Study Throws Wet Blanket on Intermittent Fasting / Time Restricted Eating?

Everybody has heard of intermittent fasting / time restricted eating, right?  If not, it’s when you spend more time NOT eating than you do eating (think overnight fast – hence, Break-FAST).  It’s pretty clear that there are significant benefits to NOT eating for over 12 hours – the body has time to clear stuff out and potentially rebuild while not digesting food.  

The new study shows that when you push the NOT EATING window to 16 hours, you may be asking for trouble.  While the study is observational and has many limitations, the results are approaching astounding.  Risks of dying are significantly increased between 90 and 300%, depending on your baseline conditions.  If you’ve got cancer, the 8 hour or less feeding window translated to a 3 times greater risk of dying.  YIKES!

While I’m a big proponent of time restricted eating, I have always cautioned against the extremes here.  I’ve always thought that, on average, the optimal feeding window is around 10 hours – a 14 hour overnight fast (stop eating at 8, breakfast at 10).   For women, anything more than that seems to regularly make them feel worse.  Guys can tolerate longer, but this study has to make one wonder if that’s a good idea.  

As usual, the right answer will fall into the “it depends” category.  Individualized approach is always the best, but these data are hard to ignore, despite their limitations.

FROM MEDSCAPE / BY MEGAN BROOKS

Intermittent Fasting Linked to Higher CVD Death Risk

A new study raises a cautionary note on time-restricted eating (TRE), a type of intermittent fasting that is gaining popularity.

The observational analysis of over 20,000 US adults showed that those who limited their eating to a period of less than 8 hours per day had a higher risk for cardiovascular mortality compared with peers who ate across the typical 12-16 hours per day. This was the case in the overall sample and in those with cardiovascular disease (CVD) or cancer.

Lead author Victor Wenze Zhong, PhD, cautioned that the findings "require replication and we cannot demonstrate 8-hour TRE causes cardiovascular death in this observational study."

"However, it's important for patients, particularly those with existing heart conditions or cancer, to be aware of the positive association between an 8-hour eating window and cardiovascular death," Zhong, professor and chair, Department of Epidemiology and Biostatistics, School of Public Health, Shanghai Jiao Tong University School of Medicine, Shanghai, China, told theheart.org | Medscape Cardiology. 

The results (Abstract P192) were presented March 18 at the American Heart Association (AHA) Epidemiology and Prevention | Lifestyle and Cardiometabolic Health Scientific Sessions 2024.

'Provocative' Results 

Short-term randomized controlled trials have suggested that 8-hour TRE may improve cardiometabolic risk profiles, but the potential long-term effects of this eating pattern are unknown. 

The observation that TRE may have short-term benefits but long-term adverse effects is "interesting and provocative" and needs further study, Christopher D. Gardner, PhD, professor of medicine at Stanford University in California, who wasn't involved in the study, said in a conference statement, and he agreed that much more research is needed. 

The researchers analyzed data on dietary patterns for 20,078 adults (mean age, 48 years; 50% men; 73% non-Hispanic White) who participated in the 2003-2018 National Health and Nutrition Examination Surveys (NHANES). All of them completed two 24-hour dietary recall questionnaires within the first year of enrollment. Deaths through the end of 2019 were determined via the National Death Index.

During a median follow-up of 8 years, there were 2797 deaths due to any cause, including 840 CV deaths and 643 cancer deaths. 

In the overall sample, compared with an eating duration of 12-16 hours, 8-hour TRE was significantly associated with an increased risk for CV mortality (hazard ratio [HR], 1.91; 95% CI, 1.20-3.03).

This association was also observed in adults with CVD (HR, 2.07; 95% CI, 1.14-3.78) and adults with cancer (HR, 3.04; 95% CI, 1.44-6.41). 

Other eating durations were not associated with CV mortality, except for eating duration of 8 to less than 10 hours in people with CVD (HR, 1.66; 95% CI, 1.03-2.67). 

No significant associations were found between eating duration and all-cause or cancer mortality in the overall sample and CVD/cancer subsamples, except that eating duration of more than 16 hours was associated with a lower risk for cancer mortality in people with cancer (HR, 0.47; 95% CI, 0.23-0.95).

Quality More Important Than Timing 

Zhong noted that the study doesn't address the underlying mechanisms driving the observed association between 8-hour TRE and CV death. 

"However, we did observe that people who restricted eating to a period less than 8 hours per day had less lean muscle mass compared with those with typical eating duration of 12-16 hours. Loss of lean body mass has been linked to higher risk of cardiovascular mortality," Zhong said. 

"Based on the evidence as of now, focusing on what people eat appears to be more important than focusing on the time when they eat. There are certain dietary approaches with compelling health benefits to choose, such as DASH diet and Mediterranean diet," Zhong told theheart.org | Medscape Cardiology.

Intermittent fasting is "certainly an interesting concept and one on which the potential mechanisms underlying the improvements in short outcome studies and preclinical studies in animals are strongly being pursued," Sean Heffron, MD, cardiologist at the Center for the Prevention of Cardiovascular Disease at NYU Langone Heart, New York, NY, who wasn't involved in the study, told theheart.org | Medscape Cardiology. 

Heffron expressed skepticism about the study results calling them "far from complete" and noted that data on diet was based on only 2-day diet records without correction for confounding variables. 

Heffron also noted that the restricted diet group has more smokers and more men. "I would "strongly anticipate that once appropriate corrections are made, the findings will no longer persist in statistical significance," Heffron said.

He emphasized the need for more rigorous research before making clinical recommendations. When patients ask about intermittent fasting, Heffron said he tells them, "If it works for you, that's fine," but he doesn't provide a recommendation for or against it. 

Vitamin D -- it's not about COVID anymore

Vitamin D has been the source of some controversy for some time now.  Years ago there was debate about whether we should measure it at all (still some camps out there holding to that) because it wasn’t shown to relate to any clear diseases, increased risk, or if supplementing it made a difference.  More recently, COVID demonstrated that those with low vitamin D levels were more likely to end up in the Intensive Care Unit (86% of ICU COVID patients had low levels – under 29), and thus more likely to die.  Lots of people argued that supplementing vitamin D as prophylaxis against serious illness (including myself) was a good idea, but conventional evaluations of that didn’t yield confirmatory results (some studies were poorly done, but others were done well).  It makes for a bit of a morass when you’re trying to decide what to do.  For the record, my normal vitamin D level (25-OH to be specific) tends toward the low side, so I supplement daily.  

