October 2020
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MEDS eNews

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Vol. 3 No. 46

‘Exciting finding’ indicates T2D benefits
from long-term testosterone therapy

LAGUNA NIGUEL, CALIF. – Long-term testosterone therapy (Tth) completely prevents pre-diabetes progression to type 2 diabetes (T2D) among men with hypogonadism, according to a recent study that also indicates that it improves glycemia, lipids, and Aging Males’ Symptoms (AMS) scale scores.

The research published in March in Diabetes Care is deemed “an exciting finding” by
Ji Hyun Chun, PA-C, BC-ADM, president of the American Society of Endocrine Physician Assistants (ASEPA).

Chun---who is affiliated with OptumCare Medical Group, Laguna Niguel, Calif., and is a faculty member of Metabolic & Disease Summit (MEDS)---notes that the observational study concludes that Tth offers potential for men with pre-diabetes and hypogonadism, and looks for validations from future research.

“I would love to see the study replicated in other studies and settings to draw conclusions which can further guide us on this topic matter,” he says. “We would especially need a well-designed randomized-controlled trial so we have a better matched placebo group.”

As the study, which involved 316 men with pre-diabetes and symptoms of hypogonadism, notes that pre-diabetes represents a window of opportunity for intervention to prevent T2D, Chun suggests that this “window” can best be utilized through careful screening for potential hypogonadism, and appropriate work-ups.

“Keep in mind,” he urges, “that ‘active’ testosterone (free and/or bio-available testosterone) levels need to be checked in this setting. Many patients with dysglycemia are overweight or obese, which lowers sex-hormone binding globulin (SHBG), and thereby have lower total testosterone, but might have normal ‘active’ testosterone levels.”

Chun adds that “another important point mentioned in the study is the presence of symptoms of hypogonadism in treatment decision-making.”

“If patients with pre-diabetes have true hypogonadism (biochemical and symptomatic), and other reversible causes are ruled out,” he says, “Tth may improve their metabolic health and help them from progressing to overt diabetes.”

While Chun calls this research and its conclusion “an exciting finding from an observational study,” he also urges caution.

“As in any study results,” Chun says, “one should carefully review the study setting (in this case, an observational study that was non-blinded, non-randomized, not propensity matched, and funded by industry) and acknowledge its strength (i.e., real-world data) and weakness before drawing a conclusion.”

One aspect of the study is its mention of the importance of weight loss, as pre-diabetics are urged to aim at 10% weight loss, with Tth yielding nearly that (9%).

“As we have seen the overlap of obesity and diabetes,” Chun says, “we know that weight management is the cornerstone in managing metabolic syndrome regardless of its stage (euglycemia, prediabetes, diabetes). It is very intriguing to see this significant improvement in weight, and more importantly, its sustainability in this particular registry. I am curious on what is different in this population other than the Tth that led to this significant weight benefit.”

“We all know,” he adds, “that just going on testosterone would not drop someone's weight. We have to give adequate guidance on the needed lifestyle intervention to achieve that. It is plausible to think that Tth would make patients with symptomatic hypogonadism feel better, and have more energy to increase their physical-activity levels, and would be more likely to keep and build lean muscles with exercise and thereby improve their metabolic health.”

Chun also asserts that “discussing this needed lifestyle intervention and setting the right expectation by nurse practitioners (NPs) and physician assistants (PAs) is very important.”

He concludes, too, that, in wake of this study, “there certainly will be an increase in interest and requests from patients in both checking testosterone and using testosterone. Unlike other chronic disease states (i.e., diabetes, hypertension, dyslipidemia, osteoporosis) where patients’ perceived risks outweigh benefits, it is exactly the opposite in hypogonadism---patients are more willing to get on treatment. It is left to us to carefully listen to our patients’ symptoms, concerns, and expectations and guide them to what's best for their overall health.”

CITATION: Aksam Yassin, Ahmad Haider, et. al. Testosterone Therapy in Men With Hypogonadism Prevents Progression From Prediabetes to Type 2 Diabetes: Eight-Year Data From a Registry Study. Diabetes Care. Published online March 18, 2019.


Osteoporosis study notes good calibration
in FRAX-predicted versus MOF probability

LOS ANGELES – A study published in August in the Journal of Bone and Mineral Research indicates good calibration in Fracture Risk Assessment Tool (FRAX)-predicted versus observed 10-year major osteoporotic fracture (MOF) and hip-fracture probability.

