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News from European Society of Cardiology Aug31-Sept4

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News from European Society of Cardiology Aug31-Sept4 The future of lipid-lowering drugs Vasculaire geneeskunde ‘From bench to bedside’ 11 september 2020 Hotel Theater Figi, Zeist Jan Albert Kuivenhoven Department of Pediatrics, Section Molecular Genetics University Medical Center Groningen, the Netherlands A current plethora of lipid-lowering drugs...... Registered ACL Five evidence-based drugs HMGCR to reduce LDLc* Treating homozygous familial hypercholesterolemia ∗ INCLIRISAN Treating rare monogenic disorders - lysosomal adic lipase deficiency - familial LCAT deficiency - lipoprotein lipase deficiency - familial chylomicronemia syndrome ∗ Under development NPC1L1 ABE Treating homozygous familial June, 2020 hypercholesterolemia Adapted from HegeleRA, CircRes 2019 ∗ Increasing cellular chol.efflux Phase II & III clinical trials to reduce high Lp(a), Tg, LDLc ∗ * Validated with Mendelian Randomization studies * Bempedoic acid/Ezetimibe - NDA filed Febr 2019 Lipid-lowering drugs • To reduce - LDL cholesterol - reduce atherosclerotic cardiovascular disease (ASCVD) - Triglycerides - ASCVD - severe hypertriglyceridemia - patients witn insulin resistance - Lipoprotein(a) - ASCVD • To treat rare monogenic disorders of lipid metabolism • To modulate steps in the reverse cholesterol pathway to reduce atherosclerosis Managing very severe hypercholesterolemia Extracorporeal removal of lipoproteins Nonspecific plasma exchange / plasmapheresis / specific targeted approaches to remove LDL/Lp(a). No randomized ASCVD outcome trials Block hepatic production of VLDL (precursor of LDL) Mipomersen – antisense oligonucleotide (ASO) against APOB Lomitapide – inhibitor of lipidation of ApoB by microsomal transport protein (MTP) ApoB mRNA Triglycerides - Monoclonal Ab against VLDL ANGPTL3 (Evinakumab) ASO MTP - Gene therapy (ongoing) ApoB protein Lipidation of apoB AAV8.TBG.hLDLR (RGX-501) LDL cholesterol lowering to treat ASCVD Block hepatic cholesterol synthesis Citrate Liver • HMGCR inhibition (statins) LDLR Acetate Citrate Lyase • ACL inhibition (bempedoic acid, Need of Lysosomal functional Acetyl-CoA Nexletol/Nexlizet) (since Febr 2019) degradation LDLc LDLR HMGCR Prevent lysosomal degregation of LDLR LDLR • PCSK9 inhibition - monoclonal antibodies (alirocumab, evolocumab) Cholesterol - antisense oligonucleotide therapy (Inclirisan) - ABE (one time lifelong?) Blocking intestinal cholesterol re-uptake Small Intestine NPC1L1 • NPC1L1 inhibition (ezetimibe) Reduced cholesterol uptake • Bile acid sequestrants (colesevalam) ABCG5/G8 Triglyceride-lowering drugs to treat ASCVD Omega-3 (n-3) fatty acid preparations (‘fish oils’) • Vascepa (eicosapent ethyl). Reduce-it. 25% risk reduction on top of statin therapy. Effects beyond triglycerides anticipated. • Epanova (eicosapentaenoic acid and docosahexaenoic acid) - ongoing Fibrates (PPAR alpha agonists: gemfibrozil/fenofibrate/bezafibrate) • not indicated to treat ASCVD (inconsistent outcome trials – especially in combination with statins) Pemafibrate • Selective PPAR modulator that reduces TG levels by ≤ 45% and improves a wide range of quantitative metabolic subphenotypes, except for LDL-C levels. Large phase III ASCVD trial (Prominent) A new drug to treat (severe) hypertriglyceridemia and possibly insulin resistance Downregulation of apolipoprotein CIII (apoCIII) - familial chylomicronemia syndrome - familial partial lipodystrophy - improving insulin sensitivity ASO (volanesorsen) Monoclonal antibodies (in the works) Phase III trials in 66 FCS patients completed (NEJM 2019; adverse effects) New drugs to possibly treat (severe) dyslipidemia and possibly type 2 diabetes - familial chylomicronemia syndrome Downregulation of angiopoetin-like protein 3 (Angplt3) - familial hypercholesterolemia - lipodystrophies - type 2 diabetes Monoclonal antibodies (Evinakumab) ASO (IONIS-ANGPTL3-LRx (Gal-Nac)) - hypolipidemic effects (Tg, LDLc and HDLc) Hypolipidemic effects in healthy volunteers - reducing LDLc independent of LDLR! with hypertriglyceridemia Phase II trial in - phase III trial completed for FH (NEJM, Raal T2D patients (Jan, 2020) – 