Ileana L. Piña, MD, MPH: Hello. I'm Ileana Piña, from Thomas Jefferson University in Philadelphia, Pennsylvania, and this is my blog. It's a little bit different blog because I'm really interviewing a good friend about these glucagon-like peptide 1 (GLP-1) inhibitors.
Some of our heart failure patients are getting their GLP-1 inhibitors from their primary care physicians, but many questions have arisen with the trial called SUMMIT.
With us today is Barry Borlaug, who is in charge of the research section with the cardiovascular section of Mayo, and that is Mayo, Rochester, where it must be much colder even than here in Philadelphia.
Barry, congratulations on that trial. Tell our audience a little bit about how the trial was structured because it's important how we get into your information.
Barry A. Borlaug, MD: Thanks, Ileana. SUMMIT was a randomized, double-blind, placebo-controlled trial, testing the GLP-1/glucose-dependent insulinotropic polypeptide (GIP) agonist tirzepatide vs placebo in patients with heart failure with preserved ejection fraction (HFpEF). Unlike some other trials, this was real HFpEF with an ejection fraction of 50% or above.
Patients were randomized 1:1 to tirzepatide, titrated up to 15 mg once weekly, or placebo and treated for a minimum of 52 weeks. The dual primary endpoints were worsening heart failure or cardiovascular death and quality of life by the Kansas City Cardiomyopathy Questionnaire (KCCQ) clinical summary score.
The median duration of follow-up was 2 years. We continued follow-up until the last patient enrolled completed the full 52-week period of treatment.
We found that, as compared to placebo, tirzepatide reduced the risk of worsening heart failure or cardiovascular death by 38%, which was statistically significant, and also improved the KCCQ clinical summary score.
In addition to that, we also looked at other patient-centered outcomes like 6-minute walk distance and biochemical markers like C-reactive protein (CRP). We saw that there was also a significant improvement in exercise function measured by 6-minute walk distance and about a 40% decrease in CRP levels.
Piña: How long did the total trial last, including the time that the drugs were being administered?
Borlaug: The longest duration of follow-up was 3 years, and the median follow-up was 2 years.
Piña: Were any of these patients also on sodium-glucose cotransporter 2 ( SGLT2) inhibitors ?
Borlaug: Very poor. A s you know, physician-reported heart failure severity often doesn't agree with patient reports. Overall, 72% of the patients were judged by their physicians to have class II heart failure, but the mean KCCQ score was just over 53, so pretty severe patient-reported limitations or severe HFpEF. Despite this -- and this is often the case in HFpEF and obesity-related HFpEF -- the median N-terminal pro-B-type natriuretic peptide ( NT-proBNP) was only 175.
Piña: I was very surprised at that. Very surprised. That really is low. That was NT-proBNP. That wasn't BNP.
When you lose the fat, you lose the weight, do you just lose it in the rest of the body? Where else have you looked? What did your cardiac magnetic resonance (CMR) study show?
Borlaug: We did do a CMR substudy. This is a smaller cohort of all patients that were participating at centers in this additional voluntary study. Cardiac MRI was done at study entry and then at 52 weeks. The primary endpoint of that was change in left ventricular ( LV) mass. We know from prior studies looking at weight loss interventions that LV mass is the most consistently reduced measure of cardiac structure and function.
Indeed, we found that to be the case. There was a statistically and clinically significant reduction in left ventricular mass by CMR. We also looked at pericardiac fat. Visceral fat is defined as fat stored around internal organs, and it may be present in the abdomen -- so abdominal visceral adipose tissue, in the mesentery, or around the kidneys -- but also it exists around the heart.
Within the pericardial space, that's called epicardial adipose tissue, and then around the pericardium, there's pericardial adipose tissue. We combined those to refer to that as pericardiac adipose tissue. That also was markedly reduced by tirzepatide as compared to placebo.
Piña: I also noticed the reduction in LV mass, which you just mentioned. What kind of reduction? Do we know microscopically what's different about that muscle? Have you been doing that?
Borlaug: That's a really important question. When people lose weight with incretins or most weight loss therapies, it's not just fat. It's skeletal muscle mass as well. The amount that was lost in the SUMMIT trial is not known because you need to do more advanced evaluations to assess that, things like dual-energy x-ray absorptiometry or imaging.
That was not performed, so we can't make any inferences as to what extent it was fat loss vs lean tissue loss vs water loss or something like that.
That is a significant issue with these drugs and with all weight loss interventions. We need more dedicated mechanistic-type studies to look more carefully at that.