The study’s authors---including Carolyn J. Crandall, David Geffen School of Medicine at University of California, Los Angeles, and John T. Schousboe, University of Minnesota, Minneapolis---examined, among women 40-and-older, the performance of the FRAX and FRAX-based osteoporosis-treatment thresholds under the U.S. National Osteoporosis Foundation (NOF) and UK National Osteoporosis Guideline Group (NOGG) guidelines.

They used registry data for all women aged 40-and-over in Manitoba, Canada, with baseline bone mineral density (BMD) testing (54,459 patients). Incident MOF, hip fracture, and clinical fracture were assessed from population-based health-services data, with a mean follow-up of 10.5 years.

Age-stratified hazard ratios (HRs) were estimated from Cox regression models. The researchers assessed the sensitivity, specificity, positive predictive value (PPV), number needed to screen (NNS), and number needed to treat (NNT) to prevent a fracture for osteoporosis-treatment thresholds under the NOF and NOGG guidelines.

Femoral neck T-score and FRAX (with-and-without BMD) predicted all fracture outcomes at all ages.

The gradient of risk for fracture prediction from femoral neck T-score and FRAX (with- and-without-BMD) as continuous measures was strong across the age spectrum. The sensitivity and PPV of the strategies based on dichotomous cut-offs were low, especially among women aged 40-to-49 years (who have lowest incidence rates).

The researchers conclude that threshold-based approaches should be reassessed, particularly among younger women.

CITATION: Crandall CJ, Schousboe JT, et. al. Performance of FRAX and FRAX-Based Treatment Thresholds in Women Aged 40 Years and Older: The Manitoba BMD Registry. Journal of Bone and Mineral Research. 2019 Aug;34(8):1419-1427.


Mid-life obesity linked to higher mortality
even when BMI normal in early adulthood

MELBOURNE, AUSTRALIA – Mid-life obesity is associated with higher mortality even when body mass index (BMI) is normal in early adulthood, according to recent research highlighting the importance of weight management throughout adulthood.

The prospective-cohort study published in August in BMJ Open also indicates that prolonged borderline obesity is associated with elevated risk of death from all-causes and obesity-related cancers relative to maintaining lower-normal BMI across adulthood.

Its authors---including Yi Yang and Pierre-Antoine Dugué, University of Melbourne, Melbourne, Australia---report that since chronic obesity will probably be a major health issue for future generations, policies and prevention programs are needed to target obesity beginning early in life.

The researchers assessed data on 29,881 adults enrolled in the Melbourne Collaborative Cohort Study aged from 40-to-70 between 1990-and-1994, with BMI data for at least three time points. Outcomes included deaths from any cause before March 31, 2017, and deaths from obesity-related cancers, cardiovascular diseases (CVDs) and other causes before Dec. 31, 2013.

The authors identified six group-based BMI trajectories:

  • lower-normal stable (TR1)
  • higher-normal stable (TR2)
  • normal-to-overweight (TR3)
  • chronic-borderline obesity (TR4)
  • normal-to-class I obesity (TR5)
  • overweight-to-class II obesity (TR6)

Generally, compared with maintaining lower-normal BMI throughout adulthood, the lowest mortality was experienced by participants who maintained higher-normal BMI; obesity during mid-life was associated with higher all-cause mortality even when BMI was normal in early adulthood, and prolonged borderline obesity from early adulthood was also associated with elevated mortality.

These associations were stronger for never-smokers and for death due to obesity-related cancers. Being overweight in early adulthood and becoming class II obese was associated with higher CVD mortality relative to maintaining lower-normal BMI.

CITATION: Yi Yang, Pierre-Antoine Dugué, et. al. Trajectories of body mass index in adulthood and all-cause and cause-specific mortality in the Melbourne Collaborative Cohort Study. BMJ Open. Received February 26, 2019. Revised June 7, 2019. Accepted July 8, 2019. First published August 10, 2019. Online issue publication August 10, 2019.


Research into heart failure, CKD issues
ties C‐terminal FGF23 levels, mortality

GRONINGEN, NETHERLANDS – Recent research indicates that exogenous erythropoietin increases C‐terminal FGF23 levels markedly over a period of 50 weeks---elevated levels of which, even at baseline, are significantly associated with an increased mortality risk.