90% success Aug, 2020) Promise to lower Lp(a) to reduce atherosclerosis Lp(a) is • atherogenic via its LDL-like moiety • proinflammatory via its OxPL content • antifibrinolytic via its apo(a) moiety Risk factor for both ASCVD and calcific aortic valve disease Mendelian Randomization studies: LPA is causally related to ASCVD PCSK9i lower Lp(a) to a limited extent. ASO: APO(a)LrX. A phase 2 dose-ranging and safety study ongoing in patients with hyperlipoproteinemia[a] and cardiovascular disease; Phase 3 outcomes trial initiated in Dec 2019 (n=7600; Lp(a) above 70mg/dl). Outcome 2024 Current options to treat atherogenic dyslipidemia Decreasing LDLc • statins • ezetimibe • bile acid sequestrants • monoclonal Ab’s against PCSK9 • mipomersen, lomitapide • awaiting ASO against PCSK9 and LDLR gene therapy • ABE against PCSK9 and ANGPTL3 Decreasing triglycerides (remnant cholesterol?) • eicosapent ethyl (Vascepa). Effects not only mediated by moderate Tg reduction? • other fish oil based therapies: Epanova • awaiting outcomes trials to downregulate ApoCIII and Angptl3 Decreasing Lp(a) – hypothesis tested • awaiting outcome trials with ASOs Are these drugs actually used? Adherence to guidelines to prevent cardiovascular diseases: The LifeLines cohort study J W Balder 1, S Scholtens, J K de Vries, L M van Schie, S M Boekholdt, G K Hovingh, P W Kamphuisen, J A Kuivenhoven PMID: 26314714 Results: For primary prevention, 77% (2515 of 3268) of those eligible for LLD treatment did not report using these drugs, while for secondary prevention this was 31% (403 of 1302). Patients with diabetes mellitus were treated best (67%) for primary prevention. Notably, of the patients with stroke, only 47% (182 of 386) reported LLD treatment. Future of novel lipid-lowering drugs. Promising but vulnerable ‘Newcomers’ largely dependent of ACL HMGCR 1. long-term safety of monoclonal antibodies - PCKS9i – alirocumab, INCLIRISAN evolocumab - ANGPTL3 – evinacumab - APOC3 2. efficacy and safety of antisense oligonucleotide (ASO) drugs - PCSK9 - inclirisan NPC1L1 - APOC3 - volanesorsen Adapted from HegeleRA, CircRes 2019 - LPA - APO(a)LRx 3. All are expensive and (as yet) not available to most high risk patients. The future of lipid-lowering drugs – small molecule inhibitors? ACL HMGCR When costs remain a main hurdle INCLIRISAN - bempedoic acid GPR146i - gemcabene - GPR146 antagonists?* GPR146 deficiency protects against hypercholesterolemia and ∗ atherosclerosis. Cell, Nov 27, 2019 NPC1L1 Adapted from HegeleRA, CircRes 2019 ∗ Treating ‘residual atherosclerosis risk’ associated with high TG and low HDLc. Antihyperglycemic agents Glucagon-like peptide 1 receptor agonists (GLP1-RA) and sodium-glucose cotransporter-2 inhibitors (SGLT2i) have emerged as 2 new classes of antihyperglycemic agents that also reduce cardiovascular risk in multiple RCT trials. E. J. Northa and J.D. Newman, Curr Opin Cardiol 2019 Zelniker TA et al Circulation. 2019 Treating ‘residual atherosclerosis risk’ associated with high Tg and low HDLc. Guided lifestyle intervention. Alternate Day Fasting Improves Primary care-led weight management for Physiological and Molecular Markers of remission of type 2 diabetes (DiRECT): an Aging in Healthy, Non-obese Humans. open-label, cluster-randomized trial. Mean bodyweight fell by 10·0 kg (SD 8·0) - almost half of participants achieved remission to a non-diabetic state and off antidiabetic drugs Stekovic S. Cell Met 2019, Sept 3. Lean ME, Lancet. 2018 Thoughts associated with the future of lipid-lowering drugs No 1 - Lifestyle advice. Need of governmental intervention. Works! No 2 - Adherence to guidelines with currently available drugs No 3 - Focus on lowest cost drugs with good efficacy Stop the chase for new drugs that are never going to used in the general patient at increased ASCVD risk When combining guided lifestyle interventions with available drugs, we already work towards personalized lipid-lowering therapy Atherosclerosis starts in childhood How should we best proceed? Start early! Treated when clinical events have occured Thank you for your attention! Background literature 1) Hegele RA et al. CircRes 2019 2) Ray K, Lancet, Sept 2019; x< 3) Zwol WV et al J Clin Med. 2019; PMID: 31340607.
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