Now we have a review of small group of sedentary, nonsmoking Spaniards who had a bunch of metabolic parameters measured and compared.  What it showed was an inverse relationship between Vitamin D levels and virtually every cardiovascular risk factor you can think of . In other words, Vitamin D goes down, everything else bad goes up.  Their argument is that we could measure Vitamin D levels as an easy way to monitor cardiovascular risk.  Of course, in the US, to have the Vitamin D levels paid for by insurance companies, you have to be diagnosed with a Vitamin D disorder!  Ahhh, the beauty of American medicine.

By the way, I measure Vitamin D in everyone regularly.   It’s inexpensive to supplement, easy to avoid the virtually unheard of problems associated with excessive Vitamin D, and it just might avoid problems in the 300 or so mechanisms for which Vitamin D is essential.  

Concerned about your cardiovascular risks?  We have cutting edge approaches to evaluating and managing those risks, and establishing the presence of real issues before they become problems.  Let’s discuss your situation – first conversation is complementary.

From medscape / by Shrabasti Bhattacharya

Low Vitamin D Levels May Signal CVD Risk in Young Adults

TOPLINE:

Circulating levels of serum 25-hydroxyvitamin D (25[OH]D) may be a marker of cardiovascular disease (CVD) risk in healthy young adults, small study finds.

METHODOLOGY:

• A secondary analysis of the Activating Brown Adipose Tissue Through Exercise (ACTIBATE) trial assessed the association between serum 25(OH)D levels and CVD risk factors.

• The cross-sectional study used baseline data of in 177 healthy sedentary adults ages 18-25 years (65% women; all White individuals), who were recruited between October 2015 and December 2016 from Granada, a region in the south of Spain.

• Study participants were nonsmokers, led a sedentary lifestyle, and did not have a prior history of CVD or chronic illnesses.

• The CVD risk factors included anthropometrical and body composition profiles, glucose and lipid metabolism, liver, and pro- and anti-inflammatory biomarkers.

• 25(OH)D serum concentrations were measured with a competitive chemiluminescence immunoassay and defined as deficient (< 20 ng/mL), insufficient (21-29 ng/mL), or normal (> 30 ng/mL).

TAKEAWAY:

• The vitamin D levels correlated inversely with body mass index (BMI; standardized regression coefficient [β], −0.177; P = .018), fat mass index (β, −0.195; P = .011), and systolic blood pressure (β, −0.137; P = .038), after adjusting for sex.

• Glucose metabolism markers (serum glucose and insulin concentrations, insulin/glucose ratio, and homeostatic model assessment of insulin resistance index) also correlated inversely with vitamin D levels.

• The trend was similar for liver markers serum γ-glutamyl transferase and alkaline phosphatase) and the anti-inflammatory marker interleukin-4.

• BMI, waist/hip ratio, fat mass index, blood pressure, and levels of glucose, insulin, triglycerides, and liver markers were higher in the 44 participants with vitamin D deficiency vs 41 participants with normal vitamin D levels.

IN PRACTICE:

"Collectively, these findings support the idea that 25(OH)D concentrations may be used as a useful marker of CVD status, which can be easily monitored in young individuals," the authors wrote.

SOURCE:

This study was led by first author Francisco J. Amaro‑Gahete, MD, PhD, from the Department of Physiology, Faculty of Medicine, University of Granada, Spain, who also holds positions in other institutions. It was published online on January 4, 2024, in the Journal of Endocrinological Investigation.

LIMITATIONS:

This study could not establish causal relationships due to its cross-sectional design. The results might not apply to younger or older people from different locations and ethnic backgrounds. The gold standard method for analyzing vitamin D levels, liquid chromatography–mass spectrometry, was not used in this study.

DISCLOSURES:

This study was supported by the Spanish Ministry of Economy and Competitiveness, Spanish Ministry of Education, AstraZeneca HealthCare Foundation, and other sources. The authors declared no conflicts of interest.

Itching can be a real *itch

Itching is a real problem for many people.  We all get an itch periodically, and if you’re lucky, you scratch it and it goes away. 

SIDE NOTE: Itching is on of human’s most noxious – worst – stimuli.  We scratch because the pain induced from scratching is less problematic for us than the itch.

There are, however, people who have a chronic itch.  This article discusses some of the treatment options they try, and I have to laugh a bit.  The expert is from John Hopkins Itch Center – clearly one of the premier institutions in the world, and yet, there is NO discussion of identifying and removing the cause of said itch!  The symptoms and the world is a better place – UNTIL THE NEXT TIME!  Seriously?

There are some conditions that, even in conventional medicine, are known to cause itch – allergic reactions, thus you take an anti-histamine.  But it can be much more that allergies.

Let’s think about how the body handles stuff that no longer belongs in the body – waste products of all kinds.  If something is supposed to be disposed of through the bowels or the kidneys, but the system isn’t up to that (for any number of reasons we won’t go into here), the body will try an alternative path.  That path could be through the skin (think sweating).  But it that “stuff” isn’t supposed to go through the skin, the body might react – sometimes with a rash, but sometimes simply with an itch.  If you can “open up” the correct path (colon or kidney for example), you can get the rash to go away.  I have plenty of folks for whom this approach works and works well.  

My logo is about coming out of the box – I suggest the box discussed here is still a bit too small.

FROM MEDSCAPE MEDICAL NEWS / By Damian McNamara

Think Outside the Traditional Toolbox to Treat Itch

"Itch may not be as sexy as Mohs surgery or aesthetic procedures," but treating it is important and meaningful to patients, particularly those who've found little relief previously, Shawn G. Kwatra, MD, said at the annual ODAC Dermatology, Aesthetic & Surgery Conference.

Chronic itch is common, with presentations that range from annoying to debilitating. There are many over-the-counter and prescription treatments patients can and likely have tried by the time they seek a dermatologist for help.

In doctors' defense, it can be highly challenging to know which approach is optimal for each individual with pruritus, added Kwatra, associate professor of dermatology at Johns Hopkins University, Baltimore, Maryland.

Cooling agents, topical capsaicin, topical anesthetics like pramoxine 1%, various forms of lidocaine, strontium, opioid modulators like naltrexone, oral Janus kinase inhibitor (JAK) inhibitors, and medical marijuana are among some of the "outside the box" tools in Kwatra's itch toolbox.

Often a Medical Puzzle

Frequently, patients come to the dermatologist complaining of itch, "but you don't see much on their skin." After a trial of antihistamines, and some topical steroids, the doctor might put up their hands and think: I tried, but I don't know what else to do. "This actually happens a lot," said Kwatra, who is also director of the Johns Hopkins Itch Center.

This means itch can frustrate providers as well. But for patients, the impact on their quality of life can be on the same level as recovering from a stroke or living with heart failure, Kwatra said. Finding relief for their itch is where "we can make a big difference for patients."

