FDA Reviewers Question Patient Selection for Alzheimer's Drug Candidate

 Whether certain groups of early Alzheimer's patients are more likely than others to benefit from investigational donanemab is a key question FDA advisors will try to untangle when they meet on June 10

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In briefing documentsopens in a new tab or window released ahead of next Monday's meeting of the agency's advisory committee, FDA staffers questioned whether tau levels should play a role in determining who might qualify for donanemab treatment, if the drug is eventually approved.

The Peripheral and Central Nervous System Drugs committee will discuss whether the benefits of donanemab outweigh its risks for people with early Alzheimer's disease. If approved, donanemab will be the third amyloid-targeted drug to come to market: the first being the controversial aducanumab (Aduhelm), which received accelerated approval but was subsequently abandonedopens in a new tab or window, and the second being lecanemab (Leqembi), which received full FDA approvalopens in a new tab or window last year.

Donanemab, which targets a modified form of beta amyloid known as N3pG, was tested in the phase III TRAILBLAZER-ALZ 2 trialopens in a new tab or window (referred to as Study AACI in the FDA's briefing documents) of 1,736 early Alzheimer's patients.

The drug met the primary endpoint of change from baseline in the Integrated Alzheimer's Disease Rating Scaleopens in a new tab or window (iADRS), slowing decline relative to placebo. At 76 weeks, mean change on the iADRS was -10.19 in the donanemab group versus -13.11 in the placebo group for all participants in the study (P<0.001).

Among those who had low or medium tau pathology -- 68.1% of the study population -- mean change was -6.02 in the donanemab group versus -9.27 in the placebo group (P<0.001). Scores on the iADRS range from 0 to 144, with lower scores indicating greater impairment.

On a key secondary endpoint, the Clinical Dementia Rating-Sum of Boxes (CDR-SB) score, mean change at 76 weeks was 1.72 with donanemab and 2.42 with placebo (P<0.001) in the total study population. For those with low or medium tau, CDR-SB change was 1.20 with donanemab and 1.88 with placebo (P<0.001). CDR-SB scores range from 0 to 18 with higher scores indicating greater impairment.

People with no or very low tau were excluded from the study, leading FDA reviewers to question whether donanemab should be restricted to Alzheimer's patients with a specific tau burden. In documents drugmaker Eli Lilly preparedopens in a new tab or window before the meeting, however, the company argued that they expected donanemab to show benefits regardless of tau levels and that tau can be an important marker of disease progression but does not predict drug response.

FDA staffers pointed out that Lilly changed the primary endpoint from CDR-SB to iADRS during the pivotal trial, and the FDA did not agree with the change.

Like other anti-amyloid drugs, donanemab's safety issues center around amyloid-related imaging abnormalities with edema or effusion (ARIA-E), ARIA with microhemorrhages and hemosiderin deposits (ARIA-H), cerebral hemorrhage, and infusion-related reactions. Lecanemab carries a black box warning for ARIAopens in a new tab or window, which occurs more frequently in APOE4 homozygotes.

In TRAILBLAZER-ALZ 2, 24% of donanemab-treated participants had ARIA-E and 31.4% had ARIA-H. Two ARIA-related deaths were attributed to donanemab. Intracerebral hemorrhages greater than 1 cm in diameter were reported in 0.5% of donanemab-treated patients, and infusion reactions occurred in 8.7% of the donanemab group.

Data from a third-party vendor that included mortality outcomes for participants who discontinued the trial suggested that 19 deaths occurred among people on donanemab (2.3%) compared with 16 deaths among people on placebo (1.9%) during the study period, the FDA noted. But other than ARIA-related deaths, "the deaths did not appear to be causally related to donanemab and there was no unusual grouping of deaths that would suggest a causal relationship," the agency wrote.

In TRAILBLAZER-ALZ 2, donanemab was dosed until amyloid was cleared, not continuously like other anti-amyloid agents. The FDA has asked its advisory committee to discuss this idea Monday.

