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Mechanistic insights have driven the development of novel targets and treatments, and even in the case of glucose lowering drugs, led to a paradigm shift in management.
The lipoprotein(a) story: from risk factor to causality to clinical trials
First described in 1963 (1), over the last decade there has been a resurgence of interest in lipoprotein(a) [Lp(a)] driven by pathophysiological, epidemiologic and genetic insights. As discussed by Professor Sam Tsimikas (University of California San Diego – School of Medicine, USA), multiple lines of evidence demonstrate that Lp(a) is a causal mediator of cardiovascular disease and calcific aortic valve disease. Importantly, elevated levels of Lp(a) are common; an analysis of more than 500,000 samples indicated that about one in four people have Lp(a) levels >50 mg/dL, increasing to about one in three in a tertiary referral centre (2).
Structurally, Lp(a) is composed of an apolipoprotein B (apoB)-containing LDL-like particle, covalently linked to the plasminogen-like glycoprotein apo(a) (3). Circulating plasma Lp(a) levels are primarily determined by the LPA gene locus encoding apo(a). More than 40 different isoforms exist varying by the size of the apo(a), specifically the number of Kringle IV repeats. Lp(a) has proatherogenic effects (attributed to the LDL component), proinflammatory effects (due to oxidised phospholipids bound to apo(a)), and prothrombotic effects.
In both primary and secondary prevention settings, and even in patients on statin background, elevated Lp(a) is a strong causal mediator of cardiovascular disease (4-6). The 2019 ESC/EAS guidelines for lipid management recommend Lp(a) measurement at least once so as to identify those individuals with very high inherited Lp(a) >180 mg/dL who may have a lifetime risk of atherosclerotic cardiovascular disease equivalent to the risk associated with heterozygous familial hypercholesterolaemia.
The stage is now set for testing the Lp(a) hypothesis. Pharmacological innovation, especially the development of GalNAc conjugated antisense drugs, has been critical. In the latest report, the hepatocyte-directed antisense oligonucleotide AKCEA-APO(a)-LRx reduced Lp(a) by 80% at 6 months in patients with established cardiovascular disease, with a favourable safety profile (7). Moreover, 98% of patients attained an Lp(a) value <50 mg/dL at this dose. The HORIZON trial (NCT04043552) will test the impact of Lp(a) lowering on major cardiovascular events. APO(a)-LRx will be administered among 7,680 patients with established coronary artery disease on optimal background therapy, including statins, and with Lp(a) levels ≥70 mg/dL or ≥90 mg/dL. The trial is anticipated to report in 2024, providing the final chapter in the Lp(a) story.
Immune modulation in atherosclerosis
While there is an impressive body of evidence for the role of the immune system in atherosclerosis, many of the immunomodulatory strategies have failed to show benefit. Professor Ziad Mallat (University of Cambridge, Addenbrooke’s Hospital, UK) discussed evidence for two interesting modalities, vaccination and tolerisation. Underlying both is mechanistic evidence that adaptive immune responses are driven by lymphocytes, with T cell and B cell responses playing prominent roles.
T cell activation has a major role in plaque progression; in contrast, Tregs are essential for maintenance of immune homeostasis, and suppress atherosclerosis by production of anti-inflammatory mediators, such as interleukin-2 (IL-2) (8). This may therefore represent a potential therapeutic target (9). At very low doses, IL-2 selectively activated Treg cells in patients with stable ischaemic heart disease and acute coronary syndromes and was safe without any increase in circulating effector T cells (10). These findings provide a basis for further investigation in the IVORY trial, an 8-week trial in patients with acute coronary syndrome. Mechanistic studies are also ongoing to better understand how IL-2 effects the Treg pool.
B cells represent another potential target for immunomodulation. Whereas B cell depletion suppresses atherosclerosis, maturation of B cells is not only atherogenic but also triggers monocyte mobilisation with a detrimental effect on tissue remodelling after myocardial infarction (11). In the RITA-MI 1 study, depletion of circulating B cells with the monoclonal antibody rituximab reduced infarct size and limited remodelling post myocardial infarction, with echocardiographic studies showing improvement in cardiac function. These findings set the stage for the RITA-MI 2, in which the effect of single infusion of rituximab will be investigated in STEMI patients.
Will non-coding RNAs change our understanding of vascular biology and disease?
According to Professor Stefanie Dimmeler (Goethe University Frankfurt, Germany) the answer is undoubtedly yes! Previously thought to be nonfunctional, emerging understanding of the contribution of non-coding RNAs to normal homeostasis and disease pathogenesis has driven the search for new targets and treatments (12). Non-coding RNAs can be broadly categorised as microRNAs (17–22 bases) and long noncoding RNAs (>200 bases). MicroRNAs have been shown to decrease target gene expression by altering transcript stability or impacting mRNA translation. Over 30 have been identified, with documented in vivo function in over 20, and two have recently entered clinical development. MiR92a was shown to inhibit vessel growth, reduce infarct size and improve vascular function in preclinical models, and in a phase 1 study an antisense oligonucleotide to miR-92a-3p inhibited miR-92a and related targets in humans (13). Other studies have investigated the potential for targeting miR132 in heart failure.
