin lipid-modifying agent to statin therapy conferred no significant increment in cardiovas-cular benefit over that seen with a statin alone.3-6 In addition, in a clinical trial of rosuvastatin,7 the beneficial effect of this statin was found to correlate not only with its effect on LDL choles-terol levels but also independently with its ability to reduce the level of high-sensitivity C-reactive protein, a marker of inflammation.8 Given these findings, the 2013 cholesterol treatment guide-lines of the American College of Cardiology and the American Heart Association heavily empha-sized statin therapy as the preferred treatment option for patients with established cardiovascu-lar disease or hyperlipidemia.9With this background, the report by Cannon et al. of the Improved Reduction of Outcomes: Vytorin Efficacy International Trial (IMPROVE-IT),10 now published in the Journal, offers important new evidence in favor of the LDL hypothesis. In IMPROVE-IT, 18,144 patients who had had an acute coronary syndrome were randomly as-signed to either simvastatin (40 mg) plus ezeti-mibe (10 mg) or to simvastatin (40 mg) plus placebo. At 1 year, the mean LDL cholesterol level was 53.2 mg per deciliter (1.4 mmol per liter) in the simvastatin-plus-ezetimibe group, and 69.9 mg per deciliter (1.8 mmol per liter) in the simvas-tatin-monotherapy group. The primary end point was a composite of cardiovascular death, major coronary event (nonfatal myocardial infarction, unstable angina, or coronary revascularization), The New England Journal of Medicine Downloaded from nejm.org at UMass Medical School on April 30, 2018. For personal use only. No other uses without permission.  Copyright © 2015 Massachusetts Medical Society. All rights reserved. Editorialn engl j med 372;25 nejm.org June 18, 2015 2449or nonfatal stroke. At 7 years, the rate of the primary end point was significantly lower, by 2.0 percentage points, in the simvastatin-plus-ezetimibe group than in the simvastatin-mono-therapy group (32.7% vs. 34.7%). No significant differences in rates of adverse events were seen between the two study groups.IMPROVE-IT is a landmark study in that it is the first clinical trial to show a benefit of adding a nonstatin lipid-modifying agent to statin ther-apy. Ezetimibe, the added agent in this trial, works by reducing the intestinal absorption of cholesterol, a distinct mechanism that is unre-lated to that of statins. And yet, the event-rate reduction with the addition of ezetimibe was precisely the same as that predicted by the CTT analysis of statin trials described above (see Fig. 2 in the article by Cannon et al.),10 which suggests that reduction of LDL cholesterol levels per se explains the effect of statins on coronary heart disease.These results offer important hope to patients who have unacceptable side effects from statin therapy and to those who may not achieve ade-quate LDL reduction with statins. The 2013 guidelines do not recommend the use of spe-cific targets for LDL cholesterol levels, but they do acknowledge that some patients may have an “insufficient response to statin therapy” and that in such patients the addition of a nonstatin agent may be considered.9 The results of  IMPROVE-IT should, at a minimum, reinforce such a recommendation and will undoubtedly rekindle arguments in favor of targets for LDL cholesterol levels.The results of IMPROVE-IT also imply that other interventions to reduce LDL cholesterol levels may prove to be beneficial. In this regard, the recent development of PCSK9 inhibitors is of note. These agents reduce LDL-receptor degrada-tion, thereby enhancing LDL clearance from the circulation, and they have been shown to reduce LDL cholesterol levels by as much as 60%.11,12Definitive clinical outcomes trials with these agents are ongoing.IMPROVE-IT should not be interpreted as showing anything uniquely beneficial about the use of ezetimibe. Indeed, the real implication of IMPROVE-IT is to suggest that all reductions in LDL levels, regardless of mechanism, are of equivalent benefit. Thus, a patient who is cur-rently being treated with 40 mg of simvastatin would be expected to benefit just as much from a higher-intensity statin regimen (e.g., 40 to 80 mg of atorvastatin or 20 to 40 mg of rosuvastatin) as from the addition of ezetimibe, assuming equiv-alent reductions in LDL cholesterol levels.A sobering observation was that 42% of the participants in IMPROVE-IT, regardless of treat-ment assignment, discontinued the study medi-cation prematurely. As