Management of cardiometabolic conditions


At the Amgen Australia Cardiometabolic Assembly held in July 2022, experts presented on the latest advances in the management of dyslipidaemia and hypertension, along with discussing the importance of managing obesity.

New kids on the block for the management of dyslipidaemia

Professor Toth, Director of Preventive Cardiology at the CGH Medical Center and Adjunct Professor of Medicine, Division of Cardiology at John Hopkins University School of Medicine (USA), opened the session with an overview of “new players in the field” for the management of dyslipidaemia. He focused on three new drug approaches, all of which utilise different pathways to lower low-density lipoprotein (LDL) cholesterol, allowing more treatment options for patients who are not achieving the desired results with current therapies.

Novel, non-statin therapies were his first focus. “Bempedoic acid is the newest non-statin player in the field. It is an ATP-citrate lyase inhibitor and has been shown to be a relatively good drug for reducing LDL cholesterol. A variety of studies have been done with bempedoic acid showing around an 18-20% reduction in LDL and it has reasonably good safety,” 1 he said. “An outcomes trial is also being done looking at bempedoic acid compared to placebo in patients with a statin intolerance that we are very much looking forward to seeing how that turns out,” he added.

Looking at monoclonal antibodies, Prof. Toth discussed evinacumab, which inhibits a protein called angiopoietin-like 3 (AGPTL3) leading to decreased levels of triglycerides and LDL-C.2It turns out that with evinacumab you’re activating multiple means by which to eliminate LDL from the circulation. It’s an elegant surprise and a new means by which to treat patients with homozygous familial hypertension,” he explained.

Prof. Toth went on to describe how ribonucleic acid (RNA) is playing a role in management of dyslipidaemia: “RNA-targeted therapeutics inhibit cognitive messenger RNA to prevent the synthesis of disease-causing proteins.” Technology has advanced to the point where RNA targeted therapeutics “ensure stability, efficient delivery, highly specific drug target interaction, avoid off-target interaction and uptake by organs you don’t want to waste the drug on – and you’re also providing the patient with a favourable side-effect profile,”3,4 he explained. One example of this type of therapy is inclisiran (a small interfering RNA), which he noted, “Leads to about a 50% reduction in serum circulating levels of LDL… and because of the mechanism of action, inclisiran can be dosed twice a year”.5

Two additional RNA therapies are currently under investigation: pelacarsen (an antisense oligonucelotide therapy), which is in phase II trials and olpasarin (a small interfering RNA therapy), which is in phase I trials.6-8

Clinical consequences and management of hypertriglyceridaemia

Prof. Toth highlighted, “There are a lot of interesting things on the horizon. The manipulation of silencing RNA, antisense oligonucleotides are revolutionising our management of dyslipidaemia, and there’s going to be so much more to come because there are so many more components of lipid and lipoprotein metabolism that most of us have never heard of that are also going to be tested in the future”.

“We don’t have a trial that unequivocally demonstrates that reducing triglycerides per se reduces risk for future cardiovascular events… but the Mendelian inheritance studies, the genome wide association studies and the prospective longitudinal cohorts from around the world are demonstrating that triglycerides are, in fact, a risk factor to be taken seriously,” Prof. Toth explained, and added, “Hypertriglyceridaemia is associated with insulin resistance, multiple genetic polymorphisms, and does correlate with risk for coronary and peripheral arterial atherosclerosis.”

When it comes to management Prof. Toth pointed out, “Lifestyle modification is an important component of hypertriglyceridaemia management. Fenofibrate therapy correlates with reductions in a wide range of macro- and microvascular endpointsthe two big trials done with fenofibrate primary endpoints were both negative,9,10 but I still believe it’s important to look at fenofibrate because of its capacity to reduce microangiopathic events.” When it comes to the combination of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DPA), he noted that there has been no demonstration of cardiovascular benefits to date,11but noted, “EPA monotherapy has been shown to be efficacious for reducing cardiovascular endpoints in patients with hypertriglyceridaemia.12 To conclude, Prof. Toth stated, “There’s no doubt in my mind that triglycerides matter, so we have work to do.” 

Obesity, drugs and surgery

Professor John Dixon, Adjunct Professor at both the School of Primary Health Care, Monash University and the Iverson Health Innovation Research Institute at Swinburne University, Melbourne, shared his experience and perspectives on obesity management in Australia.