The committee will vote on two questions: whether available data show that donanemab effectively treats the Alzheimer's population that was enrolled in the drug's clinical trials and whether the drug's benefits outweigh its risks. The FDA isn't required to follow its advisory committees' recommendations, but it often does.

https://www.medpagetoday.com/neurology/alzheimersdisease/110530

SCOTUS Sides With Native American Tribes in Healthcare Funding Dispute With Feds

 The Supreme Court sided with Native American tribes Thursday in a dispute with the federal government over the cost of healthcare when tribes run programs in their own communities.

The 5-4 decision means the government will cover millions in overhead costs that two tribes faced when they took over running their healthcare programs under a law meant to give Native Americans more local control.

Covering those costs is "necessary to prevent a funding gap," Chief Justice John Roberts wrote in the majority opinion, joined by the three liberal justices and fellow conservative Justice Neil Gorsuch. Not reimbursing them forces tribes to "pay a penalty for pursuing self-determination."

The Department of Health and Human Services (HHS) had argued it isn't responsible for the overhead costs associated with billing insurance companies, Medicare, and Medicaid.

Paying those costs for all tribes that run their own healthcare programs could total between $800 million and $2 billion per year, the agency said.

"The extra federal money that the Court today green-lights does not come free," Justice Brett Kavanaugh wrote in the dissent, which was joined by other conservative Justices Clarence Thomas, Samuel Alito, and Amy Coney Barrett. "In my view, the court should leave those difficult appropriations decisions and tradeoffs to Congress."

The federal Indian Health Service (IHS) has provided tribal healthcare since the 1800s under treaty obligations, but the facilities are often inadequate and understaffed, the San Carlos Apache Tribe in Arizona said in court documents.

Healthcare spending per person by the IHS is just one-third of federal spending in the rest of the country, the Northern Arapaho Tribe in Wyoming said in court documents. Native American tribal populations have an average life expectancy of about 65 years, nearly 11 years less than the U.S. as a whole.

Attorney Adam Unikowsky, who represented the Northern Arapaho Tribe, said the decision puts tribes on equal footing with IHS on healthcare and will "promote tribal sovereignty and provide resources for healthcare in under-served communities."

The tribes contracted with IHS to run their own programs ranging from emergency services to substance-abuse treatment. The agency paid the tribes the money it would have spent to run those services, but the contract didn't include the overhead costs for billing insurance companies or Medicare and Medicaid, since other agencies handle it when the government is running the program.

The tribes, though, had to do the billing themselves. That cost the San Carlos Apache Tribe nearly $3 million in overhead over 3 years and the Northern Arapaho Tribe $1.5 million over a 2-year period, they said. Two lower courts agreed with the tribes.

HHS appealed to the Supreme Court, arguing that tribes do get some money for overhead costs but the government isn't responsible for costs associated with third-party income.

The majority of federally recognized tribes now contract with IHS to run at least part of their own healthcare programming.

https://www.medpagetoday.com/washington-watch/washington-watch/110534

Sudden cardiac arrest occurring in temporal proximity to consumption of energy drinks

 

• Katherine A. Martinez, BS
• Sahej Bains, BS
• Raquel Neves, MD
• John R. Giudicessi, MD, PhD
• J. Martijn Bos, MD, PhD
• Michael J. Ackerman, MD, PhD 

4DOI:https://doi.org/10.1016/j.hrthm.2024.02.018

Abstract

Background

Energy drinks potentially can trigger life-threatening cardiac arrhythmias. It has been postulated that the highly stimulating and unregulated ingredients alter heart rate, blood pressure, cardiac contractility, and cardiac repolarization in a potentially proarrhythmic manner.

Objective

The purpose of this study was to describe our experience regarding sudden cardiac arrest (SCA) occurring in proximity to energy drink consumption in patients with underlying genetic heart diseases.

Methods

The electronic medical records of all SCA survivors with proven arrhythmias referred to the Mayo Clinic Windland Smith Rice Genetic Heart Rhythm Clinic for evaluation were reviewed to identify those who consumed an energy drink before their event. Patient demographics, clinical characteristics, documented energy drink consumption, and temporal relationship of energy drink consumption to SCA were obtained.

