Buprenorphine Dispensing Declined After 2021 Despite Gains in Access and Emergency Department Use

August 31, 2026

Key Points

• Pharmacy dispensing of buprenorphine increased from 2019 through 2021 but declined from 2021 through 2025 in both rural and urban US counties.
• The number of buprenorphine prescribers increased, while the number of patients and prescriptions managed per prescriber decreased.
• Pharmacy availability of buprenorphine increased from approximately 65% of counties in 2019 to 80% of rural and 72.4% of urban counties in 2025.
• Emergency department (ED) adoption of buprenorphine increased substantially between 2019 and 2025, but overall adoption remained relatively low.
• Treatment initiation and 180-day treatment retention were higher in urban than rural counties.
• The findings suggest persistent geographic and health-system barriers to treatment for opioid use disorder (OUD), particularly in rural communities.

Study Overview

Buprenorphine dispensing through US pharmacies increased between 2019 and 2021 but subsequently declined through 2025, according to an analysis published in the Morbidity and Mortality Weekly Report.

The study, led by Gery P. Guy Jr., PhD, a health scientist at the Centers for Disease Control and Prevention, and colleagues, examined changes in buprenorphine access and use between 2019 and 2025. The researchers evaluated both pharmacy-dispensed buprenorphine and buprenorphine administration in emergency departments, with particular attention to differences between rural and urban counties.

The analysis comes amid a substantial ongoing burden of opioid-related disease in the United States. According to the researchers, 54,045 deaths involving opioids occurred in 2024, while approximately 4.8 million people were estimated to have OUD.

Despite the availability of effective medication treatment, the investigators noted that:

“Buprenorphine remains underused.”

The researchers suggested that geographic differences in access may contribute to this treatment gap.

“Geographic variation in access might contribute to underuse, reflecting differences in prescriber and pharmacy availability and health system capacity.”

Data Sources and Study Design

Guy and colleagues analyzed prescribing and treatment data from 2019 through 2025 using information from IQVIA and the Premier Healthcare Database.

The analysis included several measures of buprenorphine access and utilization, including:

• Pharmacy dispensing
• Number of prescribers
• Patients per prescriber
• Prescriptions per prescriber
• Average prescription supply
• Pharmacy availability
• Treatment initiation
• 180-day treatment retention
• ED adoption of buprenorphine
• Rates of ED-administered buprenorphine

The researchers compared these measures between rural and urban counties.

Pharmacy Dispensing Trends

Pharmacy dispensing of buprenorphine increased from 2019 to 2021. The increase was particularly pronounced in rural counties.

During this period, the annual percent change (APC) in dispensing was approximately 7% in rural counties, compared with 0.7% in urban counties.

After 2021, however, dispensing declined in both geographic settings.

Although dispensing decreased more rapidly in rural areas, the researchers reported that dispensing rates remained higher in rural counties.

“Rates remained higher in rural counties despite decreasing more rapidly in rural counties.”

Buprenorphine Pharmacy Dispensing Trends

The pattern indicates that the increase in access observed before and during the early COVID-19 period was not sustained through 2025.

Prescription Supply Increased

Although dispensing declined after 2021, the average amount of medication supplied with each prescription increased over the entire 2019-2025 period.

In rural counties, the average prescription supply increased from 17.4 days to 22.2 days.

In urban counties, the average prescription supply increased from 17.6 days to 22.6 days.

Average Prescription Supply

Thus, the decline in the number of dispensed prescriptions should be interpreted alongside the increase in the duration of medication supplied per prescription.

Growth in the Number of Prescribers

The number of buprenorphine prescribers per 1,000 population increased between 2019 and 2025.

In urban counties, the number increased from 0.1 to 0.4 prescribers per 1,000 people.

In rural counties, the corresponding increase was from 0.1 to 0.2 per 1,000 people.

Prescribers per 1,000 Population

Despite the increase in prescriber availability, the overall volume of patients and prescriptions managed by individual prescribers declined.

Patients and Prescriptions per Prescriber

Between 2019 and 2025, the number of patients per prescriber decreased substantially.

In urban counties, patients per prescriber declined from 48.7 to 25.7.

In rural counties, the number decreased from 60.1 to 36.3.

The number of prescriptions per prescriber also decreased.

In urban counties, prescriptions per prescriber fell from 312.8 to 116.

In rural counties, the corresponding decline was from 469.2 to 195.8.

