-- Also in TTHealthWatch: beyond BMI for predicting atherosclerosis
TTHealthWatch is a weekly podcast from Texas Tech. In it, Elizabeth Tracey, director of electronic media for Johns Hopkins Medicine in Baltimore, and Rick Lange, MD, president of Texas Tech Health El Paso, look at the top medical stories of the week.
This week's topics include an oral medication for obesity, stem cells after myocardial infarction (MI) and heart failure, blood markers and multiple sclerosis (MS), and looking beyond body mass index (BMI) for atherosclerosis.
Program notes:
0:37 An oral med for obesity
1:37 5-10% stopped medication
2:35 Need head to head trials with injectable
3:00 Stem cell infusion after MI and heart failure
4:01 Reduced heart failure in recipients
5:01 Twice as many in the control arm
6:01 Moving past BMI in predicting atherosclerosis
7:01 Especially in overweight but not obese
8:01 Almost 3,000 participants in Brazil
8:25 Blood samples precede MS
9:04 Seen 7 years beforehand
10:02 Twin studies and relatives
11:03 Way to intervene earlier
11:15 Applaud OpenAI
13:00 End
Transcript:
Elizabeth: Can we use stem cells to help prevent heart failure in people who've had a heart attack?
Rick: Going beyond BMI to assess coronary atherosclerosis.
Elizabeth: Can we see MS coming years ahead of time by looking at blood samples?
Rick: And an oral molecule for obesity treatment.
Elizabeth: That's what we're talking about this week on TTHealthWatch, your weekly look at the medical headlines from Texas Tech University Health Sciences Center in El Paso. I'm Elizabeth Tracey, a Baltimore-based medical journalist.
Rick: And I'm Rick Lange, president of Texas Tech Health El Paso.
Elizabeth: Rick, how about if we turn first to the New England Journal of Medicine? Lots of success we've had with injectable medicines for treating obesity, and here is an oral med.
Rick: As we've talked before, overweight and obesity affects more than 2.5 billion persons worldwide, and clinical guidelines now recommend obesity management medications for patients that have obesity. Enter the scene, a small molecule, non-peptide, oral, GLP-1 receptor agonist called orforglipron. And in the phase 3, multinational, randomized trial, they looked at different doses of this -- 6 mg, 12 mg, or 36 mg -- and compared it to placebo. They recommended that individuals have a healthy diet and physical activity for 72 weeks.
The patients who received the highest dose of orforglipron had an average 11% weight reduction. More than one-third had a reduction of at least 15% and nearly one-fifth had a reduction of at least 20%. All of the measured cardiometabolic biomarkers improved. This is great news.
In terms of side effects, 5% to 10% of people in the orforglipron group and about 2.5% in the placebo group stopped the medication because of side effects -- nausea, vomiting, increased gas, and they're mostly mild to moderate. They seem to occur primarily in the dose escalation phase. But overall, an effective therapy, well-tolerated in the vast majority of individuals.
Elizabeth: Really good news, of course. What's of interest to me is, I'm wondering about cost relative to the ones that are out there already because we have been talking also a lot about how much these things cost.
Rick: That data isn't available because it's not yet on the market. But as you know, the more agents we have out there, it seems to drive the cost down. Stay tuned. Hopefully this will be approved by the FDA. Importantly, we'll know the cost and it will drive not only this, but the injectable cost down as well.
How does it compare to the other agents? We really don't know. That needs to be done in a head-to-head fashion because the agents that have been tested so far show not an 11%, but a 15% to 20% reduction. We actually need head-to-head trials in the future to say, "Is one more effective than the other?"
Elizabeth: I would think that just from a patient compliance and acceptance standpoint, the oral med is going to win out.
Rick: And it may in terms of patient preference. What we need is hard endpoints. Does it reduce cardiovascular mortality? That's information that would be forthcoming.
Elizabeth: Let's turn from here to the BMJ, the utility of stem cell infusion after someone's had a myocardial infarction to see whether they can prevent the development of heart failure.