Results of the study published in August in the Journal of the American Heart Association underline, in a randomized-trial setting, a strong relationship between erythropoietin and FGF23 physiology in patients with chronic heart failure and chronic kidney disease (CKD).

The authors---including Michele F. Eisenga, University of Groningen, Groningen, Netherlands, and Mireille E. Emans, Ikazia Hospital, Rotterdam, Netherlands---report that baseline cFGF23 levels are strongly associated with an increased risk of mortality. They also state that the currently-identified association between exogenous EPO and cFGF23 levels could be the potential link between exogenous EPO and detrimental outcomes in this patient setting.

The authors recommend further research to establish whether adverse outcomes associated with EPO treatment are truly attributable to a direct effect of exogenous EPO on cFGF23 levels.

Using the Erythropoietin in CardioRenal Syndrome (EPOCARES) study, the researchers randomized 56 anemic patients with both chronic heart failure and CKD into three groups, of which two received epoetin beta 50 IU/kg per week for 50 weeks;  the third group served as control.

Measurements were performed at baseline, and after two, 26, and 50 weeks. Data were analyzed using linear mixed‐model analysis. After 50 weeks of erythropoietin‐stimulating agent treatment, hematocrit and hemoglobin levels increased.

Similarly, C‐terminal FGF23 levels, in contrast to intact FGF23 levels, rose significantly due to erythropoietin‐stimulating agents as compared with controls.

During median follow‐up for 5.7 years, baseline C‐terminal FGF23 levels were independently associated with increased risk of mortality.

CITATION: Michele F. Eisenga, Mireille E. Emans, et. al. Epoetin Beta and C‐Terminal Fibroblast Growth Factor 23 in Patients With Chronic Heart Failure and Chronic Kidney Disease. Journal of the American Heart Association. Originally published 17 Aug. 2019.


Severe-asthma patient assessment backs
multi-disciplinary pulmonary rehabilitation

TRADATE, ITALY – Authors of a study published in August in the Journal of Asthma indicate that their research on a large sample of severe-asthma patients provides evidence that a multi-disciplinary pulmonary rehabilitation (PR) program is effective in terms of exercise capacity and symptoms.

The researchers---including Elisabetta Zampogna and Rosella Centis, Istituti Clinici Scientifici Maugeri, IRCCS, Tradate, Italy---also report that exercise capacity improves in the presence of bronchiectasis and/or obstructive sleep apnea (OSA).

The authors, noting that PR is a multi-modal treatment that is poorly investigated in severe asthma where respiratory symptoms remain uncontrolled despite intensive pharmacological therapy, investigated the effectiveness of PR on functional exercise, dyspnea, and muscle fatigue in severe-asthma patients.

They assessed 317 patients affected with severe asthma according to Global Initiative for Asthma (GINA) guidelines who underwent a multi-disciplinary three-week rehabilitation program with an adherence of more-than-80% to PR, and who could complete a Six Minute Walking Test (6MWT).

PR included:

  • endurance training
  • educational meetings
  • chest physiotherapy
  • breathing exercises
  • psychological support

Six-minute walking distance and Borg scale for dyspnea and muscle fatigue were recorded before-and-after rehabilitation.

Of the 371 patients analyzed, 39 had bronchiectasis, 163 OSA, and 17 had both. PR significantly improved 6MWT distance, Borg dyspnea and muscle fatigue, and mean peripheral capillary oxygen saturation (SpO2) recorded during 6MWT.

CITATION: Elisabetta Zampogna MSc, Rosella Centis, BScEcon, et. al. Effectiveness of pulmonary rehabilitation in severe asthma: a retrospective data analysis. Journal of Asthma. Received 25 Feb. 2019. Accepted 16 July 2019. Accepted author version posted online: 18 July 2019. Published online: 13 Aug. 2019.


Clinician Reviews article offers advice
on ways to cut patients’ insulin costs

A Q-and-A posted recently in Clinician Reviews offers suggestions to reduce patients’ insulin costs. Written by Alyssa Kanagaki Greenleaf, BA, MHS, PA-C, Hartford Healthcare Medical Group Endocrinology in Southington and New Britain, Connecticut, the article offers such advice as: trying older insulins, switching to a syringe and vial, patient-assistance programs, co-pay cards, and shopping for the best deal. The writer cautions that patients “must be advised that not taking their prescribed insulin, or taking less insulin than prescribed, is not a safe alternative.” The article can be accessed at



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