Results

Among 144 SCA survivors, 7 (5%; 6 female; mean age at SCA 29 ± 8 years) experienced an unexplained SCA associated temporally with energy drink consumption. Of these individuals, 2 had long QT syndrome and 2 had catecholaminergic polymorphic ventricular tachycardia; the remaining 3 were diagnosed with idiopathic ventricular fibrillation. Three patients (43%) consumed energy drinks regularly. Six patients (86%) required a rescue shock, and 1 (14%) was resuscitated manually. All SCA survivors have quit consuming energy drinks and have been event-free since.

Conclusion

Overall, 5% of SCA survivors experienced SCA in proximity to consuming an energy drink. Although larger cohort studies are needed to elucidate the incidence/prevalence and quantify its precise risk, it seems prudent to sound an early warning on this potential risk.

https://www.heartrhythmjournal.com/article/S1547-5271(24)00189-9/fulltext#%20

What Will New Weight-Loss Drugs Mean for Endometrial Cancer?

 

GLP-1 receptor agonists may be able to tackle the major modifiable risk factor

Obesity has been recognized as an endometrial cancer risk factor since at least the 1960sopens in a new tab or window and remains the single most impactful risk factor for the disease.

In a 2010 meta-analysisopens in a new tab or window, every 5 kg/m² increase in body mass index (BMI) was associated with a 60% greater risk of endometrial cancer. Another meta-analysis showed that women with obesity have a 2.54-fold higher relative riskopens in a new tab or window than normal-weight women. The link appears to be particularly strong for younger womenopens in a new tab or window.

However, obesity is a modifiable risk factor, and the new generation of effective weight-loss injectables like semaglutide (Ozempic, Wegovy) and tirzepatide (Mounjaro, Zepbound) are creating hope for counteracting the rising incidence of endometrial cancer and fighting the cancer in those who develop it.

"We know that bariatric surgery can be an effective complementary tool for patients with endometrial cancer," particularly for those interested in maintaining their uterus among the roughly 25% of premenopausal patients, said Leslie R. Boyd, MD, director of the division of gynecologic oncology at NYU Langone's Perlmutter Cancer Center in New York City.

Among these women, those with obesity or morbid obesity are often advised to pursue a combination of hormonal therapy and bariatric surgery, she noted, "the rationale being that medical weight loss tends to be slower and less likely to be maintained. Now that we have all the GLP-1 receptor agonists, it'll be interesting to see how that changes."

Women who aren't interested in bariatric surgery might find medication more appealing, she added. "It is complicated by the fact that progesterone therapy, which is the hormonal therapy that is effective in fighting the cancer, increases appetite and is strongly associated with weight gain. So it's another reason why ... using not just medical or hormonal therapy, but also bariatric therapy or bariatric surgery, is impactful for many of these patients."

The role of estrogen didn't become clear until the 1970s when the "natural experiment" of unopposed estrogen use for menopausal symptoms led to a high risk of endometrial cancer,opens in a new tab or window revealing the key driver of incidence.

Indeed, adding progestin to estrogen for women with an intact uterus, mimicking more closely the natural balance in the body, reduced that risk, though it didn't eliminate it. Decades of follow-up in studiesopens in a new tab or window like the Breast Cancer Detection Demonstration Projectopens in a new tab or window showed that postmenopausal women taking estrogen plus progestin had a 2.6-fold increased risk of endometrial cancer, with a higher risk with sequential dosing (rate ratio 3.0, 95% CI 2.0-4.6).

"That was a very good clue into the risk factors associated with endometrial cancer," said Immaculata De Vivo, PhD, of Brigham and Women's Hospital in Boston, who has spent decades researching these risks.

Now it has become clear that the two factors are really interconnected. According to a reviewopens in a new tab or window in the Annals of Oncology, "the combination of hyperestrogenism, inflammation, and insulin resistance that is caused by obesity creates a metabolic state that drives tumorigenesis."

