Kevin Kunzmann

In a presentation at The Metabolic Institute of America’s (TMIOA) 2021 Heart in Diabetes sessions in New York, NY , Andrea Dunaif, MD, Professor of Medicine in the Department of Medicine and new Chief of the Hilda and J. Lester Gabrilove Division of Endocrinology, Diabetes and Bone Disease for the Mount Sinai Health System, spoke of what she describes as an “ongoing controversy” regarding the potential increased risk for cardiovascular disease in women with 

“Tremendous advance have been made in the past 10 years on elucidating causal pathways through genetic pathways,” Dunaid said.

Androgen production, granulose cell function, and age in menopause were considered some of the causal pathways.The causality of insulin resistance had also been proven in studies that showed the genes that cause resistance and increased body mass index also contributed to PCOS. Dunaif cited the Rotterdamn Criteria, diagnostic criteria developed in recent years that focused on key clinical features such as hyperandrogenism, ovulatory dysfunction, and poor metabolic outcomes.

“These are the women that have profound insulin resistance, and there’s pretty good data that they’re about, independent of obesity, at 4-fold increased risk of type 2 diabetes with a significantly younger age of onset,” Dunaif said.

Dunaif added that younger women with PCOS who have developed type 2 diabetes due to the disease were likely at marked cardiovascular disease risk. Despite ongoing discussions of the potential cardiovascular risk associated with the disorder, little data exists on the subject.

“Unfortunately, there have been no long-term respective cohort studies to an age which women start having increased events to answer this question,” Dunaif said. “So, we’re left with other types of data.”

An increased risk of cardiovascular disease was recorded in an early Scandanavian study involving 18,112 patients with PCOS, but the data focused solely on younger female patient populations.

A similar cohort study in Denmark, which offered a more robust definition of PCOS, observed the long-term health trajectory of older women with the disease and also found an increased risk of cardiovascular disease.

study found that women with irregular menstrual cycles found a 1.5 increased risk for cardiovascular events. Though incomplete, Dunaif considered it to be the best data on the subject of PCOS and cardiovascular health.

Aside from the limited studies, Mandelian Randomization has been a key component in the study of PCOS and the potential link to cardiovascular risk.

Mandelian Randomization uses genetic variants that are correlated with exposure to PCOS, such as body mass index, to determine a causal relationship. However, much of the data requires corroboration.

Overall, though women with PCOS have not been studied to an age when cardiovascular events are considered common, Dunaif noted that the risk of type 2 diabetes by 4-fold, and the disease was linked to several traditional and emerging CVD risk factors.

At the end of the presentation, Dunfaid added that menses continue to act as a “vital sign” for cardiovascular disease, and urged patients and clinicians to incorporate the test.

“Menses that (patients are) either skipping or cycle lengths greater than 40 days are associated with increased risk across a lifespan for type 2 diabetes, and even more concerning, with premature mortality,” Dunaif said. “So, 1 simple question and you can really help your patients.”

Articles

An overlooked aspect of an under-discussed condition, Andrea Dunaif, MD, provided an overview of the cardiovascular risk seen among women with polycystic ovary syndrome. 

Understanding Cardiovascular Risk in Polycystic Ovary Syndrome, With Andrea Dunaif, MD

This article was originally published on 

If the COVID-19 pandemic has caused a lost year of healthcare for chronic disease patients, as so many clinicians describe in their practice, then it may take even more years to understand the total effect of such significant lapses in care between the beginning and the eventual end of the distance-driving health crisis.

And some chronic diseases are less forgiving than others; that lost year may make all the difference. In the case of millions of US patients with 

, that year could cost them their vision.

Consider that about one-third of all adults aged ≥40 years old with diabetes suffer from at least 1 symptom of diabetic retinopathy (DR), and that about 5% of all diabetic patients may suffer severe vision loss. Now consider that, per the Centers for Disease Control and Prevention (CDC) last year, 

more than 34 million Americans have diabetes

, and another 88 million have prediabetes.

Couple all that with context: new diabetes cases significantly decreased from 2008-2018 among adults, yet significantly increased among pediatric and adolescent persons. And new cases are notably greater among non-Hispanic blacks and people of Hispanic origin than that of non-Hispanic Asians and non-Hispanic whites—a trend which shows that greater US diabetes burden is falling on groups with lesser healthcare access and treatment retention across other chronic conditions.