Consider Cooling Agents

Many of these therapies are inexpensive and widely available. Cooling agents like menthol, camphor, or calamine can reduce activity of the transient receptor potential (TRP) channels in the skin associated with itch. This ion channel also senses temperature, pressure, and other sensations.

Another option is topical capsaicin, which works through the same ion channels. It binds to the TRPV1 receptors in sensory nerve fibers and causes desensitization. Initially, four to six applications a day are required to reduce itch. After that, patients can apply the medication less frequently. "You have to tell folks we know it's going to work, but it's going to burn a lot initially," Kwatra said. "In real world practice, I'm not using it often."

A 1.8% capsaicin patch, approved for treating postherpetic neuralgia, can be used to treat pruritus as well. "You put the patch on for one hour and you can have a true clinical response," he noted.

Another option for itch relief, the topical anesthetic pramoxine 1%, "is probably underutilized for our patients," Kwatra said. Pramoxine 1% works fast — as quickly as 2 minutes — and lasts up to 8 hours and is well-tolerated with low toxicity, he added. The agent is applied three to four times a day and relieves itch by reducing the transmembrane permeability of sodium ions on the skin. "This is something widely available and cheap."

Lidocaine, another topical anesthetic, is available compounded, over the counter, and as a spray or patch. "I would be careful before you use high doses, like 10%" because of tolerability issues, Kwatra cautioned. He generally starts with lower concentrations.

Topical strontium is really interesting as a strategy, Kwatra said. Strontium is a soft, white metal that competes with calcium for receptor binding. There are over-the-counter formulations available as a scalp solution or lotion, which, he said, "are ways to go with more episodic itching."

Topical oatmeal can also relieve itch in some patients. "There is actually some good scientific evidence for topical oatmeal preparations," he said.

Steroid-Sparing Novel Topicals

Topical ruxolitinib (a JAK inhibitor approved for atopic dermatitis and vitiligo); topical roflumilast (a phosphodiesterase-4 inhibitor) and topical tapinarof (an aryl hydrocarbon receptor agonist), both approved for treating psoriasis; and the atopic dermatitis drug crisaborole fall into this category of topicals with potential for treating itch, he said, noting that use for treating itch is off label.

Off-label use of biologic agents are also possible treatment options for itch, dupilumab and tralokinumab, both US Food and Drug Administration (FDA)–approved for treating atopic dermatitis. Emerging agents that may prove useful for treating itch include lebrikizumab, nemolizumab, amlitelimab, and rocatinlimab, he said.

In terms of oral therapies, the FDA has approved two oral JAK inhibitors for atopic dermatitis, abrocitinib and upadacitinib, which could prove useful for itch as an off-label indication, according to Kwatra.

Naltrexone Off Label

An emerging therapeutic concept for treating itch is using an opioid antagonist like naltrexone. Morphine causes more itch, so the theory is a reversal agent might help reduce it. The challenge is that naltrexone only comes as a 50 mg tablet, "and I find the high dose makes people nauseous and vomit," he added.

Don't Forget Devices

He referred to a "great paper" that he said has been "totally overlooked," published in 2001, which evaluated a device that stimulates C fibers in the skin to reduce itch. In the study, 19 patients used the device to treat local areas 20 minutes daily for 5 weeks. Punch biopsies of the affected areas were taken at baseline and after treatment. Mean itch ratings decreased from 78% to 42%, and the number of immunoreactive nerve fibers in the epidermis decreased by 40% at the end of treatment.

"Electrical neurostimulation is better for localized pruritus. There is limited case series evidence, but it's something to think about," Kwatra said.

He and his colleagues also have a case study in press that explored the use of injected botulinum toxin to relieve recalcitrant, chronic itch in a 65-year-old man "who failed everything."

If you want to save lives, you've got to catch it early. But is it worth it?

Ovarian Cancer is not something I spend a lot of time working on, but it’s a terrible disease, mostly because it’s usually diagnosed very late, making it very difficult to successfully treat.  Sure, the BRCA gene story has segment some of those people, but then they’re having prophylactic surgery (removal of breast and/or ovaries) to avoid the future possibility of cancer.  One would think that a better option is needed.

The study presented is really interesting in how effective it is at identifying early disease and thereby limiting surgical removal of actual diseased organs and effecting cures.  A simple blood test done regularly over time can screen people and help target those with hints of problems, escalating interventions as required.  This approach clearly works, and actually works very well.  

Now the problem is the money.  How much does it cost to save someone’s life?  There is a metric known as QALY (Quality Adjusted Life Year) that’s used to calculate the “value” of an intervention.  Sometimes the calculation gets very complex, but it usually only takes into account the health care costs, not the societal costs, so it’s not always a great way to measure “value”.  A standard, conservative figure for QALY value is $50,000.  That means that a treatment would cost $50,000 for every year of life saved.  Some inexpensive blood pressure medications come in around $15-30,000; an annual screening mammogram for women over 50 works out around that $50k number.  The challenge comes in when you stretch the target audience – for women over 40, the number rises to around $200k.  In the case of screening for prostate cancer, there’s never been a figure calculated because it’s not clear screening actually saves lives, but that’s another story.

Here we have a very clear option for screening that is very good at finding the target.  It now will have to wait for the economics to be determined and whether or not saving these lives “is worth it”.

From the Journal of Clinical Oncology / By Chae Young Han, PhD, Karen H. Lu, MD, Gwen Corrigan, Alexandra Perez, CMA, Sharlene D. Kohring, HSD, Joseph Celestino, BS, Deepak Bedi, MD, Enrique Bedia, MD, Therese Bevers, MD, David Boruta, MD, Matthew Carlson, MD, Laura Holman, MD, Leroy Leeds, MD, Cara Mathews, MD, Georgia McCann, MD, Richard G. Moore, MD, Matthew Schlumbrecht, MD, Brian Slomovitz, MD, Dan Tobias, MD, Yvette Williams-Brown, MD, Michael W. Bevers, MD, Jinsong Liu, MD, Terrie G. Gornet, BS, Beverly C. Handy, MD, Zhen Lu, MD, Jacob S. Bedia, BS, Steven J. Skates, PhD, and Robert C. Bast Jr, MD

Abstract

Clinical trials frequently include multiple end points that mature at different times. The initial report, typically based on the primary end point, may be published when key planned co-primary or secondary analyses are not yet available. Clinical Trial Updates provide an opportunity to disseminate additional results from studies, published in JCO or elsewhere, for which the primary end point has already been reported.