Prescriber Workload Measures

These changes occurred despite growth in the number of prescribers, suggesting that increasing the number of clinicians alone did not necessarily translate into sustained increases in buprenorphine utilization.

Pharmacy Availability Improved

The proportion of counties with pharmacies dispensing buprenorphine increased from 2019 to 2025.

In rural counties, pharmacy availability increased from 64.9% to 80.0%.

In urban counties, availability increased from 64.8% to 72.4%.

Pharmacy Availability

The improvement was therefore greater in rural counties.

Treatment Initiation and Retention

Despite higher pharmacy dispensing rates in rural counties, treatment initiation and longer-term retention were higher in urban areas.

Median monthly treatment initiation was:

• 14.2 per 100,000 people in urban counties
• 11.8 per 100,000 people in rural counties

The difference was also evident in 180-day treatment retention.

Retention at 180 days was:

• 23.1% in urban counties
• 17.7% in rural counties

Treatment Initiation and Retention

These findings demonstrate that availability of medication does not necessarily translate into equivalent treatment initiation or sustained treatment retention across geographic settings.

Emergency Department Use of Buprenorphine

One of the more substantial changes identified during the study period was the increase in ED adoption of buprenorphine.

Among rural counties, ED adoption increased from 2.3% in 2019 to 10.3% in 2025, corresponding to an average annual percent change (AAPC) of 23.3%.

In urban counties, adoption increased from 6.7% to 31.4%, corresponding to an AAPC of 30.3%.

ED Adoption of Buprenorphine

Although adoption increased substantially, the researchers emphasized that overall ED adoption remained low, particularly in rural communities.

ED-Administered Buprenorphine

The rate at which EDs administered buprenorphine also increased during the study period.

The AAPC was:

• 6.9% in rural counties
• 18.4% in urban counties

The researchers suggested that this growth may reflect increasing awareness of buprenorphine treatment as well as policies and implementation strategies designed to facilitate its use.

They specifically identified interventions such as:

• Provider education
• Peer support
• Clinical decision-support tools

The researchers wrote that these factors likely contributed to the increasing use of buprenorphine in ED settings.

ED Buprenorphine Administration

Why Rural Dispensing May Have Been Higher

The researchers proposed several possible explanations for the relatively higher dispensing rates observed in rural counties.

One possibility was the effect of COVID-19-related telehealth policies and flexibilities. These changes may have been particularly important in rural areas where patients often face longer travel distances and fewer specialty-care options.

The investigators wrote:

“Higher dispensing rates in rural areas might reflect benefits of COVID-19-related telehealth flexibilities, particularly in areas with longer travel distances and more limited access to specialty care.”

Another explanation relates to the limited availability of opioid treatment programs in rural communities.

The authors noted:

“Higher dispensing rates in rural areas might also indicate increased reliance on office-based buprenorphine, because opioid treatment programs are less available in rural areas.”

They therefore suggested that office-based prescribing may have an especially important role in rural OUD treatment.

“Together, these findings suggest that office-based prescribing is a particularly important treatment pathway in rural communities, where fewer specialty providers and more formidable geographic barriers might limit access to other forms of OUD care.”

Persistent Barriers to ED-Based Treatment

Despite the marked increase in ED adoption, the investigators concluded that buprenorphine use in emergency departments remained relatively limited.

They characterized this as evidence of:

“missed opportunities for treatment and persistent implementation barriers”

Potential barriers identified by the researchers included:

• Limited behavioral health support
• Inadequate care-coordination infrastructure
• Insufficient staffing
• Difficulties establishing standardized OUD medication-administration protocols

These barriers can prevent emergency departments from consistently initiating medication treatment even when clinicians recognize the need for OUD care.

Potential Role of the Emergency Department in Treatment Linkage

The researchers emphasized that ED-based buprenorphine administration can do more than provide an initial medication dose.

Initiating treatment before discharge can potentially establish a direct connection between emergency care and continuing OUD treatment.

The authors wrote:

“ED-based administration can strengthen linkage to care by connecting patients directly to follow-up treatment before discharge, providing support from trained peer recovery specialists with lived experience, and offering case management to help coordinate ongoing services.”

This approach could integrate medication treatment with behavioral health services, peer support, and longitudinal care coordination.

Overall Findings

The study demonstrates several simultaneous trends in US buprenorphine treatment between 2019 and 2025.

Pharmacy dispensing increased during the earlier part of the study period but subsequently declined. At the same time, the number of prescribers increased, prescription durations became longer, and pharmacy availability expanded.