In this study, they had 420 patients with a first ST-segment elevation, acute myocardial infarction and a left ventricular ejection fraction of less than 40%. And they were randomized in a 1:2 ratio to receive the intervention or the standard care. Let me repeat that. One third went to the intervention. Two thirds were in the standard care.
They were looking at their primary endpoint of heart failure and their secondary endpoints included readmission to the hospital for heart failure, all-cause mortality, cardiovascular mortality, and readmission to hospital for MIs. They also looked at changes in the left ventricular ejection fraction within 6 months and they followed them up for a median of 33.2 months.
Basically what they found was that these stem cells did have a preventive effect. Those who got them, 2.77 per 100 person-years, versus 6.48 per 100 person-years in those who did not. The readmission to hospital for heart failure declined significantly in those who received the infusion, 0.92 versus 4.20 per 100 person-years. It did not have any impact on readmission to hospital for MI, all-cause mortality, or cardiovascular mortality. They did note that the left ventricular ejection fraction in their intervention group did improve, but it improved in both groups. It improved greater in the group that got the stem cell infusion versus the one that did not. I think that there were a lot of things about this study that I was left with a lot of questions about.
Rick: These were stem cells derived from the cord blood of babies.
Several things about the study. One, it was done in Iran and it wasn't done in a multinational way. We've talked before about the fact that the FDA to approve things, the studies have to be done in the United States. The way it was randomized is strange and usually you would put twice as many people in the treatment arm as you do in the control arm.
Previous studies that have looked at other types of stem cells have also shown that there has been no change in cardiovascular mortality or overall mortality. So they looked at a single endpoint and that was the incidence of heart failure. This study wasn't blinded, they didn't have a sham arm, so this is provocative. For this study to receive any traction, it needs to be repeated elsewhere.
Elizabeth: Absolutely. The other thing that, of course, I noted in here was how few women were enrolled in this study. And I would question the authors about why they harvested the stem cells from full-term male infants, but not from full-term female infants.
Rick: Yeah. Even though they had very few females, they said that the females were the ones that seemed to receive the benefit more so than the males. And we know that women that have heart attacks are more likely to experience heart failure than their male counterpart. I don't consider this a definitive study. I'd like to see it replicated elsewhere.
Elizabeth: Moving on.
Rick: We're going to switch gear and talk about moving past BMI, looking at coronary atherosclerosis.
We know that obesity results in multiple impaired health outcomes. They have a higher incidence of cardiovascular disease. It's easy to measure obesity as body mass index. But we've talked before about the fact that there are different types of fat. If it's more central, it's more likely to be pro-inflammatory and associated with cardiovascular disease. Measurement of BMI, although widely accepted, probably doesn't give us all the information we want.
What these authors did is they looked at multiple measurements of obesity. They looked at body mass index, waist circumference, and they looked at the waist-to-height ratio as predictors of coronary artery calcium incidence. They took individuals that were middle-aged, and they had coronary calcium scores of zero, and then they followed them over the course of over 5 years.
Almost 16% developed some coronary calcification. The waist-to-height ratio was positively associated with the coronary calcium incidence with an odds ratio of about 20%. And by the way, it was the only independent predictor of coronary artery calcification. This was particularly relevant in individuals that weren't obese, just overweight. The waist-to-height ratio was predictive of the progression of coronary atherosclerosis. This waist-to-height ratio provided additional predictive things over the usual risk factors.
Elizabeth: Let's note that this is in The Lancet, and this is actually an analysis of the Brazilian Longitudinal Study of Adult Health. So I would ask you to comment on that.
We have also noticed that when we're trying to get our arms around risk factors and populations in whom those are especially predictive, we've noted, for example, that even at normal BMIs, people of Asian descent, if they have visceral fat, are at much higher risk and develop, for example, type 2 diabetes much quicker, even though their weight or their BMI doesn't seem to indicate that they should be at risk. People of South American ancestry, what are your thoughts about that? How applicable is this to other folks?