Purpose

The Normal Risk Ovarian Screening Study (NROSS) tested a two-stage screening strategy in postmenopausal women at conventional hereditary risk where significantly rising cancer antigen (CA)-125 prompted transvaginal sonography (TVS) and abnormal TVS prompted surgery to detect ovarian cancer.

Methods

A total of 7,856 healthy postmenopausal women were screened annually for a total of 50,596 woman-years in a single-arm study (ClinicalTrials.gov identifier: NCT00539162). Serum CA125 was analyzed with the Risk of Ovarian Cancer Algorithm (ROCA) each year. If risk was unchanged and <1:2,000, women returned in a year. If risk increased above 1:500, TVS was undertaken immediately, and if risk was intermediate, CA125 was repeated in 3 months with a further increase in risk above 1:500 prompting referral for TVS. An average of 2% of participants were referred to TVS annually.

Results

Thirty-four patients were referred for operations detecting 15 ovarian cancers and two borderline tumors with 12 in early stage (I-II). In addition, seven endometrial cancers were detected with six in stage I. As four ovarian cancers and two borderline tumors were diagnosed with a normal ROCA, the sensitivity for detecting ovarian and borderline cancer was 74% (17 of 23), and 70% of ROCA-detected cases (12 of 17) were in stage I-II. NROSS screening reduced late-stage (III-IV) disease by 34% compared with UKCTOCS controls and by 30% compared with US SEER values. The positive predictive value (PPV) was 50% (17 of 34) for detecting ovarian cancer and 74% (25 of 34) for any cancer, far exceeding the minimum acceptable study end point of 10% PPV.

Conclusion

While the NROSS trial was not powered to detect reduced mortality, the high specificity, PPV, and marked stage shift support further development of this strategy.

Weight Loss Drugs Often Stall

Most people are familiar with the concept of a weight setpoint.  The setpoint is the body’s somewhat “natural” weight – seems like we always drift back to a particular number.  When we diet, if we get too severe in our restriction, the body moves into a kind of starvation state, our energy utilization (fat burn) drops and we hang onto the weight.  And we slowly drift back to where we were (unless you’ve yo-yo’d so much that you actually end up drifting even higher).  It’s really hard to reset our set points.  

The new GLP-1 weight loss medications – Wegovy, Ozempic, Mounjaro have proven themselves to be very helpful for many, if not most people.  Most overweight people (that’s nearly ½ of America) have some measure of insulin resistance, and thus these medications make sense, and work.  Of course, like all medications, there can be side effects, and some can be really severe.  Even so, they are a tremendous step forward for many, many people who have struggled with their weight.

As many of us would have expected, it appears that the GLP-1 meds may not be able to eliminate the set point problem.  It is likely that most people will be able to RESET their set points to a lower number, then seemingly virtually everyone will plateau.  This is no surprise – a metabolic process will work according to the overall environment.  Likely the situations that influenced the weight gain in the first place will continue to have some sway of the future.  

It doesn’t mean that people should avoid the medication.  If there’s a good reason to start it, it’s worth the try.  Only understand that the weight loss rainbow may not end in a kettle of gold.  Though for many, it’s a lot more than spare change!

FROM MEDPAGE TODAY/ BY SOPHIE PUTKA

The GLP-1 Agonist Plateau No One's Talking About

— Weight stabilization is no surprise to specialists, but for patients it's more complicated

The declines in body weight that patients experience with injectables like semaglutide (Ozempic, Wegovy) and tirzepatide (Mounjaro) are no exception to the concept that nothing lasts forever.

Eventually, everybody reaches a "plateau," even on newer GLP-1 receptor agonists. It's a phase at which the body reaches a new "settling point," specialists said, and weight, along with other metabolic markers like blood pressure and HBA1c stabilize, or fluctuate only slightly. For some, this may mean a gradual increase in appetite or "food noise"; others may be able to maintain their current state.

Studies have shown that, on average, this plateau happens at a little over a year with semaglutide. Even so, physicians say some patients are surprised to learn that there's a limit to what these medications can do.

"Everyone will plateau, of course. No one on my watch has disappeared. No one has vanished," Jody Dushay, MD, an endocrinologist at Beth Israel Deaconess Medical Center in Boston, told MedPage Today. "It's alarming to me that people find that surprising, but everyone will reach a plateau and there's no way to know when you start the medication what that will be, what percent weight loss that will be, and how quickly they will reach it."

Gitanjali Srivastava, MD, an obesity medicine specialist at Vanderbilt University Medical Center in Nashville, Tennessee, noted that "we see that often and it's a question that gets asked frequently. There's going to be a new homeostatic balance that's achieved, and we see that with any other disease phenomenon."

For example, Srivastava told MedPage Today that a patient will not become hypotensive after a certain amount of time on a blood pressure medication, or have blood glucose levels decrease indefinitely with diabetes medications. "Evolutionarily, we need to be able to do that, so we can protect against the extremes," she added. "Because the alternative is that you continue to wither away, and that can be dangerous."

It's still unclear what may predispose patients to longer or shorter responses to GLP-1 agonists, but Dushay said that, typically, early responses tend to predict later ones. If a patient experiences steep weight loss on lower doses of semaglutide, for example, they can stay on a lower dose for longer, with more time to uptitrate if necessary. Patients on semaglutide for type 2 diabetes also tend to experience less weight loss overall, she said.

Karl Nadolsky, DO, an endocrinologist and obesity medicine specialist at Holland Hospital in Michigan, told MedPage Today in an email that "a history of childhood obesity with any suspicion [of] specific genetic or syndromic etiology" might also hint at a predisposition to hyporesponse.

Specialists have said that before prescribing this class of medication, they thoroughly discuss what to expect, from side effects to plateauing and the possibility of non-response. Dushay noted that it's important that providers set these expectations with patients, and for patients to seek out doctors who have the time and clinical experience to do so.

In clinical trials that looked at semaglutide 2.4 mg per week, participants' weight loss tapered off around week 60, with about 10% to 15% of body weight lost. Semaglutide's effect on blood pressure and HBA1c appeared to plateau even earlier. Spanning 2 years, patients hit a weight plateau once again around 60 weeks, and were able to maintain that weight for the remainder of the study. In the Surmont Trial which looked at various doses of tirzepatide for 72 weeks, participants on the 5-mg dose had reached a plateau within 60-72 weeks, but this was not the case on the higher doses. A 2-year trial is expected to offer more insight.

However, clinicians are more interested in what such averages hide. It's nearly impossible to know how well a patient will respond to semaglutide or tirzepatide, and individuals may have wildly different medical histories, medications, and comorbidities that all affect how well, and for how long, a given drug may work.