Emergency department adoption of buprenorphine also increased considerably, particularly in urban counties.

However, important geographic differences persisted. Rural counties had higher dispensing rates but lower treatment initiation and 180-day retention compared with urban counties.

Summary of Major Findings

Clinical and Public Health Implications

The findings suggest that improving OUD treatment access requires more than simply increasing the number of clinicians authorized or available to prescribe buprenorphine.

Although prescriber numbers and pharmacy availability increased, pharmacy dispensing declined after 2021. In addition, rural areas experienced lower treatment initiation and retention despite having higher dispensing rates.

The findings highlight several potentially important components of OUD treatment infrastructure:

1. Prescriber availability — expanding the number of clinicians able to provide buprenorphine.
2. Pharmacy access — ensuring that prescriptions can be filled consistently.
3. Telehealth — maintaining mechanisms that reduce geographic barriers to treatment.
4. ED initiation — starting treatment during acute-care encounters when appropriate.
5. Care coordination — ensuring patients have follow-up after ED initiation.
6. Peer support — incorporating trained individuals with lived experience into treatment pathways.
7. Behavioral health integration — addressing the broader needs of patients with OUD.
8. Long-term retention strategies — improving continuation of treatment beyond initial medication initiation.

Conclusion

From 2019 through 2025, the US buprenorphine treatment landscape showed both progress and persistent gaps. Pharmacy availability and the number of prescribers increased, prescription supplies became longer, and ED adoption of buprenorphine expanded substantially.

However, pharmacy dispensing declined after 2021, and treatment initiation and 180-day retention remained lower in rural than urban counties. ED adoption, although markedly higher in 2025 than in 2019, remained relatively limited overall.

The findings suggest that improving access to buprenorphine will require attention not only to medication availability but also to geographic barriers, treatment initiation, continuity of care, behavioral health resources, care coordination, staffing, and implementation infrastructure.

For rural communities in particular, the study suggests that office-based prescribing and telehealth may remain important mechanisms for overcoming geographic and specialty-care limitations, while ED-based initiation may provide an additional opportunity to connect patients with ongoing OUD treatment.

Study Finds No Association Between Circumcision and Autism

Key Points

• In an analysis of 2,771 boys enrolled in the NIH Environmental Influences on Child Health Outcomes (ECHO) cohort, circumcision was not associated with a subsequent diagnosis of autism.

• After adjustment for potential confounding factors, the association remained nonsignificant (OR, 0.83; 95% CI, 0.59-1.17).

• Autism was diagnosed in approximately 6% of circumcised boys compared with 9% of uncircumcised boys.

• Fewer than 5% of circumcised boys received neonatal acetaminophen, providing little support for neonatal acetaminophen exposure as an explanation for the observed findings in this cohort.

• Circumcision was also not associated with higher scores on measures of social responsiveness or emotional and behavioral difficulties.

Study Overview

A study using data from the National Institutes of Health’s Environmental Influences on Child Health Outcomes (ECHO) cohort found no statistically significant association between circumcision and autism among male children in the United States.

The analysis was prompted in part by public statements in 2025 suggesting that circumcision might be associated with autism and that acetaminophen administered for pain after circumcision could potentially account for such an association.

Monica McGrath, ScD, MHS, a research professor in the Department of Epidemiology at the Johns Hopkins Bloomberg School of Public Health, and colleagues examined longitudinal health information collected through the ECHO cohort. The data covered the period from February 2003 through September 2025.

The investigators specifically evaluated whether boys who underwent circumcision were subsequently more likely to receive an autism diagnosis than boys who were not circumcised.

Study Population

The study included 2,771 boys from the ECHO cohort.

Of these, 1,840 (66%) were circumcised, whereas 931 (34%) were not. Overall, 192 boys (7%) had been diagnosed with autism, with the diagnosis occurring at a mean age of 3.8 years.

Participant and Autism Data

Circumcision and Autism

The researchers found that autism was diagnosed in approximately 6% of circumcised boys, compared with 9% of boys who were not circumcised.

However, after adjustment for potential confounding variables, circumcision was not significantly associated with autism. The adjusted odds ratio was 0.83, with a 95% confidence interval of 0.59 to 1.17.

Because the confidence interval includes 1.0, the findings do not demonstrate a statistically significant difference in autism risk associated with circumcision.