In contrast, long non-coding RNAs are less well explored. Most are expressed at low levels and are poorly conserved. Studies are just beginning to understand their function, with two appearing to be particularly interesting: MALAT1 and Meg3. MALAT1 has effects on endothelial proliferation, neovascularisation, diabetic retinopathy, myocarditis and atherosclerosis. In an experimental model of atherosclerosis, lesion formation was reduced in mice lacking MALAT1, suggesting an important function for this long non-coding RNA in promoting atherosclerosis. The other long non-coding RNA, Meg3, is upregulated by ageing, with induction of senescence (14). Silencing MEG3 in vivo induced recovery after hind limb ischaemia, and in humans, prevented cardiac fibrosis. Improved understanding may offer new targets and approaches in the future.
Finally, Professor Stefano Del Prato (University of Pisa, Italy) gave a timely review of the role of glucose-lowering drugs in preventing cardiovascular disease.
Guidelines have evolved with the advent of novel glucose-lowering agents, specifically the sodium-glucose co-transporter-2 (SGLT-2) inhibitors and the glucagon-like peptide-1 (GLP1) receptor agonists. Regulatory requirements for cardiovascular outcomes studies for any new glucose lowering drug were instrumental for identifying substantial effects on cardiovascular disease risk.
The two drug categories could, however, be differentiated in terms of effects on heart failure and hospitalisation. Trials with SGLT2 inhibitors showed a 30% reduction in risk with no significant benefit in trials with the GLP-1 receptor agonists (15). Across the four outcomes studies with the SGLT-2 inhibitors there was a consistent effect on heart failure hospitalisation, although effects on major adverse cardiovascular events (MACE) and cardiovascular death differed, possibly reflecting differences in study design and population. This benefit on heart failure was also demonstrated in a real-world study (16). Moreover, the DAPA-HF study showed significant benefit on heart failure in patients without diabetes (17). There is also evidence of protection in terms of renal disease with both groups of drugs, although the magnitude of benefit was less with the GLP-1 receptor agonists (15). These effects were independent of baseline kidney function.
What now is the target for glucose lowering drugs in diabetes?
These novel agents have led to a paradigm shift in treatment strategies, integrating evidence for glycaemic control and modification of organ damage. For newly diagnosed patients or those with early stage diabetes without complications, the focus should be on glucose control using agents with a low risk of side effects to reduce microvascular complications, including effects in the heart. In patients with advanced disease and with prevalent ASCVD or heart failure, a SGLT-2 inhibitor is indicated.
- Berg K. 1963. A new serum type system in man–the LP system. Acta Pathol Microbiol Scand 1963;59:369–382.
- Varvel S, et al. Prevalence of elevated Lp(a) mass levels and patient thresholds in 532 359 patients in the United States. Arterioscler Thromb Vasc Biol 2016;36:2239–2245.
- Tsimikas S. A test in context: Lipoprotein(a): Diagnosis, prognosis, controversies, and emerging therapies. J Am Coll Cardiol 2017;69:692–711.
- Willeit P, et al. Baseline and on-statin treatment lipoprotein(a) levels for prediction of cardiovascular events: individual patient-data meta-analysis of statin outcome trials. Lancet 2018;392;1311-1320.
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- Bittner VA, et al. Effect of alirocumab on lipoprotein(a) and cardiovascular risk after acute coronary syndrome. J Am Coll Cardiol 2020;75:133-144.
- Tsimikas S, et al. Lipoprotein(a) reduction in persons with cardiovascular disease. N Engl J Med 2020;382:244-255.
- Fernandez DM, et al. Single-cell immune landscape of human atherosclerotic plaques. Nature Med 2019;25:1576-1588.
- Klatzmann D, et al. The promise of low-dose interleukin-2 therapy for autoimmune and inflammatory diseases. Nat Rev Immunol 2015; 15:283-294.
- Zhao TX, et al. 2019 ATVB Plenary Lecture: Interleukin-2 therapy in cardiovascular disease: the potential to regulate innate and adaptive immunity. Arterioscler Thromb Vasc Biol 2020; 40:853-864.
- Zouggari Y, et al. B lymphocytes trigger monocyte mobilization and impair heart function after acute myocardial infarction. Nat Med 2013;19:1273-1280.
- Das S, et al. Noncoding RNAs in cardiovascular disease: current knowledge, tools and technologies for investigation, and future directions. A Scientific Statement From the American Heart Association. Circ Genom Precis Med 2020;13:e000062.
- Abplanalp WT, et al. Efficiency and target derepression of anti-miR-92a: results of a first in human study. Nucleic Acid Ther 2020; doi: 10.1089/nat.2020.0871.
- Boon RA, et al. Long Noncoding RNA Meg3 Controls Endothelial Cell Aging and Function: Implications for Regenerative Angiogenesis. J Am Coll Cardiol. 2016 Dec 13;68(23):2589-2591.
- Zelniker TA, et al. SGLT2 inhibitors for primary and secondary prevention of cardiovascular and renal outcomes in type 2 diabetes: a systematic review and meta-analysis of cardiovascular outcome trials. Lancet 2019;393:31-39.
- Patorno E, et al. Empagliflozin and the risk of heart failure hospitalization in routine clinical care. Circulation 2019;139:2822-2830.
- McMurray JJV, et al. Dapagliflozin in patients with heart failure and reduced ejection fraction. N Engl J Med 2019;381:1995-2008.