Hypercholesterolemia is a major modifiable risk factor for coronary heart disease (CHD) and interventions to lower plasma cholesterol were shown to reduce cardiovascular risk. The Cholesterol Treatment Trialists’ collaborators meta-analyses have consistently demonstrated that cholesterol-lowering statin drugs are effective for the prevention of major vascular events [1,2], most recently demonstrating a similar effectiveness in men and women . There has been debate whether the success of statin therapy to reduce CHD is a class specific effect and might at least partially be attributed to nonlipid-lowering ‘pleiotropic effects’ of statins . This hypothesis has gained special attention in light of negative clinical outcome trials for other lipid-modifying agents over the last years [5–8]. The recent publication of the IMPROVE-IT study now offers strong support that lowering LDL-cholesterol (LDL-C) is effective in preventing coronary events, regardless of the agent used [9▪▪]. In this trial, 18 144 patients who had an acute coronary syndrome received either ezetimibe (10 mg) or placebo on top of simvastatin (40–80 mg). Adding ezetimibe to simvastatin further decreased LDL-C by 16 mg/dl compared with monotherapy (53.7 mg/dl versus 69.5 mg/dl). This was associated with a significant reduction of absolute risk by 2% for the primary composite endpoint of cardiovascular death, major coronary events or nonfatal stroke at 7 years. The clinical benefit of adding ezetimibe was modest, but falls in line with the expected effects of lowering LDL-C by 16 mg/dl with the use of statin therapy . Thus, IMPROVE-IT is the first clinical outcome trial, demonstrating that LDL-C reduction by a nonstatin lipid therapy reduces CVD events and adds important new evidence to the ‘lower is better’ hypothesis for LDL-C.
Proprotein convertase subtisilin/kexin type 9 (PCSK9) inhibitors are a novel class of therapeutics that have received much attention because of their profound LDL-C-lowering effects. Recently, efficacy and safety data for alirocumab (ODYSSEY LONG TERM) and evolocumab (OSLER 1 and OSLER-2), monoclonal antibodies to PCSK9, have been published [10▪▪,11▪▪]. In both studies, subcutaneous injection of the PCSK9 antibody reduced LDL-C by ∼60% on top of statin therapy, resulting in a median LDL-C of 48 mg/dl. In accordance with the previous studies, PCSK9 inhibition also significantly lowered plasma levels of lipoprotein(a) by yet-to-be determined mechanisms. In both studies, no excess of serious adverse events was observed; also not in the group of patients who had extremely low LDL-C levels (<25 mg/dl). In both studies, neurocognitive events, however, tended to be higher in the treatment group, an observation that warrants careful monitoring in long-term studies.
Most excitingly, both trials carried out post-hoc analyses and demonstrated a significant reduction of major cardiovascular events in the PCSK9 inhibitor group by approximately 50%. Similar findings were obtained in a recent meta-analysis of 24 randomized-controlled trials from phase 2 and phase 3 studies with PCSK9 inhibitors . These results are very encouraging, but need to be interpreted with great caution, as the number of events was low and follow-up time was limited to 12–18 months. Long-term clinical studies, adequately powered to assess the effect of PCSK9 inhibition on cardiovascular events, are ongoing and will provide a definite answer in the near future. As PCSK9 loss-of-function mutations in humans are associated with significantly lower LDL-C levels and a substantial protection from CHD , one might speculate that outcome trials will yield a positive result. Similarly, a human genetics study on loss-of-function mutations in NPC1L1, the gene which codes for the protein target of ezetimibe, demonstrated a reduced risk of CHD  and thereby correctly predicted the outcome of the IMPROVE-IT study. Will genetics get it right again?
Financial support and sponsorship
The author's research work was supported by grants from the German Research Foundation (Deutsche Forschungsgemeinschaft SFB 1052/B07; BU2263/3-1) and LIFE – Leipzig Research Center for Civilization Diseases, University of Leipzig. LIFE is funded by means of the European Union, by the European Regional Development Fund (ERDF) and by means of the Free State of Saxony within the framework of the excellence initiative.