Autism Outcomes According to Circumcision Status

The numerical difference in unadjusted percentages therefore should not be interpreted as evidence that circumcision protects against autism. After accounting for potential confounding factors, the study did not identify a statistically significant association.

Other Neurobehavioral Measures

The investigators also assessed whether circumcision was associated with measures of social responsiveness or broader behavioral difficulties.

No significant association was identified between circumcision and elevated scores on the Social Responsiveness Scale, which evaluates social impairment.

Similarly, circumcision was not associated with elevated scores on the Child Behavior Checklist, a standardized instrument used to identify emotional and behavioral problems in children.

Secondary Outcomes

Neonatal Acetaminophen Exposure

The investigators also examined neonatal acetaminophen exposure because acetaminophen administered for pain after circumcision had been proposed as a possible pathway linking circumcision with autism.

The study found that fewer than 5% of circumcised boys received acetaminophen as neonates.

Consequently, the researchers concluded that neonatal acetaminophen exposure could not explain the relationship in this population, particularly because the study itself did not identify an association between circumcision and autism.

Why the Study Was Conducted

The researchers said the study was motivated by public discussion in 2025 concerning a possible relationship between circumcision and autism.

McGrath explained that the research team became interested in the question after hearing concerns from people in their professional and personal circles following media reports about statements linking male circumcision with autism.

“We knew the ECHO Cohort had relevant data to help investigate this question.”

The ECHO cohort was particularly useful because it contains longitudinal information concerning children’s health and environmental exposures, with some participants followed from the preconception period onward.

Context Regarding Acetaminophen and Autism

The study was conducted amid broader debate concerning whether acetaminophen exposure could contribute to autism or other neurodevelopmental outcomes.

The article notes that the Trump administration had previously drawn a connection between prenatal acetaminophen exposure and autism or attention-deficit/hyperactivity disorder. However, the evidence cited in the article does not establish a causal relationship.

A systematic review and meta-analysis published in a Lancet journal in 2026 reportedly did not demonstrate a causal relationship, while the American Academy of Pediatrics has emphasized that extensive research does not support the concept of a single underlying cause of autism.

These broader findings are important when interpreting the present study because an observed association between an exposure and autism would not, by itself, establish causation.

Interpretation

The principal finding of this cohort analysis is that circumcision was not significantly associated with autism diagnosis after adjustment for potential confounding factors.

Although the unadjusted prevalence of autism was numerically lower among circumcised boys than among uncircumcised boys, the adjusted estimate did not demonstrate a statistically significant association.

The findings were also consistent across additional behavioral and social measures, with no evidence that circumcision was associated with increased Social Responsiveness Scale or Child Behavior Checklist scores.

The investigators further reported that neonatal acetaminophen exposure was uncommon among circumcised boys in the cohort.

Authors’ Perspective

McGrath said the results could provide reassurance to families considering circumcision:

“These findings may provide reassurance for families who are considering or have elected circumcision for their son.”

She also noted that the research group is continuing to investigate other potential factors that could contribute to the increasing number of autism diagnoses.

“My colleagues and I continue to evaluate other factors that may explain the rise in autism diagnoses.”

Clinical and Research Perspective

The findings provide no evidence from this cohort that circumcision is associated with an increased likelihood of autism.

Importantly, the study addresses association rather than causation. Its results indicate that, within the population examined and after statistical adjustment for measured confounding factors, circumcision was not significantly associated with autism diagnosis.

The findings also do not establish that circumcision reduces autism risk. The lower unadjusted proportion of autism among circumcised boys should therefore not be interpreted as a protective effect.

Further research using large, longitudinal cohorts may help clarify the contributions of genetic, prenatal, environmental, developmental, and other factors associated with autism.

Bottom Line

In this analysis of 2,771 boys from the NIH ECHO cohort, circumcision was not significantly associated with autism after adjustment for potential confounding factors (OR, 0.83; 95% CI, 0.59-1.17). Circumcision was also not associated with increased measures of social impairment or childhood behavioral difficulties. Because fewer than 5% of circumcised boys received neonatal acetaminophen, the findings also provide little support for neonatal acetaminophen exposure as a mechanism explaining an association between circumcision and autism in this cohort.

