Practice Update: Diabetes

MY PERSPECTIVE 21

Dr Peter Libby on New Territory in Targeting Triglycerides By Peter Libby MD

atherosclerotic risk, provide support for therapeutic targeting of ANGPTL3 experi- mentally in mice, and illustrate the feasibility of two distinct mechanisms for targeting ANGPTL3 in humans. The monoclonal anti- bodies strategy joins a number of other approaches that use biological agents to treat cardiovascular risk factors. While ear- lier generation antisense oligonucleotides provoked unacceptably high adverse reac- tions, such as flulike syndromes and not infrequent serious injection site reactions, later generation antisense oligonucleo- tides have improved characteristics and use hepatocyte targeting strategies that permit achieving biological effects (on proteins that are manufactured in the liver) at much lower doses than previously employed. A new era in lipidology appears on the horizon. Refocusing on triglyceride-rich lipoproteins as a therapeutic target and applying newer biological strategies offer us new tools for managing residual risk in individuals who have high triglyceride con- centrations, despite all current therapies, including those that lower LDL effectively. In the current era of epidemic obesity and diabetes, dyslipidemia characterized by high triglycerides and low HDL repre- sents an increasing challenge for clinicians. The shifting attention to triglycerides from HDL may provide us with a new avenue to address this category of residual risk in our contemporary patient population. Disclosures: Dr Libby has served as an unpaid consultant to Ionis and Regeneron. References 1. Lincoff AM, Nicholls SJ, Riesmeyer JS, et al. Evacetrapib and cardiovascular outcomes in high-risk vascular disease. N Engl J Med 2017;376(20):1933-1942. 2. Nicholls SJ, Ruotolo G, Brewer HB, et al. Cholesterol efflux capacity and pre-beta-1 HDL concentrations are increased in dyslipidemic patients treated with evacetrapib. J Am Coll Cardiol 2015;66(20):2201-2210. 3. Musunuru K, Kathiresan S. Surprises from genetic analyses of lipid risk factors for atherosclerosis. Circ Res 2016;118(4):579-585. 4. Khera AV, Kathiresan S. Genetics of coronary artery disease: discovery, biology and clinical translation. Nat Rev Genet 2017;18(6):331-344. 5. Libby P. ANGPTL3 deficiency and protection against CAD. PracticeUpdate 2017. 6. Libby P. Triglycerides on the rise: should we swap seats on the seesaw? Eur Heart J 2015;36(13):774-776. 7. Dewey FE, Gusarova V, Dunbar RL, et al. Genetic and pharmacologic inactivation of ANGPTL3 and cardiovascular disease. N Engl J Med 2017 May 24. doi: 10.1056/NEJMoa1612790. [Epub ahead of print] 8. Graham MJ, Lee RG, Brandt TA, et al. Cardiovascular and metabolic effects of ANGPTL3 antisense oligonucleotides. N Engl J Med 2017 May 24. doi: 10.1056/NEJMoa1701329. [Epub ahead of print] www.practiceupdate.com/c/54242

observational evidence, researchers have traditionally adjusted triglycerides for HDL, a statistical maneuver that markedly atten- uates the relationship of triglycerides with cardiovascular events. But what if we bet on the wrong member of this dyad, and rather than adjusting triglycerides for HDL, should have done the contrary? Indeed, I have argued that the data drive us ineluc- tably to this conclusion. 6 Therefore, rather than attempting to raise HDL, should we target triglycerides or the various factors that determine triglyceride concentrations, shown by recent human genetic studies to contribute to cardiovas- cular events? A pair of papers in the New England Journal of Medicine provide strong support for this contention. 7,8 Both studies found that interruption of ANGPTL3, by either a monoclonal antibody strategy or by administration of an antisense oligonucleo- tide, could alleviate atherogenesis in mice. One study reinforced the human genetic case for a causal role by probing large human populations for variants that impair the function of ANGPTL3. 7 They found that participants who had genetic variants that limited function of ANGPTL3 had reduced plasma triglycerides compared with con- trols. In a small number of humans treated with a monoclonal antibody that neutralizes ANGPTL3, the authors found a dose-de- pendent decrease in circulating triglyceride levels by up to 75%, which endured for almost 1 month. The second paper used an oligonucleotide approach and documented not only decreases in the plasma levels of ANGPTL3, but in tandem, considerable reductions in triglycerides (to about 1/3 to almost 2/3 below baseline levels). 8 Together, these studies reinforce the cau- sality of determinants of triglyceride-rich lipoproteins as contributors to human

Dr Libby is Mallinckrodt Professor of Medicine

at Harvard Medical School in Boston, Massachusetts. T he last decade witnessed intense interest in raising high-density lipo- protein (HDL) as a strategy for reducing cardiovascular risk. A wealth of observational epidemiologic evidence fed this enthusiasm. Yet, numerous attempts to raise HDL have failed to reduce car- diovascular events. Most recently, the ACCELERATE trial showed the futility of evacetrapib, a cholesteryl ester transfer protein inhibitor, to improve cardiac out- comes in a large-scale investigation. 1 This failure occurred despite the apparent beneficial effects of plasma from eva- cetrapib-treated patients on cholesterol efflux in vitro and raising the subclass of HDL (pre-beta1) deemed to be important in reverse cholesterol transport. 2 Moreover, human genetic studies have failed consist- ently to support a protective effect against cardiovascular events of lifelong exposure to higher levels of HDL. 3,4 In stark contrast to this disappointment, the human genetic studies sporting a causal role for triglyceride-rich lipopro- teins at the genes that encode proteins that regulate their levels continue to accu- mulate at an accelerating pace. 4 We have previously reviewed some of these stud- ies for PracticeUpdate, including recent evidence supporting a causal role for angiopoietin-like factor 3 (ANGPTL3) in cardiovascular events. 5 Triglycerides tend to vary inversely with HDL. Convinced by the weight of the

VOL. 1 • NO. 2 • 2017