The “Big 4” of Cardiometabolic Risk: A Call for Early, Multidisciplinary Management
In this Q&A on her presentation at the American College of Cardiology 2025 Annual Meeting, Anum Saeed MD, assistant professor of medicine at the University of Pittsburgh, details why obesity, insulin resistance, hypertriglyceridemia, and MASLD demand urgent, integrated care. Dr Saeed discusses how cardiologists must think beyond LDL-C and blood pressure—leveraging GLP-1 receptor agonists, SGLT-2 inhibitors, and emerging therapies—to reduce cardiovascular events and shift away from siloed care to a more multidisciplinary management approach.
Additional Resources: Harrison SA, Bedossa P, Guy CD, et al. A Phase 3, Randomized, Controlled Trial of Resmetirom in NASH with Liver Fibrosis. N Engl J Med. 2024;390(6):497-509. doi:10.1056/NEJMoa2309000
Consultant360: Can you just discuss the key themes of your presentation at ACC.25?
Anum Saeed, MD: Yeah, so my presentation was entitled, “How to Manage the Big 4: Obesity, Insulin Resistance, Hypertriglyceridemia and Liver Disease”. I essentially reviewed the big four conditions that independently heighten cardiovascular risk: obesity, insulin resistance, hypertriglyceridemia, and metabolic dysfunction associated liver disease (MASLD).
Consultant360: I’m sure there's plenty of reasons, but why is this topic particularly relevant right now?
Dr Saaed: Each of these big four conditions are independently high risk, but they also often occur together and there's sort of a spectrum that goes from low to high, meaning you can start with obesity then insulin resistance, then hypertriglyceridemia, and eventually end in that sort of arc like fashion. You can end up with NASH OR MASLD.
So, it's important because addressing weight loss and glycemic control and hypertriglyceridemia have shown major cardiovascular disease benefits in recent trials. And now that we have medications beyond lifestyle and exercise, that we can use effectively. Cardiologists should address these issues very early, so these conditions do not progress to cardiovascular disease events themselves.
Additionally, these big 4 conditions are interconnected. Addressing one of them early will often benefit the other or not lead to the progression to the others. We have lifestyle and medications that improve glycemic control and lower your weight, and they can improve progression to Type 2 diabetes. They can reduce your triglycerides; they can even improve your MASLD or metabolic dysfunction-associated liver disease. And we now have the SGLT-2 inhibitors and GLP-1 receptor agonists, which have multisystemic benefits and truly have a pleiotropic effect. They're very good for metabolic cardiologists because they have this pleiotropic effect in improving weight loss, decreasing hemoglobin A1C, and overall also showing effects on the liver and reducing liver fat.
So I think the bottom line is to reduce cardiovascular disease events, we must think beyond systolic blood pressure and LDL-C management and look at patients' cardiometabolic system as a whole spectrum.
Consultant360: Perfect. And then beyond the interconnectedness of the big four like you mentioned, what are the most important takeaways for clinicians in practice that you can describe from your presentation?
Dr Saeed: I prepared this presentation to review the management of all four conditions. Let’s start with obesity management, which has greatly evolved. Traditional advice, like diet and exercise, can lead to about 5% to 10% weight loss at best, which is often transient. But now we have very effective anti-obesity drugs like the GLP-1 receptor agonists, which show profound and sustained weight loss in a lot of people across the world. For clinicians working in this space, we should treat obesity aggressively, be bold, and go beyond traditional advice and layer lifestyle interventions on very quickly with pharmacotherapy agents.
But again, review the guidelines, talk to your patients, discuss, and provide multidisciplinary care where you are sending them to bariatric surgery if they have the actionable BMI with or without comorbidities. So that sort of balance is there because again, even though these medications are here, they are not always accessible to a lot of our patients as far as insulin resistance is concerned.
The second thing that I talked about in my presentation is how we are tailoring Type 2 diabetes management to reduce cardiovascular disease. We're also making sure that we treat insulin resistance early, which again, lifestyle and diet intervention, including exercise in a low carbohydrate diet really yields a lot of results for insulin resistance. But as does metformin, as does SGLT-2 inhibitors. So, I think people who are high risk, you do have a role beyond exercise and diet with your medications such as metformin or with SGLT-2 inhibitors or GLP-1 agonists.
And the third thing that we have looked at is Hypertriglyceridemia, which always kind of gets placed behind LDL cholesterol for the right reasons, because LDL cholesterol does contain the most atherogenic burden in our bloodstream which directly leadsto cardiovascular disease and events. But these are triglyceride-rich particles that do cause inflammation that are associated with cardiovascular disease as well. And we often call them the residual risk markers. So again, thinking beyond, and in addition to lifestyle interventions, I think for patients who are quite high risk and have cardiovascular disease, treating the hypertriglyceridemia is important and we can do it by icosapent ethyl.
We do have other medications which are in the works like the apo c-III inhibitor, olezarsen, which is now commercially available to prevent acute pancreatitis in patients with extremely high triglycerides due to multifactorial or familial chylomicronemia.
And lastly, MASLD. It's basically everywhere. If you do an ultrasound on our patients with obesity or diabetes, many will have fatty liver. Right. So why does it matter to cardiology? I think this is the case I'm laying down that MASLD are not just the benign liver issue, they are a risk multiplier for heart disease. These patients often have high risk profiles and studies show that they're more likely to die because of cardiovascular causes than liver failure. So, we've lacked the specific therapy for a while and only focused on lifestyle and interventions, which are important. But most recently, we've had some emerging therapies like resmetirom, which is neural thyroid hormone. One trial showed that 30% of patients on resmetirom at 100 mgs achieved NASH resolution. So you're talking 10% resolution with diet and lifestyle in the placebo group, but 30% in the 100mg resmetirom group and approximately 26% had improvement in fibrosis of the liver. So those who had more than stage 1 or over improvement fibrosis at baseline had improvement that was 26% versus 14% in placebo. So really this is what led the FDA to approve resmetirom in 2024 as an actual therapy. So again, treating for our patients with MASLD or NASH, we should anticipate that we are aggressively going to treat the risk factors and components of metabolic syndrome, but we should also anticipate that co-management with hepatology as cardiologists. We can start them on therapies in conjunction with our hepatology colleagues and even think about GLP-1 receptor agonists because weight loss will reverse a lot of this fatty liver disease. So, there seems to be a new era in the cardiometabolic space.
Consultant360: That was a great answer. I really appreciate that.
Dr Saeed: I know you asked for key points, but I just wanted to make sure I properly explained my presentation to the audience.
Consultant360: Absolutely. All good. And then my last question: are there any gaps in our knowledge that remain that you maybe alluded to in your presentation but didn't get to or something that you're looking forward to talking about maybe in the future?
Dr Saeed: Definitely. I think there are real gaps in co-management and true disciplinary models in the cardiometabolic space. We’re still sort of working in silos.
I think that we still have some ways to go as far as the future data that's going to come across and how the GLP-1s and their pleiotropic effects such as on the liver. Finally I think, further impact on CVD by treatment of hypertriglyceridemia and HDL-cholesterol (which we did not really talk about) remains to be seen.