Gestational Diabetes Associated With Earlier Onset of Type 2 Diabetes in Later Life

September 22, 2026

Key Points

• Women with a history of gestational diabetes (GDM) developed type 2 diabetes at a substantially younger age than women without previous GDM.
• Median age at type 2 diabetes diagnosis was 43.5 years among women with previous GDM compared with 56.3 years among those without a history of GDM.
• Approximately 40% of women with previous GDM developed type 2 diabetes before age 40 years, compared with approximately 6% of women without previous GDM.
• Women with previous GDM were also more likely to require insulin soon after type 2 diabetes diagnosis and had lower fasting C-peptide concentrations.

Study Overview

Women who develop gestational diabetes during pregnancy may face not only a higher long-term risk of type 2 diabetes but also an earlier onset of the disease, according to findings from the Danish Centre for Strategic Research in Type 2 Diabetes (DD2) cohort.

The analysis included 2,865 women with a previous pregnancy. Of these, 173 had a history of gestational diabetes and 2,692 had no history of GDM.

The findings were scheduled for presentation as oral abstract 173 at the European Association for the Study of Diabetes (EASD) Annual Meeting, September 28 through October 2, 2026, in Milan.

Maria Houborg Petersen, MD, PhD, a postdoctoral researcher at Steno Diabetes Center Odense, Denmark, said the investigators anticipated an earlier onset of type 2 diabetes among women with previous GDM but were surprised by the magnitude of the difference.

Earlier Diagnosis of Type 2 Diabetes

Women with a history of GDM were diagnosed with type 2 diabetes at a median age of 43.5 years, compared with 56.3 years among women who had never experienced GDM.

The difference corresponds to a 12.8-year difference in median age at diagnosis between the 2 groups.

The investigators therefore identified previous GDM as a marker associated with substantially earlier development of type 2 diabetes.

A Potentially Distinct Type 2 Diabetes Phenotype

Petersen suggested that the implications of previous GDM may extend beyond simply increasing the likelihood of developing type 2 diabetes.

“Women with previous gestational diabetes are not only at high risk of developing type 2 diabetes later in life, they also seem to develop a distinct type 2 diabetes phenotype characterized by potentially greater severity and elevated risk of diabetes complications over time.”

One finding supporting this possibility was the greater proportion of women who required insulin soon after their diabetes diagnosis.

Insulin Use and β-Cell Function

The approximately 10.4% vs 5.2% difference indicates that insulin use soon after diagnosis was about twice as frequent among women with previous GDM.

Fasting C-peptide concentrations were also lower among women with previous GDM. Because C-peptide reflects endogenous insulin secretion, the finding may be consistent with differences in pancreatic β-cell function, although the study did not establish the underlying mechanism.

Similarities in Conventional Metabolic Measures

Despite the earlier diabetes onset and differences in insulin use and C-peptide concentrations, several metabolic characteristics were reportedly similar between the groups.

There were no differences in:

• Body mass index
• HbA1c
• Fasting glucose
• Measures of insulin resistance
• Measures of insulin sensitivity

This is notable because the earlier development of type 2 diabetes among women with previous GDM was not accompanied by reported differences in these commonly measured metabolic parameters in the available analysis.

Diabetes Complications

The researchers also evaluated several diabetes-related complications.

The prevalence of nephropathy, neuropathy, and cardiovascular disease was similar between women with and without previous GDM.

A difference in diabetic retinopathy was identified, but the investigators could not determine whether it was clinically meaningful because the number of retinopathy cases was small.

Therefore, although Petersen proposed that women with previous GDM may have a phenotype associated with greater long-term complication risk, the data provided do not demonstrate a higher prevalence of most evaluated complications at the time of this analysis.

Why the Findings Matter

The findings reinforce the importance of long-term diabetes surveillance after gestational diabetes.

Petersen emphasized that regular screening for type 2 diabetes is already recommended for women with previous GDM, but adherence to screening remains inadequate.

“We already recommend regular screening for type 2 diabetes to these women.”

She added:

“Unfortunately, adherence to this screening is poor. We need to make sure more women attend to regular screening.”

The study therefore highlights a potential opportunity for clinicians to improve follow-up after pregnancy complicated by GDM.

Implications for Clinical Practice

The investigators suggested that women with previous GDM who subsequently develop type 2 diabetes may warrant particularly attentive follow-up.

Petersen stated:

“Furthermore, if these women develop type 2 diabetes, we might need to follow them closer and make sure to treat them intensively, because they might be at higher risk of developing diabetes complications over time.”

This statement represents the investigator’s interpretation of the findings rather than evidence from a randomized treatment trial demonstrating that more intensive treatment improves outcomes specifically in women with previous GDM.