Adipose tissue creates estrogen via peripheral aromatization of fat, and thus obesity creates a non-ovarian source of unopposed estrogen.

And while obesity has classically been thought to be the primary driver for the lower-risk, type 1 endometrial cancers, "actually, you are at higher risk of high-grade endometrial cancers if you are obese as well. So it's certainly impactful for all types of the disease," noted Boyd.

Part of the reason for that discovery has been getting large enough sample sizes to give the statistical power to settle the question, De Vivo said, pointing to the Epidemiology of Endometrial Cancer Consortium (E2C2) that she leads, which now has data for some 45,000 women.

A pooled analysis of E2C2 data showed a modest role of hypertensionopens in a new tab or window that is independent of BMI (OR 1.14, 95% CI 1.09-1.19). While diabetes is also associated with endometrial cancer, it is not clear if this is independent of its link to obesity, De Vivo said.

E2C2 is also working to understand potential differences in risk factors for women of color, since most studies had historically only included white women, she added.

Boyd noted that given that endometrial cancer is so hormonally sensitive, it's an open question whether hormone disruptors could be part of the disparities across race and ethnicity.

"Black women get endometrial cancer about as frequently as white women, but they are much more likely to die from it because they are more likely to get high-risk subtypes," she explained. "It's a significant problem. And the overall increase in high-risk subtypes amongst Black and white women, although mostly Black women are driving this, have led to the increase in mortality. And so endometrial cancer is one of the few cancers now in the United States that is increasing in both mortality and incidence, which is why it's such a problem."

A retrospective analysis of the Sister Studyopens in a new tab or window showed that use of straightening products in the previous 12 months was associated with a higher incidence of uterine cancer, including endometrial cancers (HR 1.80, 95% CI 1.12-2.88). The association was stronger with more frequent use (HR 2.55 for more than four times a year vs never, 95% CI 1.46-4.45).

While use of hair relaxers is more common among women of color, the National Cancer Instituteopens in a new tab or window has cautioned that the low quality of evidence is insufficient to make any conclusions.

Getting to the bottom of mechanisms will likely help more than just women with endometrial cancers, De Vivo said. "What we can learn from this very exquisitely hormonally sensitive cancer, we can apply to more common cancers like breast and ovarian."

Disclosures

Boyd disclosed a relationship with AstraZeneca.

De Vivo disclosed funding from the NIH.

https://www.medpagetoday.com/spotlight/asco-endo-cancer/110543

Cervical cancer screening using DNA methylation triage

 

Lena Schreiberhuber, 

James E. Barrett, 

Jiangrong Wang, 

Elisa Redl, 

Chiara Herzog, 

Charlotte D. Vavourakis, 

Karin Sundström, 

Joakim Dillner & 

Martin Widschwendter 

Abstract

Cervical cancer (CC) screening in women comprises human papillomavirus (HPV) testing followed by cytology triage of positive cases. Drawbacks, including cytology’s low reproducibility and requirement for short screening intervals, raise the need for alternative triage methods. Here we used an innovative triage technique, the WID-qCIN test, to assess the DNA methylation of human genes DPP6, RALYL and GSX1 in a real-life cohort of 28,017 women aged ≥30 years who attended CC screening in Stockholm between January and March 2017. In the analysis of all 2,377 HPV-positive samples, a combination of WID-qCIN (with a predefined threshold) and HPV16 and/or HPV18 (HPV16/18) detected 93.4% of cervical intraepithelial neoplasia grade 3 and 100% of invasive CCs. The WID-qCIN/HPV16/18 combination predicted 69.4% of incident cervical intraepithelial neoplasia grade 2 or worse compared with 18.2% predicted by cytology. Cytology or WID-qCIN/HPV16/18 triage would require 4.1 and 2.4 colposcopy referrals to detect one cervical intraepithelial neoplasia grade 2 or worse, respectively, during the 6 year period. These findings support the use of WID-qCIN/HPV16/18 as an improved triage strategy for HPV-positive women.

https://www.nature.com/articles/s41591-024-03014-6

Paxlovid Fails First Test in Long COVID

 A 15-day course of the antiviral nirmatrelvir-ritonavir (Paxlovid) didn't improve symptoms of long COVID, according to a randomized controlled trial that was stopped early for lack of efficacyopens in a new tab or window

.