Prof. Dixon emphasised the need to recognise the value of pharmacological and surgical management of obesity: “Drugs and surgery for the management of obesity are the way we have to go. We’ve got drugs that are making a big change [in the field of weight management]. The perception by society is that most people living with obesity have a behavioural problem – yet the biology and science tell us something very different. More than a million people in Australia are living with clinically severe obesity but the uptake of surgery or medication is negligible – one or two percent. Most people die without having any effective treatment for their disease and I can’t find one paper that mentions therapeutic inertia for managing weight. The American Heart Association just last week declared that obesity wasn’t a behaviour, but a risk factor like high blood pressure, cholesterol and blood glucose. Indeed, what we tend to find is that there’s more people recognising that, while we haven’t been able to prevent obesity, we can certainly treat it and we are getting better and better at it,” he said.

With more and more Australians living with clinically severe obesity and the literature increasingly supporting obesity as a risk factor instead of a behavioural issue, Australian physicians have the tools to start treating it now, said Prof. Dixon.

Tackling obesity and diabetes together

Associate Professor Samantha Hocking of the Boden Institute, Charles Perkins Centre, University of Sydney and the Department of Endocrinology at the Royal Prince Alfred Hospital in Sydney gave an overview of two new anti-diabetic drugs that have come out in the last few years since coronavirus disease-2019 (COVID-19), known collectively as the ‘tides; semaglutide and tirzapetide. “Semaglutide is an example of a human glucagon-like peptide-1 (GLP-1) molecule that has been modified to resist breakdown by dipeptidyl peptidase-4 (DPP-4). It also has a fatty acid chain added so that it has a long half-life and can be dosed weekly,” 13-15 she explained. “Tirzapetide is the first once-weekly dual glucose-dependent insulinotropic polypeptide (GIP) and GLP-1 receptor co-agonist,” she added.16

A/Prof. Hocking noted, “The combination of GLP-1 and GIP is powerful. We’re seeing very impressive glucose-lowering, large weight reduction and improvement in cardiovascular risks on top of a good safety profile.17 And, of course, we are very much hoping that this will result in cardiovascular benefit, but we have to wait for the SURPASS-CVOT trial to be published.” The SURPASS-CVOT is a trial assessing tirzepatide compared with dulaglutide on major cardiovascular events in participants with type 2 diabetes.

Is this farewell to diabetes and obesity with the impressive results that we’re seeing? It’s early days and we need to know how durable the ‘tides are. We also need to wait for the cardiovascular outcome trial, then we need to think about how these extend to other obesity-related diseases, like metabolic associated fatty liver disease and obstructive sleep apnoea. Finally, we need to ask if it’s possible that there could be unforeseen concerns that appear over time,” A/Prof Hocking concluded.

Three fundamentals of hypertension management

Winthrop Professor Markus Schlaich, Dobney Chair in Clinical Research Medical School, Royal Perth Hospital Unit at the University of Western Australia set the scene for the issue of hypertension stating, “Hypertension is a big problem in its own right… but it’s a really complex scenario where the approach must be to treat all [risk factors].”18,19

Prof. Schlaich offered insights on three aspects of hypertension management he considers relevant in the context of treating more than just hypertension:

  1. Salt: “We know in the hypertension world, and still a bit slightly controversial topic. But in the context of hypertension, lower salt is a good thing. And we know that it’s predominantly processed foods that contain a lot of salt, so people are not necessarily willingly adding salt as such, and they still have a high salt intake which is associated with increased cardiovascular risk.”20
  2. Medication: “We’re very fortunate in the obesity and diabetes space with fantastic new drugs, but there haven’t really been all that many new drugs available in the hypertension space. The way to go is to combine drug treatments as we do in dyslipidaemia or diabetes and ideally give patients single pill combinations. However, what is important is under what circumstances you should use which drugs and there’s a very nice table in the guidelines21 that will be renewed with updates quite soon.”
  3. Obstructive sleep apnoea (OSA): “In an episode of OSA, there is essentially no flow and during that period blood pressure drops as the pressure in the chest cavity falls…as soon as the patient starts breathing again you see the blood pressure go back up and this happens the entire night and will extend into the day as well, raising blood pressure in these patients.”22 

Disclosure

This article was commissioned by Amgen. The content is based on studies and the presenter’s opinion. The views expressed do not necessarily reflect the views of the sponsor. Before prescribing please review the full product information of relevant products via the TGA website. Treatment decisions based on these data are the responsibility of the prescribing physician.

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