Potential Clinical Considerations

1. Long-term screening: Women with previous GDM should remain engaged with recommended diabetes surveillance after pregnancy.
2. Earlier detection: The substantially younger median age at diagnosis suggests that type 2 diabetes may emerge relatively early in this population.
3. Attention to β-cell function: Lower fasting C-peptide levels and greater early insulin use raise questions about differences in insulin secretory capacity.
4. Monitoring after diagnosis: Clinicians may need to pay particular attention to glycemic control and diabetes complications once type 2 diabetes develops.
5. Further phenotyping: More detailed metabolic studies are needed to determine whether previous GDM identifies a biologically distinct form of type 2 diabetes.

Proposed Areas for Further Research

Petersen called for more detailed investigation into the metabolic phenotype of women who develop type 2 diabetes after GDM.

She specifically proposed studies involving hyperinsulinemic-euglycemic clamp investigations to characterize insulin sensitivity and β-cell function, along with muscle and adipose tissue biopsies.

“This should include clamp investigations of insulin sensitivity and beta-cell function, including muscle and fat biopsies.”

The investigators also proposed longitudinal evaluation of metabolic and biochemical characteristics.

“Furthermore, we need to make further follow-up over time on metabolic and biochemical data on women with type 2 diabetes and previous gestational diabetes compared to women with type 2 diabetes without previous gestational diabetes.”

Such studies could help determine whether previous GDM is associated with specific abnormalities in insulin secretion, insulin sensitivity, adipose tissue biology, or skeletal muscle metabolism.

Study at a Glance

Conclusion

In this analysis of women enrolled in the DD2 cohort, a history of gestational diabetes was associated with substantially earlier development of type 2 diabetes. Median age at diagnosis was 43.5 years among women with previous GDM compared with 56.3 years among women without previous GDM, while approximately 40% of the former group developed diabetes before age 40 years.

Women with previous GDM also had greater early insulin use and lower fasting C-peptide concentrations, raising the possibility of differences in insulin secretory capacity. However, BMI, HbA1c, fasting glucose, insulin resistance, and insulin sensitivity did not differ between groups.

The findings support continued emphasis on postpartum and long-term diabetes screening after gestational diabetes. Whether previous GDM represents a distinct type 2 diabetes phenotype with greater long-term complication risk requires additional longitudinal and mechanistic investigation.

Source: Petersen MH, et al. Oral abstract 173. To be presented at the European Association for the Study of Diabetes Annual Meeting; September 28-October 2, 2026; Milan, Italy.

Disclosure: Maria Houborg Petersen reported no relevant financial disclosures.

Ophthalmologists Show Highest Accuracy for Thyroid Eye Disease Referrals

September 14, 2026

A retrospective study presented at the Women in Ophthalmology Summer Symposium found that ophthalmologists had the highest accuracy among the major referring specialties for identifying patients with thyroid eye disease (TED). The findings suggest that ophthalmologists may have an important role in screening patients and directing them to specialized TED services, particularly in areas where multidisciplinary expertise is not readily available.

Study Findings

Emma Tsai, MD, and colleagues conducted a retrospective, cross-sectional analysis of referral patterns at a multispecialty academic TED clinic. The investigators reviewed 122 new patient referrals collected over a 1-year period and assessed the referring physician’s specialty, the patient’s final diagnosis, and TED disease activity and severity.

Endocrinologists accounted for the largest proportion of referrals, followed by ophthalmologists and optometrists.

Key finding: Although endocrinologists generated the greatest proportion of referrals, ophthalmologists demonstrated the highest referral accuracy (91.9%) among the three specialties evaluated.

Ophthalmologists Had the Highest Referral Accuracy

The accuracy of referrals varied considerably among the specialties. Ophthalmologists correctly identified patients requiring evaluation for TED in 91.9% of referrals, compared with 85.4% for endocrinologists and 80.6% for optometrists.

The investigators also observed differences in the proportion of referred patients who had active disease. Active TED was identified in 55.9% of patients referred by ophthalmologists and 57.1% of those referred by endocrinologists, compared with 32.0% of patients referred by optometrists.

These findings indicate that referrals from ophthalmologists and endocrinologists were more frequently associated with active TED than referrals from optometrists in this cohort.