noted by the authors, this discontinuation rate is approximately 7% per year, which closely mirrors that seen in other trials. Since lipid-lowering is presumably intended to be a lifelong goal, this diminishment in long-term use is an important practical clinical con-cern, and one that suggests that treatment ad-herence to lipid-lowering therapy needs to be an ongoing focus of practitioner attention. It also raises questions about the practicality of long-term use of PCSK9 inhibitors, since all these agents are currently given by subcutaneous in-jection once every 2 to 4 weeks.Overall, IMPROVE-IT provides us with impor-tant information on the value of lowering LDL cholesterol levels, regardless of the agent used. These data help emphasize the primacy of LDL cholesterol lowering as a strategy to prevent coro-nary heart disease. Perhaps the LDL hypothesis should now be considered the “LDL principle.”Figure 1. Schematic Depiction of the Statin Hypothesis.The reduction in low-density lipoprotein (LDL) choles-terol with lipid-modifying agents is plotted against the reduction in cardiovascular events under either the LDL hypothesis or the statin hypothesis. The putative add-ed “pleiotropic” effects of statins (effects that are un-related to their lipid-lowering effects) are represented by the shaded area. The IMPROVE-IT trial provides im-portant new evidence in favor of the LDL hypothesis.Reduction in EventsReduction in LDL CholesterolStatin HypothesisLDL HypothesisThe New England Journal of Medicine Downloaded from nejm.org at UMass Medical School on April 30, 2018. For personal use only. No other uses without permission.  Copyright © 2015 Massachusetts Medical Society. All rights reserved. Editorialn engl j med 372;25 nejm.org June 18, 20152450Disclosure forms provided by the authors are available with the full text of this article at NEJM.org.From the University of Massachusetts Medical School, Worces-ter, MA (J.F.K.). This article was published on June 3, 2015, at NEJM.org.1. Baigent C, Keech A, Kearney PM, et al. Efficacy and safety of cholesterol-lowering treatment: prospective meta-analysis of data from 90,056 participants in 14 randomised trials of statins. Lancet 2005; 366: 1267-78.2. Davignon J. Beneficial cardiovascular pleiotropic effects of statins. Circulation 2004; 109: Suppl 1: III39-III43.3. Ginsberg HN, Elam MB, Lovato LC, et al. Effects of combi-nation lipid therapy in type 2 diabetes mellitus. N Engl J Med 2010; 362: 1563-74.4. Boden WE, Probstfield JL, Anderson T, et al. Niacin in pa-tients with low HDL cholesterol levels receiving intensive statin therapy. N Engl J Med 2011; 365: 2255-67.5. Landray MJ, Haynes R, Hopewell JC, et al. Effects of extend-ed-release niacin with laropiprant in high-risk patients. N Engl J Med 2014; 371: 203-12.6. 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: 2089-99.7. Ridker PM, Danielson E, Fonseca FAH, et al. Rosuvastatin to prevent vascular events in men and women with elevated C-reac-tive protein. N Engl J Med 2008; 359: 2195-207.8. Ridker PM, Danielson E, Fonseca FA, et al. Reduction in C-reactive protein and LDL cholesterol and cardiovascular event rates after initiation of rosuvastatin: a prospective study of the JUPITER trial. Lancet 2009; 373: 1175-82.9. Stone NJ, Robinson JG, Lichtenstein AH, et al. 2013 ACC/AHA guideline on the treatment of blood cholesterol to reduce athero-sclerotic cardiovascular risk in adults: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. Circulation 2014; 129: Suppl 2: S1-S45.10. Cannon CP, Blazing MA, Giugliano RP, et al. Ezetimibe added to statin therapy after acute coronary syndromes. N Engl J Med 2015; 372: 2387-97.11. Robinson JG, Farnier M, Krempf M, et al. Efficacy and safety of alirocumab in reducing lipids and cardiovascular events. N Engl J Med 2015; 372: 1489-99.12. Sabatine MS, Giugliano RP, Wiviott SD, et al. Efficacy and safety of evolocumab in reducing lipids and cardiovascular events. N Engl J Med 2015; 372: 1500-9.DOI: 10.1056/NEJMe1507041Copyright © 2015 Massachusetts Medical Society.The New England Journal of Medicine Downloaded from nejm.org at UMass Medical School on April 30, 2018. For personal use only. No other uses without permission.  Copyright © 2015 Massachusetts Medical Society. All rights reserved. 

Proof That Lower Is Better--LDL Cholesterol and IMPROVE-IT

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Proof That Lower Is Better--LDL Cholesterol and IMPROVE-IT

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