Prof. Jean Charles Fruchart, Prof. Michel Hermans, Prof. Pierre Amarenco
The last decade in lipid research has been widely regarded as the ‘PCSK9 decade’. Genetic studies have driven the development of novel therapies targeting the enzyme proprotein convertase subtilisin/kexin type 9 (PCSK9), the first of which are likely to be licensed later this year.
1,2
Yet while lowering low-density lipoprotein (LDL) cholesterol beyond current guideline targets is likely to confer additional benefit, as suggested by IMPROVE-IT and by preliminary PCSK9 inhibition trial analyses,
3-5 such efficacious treatments will not eliminate residual cardiovascular events in high-risk patients, especially those with atherogenic dyslipidaemia characteristic of insulin resistant conditions.
What does the future offer for reducing the residual cardiovascular risk in these patients?
Perhaps triglyceride (TG)-lowering will be the focus of the next decade, especially following the fall from grace of treatments targeting high-density lipoprotein (HDL) cholesterol. Support for this has been accumulating, building on a foundation of human genetics and early clinical studies.
6 There is now recognition that TG are not the target but instead a marker for elevated TG-rich apolipoprotein B-containing lipoproteins. The available evidence implies that it is the structural cholesterol contained in these particles, often referred to as remnants, which confers increased atherogenicity.
A number of approaches are being investigated. In a previous editorial, we have alluded to the potential of novel selective peroxisome proliferator-activated receptor alpha modulators (SPPARM?s), which offer the advantages of improved selectivity and potency compared with available fibrates.
7 An alternative approach may be targeting apolipoprotein CIII (apoCIII), which plays a critical role in the production and clearance of TG-rich lipoproteins. Indeed, this month’s Focus article
8 lends support to recent genetic studies
9.10, demonstrating a link between apoCIII, elevated TG and increased subclinical atherosclerosis, as measured by coronary artery calcium score, in patients with type 2 diabetes. This patient group is likely to benefit from apoCIII inhibition, given that they remain at high cardiometabolic risk, despite best evidence-based treatment, including statins.
Thus the search for therapeutic approaches to combat residual cardiovascular risk continues apace. The focus is not solely confined to lipid-related residual cardiovascular risk. Given that inflammation contributes to all phases of the atherothrombotic process, it is not surprising that interest has also focused on the potential of inhibition of inflammatory mediators, such as interleukin-1?, using a specific human monoclonal antibody therapy. The Canakinumab Anti-inflammatory Thrombosis Outcomes Study (CANTOS) is currently testing this possibility in patients with stable coronary artery disease with increased levels of inflammatory biomarkers such as high-sensitivity C-reactive protein.
11
We have made progress in raising awareness about the high residual cardiovascular risk that persists in patients with high cardiometabolic risk; however, much remains to be done. While PCSK9 has been the story of the last decade in lipid research, we believe that TG-rich lipoproteins or remnants are, quite rightly, the focus of the next. We hope that ongoing studies using a number of novel approaches will help in identifying the tools that clinicians need to address lipid-related residual cardiovascular risk in high-risk patients.
References
1. Repatha (evolocumab) approval status. Available at http://www.drugs.com/history/repatha.html
2. Praluent (alirocumab) approval status. http://www.drugs.com/history/praluent.html
3. 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.
4. 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.
5. 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.
6. Nordestgaard BG, Varbo A. Triglycerides and cardiovascular disease. Lancet 2014;384:626-35.
7. Fruchart JC. Selective peroxisome proliferator-activated receptor ? modulators (SPPARM?): the next generation of peroxisome proliferator-activated receptor ?-agonists. Cardiovasc Diabetol 2013;12:82.
8. Qamar A, Khetarpal SA, Khera AV et al. Plasma apolipoprotein C-III levels, triglycerides, and coronary artery calcification in type 2 diabetics. Arterioscler Thromb Vasc Biol 2015;35: DOI: 10.1161/ATVBAHA.115.305415
9. Jørgensen AB, Frikke-Schmidt R, Nordestgaard BG, Tybjærg-Hansen A. Loss-of-function mutations in APOC3 and risk of ischemic vascular disease. N Engl J Med. 2014;371:32–41.
10. Blood I, Crosby J, Peloso GM, et al; Tg, Hdl Working Group of the Exome Sequencing Project NHL. Loss-of-function mutations in apoc3, triglycerides, and coronary disease. New Engl J Med. 2014;371:22–31.
11. Ridker PM, Thuren T, Zalewski A, Libby P. Interleukin-1? inhibition and the prevention of recurrent cardiovascular events: rationale and design of the Canakinumab Anti-inflammatory Thrombosis Outcomes Study (CANTOS). Am Heart J 2011;162:597-605.