Fatima Cody Stanford, MD, MPH, MPA, MBA, an obesity medicine specialist at Massachusetts General Hospital in Boston, pointed out that a patient's expectation may not match their ultimate response to a GLP-1 agonist. "Everybody comes in and they're like, 'I want to do what this person did' -- they have their family, their friend, their sister, their brother, cousin, aunt, and I'm like, 'well, we don't know,'" she said. "The only people that I expect to respond almost identically are identical twins."

Stanford said she would like to see studies on GLP-1 agonists in the future that stratify patient response by various characteristics like genetics. Right now, she noted, weight-loss drugs require a lot of trial and error. Predicting the likelihood of success for individual patients would save time -- and money. "When a new cancer drug comes out, not everyone's like, 'ooh, there's a new cancer drug, let's just start everyone on that.' Right? Nobody does that," she said. "I want to know who the drug is right for."

"If I know that, on average, this person is going to be a really poor responder to a GLP-1 agonist, I won't [prescribe it]," she added. "It is a really arduous pathway for a lot of reasons -- access, coverage, prior authorization. It's burdensome. It's burdensome on the patient, it's burdensome on the system, it's burdensome on me."

Experts said it's common for patients to want more. For example, they may bring their blood glucose within a normal range, go off of blood pressure medications, and maintain overall positive health outcomes with a GLP-1 agonist, but hit a "plateau" and still want to lose weight.

Ultimately, this is where psychological and societal ambitions collide with clinical ones.

Patients are "having to negotiate with what society tells them, so they're still 200 pounds and society says 'for your height and weight you should be 125,' even though their health looks amazing," Stanford said. "Not always, but often, they still want to be whatever this number is."

Dushay said it's rare for patients to achieve the weight loss goal they arrive at an initial consult with. Often, Dushay's noticed, this goal is the weight they were on their wedding day. "I think that some of it is literally [that] they want to weigh that," she said. "But I think there is a big component of 'I want to rewind time.'"

"I've almost never had someone hit a plateau when they were like, 'okay, I'm good.'"

In the meantime, clinicians have strategies to move past a plateau if a patient hasn't yet met important clinical goals. Generally, some said they might increase the dose if possible, if the patient can tolerate it well. Failing that, they can supplement with a second drug that targets a different neuronal or hormonal pathway, like phentermine (Lomaira). Dushay said that in practice she's noticed that "drug holidays" or stopping and restarting a GLP-1 agonist, have typically not affected plateaus.

You didn't get Long COVID, but that doesn't mean it didn't do long term damage

Nearly everyone has had COVID by now.  If you got it early, you probably got it worse than others, but not necessarily.  Many people have suffered, and many people have continued to suffer.  Long COVID has recently be shown to have blood abnormalities (we knew that ages ago) that can prove “it’s not in your head”.  But more than that, every time one gets COVID, there’s a risk that bad things will happen – and persist.  Here’s a study that shows that if you get COVID you have 1.50 times the risk of having hypertension (high blood pressure) then if you didn’t get COVID, but if you were hospitalized for COVID, the risk of HBP goes up to 2.2x’s.  We’ve said this is a blood vessel disease, and this just bears it out. 

Don’t assume that everything is fine if you have COVID and you get over it.  Even Long COVID can be delayed by a couple of months!  Don’t assume – follow up with your doctor and make sure other problems don’t develop.

FROM AHA JOURNAL / BY VINCENT ZHANG, MOLLY FISHER, WEI HOU, LILI ZHANG, TIM Q. DUONG

Incidence of New-Onset Hypertension Post–COVID-19: Comparison With Influenza

Abstract

BACKGROUND:

SARS-CoV-2 may trigger new-onset persistent hypertension. This study investigated the incidence and risk factors associated with new-onset persistent hypertension during COVID-19 hospitalization and at ≈6-month follow-up compared with influenza.

METHODS:

This retrospective observational study was conducted in a major academic health system in New York City. Participants included 45 398 patients with COVID-19 (March 2020 to August 2022) and 13 864 influenza patients (January 2018 to August 2022) without a history of hypertension.

RESULTS:

At 6-month follow-up, new-onset persistent hypertension was seen in 20.6% of hospitalized patients with COVID-19 and 10.85% of nonhospitalized patients with COVID-19. Persistent hypertension incidence among hospitalized patients did not vary across the pandemic, whereas that of hospitalized patients decreased from 20% in March 2020 to ≈10% in October 2020 (R2=0.79, P=0.003) and then plateaued thereafter. Hospitalized patients with COVID-19 were 2.23 ([95% CI, 1.48–3.54]; P<0.001) times and nonhospitalized patients with COVID-19 were 1.52 ([95% CI, 1.22–1.90]; P<0.01) times more likely to develop persistent hypertension than influenza counterparts. Persistent hypertension was more common among older adults, males, Black, patients with preexisting comorbidities (chronic obstructive pulmonary disease, coronary artery disease, chronic kidney disease), and those who were treated with pressor and corticosteroid medications. Mathematical models predicted persistent hypertension with 79% to 86% accuracy. In addition, 21.0% of hospitalized patients with COVID-19 with no prior hypertension developed hypertension during COVID-19 hospitalization.

CONCLUSIONS:

Incidence of new-onset persistent hypertension in patients with COVID-19 is higher than those with influenza, likely constituting a major health burden given the sheer number of patients with COVID-19. Screening at-risk patients for hypertension following COVID-19 illness may be warranted.

There IS evidence that COVID shots affect your heart

This subject could get me in trouble but it's the truth. There is a very small number of people who get heart inflammation (myocarditis) after COVID immunization.  But I have test (Multifunction Cardiogram) that has shown low levels on heart inflammation in patients who shouldn't have that, but they've had the SHOT.  

As I've said time and again every medical intervention needs to be considered in context - the individual matters.  

FROM RSNA / BY TAKEHIRO NAKAHARA, YU IWABUCHI, RAITA MIYAZAWA, KAI TONDA, TOHRU SHIGA, H. WILLIAM STRAUSS, CHARALAMBOS ANTONIADES, JAGAT NARULA, MASAHIRO JINZAKI

Assessment of Myocardial 18F-FDG Uptake at PET/CT in Asymptomatic SARS-CoV-2–vaccinated and Nonvaccinated Patients

Abstract

Background

Patients who developed myocarditis after SARS-CoV-2 vaccination show abnormalities on cardiac MRI scans. However, whether myocardial changes occur in asymptomatic individuals after vaccination is not well established.

Purpose

To assess myocardial fluorine 18 (18F) fluorodeoxyglucose (FDG) uptake on PET/CT images in asymptomatic patients vaccinated against SARS-CoV-2 compared with nonvaccinated patients.

