Towards a new understanding of cardiovascular risk in diabetes

A new post-hoc analysis from Novo Nordisk of their SUSTAIN 6 and PIONEER 6 studies into semaglutide is looking to help ‘individualise’ treatment for diabetes patients by better predicting their cardiovascular lifetime risk. We spoke to lead study investigator, Utrecht University’s Dr Jan Westerink, to find out how he sees the results being used in daily practice.

The heightened risk of cardiovascular disease remains a pressing concern for type-2 diabetes patients, and one that many healthcare systems have not quite got a handle on yet.

Dr Jan Westerink, assistant professor of internal medicine, University Medical Center, Utrecht, believes that one issue is that the guidelines for addressing cardiovascular risk are too rigid, and don’t take into account each patient’s individual circumstance.

“People always say that patients and doctors should share decision making and discuss treatments with one another, but in reality, most of us just follow the guidelines.

“The problem is, if you have a high risk of cardiovascular disease, the guidelines might suggest that you are given statins and told to take them for the next 50 years, with no discussion at all.”

But Dr Westerink believes there needs to be more room for nuance and an understanding of lifetime risk.

“If you start taking a diabetes treatment with cardiovascular benefits whilst you’re relatively young, you will benefit more than a person who started taking it in their 70s.

“It's like starting a savings account; if you start young then the benefits will be a lot greater than if you started at a higher age.”

But current guidelines do not always take into account this type of reasoning.

Applying a new model

To help understand the lifetime risk of developing CVD and how diabetes drugs like semaglutide can affect this for individual patients, Novo Nordisk conducted a post-hoc analysis by applying the Diabetes Lifetime-perspective prediction (DIAL) of cardiovascular risk model to data from two of Novo Nordisk’s phase 3 trials into semaglutide – SUSTAIN 6 and PIONEER 6.

This model was specifically developed for use in people with type 2 diabetes for lifetime risk prediction of cardiovascular events as well as the years free from cardiovascular disease gained from an intervention.

It was based on data from 389,366 people with type 2 diabetes in the Swedish National Diabetes Registry and externally validated across multiple geographical regions.

Prediction models like this are recommended to help prediction and prevention of cardiovascular disease by leading cardiology associations, including the European Society of Cardiology (ESC).

“As a lifetime risk model, it estimates your life expectancy without cardiovascular disease, whilst also taking into account that you have a risk of dying from other causes,” Westerink, who was lead investigator of the analysis, says.

The two studies included 6,480 people with type 2 diabetes with high cardiovascular risk aged between 50-90 years.

The analysis showed that the addition of semaglutide to standard of care may extend life without a cardiovascular event, such as heart attack or stroke, in people with type 2 diabetes and high cardiovascular risk for up to 3 years, with the average being 18 months.

The results also showed a 20% risk reduction in ten-year risk of experiencing cardiovascular events for participants receiving semaglutide compared to standard of care alone.

With semaglutide, the average number of years during which participants did not experience a cardiovascular event was extended by 7-35 months across all age groups (50 – 90 years), with the greatest benefit seen in people aged between 50 -65 years and with high cardiovascular risk.

The team then took the MACE hazard ratio from the trial cohort – 0.76 – and applied it to patient-level lifetime risk of cardiovascular disease events derived from the DIAL model. From that, they were able to calculate the return on investment from lifetime use of semaglutide for individual patients.

For example, for a specific patient, a 61-year old man with type 2 diabetes and a history of cardiovascular disease, the DIAL model showed that adding semaglutide to standard of care reduced the 10-year risk of having a cardiovascular event by 21% and provided almost two-and-a-half years (29 months) free of cardiovascular events.

“What we found is that, as expected, if you have a large population and you calculate absolute benefits in all those individual patients and you make a histogram, you can see that they have a very wide distribution,” says Dr Westerink.

“Although there's an average hazard ratio of 0.76 and a 20% risk reduction when looking at every patient, not everybody's got to benefit to the same extent.”

“By using the results of the analysis on individual patient cases, we can show that with the use of semaglutide added to standard of care, some patients will have less than one year’s worth of benefits, and some patients will have more than two years. The mean benefit there would be 1.7 years, but it’s very different for each individual patient.”

Logical treatment

Dr Westerink hopes that insights like this could lead to recommendations for diabetes treatment becoming more personalised, based on each individual patient’s lifetime risk.

He adds that the most important aspect of this approach is its simplicity and logic.

“I've never met anybody who doesn't understand the concept when they hear it,” he says. “The only problem at the moment is that it’s not what doctors are taught to do. Everybody feels that they shouldn’t give older patients certain kinds of drugs, or that they shouldn’t just tell young people to improve their lifestyle and not medicate them at all. In reality, we know that’s not really how it’s supposed to work, and that's what makes this approach so logical.”

Dr Westerink hopes that eventually this approach will be included in international guidelines, although he acknowledges that changing practice will take “a different way of thinking” from doctors. For example, they might be required to do more in-depth interviews with patients to be able to accurately predict risk.

Westerink adds that individualising treatment in this way could ultimately lead to higher adherence.

“It lets the patient take the lead in their own treatment and lets them know exactly why they are taking a drug,” he says.

About the interviewee

Jan Westerink studied medicine at Utrecht University (1997-2003). During his training as an internist-vascular physician, he carried out three years of doctoral research and obtained his doctorate in 2012 as a result of research focused on the harmful effects of belly fat and the postprandial phase. Since 2013 he has been working as an internist-vascular physician at UMC Utrecht. There is a special interest in vascular diseases in patients with type 2 diabetes mellitus in both care and research.