The average diabetes patient—of which there are 1 for every 10 people in America—is getting younger, and more distant from clinicians, at a time when a global pandemic has already done unprecedented harm to in-person care rates and screenings.

Katherine Talcott, MD, of the Cleveland Clinic’s Cole Eye Institute, explained to 

 the multitude of ways in which COVID-19 has harmed the patients of her ophthalmology practice.

“A lot of our patients with diabetes who had been coming in have been lost to follow-up in the last year, and they have a lot worse macular edema or their diabetes is worse,” 

An epidemic of its own right, diabetes is worsening in the US, and its comorbid effects bleeds into other specialties of care. As covered in a series of research topics and presentations at the 

Association of Research in Vision and Ophthalmology (ARVO) 2021 Virtual Meeting

 last week, there is a trend heading toward a greater convergence between diabetic and related ophthalmic care.

But what is that current dynamic? And how will it change to improve the state of a patient’s diabetes, and associated visual wellbeing?

Research from the CDC, presented at ARVO 2021 by Elizabeth Lundeen, PhD, MPH, of the Division of Diabetes Translation, showed visually-impaired persons from a 2018 national health survey were 48% more likely to have diabetes than the general population.

The findings, which also illustrated significant ties between cardiovascular-associated risk factors including smoking and visual impairment, came as little surprise to Lundeen, who noted the “strong correlation” between cardiovascular, cardiometabolic, and visual health. Previous CDC research even depicted a similar relationship between stroke, cardiovascular events, and visual impairment.

“Cardiovascular health and vision health show a lot of the same risk factors, actually,” 

. “For example, a well-known risk factor for glaucoma would be (high) blood pressure—which is also a risk factor for cardiovascular disease. And age-related macular degeneration shares a lot of risk factors with cardiovascular disease.”

In fact, all 7 targeted risk factors for cardiovascular disease—even when controlled for patient demographics—were more likely to present in visually-impaired patients: smoking; physical activity; excessive alcohol intake; obesity; hypertension; high cholesterol; as well as diabetes.

The correlation is not always consistent; in fact, new ARVO research even suggested that currently available ophthalmic therapies may benefit regardless of comorbid diabetes or cardiovascular risk factors.

Talcott reported her team’s assessment of 

 which observed patients’ diabetic macular edema (DME) resolution and time to resolution when treated with intravitreal aflibercept, with consideration to baseline factors including HbA1c, hypertension, hyperlipidemia, smoking status, and more.

What they found was that ophthalmic status factors, including baseline central subfield thickness (CST) and best-corrected visual acuity (BCVA), were more influential in DME patient likelihood and time to disease clearance with aflibercept than cardiovascular risk factors were.

In fact, to Talcott’s surprise, diabetes severity at baseline did not affect treatment-based DME clearance at all—despite it being the disease which leads to DME development in the first place.

“I think it’s interesting,” she said. “Some of the preconceptions we have as clinicians as to how individual patients might do, don’t necessarily pan out when you conduct these large studies.”

The surprise of the findings speaks to the nature of collaborative care among ophthalmologists and prescribers managing the same patients with diabetes and vision impairment—a partnership in the US health system which clinicians themselves agree is subpar.

The connection between cardiovascular and cardiometabolic risk factors in visually impaired persons is not just correlative; it’s been proven causative enough that experts like Allen Ho, MD, considers such factors in the itinerary of diabetic retinopathy (DR) care.

, is significantly impacted by diet, exercise, smoking status, blood pressure, and A1c levels.

“You can be seeing well and just drop off a cliff the next day,” Ho, director of Retina Research at the Wills Eye Hospital said. “If you don’t know your A1c, that’s a risk factor for vision loss right there. It’s like driving with your eyes closed, is what I tell (patients.”

That’s reason enough for improved communication between providers with mutual interest in those risk factors—at least communication from a better mindset. Ho described the current ophthalmology-diabetes specialist connection as something mandated, and possible punitive: missing eye exam referrals for newly-diagnosed diabetics can result in penalties to physicians.

Unfortunately for clinicians like Talcott, collaborative care usually bookends a patient’s diabetes status: referral and monitoring at the beginning of their diagnosis, then reactive response when comorbid disease like DME or DR is in full effect.

“I think that we all tend to, unfortunately, focus on our problems and forget about other parts of the body,” she said. “But when we see patients who have disease that’s out of control, that usually means their diabetes is not well-controlled in other reasons as well.”