Materials and Methods

This retrospective study included patients who underwent 18F-FDG PET/CT for indications unrelated to myocarditis during the period before (November 1, 2020, to February 16, 2021) and after (February 17, 2021, to March 31, 2022) SARS-CoV-2 vaccines were available. Myocardial and axillary 18F-FDG uptake were quantitatively assessed using maximum standardized uptake value (SUVmax). The SUVmax in all patients and in patients stratified by sex (male or female), age (<40 years, 41–60 years, >60 years), and interval between vaccination and PET/CT were compared using the Mann-Whitney U test or the Kruskal-Wallis test with post ad hoc Dwass-Steel-Critchlow-Fligner multiple comparison analysis.

Results

The study included 303 nonvaccinated patients (mean age, 52.9 years ± 14.9 [SD]; 157 female, 146 male) and 700 vaccinated patients (mean age, 56.8 years ± 13.7; 344 female, 356 male). Vaccinated patients had overall higher myocardial 18F-FDG uptake compared with nonvaccinated patients (median SUVmax, 4.8 g/mL [IQR, 3.0–8.5 g/mL] vs 3.3 g/mL [IQR, 2.5–6.2 g/mL]; P < .001). Myocardial SUVmax was higher in vaccinated patients regardless of patient sex (median range, 4.7–4.9 g/mL [IQR, 2.9–8.6 g/mL]) or age (median range, 4.7–5.6 g/mL [IQR, 2.9–8.6 g/mL]) compared with corresponding nonvaccinated groups (sex: median range, 3.2–3.9 g/mL [IQR, 2.4–7.2 g/mL]; age: median range, 3.3–3.3 g/mL [IQR, 2.3–6.1 g/mL]; P < .001 to P = .015). Furthermore, increased myocardial 18F-FDG uptake was observed in patients imaged 1–30, 31–60, 61–120, or 121–180 days after their second vaccination (median SUVmax range, 4.6–5.1 g/mL [IQR, 2.9–8.6 g/mL]) (P < .001 to P = .001), and increased ipsilateral axillary uptake was observed in patients imaged 1–30, 31–60, and 61–120 days after their second vaccination (median SUVmax range, 1.5–2.0 g/mL [IQR, 1.2–3.4 g/mL]) compared with the nonvaccinated patients (P < .001 to P < .001).

Conclusion

When compared with nonvaccinated patients, asymptomatic patients who received their second vaccination 1–180 days prior to imaging showed increased myocardial 18F-FDG uptake on PET/CT scans.

Don't get stuck holding the bill!

Everybody should have some form of health insurance.  Unfortunately, coverage is very often not what people want it to be.  Regularly there are copays, co-insurance and just plain non-covered situations, so being surprised is not an uncommon occurrence.  

The story attached is a another one of those surprises.  A very expensive drug has often been dosed in an office, but over time, more people decided to do the injection themselves.  So Medicare decided that everyone should inject themselves.  The guy in the story has Parkinson’s making self-injection very difficult, and potentially impossible.  Now he’s stuck with the bill (unless the class action suit wins).  

The morale is that you need to know your responsibilities.  My practice is almost entirely cash – there really aren’t surprises.  Insurance is designed to make sure that really big ticket items will be covered.  Of course, many of those items come with a 20% copay….  

Maybe the best thing to do is make sure you get ahead of your health.  Don’t wait for the problem.  Be proactive!  We can help.

FROM MEDPAGE TODAY / BY CHERYL CLARK

A 'SAD' Story: Patient Stuck With $176K Bill After Medicare Policy Switch

— CMS abruptly decided patients can self-administer Stelara -- even those with Parkinson's

For 5 years, retiree George Beitzel went to a Sacramento-area clinic every 2 months so a nurse could give him an injection of the costly drug ustekinumab (Stelara), which his doctors prescribed for his Crohn's disease.

To have a licensed professional give the shots was especially important for Beitzel, now 84, because he has Parkinson's disease.

"I shake like a bug," making it impossible to safely give himself the injections, Beitzel told MedPage Today.

Even though Stelara is among the most expensive drugs on the market, costing upwards of $40,000 per dose, Medicare had always paid for his injections under Part B, which covers drugs delivered by a doctor's office or a clinic. With his co-payments covered by his supplemental plan, "I never had to pay a thing," he said.

But all of that changed on October 15, 2021, unbeknownst to Beitzel and the clinic that continued administering his injections for another 7 months. That's according to a class-action lawsuitopens in a new tab or window filed last week by the non-profit Center for Medicare Advocacy (CMA) on behalf of Beitzel and another patient, in U.S. District Court, Eastern District of California, against HHS Secretary Xavier Becerra.

What CMS quietly and abruptly did that day was alter its payment policy on Stelara, said CMA's Litigation Director Alice Bers. It decided -- based on Medicare claims data whose use for this purpose is controversial -- that since more than 50% of Stelara users inject the drug themselves, to reclassify the drug as a "SAD," or a self-administered drugopens in a new tab or window, for everyone, and would no longer cover it when administered in an outpatient setting.

Although he was unaware of it at the time, each injection he received at the clinic after October 15 will now cost Beitzel $43,543.47, or as much as $176,000. Medicare has told him as much in numerous letters denying his appeals.

"Some of the denial letters said Mr. Beitzel should have been aware that Stelara was not covered because he could have read it in his 2021 Medicare & You handbook," Bers said.

"That's ridiculous and added insult to injury," she said. Not only did the over 100-page handbook, which came out in the fall of 2020, not mention Stelara, she said. It had buried and vague wording that did not tell him Medicare would reclassify the drug a year later: "Part B doesn't cover other types of drugs in a hospital outpatient setting (sometimes called 'self-administered drugs' or drugs you'd normally take on your own)."

A CMS spokesperson said the agency does not comment on pending litigation.

Beitzel sought help from Melissa Brown, an attorney with McGeorge School of Law's Elder Law Clinic in Sacramento, which is co-counsel in the lawsuit.

Their request for injunctive relief is Beitzel's last effort in the year-long, paperwork- and stress-laden battle against Medicare's multi-layered and complicated appeals process, which has been fraught with frustrating, confusing, and contradictory rulings along the way, Bers said.

Now, to get SAD drugs covered, Medicare beneficiaries -- including those with frailty, movement, or seizure disorders -- must get them from their Part D drug plan pharmacies, most of which require high co-pays, if they cover expensive drugs like Stelara at all. Then they must inject it themselves or find a qualified person who could safely do it for them. Otherwise, the Stelara and other SAD drugs are no longer covered outpatient benefits.

