Cardiovascular (CV) diseases are the leading cause of death worldwide, according to the World Health Organisation.
Part of the challenge of reducing the mortality rate of CV conditions is that they are so inter-related with other conditions, including metabolic and renal disease. The International Diabetes Federation and the National Institutes of Health conclude that CV disease is the leading cause of death in people with chronic kidney disease (CKD) and Type 2 diabetes. Renal and metabolic disease also have comorbidities; for instance, Type 2 diabetes is the leading cause of CKD.
In order to achieve its aim of dealing with these shared risk factors, which are often overlooked in clinical practice, Anglo-Swedish pharma giant AstraZeneca has created a joint CV, renal and metabolism (CVRM) unit and is studying products across various indications within these three areas.
The senior vice-president of CVRM Joris Silon discusses why it is so important to look at these conditions holistically and the work AstraZeneca has done to date to achieve this.
Allie Nawrat: Thinking about CVRM, how are these diseases inter-related and why is it so important to not view them as distinct?
Joris Silon: At AstraZeneca, we follow the science, which has been evolving over the last couple of years [as we] got to know about how most of the cardiovascular diseases actually lead into heart failure, and then seeing the link between heart failure and kidney disease, and then seeing how many heart failure patients have diabetes. Then you make the conclusion that there is a commonality between these four disease areas.
We have also talked to external specialists in this area, [who] see in their clinics that the patients that have a cardiovascular background mostly have renal problems, and many of these patients have metabolic problems as well. We became interested in looking at how we can help patients that have these common comorbidities. Congresses five years ago versus now shows that [generally] the relationship of these diseases is getting more traction. This is helped by drugs, such as SGLT2 inhibitors and GLP-1 [agonists], being shown to work in different indications.
AN: What are the dangers of overlooking CVRM shared risk factors for patients?
JS: Patients are at a high risk of cardiovascular events when they have these diseases. Type 2 diabetes is called a pandemic of this century, you have 400-500 million patients with Type 2 diabetes currently, and most of them have at least one risk factor, which is a cardiovascular, renal or metabolic disease. Patients with Type 2 diabetes are two to five times more likely to develop chronic heart failure; they also have a much higher chance of developing late-stage renal disease. If you have chronic kidney disease, then evidence shows you are likely to have a history of hypertension before you develop that. No matter what entry point you take into one of these four diseases, the chances that you come out somewhere else is very, very common.
AN: How is AstraZeneca trying to overcome the siloed nature of these disease areas?
JS: [Let’s take heart failure as an example, because] it is a special cardiovascular disease; it is the end stage of most cardiovascular disease. If you have hypertension, it means that your heart needs to pump against a higher resistance, which fatigues the pump and you get compensating mechanism, which can lead to heart failure if you don’t treat your hypertension well. If you have kidney problems, the filter of the body is not working well, and so the heart needs to pump against this filter [which] leads to heart failure. If you have a myocardial infarction, the other part of the heart has to work much harder to compensate, and that can lead to heart failure. Type two diabetes can lead to heart failure. Once you have heart, failure, your prognosis is about four to five years of survival, and that’s even including patients who are younger. Therefore, we need to diagnose the disease much earlier and make sure that patients have a chance to be treated appropriately.
AstraZeneca [recently] announced a global collaboration with eko.ai, which is a company developing artificial intelligence software to help cardiologists better diagnose heart failure patients through echocardiography. Right now, a cardiologist needs to click through, trade and measure these echocardiographs, and it takes on average 30 minutes to come to a certain diagnosis. This very manual diagnosis leads to a lot of variability. eko.ai wants to democratise diagnosis by performing the analysis in one click in a couple of seconds and with no variability, and therefore we’re trying also to help to improve the diagnosis of heart failure, which will significantly help patients.
AN: Tell me about your inter-related CVRM portfolio.
JS: We are mostly invested in four disease areas; within that we have our current assets on the market for patients. In cardiovascular, we have Brilinta, which is anti-platelet drug and the standard of care for patients with acute coronary syndrome. We just announced the results from the [THALES] trial that has high level results in reducing stroke risk.
In renal, we have two very important assets for patients with chronic kidney disease who have complications. One is Lokelma, which treats hyperkalemia, a very frequent complication of chronic kidney disease and quite dangerous for cardiovascular complications.
Another one is roxadustat, which is an oral drug for the treatment of anaemia [as a complication of CKD]; it’s the first invention in 20 years since EPO [erythropoietin-stimulating] agents came onto the market. We are launching that drug in China as we speak, and we also submitted FDA approval at the end of last year. It could treat patients who are on dialysis, but also those who are not.
In metabolism, we have Farxiga, our SGLT2 inhibitor, which was originally a Type 2 diabetes drug, and is now being investigated in heart failure in patients both with and without diabetes.
AN: What are some particularly exciting developments in your CVRM portfolio?
JS: There a lot of things happening across the entire pipeline. We recently carried out a very large real world evidence trial of one million patients to see what happens in real life to patients with Type 2 diabetes who haven’t had a cardiovascular event; what is the first type of event that occurs? We saw, once again, that the most frequent first events were heart failure. This means the first thing we need to think about when treating Type 2 diabetes patients is avoiding heart failure.
We delivered a very big trial called DECLARE in 2018 where we actually showed for the first time that SGLT2 inhibitors [developed for Type 2 diabetes] can actually prevent heart failure. That was a very exciting news for clinicians, because preventing it is much better than treatment. Last year, we delivered the DAPA-HF trial of Farxiga in patients with heart failure [with reduced ejection fraction] in both patients with Type 2 diabetes, and patients without.
That was the big wow at the ESC [Congress] last year; we actually see that the results of an SGLT2 are as good whether heart failure patients have Type 2 diabetes or not. Farxiga has a very clear effect on hospitalisations, on cardiovascular death and was very safe as well. We are continuing our development of this drug.
We are now waiting for the results of a trial in heart failure patients with preserved ejection fraction [a different sub-type than DAPA-HF study]; these are coming out in 2021.
There is also a trial of our SGLT2 inhibitor in CKD patients with and without Type 2 diabetes. We will be the first one to deliver data there as well. This is a drug that comes out of the Type 2 diabetes stable, but ultimately, it could become a heart failure and a kidney disease drug.
AN: Looking to the future, how is AstraZeneca planning to continue its work in CVRM?
JS: We are doing research in inflammation. We know that inflammation has a role in the disease progression in patients who have suffered a heart attack, so by reducing inflammation we can probably give these patients a better prognosis.
CKD is also linked with inflammation and the kidney can be inflamed and lead to rapid decline of that organ. Therefore, we are now testing some molecules that we thought we were developing in heart failure in CKD as well, because we see that inflammation is an underlying cause for both diseases, so we can really combine the insights in these diseases and move our science even more rapidly.
We’re also looking at a couple of compounds in our pipeline for NASH [non-alcoholic steatohepatitis].