Importance of Multidisciplinary Care

TED can produce a broad range of ocular and systemic manifestations, making coordination among multiple medical specialties important. Tsai and colleagues emphasized that:

“These symptoms often require multidisciplinary care including oculoplastic surgery, neuro-ophthalmology, strabismus surgery and endocrinology.”

The investigators further noted that appropriate referral is important not only for ensuring patients receive appropriate treatment but also for making efficient use of specialized medical resources.

Implications for Clinical Practice

The findings may have particular relevance in regions where dedicated TED centers or multidisciplinary teams are difficult to access. In such settings, ophthalmologists may serve as an effective initial screening point for patients suspected of having thyroid eye disease.

The authors concluded:

“Referral to appropriate providers is crucial for optimal outcomes and resource allocation.”

They further suggested that, when specialized TED services are unavailable, assessment by a local ophthalmologist could potentially reduce unnecessary referrals and improve access to appropriate specialist care.

“In settings where multidisciplinary or expert TED care is hard to access, screening from a local ophthalmologist may provide more efficient utilization and avoidance of unnecessary referrals that are costly and inconvenient to the patient.”

Clinical Interpretation

The study supports several practical observations:

1. Ophthalmologists demonstrated the highest referral accuracy among the three referring specialties examined.
2. Endocrinologists were the largest referral source, accounting for approximately one-third of referrals.
3. Ophthalmologists and endocrinologists referred substantially more patients with active TED than optometrists.
4. A local ophthalmologist may be particularly useful as an initial screening clinician when access to a specialized TED center is limited.
5. Because TED can involve orbital, ocular-motility, eyelid, and endocrine manifestations, multidisciplinary management remains important.

Study at a Glance

Limitations and Context

Because the findings came from a single retrospective analysis of 122 patients at an academic TED clinic, they should be interpreted within the context of the study population and referral system. Referral patterns and diagnostic accuracy may differ among institutions, geographic regions, and health care systems. The study was presented as a poster at the Women in Ophthalmology Summer Symposium, rather than as a full peer-reviewed journal publication in the material provided.

Bottom Line

In this cohort of patients referred to an academic thyroid eye disease clinic, ophthalmologists had the highest accuracy for referring patients with TED, while endocrinologists were the most frequent source of referrals. The findings highlight the potential role of ophthalmologists as an important screening and referral point, particularly where access to specialized multidisciplinary TED care is limited.

Source: Tsai E, et al. Referral source and accuracy of thyroid eye disease diagnosis. Presented at the Women in Ophthalmology Summer Symposium, August 20-23, 2026, Monterey, California.

Higher Circulating Xylitol Levels Associated With Increased Cardiovascular Event Risk in 2 Prospective Cohorts

September 22, 2026

Key Points

• Higher circulating concentrations of xylitol were associated with an increased risk of major adverse cardiovascular events (MACE) in 2 large population-based cohorts.

• The association persisted after adjustment for several established cardiovascular risk factors, including age, body mass index, blood pressure, diabetes, and lipid concentrations.

• The observational findings support an association between circulating xylitol and cardiovascular risk but do not establish that xylitol consumption causes cardiovascular events.

Background

Xylitol is a 5-carbon sugar alcohol commonly used as a low-calorie sweetener in foods and other products. According to Marco Witkowski, MD, PhD, of Charité University Hospital in Berlin, xylitol can also be produced endogenously in relatively small amounts.

“Xylitol is a 5-carbon sugar alcohol sweetener [that] can be endogenously produced to a small extent, but it’s also highly enriched and added to artificially sweetened processed foods.”

Previous research cited by the investigators has linked circulating xylitol concentrations with cardiovascular event risk, particularly in populations with a high prevalence of cardiovascular risk factors. Experimental studies have also suggested a potential mechanism involving platelet activation and thrombosis.

Witkowski noted:

“We also know from mechanistic studies that xylitol can enhance platelet reactivity, and it also leads to an acceleration of in vivo thrombosis in animal models.”

The investigators therefore examined whether circulating xylitol concentrations were associated with cardiovascular events in the general population.

Study Design and Population

Researchers analyzed metabolomic and longitudinal clinical data from 17,710 participants enrolled in 2 large observational cohorts:

1. Canadian Longitudinal Study on Aging (CLSA)

2. European Prospective Investigation into Cancer (EPIC)-Norfolk

The cohorts differed substantially in their follow-up periods, providing an opportunity to examine the association over both intermediate and longer periods.

Characteristics of the Study Cohorts

The investigators had measurements of circulating xylitol concentrations for participants as well as longitudinal information regarding cardiovascular outcomes.