Conflicts of interest
R.B. has received reimbursement of conference fees, travel expenses and accommodation expenses from Sanofi Aventis.
REFERENCES AND RECOMMENDED READING
Papers of particular interest, published within the annual period of review, have been highlighted as:
- ▪ of special interest
- ▪▪ of outstanding interest
1. Cholesterol Treatment Trialists C, Baigent C, Blackwell L, et al. Efficacy and safety of more intensive lowering of LDL cholesterol: a meta-analysis of data from 170,000 participants in 26 randomised trials. Lancet 2010; 376:1670–1681.
2. Cholesterol Treatment Trialists C, 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. Lancet 2012; 380:581–590.
3. Cholesterol Treatment Trialists C, Fulcher J, O’Connell R, et al. Efficacy and safety of LDL-lowering therapy among men and women: meta-analysis of individual data from 174,000 participants in 27 randomised trials. Lancet 2015; 385:1397–1405.
4. Davignon J. Beneficial cardiovascular pleiotropic effects of statins. Circulation 2004; 109 (23 Suppl 1):III39–III43.
5. Group AS, Ginsberg HN, Elam MB, et al. Effects of combination lipid therapy in type 2 diabetes mellitus. N Engl J Med 2010; 362:1563–1574.
6. Group HTC, Landray MJ, Haynes R, et al. Effects of extended-release niacin with laropiprant in high-risk patients. N Engl J Med 2014; 371:203–212.
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8. 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.
9▪▪. Cannon CP, Blazing MA, Giugliano RP, et al. Ezetimibe added to statin therapy after acute coronary syndromes. N Engl J Med 2015; 372:2387–2397.
This is the first outcome study to demonstrate a reduction of cardiovascular endpoints by a nonstatin lipid lowering drug. Further, it shows that incremental LDL-C lowering with ezetimibe, on top of statin therapy, provides an incremental outcomes benefit.
10▪▪. Robinson JG, Farnier M, Krempf M, et al. Efficacy and safety of alirocumab in reducing lipids and cardiovascular events. N Engl J Med 2015; 372:1489–1499.
This study describes the results of 78-week treatment with alirocumab, a monoclonal antibody to PCSK9, in patients who were already receiving the maximum tolerated doses of statins. PCSK9 inhibition consistently reduced LDL-C by 62% on top of statin therapy and a posthoc analysis also indicated a reduction in the rate of cardiovascular events.
11▪▪. Sabatine MS, Giugliano RP, Wiviott SD, et al. Efficacy and safety of evolocumab in reducing lipids and cardiovascular events. N Engl J Med 2015; 372:1500–1509.
This study describes the results of ∼1 year treatment with evolocumab, a monoclonal antibody to PCSK9, in patients who were already receiving the maximum tolerated doses of statins. PCSK9 inhibition consistently reduced LDL-C by 61% on top of statin therapy and reduced the incidence in cardiovascular events in a posthoc analysis.
12. Navarese EP, Kolodziejczak M, Schulze V, et al. Effects of proprotein convertase subtilisin/kexin type 9 antibodies in adults with hypercholesterolemia: a systematic review and meta-analysis. Ann Internal Med 2015; 163:40–51.
13. Cohen JC, Boerwinkle E, Mosley TH Jr, Hobbs HH. Sequence variations in PCSK9, low LDL, and protection against coronary heart disease. N Engl J Med 2006; 354:1264–1272.
14. Stitziel NO, Won HH, Morrison AC, et al. Myocardial Infarction Genetics Consortium I. Inactivating mutations in NPC1L1 and protection from coronary heart disease. N Engl J Med 2014; 371:2072–2082.
FURTHER RECOMMENDED READING
▪. Ference BA, Majeed F, Penumetcha R, et al. Effect of naturally random allocation to lower low-density lipoprotein cholesterol on the risk of coronary heart disease mediated by polymorphisms in NPC1L1, HMGCR, or both: a 2 x 2 factorial mendelian randomization study. J Am College Cardiol 2015; 65:1552–1561.