Rick: Yes, I think it's clear. It's not just total body weight, and it's not just fat, but it's the type of fat one has. This is almost 3,000 participants in Brazil and it needs to be replicated in other populations.
Elizabeth: And the great thing about this particular metric is that it's easy to do.
Rick: Very easy. This has other additional benefits. It doesn't require specific cutoffs based upon sex and it doesn't overestimate the central fat that taller individuals typically have. Hopefully, this will be borne out in other populations and be a more predictive measure.
Elizabeth: Finally, let's turn to Nature Medicine, and this is a study taking a look at blood samples, putting forward the idea that we can see factors measurable in the blood that precede symptomatic onset in multiple sclerosis.
So as you know, multiple sclerosis, the most common cause of non-traumatic neurological disability in young adults, and it has often that insidious onset. These investigators were looking at high-throughput discovery proteomics and samples from presymptomatic patients with MS.
What they found was evidence of myelin injury was seen about 7 years before symptomatic onset and preceded the evidence of axonal injury by 1 year. They saw numerous changes in the serum proteome indicating that the interleukin-3 and nuclear factor-κB pathways were important in this presymptomatic stage, and they also showed increased and unsurprisingly immune cell activity.
They got these samples from the Department of Defense Serum Repository (DoDSR). They were able to analyze those and identify all of these different factors. Basically, what they're trying to say is that they think they've identified things that are going to be able to say you're at risk.
Now, one of my issues with this was that these were people who clearly developed it later and they were able to look retrospectively, and we all don't have that ability to look retrospectively 7 years ago and see what we're at risk for today. They say that they're going to look next at people they assume to be at risk for the development of MS, like twin studies and relatives of people who are already impacted. So I'm going to say I'm going to take a wait-and-see attitude toward this study.
Rick: Yeah. Very seldom do we have the opportunity to take a look back for years. I mean, apparently multiple sclerosis has a long presymptomatic phase, and by the time the symptoms occur, the axons are beginning to degenerate, and that's what we're treating. But it looks like even prior to that, the sheath that surrounds these nerves, called myelin, begins to undergo degradation, and probably from an immune response, and it may be related to the Epstein-Barr virus. It's neat to describe the progression, but you want to be able to identify early on and catch it and say, "Can we intervene?" You might be able to use these markers that could be very specific for multiple sclerosis to identify individuals that are in the presymptomatic phase and begin to intervene. That's really the hope.
Elizabeth: Right. And so I applaud them for doing this. It'd be great to have other big repositories that would be able to be analyzed for similar kinds of factors and then implement that in some way that could yield a way for us to intervene earlier before this axonal injury takes place.
I want to mention one more thing before we conclude for this week, and that's also in the BMJ. I want to applaud OpenAI, the people, of course, who created and maintain ChatGPT, because they did an internal study that was looking at signs of psychosis, mania, or suicidal attempt among their hundreds of thousands of users.
They basically estimate, based on their survey, that 0.07% of users in a given week show possible signs of mental health emergencies related to psychosis or mania. And they also estimate from this survey, their internal survey, that 0.15% of users had conversations with explicit indicators of potential suicidal planning or intent. So what this means, if you scale it up, is that each week around 1.2 million users are considering suicide and 560,000 are showing signs of psychosis or mania.
So what did they do? OpenAI went to 170 mental health experts and they said, "OK, what can we do to try to find this and actually target this?" This is, of course, because of reports of completed suicides among people who were using ChatGPT and had these probably preexisting mental health conditions exacerbated. So I just want to give them a hand for actually looking at this and for convening a group of experts to try to inform them on how to change this so that they can try to identify it.
Rick: Elizabeth, in our 20+ years of recording the podcast, this is the first time we've reported on five different studies. I look forward to the follow-up on this in the future.
Elizabeth: On that note then, that's a look at this week's medical headlines from Texas Tech.
I'm Elizabeth Tracey.
Rick: And I'm Rick Lange. Y'all listen up and make healthy choices.