The STOP-PASC trial showed no difference in improvement on a combined outcome of fatigue, brain fog, shortness of breath, body aches, and gastrointestinal and cardiovascular symptoms for nirmatrelvir-ritonavir compared with placebo-ritonavir over 10 weeks, Upinder Singh, MD, of Stanford University, and colleagues reported in JAMA Internal Medicineopens in a new tab or window.

The study was also presented at the Demystifying Long COVID North American Conferenceopens in a new tab or window in Boston.

"I don't think we've shown that Paxlovid doesn't work," Singh told MedPage Today. "We've shown that 15 days of Paxlovid given to this highly vaccinated patient population who has had symptoms for a long time, didn't show any statistically significant difference in the composite [outcome]."

Singh noted that future studies of nirmatrelvir-ritonavir in long COVID could assess patients with a shorter duration of long COVID symptoms -- the median duration in this study was 17.5 months -- and could assess combinations of drugs, and perhaps be targeted to specific symptoms.

Ziyad Al-Aly, MD, of the VA St. Louis Health Care System in Missouri, who was not involved in the study, agreed that this shouldn't be the last study of nirmatrelvir-ritonavir in long COVID.

"This is the first-ever trial and I think we need to do a whole lot more to understand this," Al-Aly told MedPage Today. "I don't think the door is closed at all on the idea of viral persistence, or on Paxlovid's effectiveness" in long COVID.

The rationale for using nirmatrelvir-ritonavir in long COVID is built on the hypothesis that long COVID is driven by viral persistenceopens in a new tab or window, though this is just one of several hypotheses. SARS-CoV-2 RNA and proteins have been shown to persist in blood and tissues, though there's never been definitive evidence of a reservoir of live, replicating virus, the researchers wrote.

As nirmatrelvir-ritonavir's primary mechanism of action is stopping viral replication, it would be thought to work in long COVID by wiping out any replicating virus, Singh explained.

For the Selective Trial of Paxlovid for Postacute Sequelae of SARS-CoV-2 infection (STOP-PASC) trial, Singh and colleagues enrolled 155 patients with long COVID. They were aiming for 200 patients, but cut enrollment short after a review by the data safety monitoring board suggested stopping for a lack of efficacyopens in a new tab or window, Singh said. The trial also caught flak when participants became upset that some researchers were not wearing masks during clinic visitsopens in a new tab or window.

Patients were studied from November 8, 2022 to September 12, 2023. At enrollment, they were randomized in a 2:1 fashion to nirmatrelvir-ritonavir (300 mg/100 mg) or placebo-ritonavir twice daily for 15 days.

The median age was 43, and 59% were female. Only one person in each group hadn't been vaccinated against COVID. The most common long COVID symptoms at enrollment were fatigue, which was reported by all participants, and brain fog, reported by 95.5%.

As with the primary endpoint, there were generally no differences between groups on individual symptoms at any time point, though the researchers noted that there were slightly higher odds of greater severity of the "most bothersome" symptom for the nirmatrelvir-ritonavir group at 10 weeks (OR 1.99, 95% CI 1.06-3.72, P=0.03) and 15 weeks (OR 2.42, 95% CI 1.27-4.60, P=0.01).

Singh noted that severity scores generally improved in both groups, but she warned that symptom burden still remained high at the end of the study for many patients. For instance, about 60% of people still had moderate-to-severe fatigue at the end of the 15-week study, she said.

Adverse events were similar in both groups, and mostly low grade. There were four serious adverse events, three in the nirmatrelvir-ritonavir group (blood loss anemia, forearm fracture, and melanoma) that were determined not to be related to the drug, and one in the placebo-ritonavir group: hepatitis, which was possibly related to the intervention.