Stelara, used by 22,000 beneficiaries in the year ending May 2023, is so expensive, costing the Medicare program nearly $2.7 billion during that period, it is one of the 10 drugs earmarkedopens in a new tab or window in August for negotiation under the Biden Administration's Inflation Reduction Act.

Since May 2022, Beitzel has stopped going to the clinic for injections. He pays his drug plan $1,390 in cost-sharing for every Stelara dose, and has a retired health provider friend give him the injections.

What's perhaps equally difficult to understand, Bers said, is that the agency says its rules don't require it or providers to give advance notice to beneficiaries that the drug is no longer covered under Part B, leaving patients to find out about the change only when the shocking bills come in the mail months later.

And because he didn't know, and the clinic either didn't know or didn't understand, Beitzel continued receiving four injections at the clinic after the policy change -- in October and December of 2021, and February and April of 2022.

Beitzel only learned something might be wrong when he received a Medicare Summary Notice (MSN) dated March 1 that his October and December doses were "non-covered," and that he may be billed $43,543,47 for each of them. It didn't say why.

"I almost fell over because I've been doing this for 5 years and it didn't cost anything and nobody ever said anything," Beitzel told MedPage Today in a call with the center's attorneys on the line. He said the infusion center's billing department told him it was a "paper mistake" and not to worry about it.

Months later, he received another MSN denial dated June 10. It said he owed another $89,438.28 for the third and fourth doses. The infusion center appealed but was denied, but for the first time provided a reason: "We find that the above services are deemed self-administered drugs. Therefore ... no payment can be made," the lawsuit said.

"I still feel distressed and stressful," Beitzel told MedPage Today as he mentioned the foot-high stack of paperwork on his case. "And when you have Crohn's, stress is not a good thing to have. Every time I read this stuff it upsets me."

The class action also names another plaintiff, identified as K.K., a 72-year-old psoriasis patient in Darien, Connecticut with a rare form of painful arthritis that damages bones in one's hands and feet. Since 2016, she also has received Stelara injections, every 3 months, all covered by Medicare's Part B. That is, until October 15, 2021, when the regional Connecticut Medicare Administrative Contractor (MAC) changed the policy the same way.

Like Beitzel, she wasn't told about the change and continued receiving injections from a nearby hospital outpatient department.

Now, in notices she received months later, Medicare says she owes more than $116,000 for two of the doses. She appealed, and during one appeal process, was told verbally by an administrative law judge that she wouldn't be responsible for the payments. But in the ruling, the judge's decision was reversed, saying, "I am not able to ignore Medicare policy and guidance."

The lawsuit said "Ms. K. experienced and continues to experience distress, anxiety, and outrage about the termination of Part B coverage for Stelara without notice and Medicare's decisions finding that she is financially liable for the cost of the injections she received at the hospital."

The lawsuit said she had to stop taking the drug because her Part D plan requires such a high cost for it. And she suffered pain and a serious rash that "looks like a third degree burn," and covered about "50% of her body and tormenting her with itching with no relief." Now, she is back on the drug through the manufacturer.

In addition to asking the court to certify the case as a class action, the lawsuit wants the court to issue a permanent injunction requiring Becerra to ensure notice is provided when a drug changes status to self-administered; waive patients' liability for the costs; and modify the program so people with medical conditions who can't inject themselves can get them administered by a healthcare professional.

Bers said the lawsuit was filed on behalf of potentially thousands of Medicare beneficiaries who could and are finding themselves with similarly outrageous amounts of debt because of surprise SAD drug policies, and not just those taking Stelara.

Medicare contractors moved three rheumatology drugs to the SAD list a decade ago, also without warning, but efforts by the American College of Rheumatology persuadedopens in a new tab or window them to move them back to Part B, the lawsuit said. But as of August, two of the three drugs, Simponi and Orencia, are back on the list.

The lawsuit also mentions that several regional MACs have proposed SAD change decisions on other drugs covered under Part B, such as the injectable biologic for psoriasis, tezepelumab-ekko (Tezspire). But effortsopens in a new tab or window by the American College of Allergy, Asthma & Immunology have thwartedopens in a new tab or window that.

Bers said her review of the 12 regional MAC decisions on Stelara consistently categorize it now as a SAD drug, but some appear to be inconsistent in their reasons for it.

To Beitzel, the Medicare agency's actions are not just hurtful and heartless, they're dangerous.

"I kept getting these letters from Medicare that I didn't understand, and it's just like a big bureaucracy is stepping on this little bitty hand," Beitzel told MedPage Today.

Beitzel said he would like to ask a Medicare representative if he would let Beitzel give him an injection, if he had the chance: "He'd see me, my hand shaking, and he'd say, 'No, I don't want you to get even close to me.'"

Treating ED reduces Alzheimer's?

The article has a clickbait title – Viagra cuts Alzheimer’s risk by 70%.  So what’s the real story?

Originally sildenafil (sold as Viagra) was researched because it increases Nitric Oxide (NO) which can be a real game changer for heart health.  As the research went on, other “things” started popping up, and the marketing machine took over from the scientists.  Now that the drug is off patent the cardiac research is showing up again.  

Since NO is huge regarding blood flow (opens vessels = vasodilates), it’s not a stretch to think that there might be first brain benefits, as well as the obvious “second brain” effects.  But this study DOESN’T PROVE ANYTHING.  It only hints at possibilities.

It’s a computer model of a biological model based off of insurance data.  Insurance data is often quite flawed, as well as a potential sampling bias in the group evaluated – maybe the folks using Viagra are less cognitively impaired than the others, so maybe the 70% is substantially overestimated.  

Could there be benefit? I think absolutely.  Is taking Viagra for this a good idea?  Probably not. Are there other things to do besides take Viagra?  Absolutely – there are numerous natural ways to improve NO levels that help all kinds of things, and it just might ward off early Alzheimer’s.  But proof?  No. 

FROM GREEK REPORTER / BY THOMAS KISSEL

Viagra Lowers the Risk of Alzheimer’s by Almost 70%, Study Finds

Research published recently suggests that Pfizer’s erectile dysfunction drug Viagra can decrease the risk of developing Alzheimer’s disease by up to 69 percent.

The research, which was published in Nature, found that the medication has a direct effect on brain health and significantly reduces the toxic proteins that can cause dementia.

The study’s findings are so promising that the drug may someday be used to counter dementia. A new team of experts is preparing to conduct another study that builds on this data but tests the generic version of Viagra, sildenafil, in patients suffering from early Alzheimer’s.

The team of researchers arrived at Viagra’s viability as a treatment for dementia after analyzing 1,600 approved drugs hoping to find one that could be repurposed to fight the root causes of dementia.