“We had access to metabolomics data that quantified xylitol in all samples and longitudinal data with major adverse cardiac events during follow-up.”

Higher Xylitol Levels Associated With Cardiovascular Events

In analyses that did not account for other cardiovascular risk factors, participants with higher xylitol concentrations had lower event-free survival than those with lower concentrations.

This pattern was observed in both cohorts, with the difference in event-free survival statistically significant at P < .0001.

After adjustment for traditional cardiovascular risk factors, participants in the highest quartile of xylitol concentration continued to demonstrate a higher risk of MACE compared with those in the lowest quartile.

Association Between Xylitol Level and MACE

Thus, compared with participants in the lowest xylitol category, those in the highest category had an approximately 57% higher relative hazard of MACE in CLSA and an approximately 18% higher relative hazard in EPIC-Norfolk, after adjustment for reported cardiovascular risk factors.

Importantly, these are relative hazard estimates, and the study information provided does not establish the absolute increase in cardiovascular events attributable to xylitol.

Association Persisted Across Multiple Subgroups

The researchers reported that the association between xylitol concentration and cardiovascular risk was consistent across several clinically relevant subgroups.

Subgroups Examined

These findings suggest that the observed association was not obviously restricted to a particular demographic or cardiovascular-risk subgroup.

However, subgroup consistency in an observational analysis does not eliminate the possibility of residual confounding or other sources of bias.

Possible Biological Mechanism

The investigators discussed a potential prothrombotic mechanism to explain the association.

Previous mechanistic work has suggested that xylitol may increase platelet reactivity. Experimental animal data have also reportedly demonstrated accelerated thrombosis after exposure to xylitol.

Witkowski characterized the potential interpretation as follows:

“In the general population, we have shown that xylitol levels in the blood are associated with event risk, and based on the known prothrombotic properties of xylitol, we can assume or speculate that even without overt cardiovascular disease, xylitol portends risk in the general population.”

The wording is important: the speaker described this as an assumption or speculation based on mechanistic evidence, rather than demonstrating that xylitol causes thrombosis or cardiovascular events in humans.

Clinical Interpretation

The study raises questions about the cardiovascular implications of elevated circulating xylitol concentrations, particularly because xylitol is increasingly used as a sugar substitute in processed foods.

However, several distinctions are important:

• The study was observational, so it demonstrates an association rather than causation.

• Circulating xylitol concentrations do not necessarily correspond directly to a person’s dietary xylitol intake.

• Xylitol can be endogenously produced, meaning blood concentrations may reflect more than consumption of xylitol-containing products.

• The reported associations persisted after adjustment for several conventional cardiovascular risk factors, but residual or unmeasured confounding cannot be excluded.

• The mechanistic evidence involving platelet reactivity and thrombosis provides a biologically plausible hypothesis, but does not prove that this mechanism accounts for the clinical associations observed.

Consequently, these findings should not by themselves be interpreted as evidence that consuming xylitol causes cardiovascular disease.

What the Study Adds

The analysis extends previous observations linking circulating xylitol concentrations with cardiovascular events by examining individuals from the general population rather than focusing exclusively on populations with substantial cardiovascular disease burden.

The consistency of the association across 2 large cohorts, including one with approximately 30 years of follow-up, strengthens the rationale for further investigation.

Future research would need to determine whether xylitol itself contributes causally to cardiovascular events and whether reducing dietary exposure changes cardiovascular outcomes. Randomized clinical trials or other studies specifically designed to address causality would be particularly important.

Study at a Glance

Conclusion

In an analysis of 17,710 participants from 2 large longitudinal cohorts, higher circulating xylitol concentrations were associated with a greater risk of major adverse cardiovascular events. The association remained after adjustment for several traditional cardiovascular risk factors and was reportedly consistent across multiple clinical subgroups.

The findings are biologically plausible given experimental evidence suggesting effects of xylitol on platelet reactivity and thrombosis. Nevertheless, the observational design prevents a conclusion that xylitol causes cardiovascular events. Further research is needed to distinguish endogenous xylitol metabolism from dietary exposure and to determine whether modifying xylitol intake affects cardiovascular outcomes.

Source: Witkowski M. Hungry heart: Nutrient deficiencies and cardiovascular disease. Presented at the European Society of Cardiology Congress, August 28-31, 2026, Munich. Disclosure: Witkowski reported no relevant financial disclosures.