A promising connector, it could be suggested, may be the advancement which both specialties may be most interested in: drug classes which treat diabetes, DME, DR, all the same.

Not only are researchers beginning to interpret the absolute value of already-established drug classes like anti-VEGF injections, which Talcott’s team showed in the case of aflibercept benefits ophthalmic disease regardless of diabetes severity. They are also venturing into consideration of diabetic agents for the management of DME and DR.

Ashay D. Bhatwadekar, PhD, RPh, associate professor at the Eugene and Marilyn Glick Eye Institute, 

presented animal model findings at ARVO 2021

 indicating gluclose-lowering SGLT-2 inhibitor dapagliflozin—a dynamic add-on agent in cardiometabolic, cardiovascular, and renal outcome risk reduction—may provide anti-inflammatory and anti-angiogenic benefit to patients with DR.

The scientific rationale of Bhatwadekar’s work was based on the valuation of SGLT-2 in glucose rates among patients with diabetes, and believing that it correlates enough with DR pathology to consider dapagliflozin for treatment.

But the broader rationale of the research was simpler than that: dapagliflozin has shown benefit in numerous comorbid outcomes in patients with diabetes. Why not diabetic retinopathy?

“Considering its use into cardiovascular conditions, I think that kind of multi-regimented use you see makes sense that you look into seeing it in diabetic retinopathy,” he explained to 

The early-stage findings were hopeful enough for Bhatwadekar to discuss progression into human trials comparing outcomes, symptoms, and levels of DR among patients treated with and without dapagliflozin. But implementation of SGLT-2 inhibitors for the direct treatment of DR or DME—or even other glycemic control drug classes, including GLP-1 agonists—is a long time away still.

What may benefit experts most in bridging the gaps between diabetes and ophthalmology in the short term may be improved screening, mixed with referral and communication that’s more “carrot” than “stick,” as Ho put it.

“We tend to communicate in a way that, in an era of digital medicine, I think can improve,” Ho said. “Even detection of diabetic retinopathy, there are devices now involving artificial intelligence (AI) that keep patients from coming in to get their eyes dilated.”

Patient-centered detection and screening tools, which are currently available at most physician’s offices and pharmacies, may soon come to smartphones, Ho suggested. At-home AI-enabled detection may provide streamlined referrals and allocation of care.

Lundeen echoed Ho’s suggestions of improved screening integration in ophthalmology, with the addendum that it may be better managed by a host of stakeholders: general practitioners, endocrinologists, and cardiologists all worker to assure vision health monitoring is a universal touchpoint in routine care.

On the other end, ophthalmologists should be looking to integrate chronic disease prevention strategies into their routine practice.

“There are opportunities to better integrate healthcare—both general healthcare being more attentive to vision health, and vice versa,” she said.

Ho suggested that even patients could be more cognizant of the risk factors associated with diabetes, including chronic ophthalmic disease, before even being approached with the matter by a clinician. Improved awareness campaigns, led by notable affected figures, could help to educate the millions at risk, rather than the thousands dedicated to treating them.

Sometimes the elephant in the room goes unnoticed if it’s been there for too long. Diabetes is not always at the forefront of a treating ophthalmologist’s priority list, because the vision-related byproducts of diabetes already are. More than any comprehensive therapy, referral strategy, technology or campaign, the continued discussion and research of diabetes' total effect on a patient among experts should be what leads to better outcomes in ophthalmology.

“I think there’s a lot of overlap that we just don’t think about, and it’s part of the questions that we don’t think about asking,” Talcott said. “There’s definitely a lot more we could be doing to better communicate and understand how different organs are related in diabetes.”

Research from ARVO 2021 details the complexities and current challenges faced when attempting to address the burden of diabetic eye disease while the number of patients with diabetes in the US continues to balloon. 

More Specialty Collaboration Needed to Address Burden of Diabetic Eye Disease


New research suggests COVID-19 is associated with a unique form of inflammation of the thyroid gland.

Conducted by a team of investigators based in Italy, results of the ENDO 2021 study suggest 1-in-3 diagnosed with moderate to severe COVID-19 during the early outbreak in Europe was still experiencing signs of thyroid inflammation after 3 months, despite thyroid function having already normalized.