“Sildenafil, which has been shown to significantly improve cognition and memory in preclinical models, presented as the best drug candidate. Sildenafil may have neuroprotective effects and reduce levels of toxic tau proteins,” said Dr. Feixiong Cheng, the lead researcher on the study, which was conducted by the Cleveland Clinic.

Despite the excitement surrounding the study’s promising results, some experts are advising people to not get their hopes up quite yet, as clinical trials are still necessary.

Coffee and Viagra offer new hope in fight against Alzheimer’s

Another recent study uncovered another unlikely weapon in the fight against dementia: coffee. Research suggests that coffee consumption may significantly decrease your chances of developing the disease.

The study sheds light on the mysterious disease, for which there is no cure as of now. While coffee does not mitigate or fight Alzheimer’s like some medications do, the study found that people with no memory loss who also drank larger than average amounts of coffee were at less of a risk of developing mild cognitive impairment, which is considered a pre-stage of Alzheimer’s disease.

“With Alzheimer’s disease, there’s currently a lack of any effective disease-modifying treatments. Our research group is specifically looking at modifiable risk factors that could delay the onset of the disease, and even a five-year delay could have massive social and economic benefits,” said lead author Samantha Gardener, who is a research fellow at Edith Cowan University in Western Australia.

“Worldwide, a high proportion of adults drink coffee every day, making it one of the most popular beverages consumed,” Gardener added.

The popularity and ubiquitousness of coffee could make it a viable method of deferring the onset of Alzheimer’s disease. But she also stressed that further studies are necessary. Gardener and her team are not yet sure what ingredient in coffee itself contributes to the delaying of Alzheimer’s.

“This is, obviously, preliminary data and it needs a lot more research before being recommended, but it’s really positive, and hopefully in the future, it can be incorporated as a modifiable lifestyle factor that can delay Alzheimer’s disease onset,” Gardener said.

Solving the cholesterol problem you never heard of

Lp(a), known as LP little “a” (Lp is lipoprotein), is an independent risk factor for cardiovascular disease.  The easiest way to think about Lp(a) is that it’s a genetically determined type of cholesterol carrier that makes the other risky cholesterols worse if it’s elevated.  

The problem has been two-fold – 

1. Lp(a) has only recently been measured by most doctors (I’ve been measuring it for about 10 years), and

2. Very little will change the Lp(a) level by much.  

As a consequence of #1, many patients who suffer “surprise” events (they have “normal” cholesterol but usual tests) are ultimately found to have elevated Lp(a). 

#2 leads to the strategy that lowering other cholesterol risks in the hope that you could avoid the consequences.  

The article attached reports the first successful attempt to meaningfully lower the Lp(a) (62%) with an oral medication, without screwing other stuff up, at least in an obvious way.  Phase I trials are small, and are testing for safety, but this one actually shows promise for efficacy as well.  For people with elevated Lp(a) this could be a real gamechanger.  It’s early, but fingers crossed.

FROM JAMA NETWORK / BY STEPHEN J. NICHOLLS, MBBS, PHD1; STEVEN E. NISSEN, MD2; CYNTHIA FLEMING, RN, MSN

Muvalaplin, an Oral Small Molecule Inhibitor of Lipoprotein(a) Formation

A Randomized Clinical Trial

Key Points

Question  Can muvalaplin, an orally administered small molecule inhibitor of lipoprotein(a) (Lp[a]) formation, achieve safe and tolerable plasma concentrations adequate to reduce steady-state Lp(a) levels without modulating plasminogen activity in humans?

Findings  In this first-in-human phase 1 study involving healthy participants, muvalaplin administered orally as single ascending doses ranging from 1 mg to 800 mg and as multiple ascending doses ranging from 30 mg to 800 mg for 14 days caused dose-dependent plasma concentration increases. Muvalaplin administration was not associated with concerns about safety or tolerability, and it reduced Lp(a) levels but not plasminogen activity.

Meaning  The observed safety, tolerability, pharmacokinetics, and exploratory pharmacodynamics of muvalaplin in healthy participants support further clinical evaluation in patients with elevated Lp(a) levels.

Abstract

Importance  Lipoprotein(a) (Lp[a]) is associated with atherosclerotic disease and aortic stenosis. Lp(a) forms by bonding between apolipoprotein(a) (apo[a]) and apo B100. Muvalaplin is an orally administered small molecule that inhibits Lp(a) formation by blocking the apo(a)-apo B100 interaction while avoiding interaction with a homologous protein, plasminogen.

Objective  To determine the safety, tolerability, pharmacokinetics, and pharmacodynamic effects of muvalaplin.

Design, Setting, and Participants  This phase 1 randomized, double-blind, parallel-design study enrolled 114 participants (55 assigned to a single-ascending dose; 59 assigned to a multiple-ascending dose group) at 1 site in the Netherlands.

Interventions  The single ascending dose treatment evaluated the effect of a single dose of muvalaplin ranging from 1 mg to 800 mg or placebo taken by healthy participants with any Lp(a) level. The multiple ascending dose treatment evaluated the effect of taking daily doses of muvalaplin (30 mg to 800 mg) or placebo for 14 days in patients with Lp(a) levels of 30 mg/dL or higher.

Main Outcomes and Measures  Outcomes included safety, tolerability, pharmacokinetics, and exploratory pharmacodynamic biomarkers.

Results  Among 114 randomized (55 in the single ascending dose group: mean [SD] age, 29 [10] years, 35 females [64%], 2 American Indian or Alaska Native [4%], 50 White [91%], 3 multiracial [5%]; 59 in the multiple ascending dose group: mean [SD] age 32 [15] years; 34 females [58%]; 3 American Indian or Alaska Native [5%], 6 Black [10%], 47 White [80%], 3 multiracial [5%]), 105 completed the trial. Muvalaplin was not associated with tolerability concerns or clinically significant adverse effects. Oral doses of 30 mg to 800 mg for 14 days resulted in increasing muvalaplin plasma concentrations and half-life ranging from 70 to 414 hours. Muvalaplin lowered Lp(a) plasma levels within 24 hours after the first dose, with further Lp(a) reduction on repeated dosing. Maximum placebo-adjusted Lp(a) reduction was 63% to 65%, resulting in Lp(a) plasma levels less than 50 mg/dL in 93% of participants, with similar effects at daily doses of 100 mg or more. No clinically significant changes in plasminogen levels or activity were observed.

Conclusion  Muvalaplin, a selective small molecule inhibitor of Lp(a) formation, was not associated with tolerability concerns and lowered Lp(a) levels up to 65% following daily administration for 14 days. Longer and larger trials will be required to further evaluate safety, tolerability, and effect of muvalaplin on Lp(a) levels and cardiovascular outcomes.