Dr Nils Kruger:

My name is Nils Kruger. I'm a physician scientist at the Brigham in Boston at Harvard Medical School.

What prompted this large-scale real-world analysis comparing GLP-1 receptor agonists and how does it complement existing cardiovascular outcome trial data?

Randomised clinical trials are the reference standard to derive medical evidence. However, randomised trials cannot answer all questions that are relevant to clinical practice. They take a long time to conduct, they are sometimes unethical in certain circumstances, and they take a lot of resources to pull the evidence together.

We have routine care data that is data generated during clinical practice. And those data entail evidence that can help physicians and patients guide decisions. And we analyse such data in order to complement existing trials in the GLP-1 medicine area, in order to compare semaglutide to tirzepatide directly, as well as do a study where we compare tirzepatide versus sitagliptin, which is an older diabetes medication and serves as a placebo proxy, in order to see what the magnitude of tirzepatide shows compared to a neutral drug.

Can you walk us through the study design and methodology?

So this is a database study including six cohorts, and in the first step we emulate an RCT. In fact, we predicted the SURPASS-CVOT trial that will also be presented at this meeting. And we took the inclusion and exclusion criteria of the trial that are publicly available, and we operationalised those inclusion and exclusion criteria into the routine data in order to derive a similar population and follow them in a similar manner in order to observe major adverse cardiovascular events, that is heart attacks, strokes, as well as death.

In those clinical practice data, we use an active comparator new user design, which means we compared tirzepatide versus dulaglutide, an older GLP-1 medicine, and then we derive a hazard ratio which we then compare to the hazard ratio of the trial in order to see if our design, data and analytics framework is fit for purpose to ask such questions in routine care data.

And what we have observed is that we derive very similar results from our database study as compared to the trial, which made us feel confident to move on to ask a question that has not been answered in a randomised trial yet.

What were the key findings?

Comparing tirzepatide versus semaglutide, we saw no major difference between the two drugs. There was only the hazard ratio was 106 for tirzepatite versus semaglutide, which means we had 6% relative increase in risk comparing to tirzepatide versus semaglutide.

But the confidence intervals were wide enough so that there was no meaningful difference between the two. When comparing tirzepatide versus sitagliptin, we saw a substantial risk reduction initiating tirzepatide, meaning that this drug might be useful in patients at high-cardiovascular risk to onboard in patients who have diabetes.

What are the clinical implications of these findings for practice?

Both semaglutide as well as tirzepatide are effective, and physicians can initiate both medications safely in their patients. We did not see major safety signals, such as gastrointestinal adverse events, or urinary tract infections, or major bacterial infections.

In fact, we did see a reduction in bacterial infections, which might also explain why, in the SURPASS-CVOT trial, we saw a significant risk reduction in terms of early death.

What are your key take-home messages for clinicians?

Both medications are highly effective in patients with type 2 diabetes who are at cardiovascular risk. Both semaglutide and tirzepatide reduced major adverse cardiovascular events. When thinking about which drug might be better, there was no substantial difference between the two. We did see a slight benefit for tirzepatide when it comes to heart failure outcomes.

However, when looking at MACE outcomes, we did see a slight increase, in the risk for tirzepatide versus semaglutide, with both events being compatible with no difference for the two drugs.

What are the next steps for this research program?

So we did see that the effects of both semaglutide and tricepatide kicked in very early, hinting towards risk reduction, not only comes from losing weight and glycemic control, but there might be other factors playing into the effects of those medicines. And this is a key area that others and us will explore further and disentangle where the effects might come from.