Optimizing Meds to Reduce CVD Risk in Diabetes; New Agent for Cholesterol

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 the Texas Tech University Health Sciences Center in El Paso, look at the top medical stories of the week.

This week’s topics include a new agent for cholesterol, acetaminophen, opioids and acute liver failure, optimizing medicines to reduce cardiovascular disease (CVD) risk for people with type 2 diabetes, and heart disease risk factors in adults 20-44 years of age.

Program notes:

0:49 New agent for cholesterol lowering

1:54 Lowered 21%

2:50 Increased uric acid levels

3:40 Acetaminophen, opioids and acute liver failure

4:38 Median age 42 years

5:40 A modest impact on rate

6:40 ‘Therapeutic misadventure’

7:40 Optimizing medicines to reduce CVD in people with diabetes

8:36 Extensive coordinated care for clinicians and patients

9:26 Cardiovascular risk in adults 20-44 years of age

10:30 Need to start early to prevent cardiovascular disease

11:25 Population wide policy change

12:15 End

Transcript:

Elizabeth: Does restricting acetaminophen with opioids reduce acute liver failure?

Rick: A new agent to lower cholesterol.

Elizabeth: Cardiovascular risk factors among young adults.

Rick: And how do we optimize cardiovascular preventative therapies in people that have diabetes?

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 University of Health Sciences Center in El Paso, where I’m also dean of the Paul L. Foster School of Medicine — and parenthetically recording today from Saigon, Vietnam.

Elizabeth: Right. Also our emphasis on cardiovascular disease, of course, in conjunction with the American College of Cardiology meeting. Why don’t we turn, Rick, first to the New England Journal of Medicine? This was an agent that we sort of foreshadowed last week we might talk about, and with which you’re familiar.

Rick: This is a new cholesterol-lowering agent called bempedoic acid, and they’ve just completed a study and reported it. It not only has cholesterol-lowering effects, but also cardiovascular effects. In essence, it’s an agent that still targets the pathway that the statins target. Its value may be in individuals that are statin-intolerant. That is, about 9% of the population states that they can’t take either a statin or a high enough dose of a statin because of muscle aches or pains. The incidence of true myalgias is actually closer to about 1% or 2%.

In this particular study, they took people that were statin-intolerant — they weren’t able to take a medium or high dose of the statin — and they randomized them to placebo or bempedoic acid, a single dose a day. Then they evaluated, what is their LDL cholesterol drop, and the second is, did it have a corresponding drop in major adverse cardiovascular events?

Now, it’s four components: death from cardiovascular causes; heart attacks; stroke; or the need for coronary revascularization. What they discovered is that the addition of bempedoic acid to a statin lowered LDL cholesterol about 21 percentage points more than just placebo. That correlated to about a 13% lower risk of the major adverse cardiovascular events.

That’s a composite of all four events. When you look at just mortality, there wasn’t a significant difference between those taking bempedoic acid and those taking placebo. But what this shows is that for people that really can’t take the dose of statins that we want, or can’t get their LDL cholesterol as low as we want, the addition of bempedoic acid could be an alternative.

Elizabeth: You also foreshadowed, I’ll remind you, last week that there was an anti-inflammatory component relative to this medication and that we talked about how reducing inflammation might be as important as reducing cholesterol.

Rick: Right. At this particular point, because the statins are well established, this is a single study so I don’t think bempedoic acid replaces the statin, but it can be used in conjunction with one.

Are there side effects? Yes. It has its own reported side effects including tendon rupture, increased uric acid levels which can lead to gout, and also can reduce glomerular filtration rate — that’s a kidney function. By the way, we don’t see those with statin use.

It can actually enhance the occurrence of muscle symptoms with statins as well. For those that are taking pravastatin or simvastatin, it actually raises the serum levels so you shouldn’t take those two. I think this is a very early study, but it adds to the armamentarium of the other drugs we have. So keep this on the radar screen, Elizabeth.

Elizabeth: Okay. But let’s also address this issue of anti-inflammatory aspects of this medicine or others that you’re aware of.

Rick: There are some modest anti-inflammatory effects. We do see a decrease in C-reactive protein. But whether it has all the pleiotropic effects and is it as potent an anti-inflammatory agent as statin? We don’t know because it’s not been directly compared to statins. Does it have some anti-inflammatory effects? Yes. Is it as good as statins? We just don’t know yet.

Elizabeth: Let’s turn to JAMA, where we’re going to spend the rest of our time this week and here is something that’s of great interest to me because of my work in the MICU. That’s this association of the FDA’s mandate limiting acetaminophen in combination with opioid products and what happens with subsequent hospitalizations and acute liver failure. We see a tremendous amount of liver failure of course on this unit, so that’s why I’m focused on this one this week.

This is an analysis of hospitalization data between 2007 and 2019 from the National Inpatient Sample, a hospitalization database, and it’s looking at this combination — acetaminophen and opioid toxicity — and acute liver failure involving that particular combination. They identified just shy of 40,000 hospitalizations involving this particular combination. Interestingly to me, anyway, 67%, about, were in women. Their median age was about 42 years.

They looked at what was the rate of hospitalizations — the predicted rate — one day prior to the FDA’s mandate and then afterwards. Previous, it was 12.2 cases per 100,000 hospitalizations and afterward it was 4.4. They calculate that rate at 11% per year after this announcement was made — that was the reduction in acute liver failure hospitalization secondary to the combination. It seems like it’s really a pretty effective thing to do.