The study was limited by its single-center nature, and a smaller sample size than originally planned due to early enrollment closure. The high rate of exclusion due to eligibility criteria also limited its generalizability and potentially missed subgroups of patients who could be responders.

Singh and colleagues concluded that "longer treatment durations, dose variations, optimal timing, and different phenotypes of PASC should be investigated in larger studies. Additionally, multiple pathways may contribute to PASC pathogenesis; therefore, in addition to testing single therapies, combination therapies (e.g., antivirals with immunomodulators) warrant exploration."

Further light will also be shed by at least three other trials of nirmatrelvir-ritonavir in long COVID, including the NIH's RECOVER studyopens in a new tab or window, which is aiming to enroll 900 patients, the PAX LC trialopens in a new tab or window at Yale, and a trial at the Karolinska Instituteopens in a new tab or window in Sweden aiming to enroll 400 patients.

"The challenge with long COVID is that it's very heterogeneous, and it's unlikely that one drug is going to ameliorate all these long COVID symptoms," Al-Aly told MedPage Today. "I think the value of this trial is teaching us how to better think about designing trials for long COVID."

Singh told MedPage Today that her group is still analyzing biomarker data and data from participants' wearables, which should shed further light on long COVID.

Future analyses could "group responders and non-responders according to biomarkers, and that would help inform the development of future trials in a smarter way," Al-Aly said.

Disclosures

The study was funded by Pfizer.

Study authors reported financial relationships with Pfizer and other pharmaceutical and healthcare companies and grant agencies.

Al-Aly reported no financial relationships with industry.

Primary Source

JAMA Internal Medicine

Source Reference: opens in a new tab or windowGeng LN, et al "Nirmatrelvir-ritonavir and symptoms in adults with postacute sequelae of SARS-CoV-2 infection: The STOP-PASC randomized clinical trial" JAMA Intern Med 2024; DOI: 10.1001/jamainternmed.2024.2007.

https://www.medpagetoday.com/infectiousdisease/longcovid/110544

Sugar Substitute Xylitol Linked to Heart, Thrombotic Risk

 The popular low-calorie sweetener xylitol was linked to increased cardiovascular and thrombotic risk, a series of experiments showed.

Metabolomic studies linked xylitol intake to higher risk for major adverse cardiovascular events (MACE), with a relative 57-80% higher risk for the top versus bottom blood-level tertiles after adjustment for other factors (P≤0.03), Stanley L. Hazen, MD, PhD, of the Lerner Research Institute at the Cleveland Clinic, reported in the European Heart Journalopens in a new tab or window.

Mechanistic animal model studies showed that xylitol raised platelet reactivity and in vivo thrombosis formation.

And an intervention study in 10 healthy individuals affirmed the same thing happens in humans. Consuming a typical dose of xylitol-sweetened drink rapidly and significantly impacted every measure of platelet activation in every volunteer compared with drinking a sugar-sweetened beverage.

"This study again shows the immediate need for investigating sugar alcohols and artificial sweeteners, especially as they continue to be recommended in combatting conditions like obesity or diabetes," Hazen said in a press releaseopens in a new tab or window. "It does not mean throw out your toothpaste if it has xylitol in it, but we should be aware that consumption of a product containing high levels could increase the risk of blood clot related events."

Xylitol is a sugar alcohol found naturally in strawberries, spinach, cauliflower, and other foods but is typically made commercially from corncobs, birch trees, or genetically engineered bacteria. It's often used in sugarless gum, breath mints, toothpaste, and added to processed foods. The FDA classifies xylitol as "generally recognized as safeopens in a new tab or window" and thus doesn't require food labels to disclose how much has been added.

"For many years the scientific community and the general population alike were convinced that artificial sweeteners were beneficial because they reduce excessive sugar intake, and hence reduce ingested calories, particularly from soft drinks, thus reducing weight gain and -- as implicitly argued -- cardiovascular risk," wrote Juerg Beer, MD, and Meret Allemann, MSc, both of the University of Zurich Laboratory for Platelet Research, in an accompanying editorialopens in a new tab or window.

