Kevin Kunzmann

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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.

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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.

The Dilemma of Coronavirus Disease 2019, Aging, and Cardiovascular Disease

Kevin Kunzmann

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Testosterone Therapy Could Reduce Diabetes Risk in Men with Low Testosterone

Why Older Patients Are More At Risk for COVID-19 : A Decline In ACE2 Expression