Piña: Do you know any data about regular skeletal muscle with these drugs? Some patients complain to me that, besides their stomach's not feeling just right, they feel like they're losing their arm muscles, for example.
Borlaug: Part of it is if you weigh 20% more, you're carrying all that extra weight around all the time. You're basically conditioning your skeletal muscles to hypertrophy because your calves and the rest of the locomotion muscles have carried that excess weight around. That stimulus is lost.
Then, of course, as people are eating less and maybe being a little less active, they do lose some muscle. That's a really important avenue for further research.
As you know, about two thirds of people with HFpEF are living with obesity. Many of them have what we call obese sarcopenia, so they're obese by BMI criteria, but they have limited skeletal muscle mass and strength; both the quality and the quantity of skeletal muscle are down.
That's something that we really need to be doing a better job of addressing either pharmacologically or with exercise training interventions.
Piña: Heart failure alone will make your skeletal muscle change. Do we know what muscle types are changing, if at all?
Borlaug: Not yet. We're conducting a separate study right now, a federally funded trial of semaglutide, a different GLP-1 receptor agonist. This is also in obesity-related HFpEF. As part of that trial, we are performing fat biopsies in a subset of patients.
We'll get a better sense of fat. We're not looking at skeletal muscle. I kind of wish we would have set ourselves up to do that. That's a really hot topic, and something we need to look further into, all the way down to the microscopic level. What's happening in terms of the types of muscle fibers -- type I, type II -- atrophy, and what's happening to intramuscular fat and intermuscular fat.
These are commonly seen with older age and with diabetes and HFpEF, so these are all really important to characterize.
Piña: Do we lose mitochondria?
Borlaug: It's an unknown. It's a really important question. It's also possible that the mitochondria work better with the weight loss. As your insulin sensitivity gets better, your glucose disposal gets better, your oxidative stress goes down, and your inflammation goes down. All of those things may enhance mitochondrial biogenesis.
This is really important, but I think you'd really need to do skeletal muscle biopsies before and after, with really sophisticated assessments. That sort of study is really urgently needed to better understand what's happening.
Piña: This is right up your alley. I can see a National Institutes of Health study being put together.
Something that I've started doing with my patients is to have them on resistance training. If they're really losing that muscle, what's going to take the place of the muscle is called fat. They're going to have hanging fat pads. I have them trying to do weights, TheraBands, and things like this. There's another piece of study that could be added to it. There's just so much we still don't know.
Borlaug: When people lose a lot of weight from a variety of interventions, like intensive lifestyle, recidivism is high, and they often gain it back. They usually don't gain the muscle back, they just gain fat back. They end up in a place that's even worse than where they started off, so this really is an important issue.
Piña: What's next for you?
Borlaug: Well, we are going to continue to look at the SUMMIT trial results. As you know, there are always the usual multiple questions that we can address in more detail with secondary analyses. We've got more of those to work on.
We're currently doing another clinical trial, as I mentioned, with semaglutide. It's different than the STEP-HFpEF studies, which were looking at quality of life and 6-minute walk distance. We're looking really specifically at the hemodynamic effects of weight loss with semaglutide. We're doing a rest and exercise invasive cardiopulmonary exercise test. We'll finally be able to see if left atrial pressure is going down, if wedge pressure with exercise is going down, and what's happening in the pulmonary pressures.
Piña: What are the mandatory parameters?
Borlaug: The main endpoints will be pulmonary wedge pressure, exercise and rest, of course, but all of the hemodynamics, including exercise performance, body composition, cardiac MRI -- you name it. We're looking at as much as we can.
Piña: Thank you so much for joining me today. I thought this was such an important topic, that it really needed to be played out.
These drugs are getting to be so common, and sometimes patients don't even think about it. They're giving me their list of medications, but they leave those out.
Borlaug: Yeah.
Piña: I have to ask them very specifically, are you getting these medications from your primary? I certainly haven't started giving them away.
This was very timely because I think many clinicians are going through this right now and really don't know what to say to the patients. Maybe even testing how resistance training improves while they're on the drug so that they don't lose a large amount of that external muscle mass, and actually change their activity level?
Good luck with the rest of these studies. It's really fascinating.
Borlaug: Thank you, Ileana. It's always great to talk with you.
Piña: Thank you. This is Ileana signing off, with hopefully some good points today.
Please stay tuned. We're going to pursue some of these avenues of education for better care of our patients. Have a great day.