The study sends "an important, timely, and serious warning signal," they noted. "Unfortunately, these sugars are indeed frequently used in the patient group at risk with obesity and diabetes."

And the concern appears to extend to other sugar alcohols used as sweeteners, such as erythritol.

Hazen's group previously conducted a similar series of analyses for erythritolopens in a new tab or window and showed a relative 1.8- to 2.2-fold increase in MACE risk among people in the top versus bottom quartile. They also found plasma erythritol levels well above thresholds associated with heightened platelet reactivity and thrombosis potential that persisted for days after challenging healthy volunteers with a typical dose of an erythritol-sweetened drink.

Other studies have linked artificially sweetened beverage intake to a modestly elevated risk of incident atrial fibrillationopens in a new tab or window (adjusted HR 1.20 over 10 years for consumption of about 8.5 cups per week, 95% CI 1.10-1.31) compared with nonconsumers.

Hazen and colleagues' xylitol research started with analysis of untargeted metabolomics performed on overnight fasting plasma samples in a discovery cohort of 1,157 of sequential stable patients undergoing elective diagnostic cardiac evaluations. Subsequent stable-isotope-dilution liquid chromatography with tandem mass spectrometry analyses specific for xylitol confirmed its association with MACE in an independent, non-overlapping validation cohort of 2,149 individuals.

Experiments with isolated human platelet, platelet-rich plasma, whole blood, and animal models showed increased platelet adhesion under flow, augmented activation of glycoprotein IIb/IIIa, and expression of p-selectin was observed using flow cytometry after addition of xylitol. In a mouse carotid thrombosis model, xylitol exposure increased calcium mobilization and platelet-leukocyte aggregates and shortened occlusion times.

Then a challenge study in 10 healthy human volunteers showed that a soft drink with 30 g of xylitol increased platelet reactivity as early as 30 minutes after ingestion compared with a sugar-sweetened drink, "strongly suggesting causality," the editorialists noted.

"The data and a myriad of questions collectively call for a closer look by the authorities and researchers alike at sugar alcohol sweeteners as a cardiovascular hazard," Beer and Allemann concluded. "Confirmatory studies, longer exposure analyses, and elucidations of mechanisms will have to confirm these not-so-clear skies for the widespread use of sugar alcohols."

Hazen's group cautioned that their observational cohort findings couldn't establish causality in MACE events, nor did they have dietary data. And the mechanistic studies, while arguing for a direct effect, focused on a relatively brief exposure of xylitol without being able to comment on the impact of chronic exposures.

Disclosures

The study was supported in part by National Institutes of Health and the Office of Dietary Supplements.

Hazen and a co-author reported being named as co-inventors on pending and issued patents held by the Cleveland Clinic relating to cardiovascular diagnostics and therapeutics and being eligible to receive royalty payments for inventions or discoveries related to cardiovascular diagnostics or therapeutics from Cleveland HeartLab, Quest Diagnostics and Procter & Gamble. Hazen also reported a relationship with Zehna Therapeutics.

Beer disclosed relationships with the Swiss National Foundation of Science, the Swiss Heart Foundation, the Kardio Foundation Baden, the Swiss Life Foundation, the Gebauer Foundation, the Novartis Foundation, Bayer, Sanofi, Daiichi, AstraZeneca, and Synlab. Allemann disclosed relationships with the Swiss Heart Foundation and the University of Zürich.

Primary Source

European Heart Journal

Source Reference: opens in a new tab or windowWitkowski M, et al "Xylitol is prothrombotic and associated with cardiovascular risk" Euro Heart J 2024; DOI: 10.1093/eurheartj/ehae244.

Secondary Source

European Heart Journal

Source Reference: opens in a new tab or windowBeer JH, Allemann M "Xylitol: bitter cardiovascular data for a successful sweetener" Euro Heart J 2024; DOI: 10.1093/eurheartj/ehae252.

https://www.medpagetoday.com/cardiology/prevention/110554