The dysfunction triggered by COVID-19 does not appear to be mediated by autoimmunity, investigators observed, and therefore warrants follow-up research in the event that patients may be at risk of permanent thyroid dysfunction.

Investigators, led by Ilaria Muller, MD, PhD, of the University of Milan, conducted a longitudinal follow-up study of patients to survive moderate to severe COVID-19 following hospitalization in acute medical units at a facility in Milan. Patients observed for this study had no history of thyroid disorders and/or treatment thereof.

Muller and colleagues assessed patients for serum thyroid function and autoantibodies, C reactive protein (CRP), full blood count (FBC), and thyroid ultrasound for every 3 months.

At the time of the ENDO 2021 presentation, 53 patients had been included in the follow-up trial. At 3 months following COVID-19 infection, all patients presented with increased median serum TSH concentrations from baseline. Serum concentrations of free-thyroxine, free0triiodothyronine, CRP, and FBC had normalized from baseline.

Negative autoantibodies to the TSH receptor were observed in all patients.

They observed atypical subacute thyroiditis in 15% of patients hospitalized for COVID-19—a significant increase from the 1% observed with such presentations in the same facility during spring 2019, prior to the pandemic.

“The atypical thyroiditis induced by COVID-19 is not associated with neck pain, affects more men than women and especially those severely ill, thus coexists with non-thyroidal illness syndrome,” investigators wrote. “Subacute thyroiditis is classically followed by subsequent occurrence of permanent thyroid dysfunction and autoimmunity, thus we have started a systematic follow-up program of these patients.”

In a statement accompanying the findings, Muller stressed the importance of continued monitoring for such uniquely affected COVID-19 patients.

“It is important to know whether SARS-CoV-2 virus has late-onset negative effects on the thyroid gland, in order to promptly diagnose, and eventually treat, the condition,” Muller said.

The study, “Early Follow-up of Atypical Thyroiditis Induced by SARS-CoV-2,” was presented at ENDO 2021.

A study from ENDO 2021 indicates moderate-to-severe COVID-19 infections are associated with atypical thyroid inflammation.

COVID-19 Could Cause Atypical Thyroid Inflammation

This article was originally published by 

A recent study from investigators in Australia suggests testosterone therapy among men with low serum testosterone could mitigate the risk of developing type 2 diabetes in this patient population.

Low testosterone levels have been linked with an increased risk of type 2 diabetes, and men who are overweight or obese often have low testosterone. In many cases, community-based lifestyle programs are a main strategy used to help reverse the risk.

Corresponding author Gary Wittert, MD, of the South Australian Health and Medical Research Institute, and colleagues wanted to find out whether pairing such a program with testosterone injection therapy might have the effect of either mitigating diabetes risk or even reversing early diabetes.

The authors designed a two-year, randomized, double-blind, placebo-controlled phase 3b trial of men ages 50-74 who were enrolled in a community-based lifestyle program developed by WW (formerly known as Weight Watchers).

The men each had a waist circumference exceeding 95 cm, serum testosterone concentrations of 14.0 nmol/L or lower (but without pathological hypogonadism), and either impaired glucose tolerance or newly diagnosed type 2 diabetes.

Of more than 19,000 men pre-screened at 6 Australian tertiary care centers, a total of 1,007 were eventually enrolled in the study, between the years 2013 and 2017. The enrollees were evenly divided between those receiving placebo (503) and those who were given an intramuscular injection of testosterone undecanoate (1000 mg). Both the placebo and the testosterone injections were given for 6 weeks, then every 3 months for the next 2 years.

The primary outcome was type 2 diabetes based on the two-hour oral glucose tolerance test (2-h OGTT) and mean change from baseline 2-h OGTT glucose, assessed by intention to treat.

After 2 years, the data showed a marked difference in the glucose test results for patients in the 2 arms of the study. Of the 413 participants in the placebo group for whom data were available, 87 (21%) had 2-h glucose levels of 11.1 mmol or higher; in the testosterone group, just 12% of patients (55 of 443 participants) met that threshold. In terms of change from glucose baseline, the mean change in the placebo group was -0.95 mmol/L and in the placebo group the mean change was -1.70 mmol/L. Those data were independent of baseline serum testosterone levels.

Wittert told HCPLive that the most likely reason for the effect of testosterone treatment is that it impacts the patient’s body composition.