The authors note that acetaminophen, of course, is found in more than 150 over-the-counter preparations for a variety of illnesses and pain, and more than 25 billion acetaminophen doses alone or in combination are sold in the U.S. annually. It looks like the FDA’s mandate to limit the amount of acetaminophen to 325 mg per tablet in these combinations with opioids was effective. However, the editorialist notes that this is actually a really modest impact on this rate and that subsequent to this we have seen acute liver failure, secondary to just acetaminophen alone, go up quite a bit.

Rick: Right. The reason why it’s a drop in the bucket, Elizabeth, is because more than 52 million people in the U.S. consume acetaminophen on a weekly basis. Many of them are really unaware. There are literally hundreds — and the editorialist says more than 500 — over-the-counter products that contain acetaminophen. So many people get it and don’t realize it. They don’t realize that the doses that they are ingesting could actually cause liver failure.

Acetaminophen toxicity is a leading cause of acute liver failure in the U.S., and close to a half of those are unintentional overdoses. While it’s good to limit the acetaminophen dose in the acetaminophen-opioid combinations, we still have a lot of work to do because it’s still prevalent throughout many other medications, combinations, and over-the-counter medication as well.

Elizabeth: I have to just point out that the editorialist says, as you have already cited, half are related to unintentional overdose or what’s called “therapeutic misadventure.” I don’t know; I’m not convinced that that’s probably a really good term to use and ultimately concludes that the best solution would be development of safer and more effective analgesics, something that we’ve been looking for, for a really long time.

Rick: Most of the analgesics have some sort of side effects, whether that would be gastrointestinal bleeding or kidney toxicity, or in this particular case, liver failure. But I want our listeners to actually pay attention. Because if they’re taking an over-the-counter analgesic, look to see if it has acetaminophen. One should make sure that they limit their dose to less than 4g a day, preferably less than 2g a day.

Elizabeth: Right. We also, of course, have to consider impact as we age and also with polypharmacy.

Rick: Absolutely. Concomitant liver disease or kidney disease all increase the risk for when you’ll develop liver failure with acetaminophen ingestion.

Elizabeth: Staying in JAMA then, let’s turn to coordinated care to optimize cardiovascular preventative therapies for people with type 2 diabetes.

Rick: This is based upon the fact that we know that there are some medications that are particularly helpful in people that have diabetes. They are helpful in reducing the cardiovascular risk associated with diabetes.

These medications include high-intensity statins, angiotensin converting enzyme inhibitors, or ACE inhibitors, or their cousins, the angiotensin receptor blockers or ARBs, and more recently the so-called SGL2 inhibitors or the GLP-1 receptor agonists. Unfortunately, very few individuals with diabetes are actually prescribed all of them. This particular study, for those that receive usual care, only about 14% were receiving all three medications.

How do we increase that? They looked at 43 different U.S. cardiology clinics and they recruited almost 1,000 [patients] to either receive usual care or what they call coordinated care. They looked at clinic-specific analysis to find out what the barriers were to providing this evidence-based medication[s]. They developed local interdisciplinary care pathways to address the barriers. They coordinated care among all the clinicians. They did clinician education. They did an audit and feedback of how well they were doing, and finally provided educational material to the participants. When they actually combined all six of these, it went from about 14.5% to as much as 38% were prescribed all three therapies.

Elizabeth: Rick, in your leadership role of course, I know that you’re examining all the time these sorts of strategies that seek to optimize care by engaging many different stakeholders, if you will, or providers or clinicians in this particular effort. What are the barriers to doing it?

Rick: As I mentioned, there were six different steps in this coordinated care effort and any one of those steps could be a barrier.

Elizabeth: I guess we’re going to be hearing a lot more about this as more evidence emerges that it’s an effective approach. Let’s then continue in JAMA and look at cardiovascular risk factor prevention treatment and control in U.S. adults between the ages of 20 and 44 years, over the last 11 years.

In this study, they took a look at the NHANES database, the National Health And Nutrition Examination Survey. They had just shy of 13,000 U.S. adults in that age group — 20 to 44 years. What they note over this time period is that the prevalence of hypertension increased from 9.3% to just about 12%. The prevalence of diabetes increased from 3% to 4.1%, and obesity from 33% to 41%.

The only thing that decreased was the prevalence of hyperlipidemia. Black adults had high rates of hypertension and that we saw this disparity among different ethnicities including Mexican Americans where they were more impacted by these things. Since we know that cardiovascular health, and health in general, is a lifelong enterprise, what they suggest is that, “Gosh, we really need to get our arms around this. This is not working out very well and bodes a real problem in cardiovascular disease for sure in upcoming years.”

Rick: This is just the beginning, because life expectancy in the U.S. is now the lowest it has been since 1996, with young and middle-aged adults seeing the most rapid declines. In fact, when they look at how heart disease contributes, you see the increase in heart disease just between 2020 and 2021 explains more than 4% of the recent shortcomings in life expectancy.

Elizabeth: If you were going to approach this problem, how would you do that?

Rick: This group is particularly hard because at that age — you remember, Elizabeth — we felt like we were immortal. We didn’t have usually health problems that were symptomatic. Often times they don’t even have insurance and they certainly don’t see a doctor on a regular basis. There are competing priorities between family and work.

This is going to take several efforts. It’s going to be population-wide policy changes, health promotions at both the community and the individual level, and we need to promote risk factor prevention and control even at a very young age. Laws and policies that address tobacco control, sugar-sweetened beverage taxes, adequate nutrition, and SNAP assistance programs for low-income families. We talked a week or so ago about the importance of family leave.

Typically in my practice, we are talking about prevention when people are 60, 70, and 80 years old. We need to begin starting at when they’re 20, 30, and 40 years old now.

Elizabeth: It sounds like a clear charge in moving forward. 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.