Triglycerides: The Past, Present, and Future PDF

European Heart Journal (2024) 00, 1–2 https://doi.org/10.1093/eurheartj/ehae515 Braunwald’s Corner...

European Heart Journal (2024) 00, 1–2 https://doi.org/10.1093/eurheartj/ehae515 Braunwald’s Corner Downloaded from https://academic.oup.com/eurheartj/advance-article/doi/10.1093/eurheartj/ehae515/7736859 by guest on 25 August 2024 Triglycerides: the past, the present, and the future 1,2 Eugene Braunwald * 1 TIMI Study Group, Division of Cardiovascular Medicine, Brigham and Women’s Hospital, Hale Building, Suite 7022, 60 Fenwood Road, Boston, MA 02115, USA; and 2Department of Medicine, Harvard Medical School, Boston, MA, USA observational studies and clinical trials, several drugs have been shown The past to reduce the levels of circulating TGs. Most attention has been focused The relationship between cholesterol (C) and arteriosclerotic cardio­ on fibrates, which act on the cell nucleus to inhibit TG production, but vascular disease (ASCVD) emerged early in the 20th century. In clinical outcomes have been either neutral or inconclusive. For example, 1910, Windaus, a German chemist, found C in atherosclerotic plaques a recent well-conducted, large placebo-controlled trial (PROMINENT) in human aortas. In 1913, Anitschkow, a young Russian experimental studied patients with hypertriglyceridaemia, diabetes, and low levels of pathologist, fed large quantities of pure C to rabbits, causing vascular LDL-C. A potent fibrate (pemafibrate) reduced TG, VLDL, and changes similar to those in developing arteriosclerotic plaques in pa­ VLDL-remnant C (see below) modestly, each by about one-fourth, but tients.1 The importance of LDL-C in the development of ASCVD did not reduce the risk of cardiac events.4 As a result of this and other grew slowly but steadily as a consequence of basic research that was disappointments, the suspicion has grown that while the association be­ appropriately rewarded by nine separate Nobel Prizes, as well as mul­ tween TG levels and atherogenesis was clear, a causal connection did tiple genetic, epidemiologic, and clinical studies. Drugs to reduce circu­ not appear to be present. This concept was supported by the finding lating C were developed and found to be effective in both primary and that in contrast to C, TGs per se have not been found in atherosclerotic secondary preventions of ASCVD; they have prolonged the lives of mil­ plaques. It was surmised that the TG may carry a culprit substance. lions of people around the world. Taken together, the C story has been In addition to carrying TGs, partially hydrolysed TG-rich lipoproteins one of the medical triumphs of the 20th century.1 also contain substantial quantities of C in their lipoprotein particles that However, despite these notable advances, lowering LDL-C did not came from nascent VLDL and chylomicron particles.5 These are fre­ abolish ASCVD, and the search was on for other dyslipidaemias that quently referred to as ‘remnant C’ (RC) (the term used in this paper) could be responsible for residual atherogenesis. Triglycerides (TG), which can be measured directly or calculated by subtracting the sum which provide important sources of energy, became obvious candi­ of LDL-C and HDL-C from total C.6 In contrast to TG, but like dates. Indeed, in 1959, Albrink and Mann2 reported that serum TG LDL-C, RC can penetrate the arterial intima and play an important was frequently elevated in some persons who had experienced a myo­ role in the development of atherosclerotic plaques. Non-HDL-C, which cardial infarction. This observation was repeatedly confirmed and ex­ is calculated by subtracting HDL-C from total C, includes the C in LDL, tended to other manifestations of ASCVD. For example, in the as well as the C from VLDL, chylomicrons, and RC, while apolipoprotein PROVE IT (TIMI 22) trial, we observed that in statin-treated post-acute B (ApoB) is on the surface of all of these atherogenic particles. Both coronary syndrome patients, an elevated TG (>150 mg/dL/1.7 mmol/L) non-HDL-C and ApoB are more accurate predictors of ASCVD risk was associated with higher cardiovascular risk than those with lower than LDL-C, which is usually calculated and is widely used.7 (normal) levels.3 However, it was observed that TG levels were not in­ Nordestgaard and Varbo6 summarized both pre-clinical and clinical dependent of LDL-C and other ASCVD risk factors. studies as follows: ‘High (circulating) TG concentrations are a marker for raised remnant rich in C, which upon entrance into the (arterial) intima, leads to low grade inflammation, atherosclerotic plaques and ultimately The present cardiovascular disease and increased mortality.’ This overview is supported Triglycerides, produced in the liver and the intestines, are carried in the by a large Mendelian randomization trial which demonstrated the adverse bloodstream largely in very low density lipoproteins (VLDLs) and chylo­ effect of RC on cardiovascular outcome.8 Thus, elevated TGs may be con­ microns and are hydrolysed by lipoprotein lipase (LpL). In both sidered to be risk markers for ASCVD, while RCs are likely true risk factors. * Corresponding author. Tel: +617 732 8989, Fax: +617 975 0955, Email: [email protected] © The Author(s) 2024. Published by Oxford University Press on behalf of the European Society of Cardiology. All rights reserved. For commercial re-use, please contact [email protected] for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact [email protected]. 2 CardioPulse The future include both an ASO and an siRNA that inhibit APOC3 and a second siRNA that blocks ANGPT3. Both siRNAs cause robust reductions Apolipoprotein CIII (APOC3) is a glycoprotein produced by the liver of RC, the likely culprit. They also reduce ApoB and non-HDL-C, that both inhibits LpL and reduces TG removal by the liver and was both of which are predictors of ASCVD risk. The next step will be to found to cause hypertriglyceridaemia in transgenic mice.9 Persons determine whether these biochemical improvements will be translated with loss-of-function variants of the APOC3 gene have low levels of cir­ into improved clinical outcomes in patients with hypertriglyceridaemia. culating TGs and a low incidence of ASCVD. These findings have made It will be interesting to determine whether a combination of the ApoC3 a logical target for the treatment of elevated TG.5,10 Two ap­ two siRNAs (plozasiran and zodasiran) will have additive actions. proaches for reducing ApoC3 are being studied; the first is antisense Downloaded from https://academic.oup.com/eurheartj/advance-article/doi/10.1093/eurheartj/ehae515/7736859 by guest on 25 August 2024 Ultimately, editing of the APOC3 and/or ANGPTL3 genes may provide oligonucleotides (ASOs), which act on the cell nucleus by inhibiting more durable inhibition. APOC3 mRNA and increasing LpL activity. Olezarsen, a drug in this class, has been studied by Bergmark et al.11 in the TIMI 73 trial that studied patients with moderate hypertriglyceridaemia. It reduced APOC3 Declarations and circulating TGs by half, accompanied by smaller but significant re­ ductions in VLDL-C, ApoB, and non-HDL-C without exhibiting serious Disclosure of Interest adverse effects; phase 3 trials with this compound are underway. The author declares no disclosure of interest for this contribution. The second approach to reducing ApoC3 is with ARO-APOC3 (plozasiran), a small interfering RNA (siRNA) which acts in the cyto­ plasm. It has been studied by Ballantyne et al.12 in a placebo-controlled References 1. Goldstein JL, Brown MS. A century of cholesterol and coronaries: from plaques to genes dose ranging phase 2 trial in persons with combined (mixed) hyperlip­ to statins. Cell 2015;161:161–72. https://doi.org/10.1016/j.cell.2015.01.036 idaemia (elevated LDL-C and TG). In addition to markedly reducing 2. 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Ballantyne CM, Vasas S, Azizad M, Clifton P, Rosenson RS, Chang T, et al. Plozasiran, an is increased in partially hydrolysed TG-bearing lipoproteins, i.e. RC; RNA interference agent targeting APOC3, for mixed hyperlipidemia. N Engl J Med 2024. https://doi.org/10.1056/NEJMoa2404143 challenging because no way to safely reduce RC was possible; and excit­ 13. Rosenson RS, Gaudet D, Hegele RA, Ballantyne CM, Nicholls SJ, Lucas KJ, et al. ing because recent research has identified promising approaches that Zodasiran, an RNAi therapeutic targeting ANGPTL3, for mixed hyperlipidemia. N may limit residual atherogenesis in LDL-C treated patients. These Engl J Med 2024. https://doi.org/10.1056/NEJMoa2404147