“It is most likely the effect is mostly mediated by a decrease in fat mass, however an increase in muscle mass and function may also be contributing,” he said.

Wittert and colleagues added a note of caution. The study included masked monitoring of hematocrit and prostate-specific antigen to assess safety. Six (1%) patients in the placebo group and 106 (22%) of patients in the testosterone group met the trigger of hematocrit greater than 54%. The prostate-specific antigen trigger of an increase of 0.75 μg/mL was met by 87 (19%) of patients in the placebo group and 109 (23%) of patients in the testosterone group.

Wittert and colleagues concluded that the increases in hematocrit might be treatment-limiting, but they said longer-term studies would be needed to better understand the durability of the treatment as well as its long-term safety.

Testosterone treatment to prevent or revert type 2 diabetes in men enrolled in a lifestyle programme (T4DM): a randomised, double-blind, placebo-controlled, 2-year, phase 3b trial

," was published online in The Lancet Diabetes & Endocrinology.

Results of a phase 3b trial suggest testosterone treatment could prevent the development of diabetes in men with low serum testosterone levels.

Testosterone Therapy Could Reduce Diabetes Risk in Men with Low Testosterone

How ACE2 Reduction Associated with Aging Affects COVID-19 Severity

" was originally published on our partner site 

A new perspective from a team of Maryland-based cardiovascular clinicians sheds insight on an often forgotten facet of the inherent COVID-19 risk carried by patients with cardiovascular history: the decline in angiotensin-converting enzyme 2 (ACE2) expression associated with aging, and the response of care most common in such patients.

In an essay published Friday morning, a trio of investigators-Majd AlGhatrif, MD, MA; Oscar Cingolani, MD; and Edward G. Lakatta, MD; of Johns Hopkins School of Medicine, the National Institute on Aging and National Institutes of Health-called for the urgent expansion of renin-angiotensin system (RAS)-based intervention assessment as part of the need for clinical understanding as to how lung complications are driving novel coronavirus (COVID-19) mortality worldwide.

As the team noted, ACE2 is not only prevalent in the pathogenesis of COVID-19, but is part of RAS signaling. Though data is scarce on the topic, it is known now that ACE2 is both targeted by SARS-CoV-2 in its entrances to cells and a critical player in anti-inflammation during RAS signaling-converting angiotensin II to angiotensin 1-7.

The age-associated decrease of ACE2 expression, which investigators have observed in the lungs of rats, is in line with “a constellation of major proinflammatory changes perpetrated by an age-associated increase in RAS signaling throughout the body,” the team wrote.

Such proinflammatory profiles are featured in patients with hypertension and diabetes-a pair of diseases highly common in older patients.

The increase of ACE2 in such patients with ACE inhibitors and angiotensin receptor blockers (ARBs) presents a paradox to investigators: how can ACE2 reduction in older, cardiovascular-risk patients put them at greater risk of COVID-19 severe symptoms when ACE2 is the gateway for the disease into cells?

The team pointed to data procured from the severe acute respiratory syndrome (SARS) epidemic of 2003, which most prominently affected persons in their 30s and 40s-despite these younger patients reporting lower disease severity and risk of mortality versus older people with pre-existing conditions.

“Similarly, in the COVID-19 pandemic, it is plausible that greater expression of ACE2 leads to higher predisposition to incur the disease,” they wrote.

Preliminary epidemiologic data from South Korea-the country with the greatest rate of population-wide testing for the disease-shows that younger adults are reporting the greatest rate of infection, despite perceived higher ACE2 levels. COVID-19 severity, however, has been observed in older patient populations, such as that of Italy’s.

“Hence, compared with young individuals, older persons with (cardiovascular disease) who already have reduced ACE2 levels will be expected to be more predisposed to exaggerated inflammation with further reduction in ACE2 expression in the context of COVID-19, manifesting with greater disease severity,” they explained.

The team hypothesized that SARS-CoV-2 binding to ACE2 creates an acutely exaggerated proinflammatory background, thereby predisposing older adults with hypertension and diabetes treated with ACE inhibitors and ARBs to correct ACE2 levels at a greater risk of disease severity and mortality.

This belief, they wrote, aligns with evidence of angiotensin II antagonists benefitting sepsis-associated acute lung injury.

Going forward, the team advised that clinicians continue treating patients with ACE inhibitors and ARB and pursue clinical investigations that consider RAS interventions for COVID-19 severity reduction.