Midwest Endocrinology Society tackles Cushing’s, Osteoporosis, Diabetes and Congenital Adrenal Hyperplasia

From the desk of Roxanne Nelson,Seattle-based writer –   For endocrine conditions ranging from the most prevalent to the most challenging to treat, experts convened at the 15^th Annual meeting of the Midwest Endocrinology Society in Minneapolis, August 17-18 to discuss new research findings and latest treatment regimens. The Midwest Endocrinology Society is designed to bring together those in the field of endocrinology for conversations to improve quality of care, increase awareness, and create a professional forum for scientific and advocacy issues that surround the field of endocrinology. The following key therapeutic areas generated significant attention and discussion among the attendees:

Osteoporosis

“There is no lack of treatment options, as several new therapies have been approved during the past few years that have added to the arsenal of therapeutic options for osteoporosis,” said E. Michael Lewiecki, MD, FACP, FACE, from the New Mexico Clinical Research & Osteoporosis Center in Albuquerque. “Recent research indicates that the sequence of osteoporosis treatment is key.”

Two broad classes of agents are recommended for osteoporosis treatment. The first are antiresorptive agents, which stop bone from breaking down, and include the bisphosphonates alendronate, risedronate, zoledronic acid and ibandronate. The other class of agents are the osteoanabolics, which build new bone. These include teriparatide, abaloparatide and romosozumab-aqqg.

“For example, when an osteoanabolic agent is administered after an antiresorptive agent, there may be a delay or attenuation of the anabolic effect,” Dr. Lewiecki said. “An anabolic followed by an antiresorptive is essential and an anabolic as the first choice is essential for very high-risk patients. An anabolic followed by another anabolic has very limited data; an antiresorptive followed by another antiresorptive is generally neutral although with denosumab after a bisphosphonate may see some additional increase in bone density.” The sequence in which these drugs are given is important.

“It has now also been incorporated into many practice guidelines, that we should consider osteoporosis a lifelong disease, and just as with any other lifelong chronic disease, there is no temporary treatment,” Dr. Lewiecki also emphasized

While less common, osteoporosis in premenopausal women can be problematic and requires appropriate evaluation and management, explained Joseph L. Shaker, MD, Medical College of Wisconsin in Milwaukee. Guidelines for treating osteoporosis based on bone mineral density (BMD) in postmenopausal women are generally not applicable to premenopausal women, and there is far less research, and consequently a lack of consensus and guidance on its diagnosis and management. Dr. Shaker emphasized that most premenopausal women with low trauma fractures or low BMD have a secondary cause of osteoporosis or bone loss.

“When you see a premenopausal woman with osteoporosis, you have to think about secondary causes, especially low estrogen,” Dr. Shaker said.  He referenced a population study from Olmstead County, Minnesota, which found that 90% of men and women aged 20–44 with osteoporotic fractures and low BMD had a secondary cause for their fractures. Conversely, several case studies of young women with osteoporosis who were treated at tertiary centers reported a much lower percentage—only 50–60% had secondary causes. Dr. Shaker reflected that this may be referral bias but that it is still very high.

Women who present with unexplained fractures or low BMD should have a thorough clinical and laboratory evaluation to search for known causes of fractures and/or bone loss, and whenever possible, treating the underlying cause should be the focus of management. Most do not need treatment, but pharmacological intervention should be initiated for those that continue to have low trauma fractures.

Diabetes

Advances in technology have greatly improved in diabetes management for people who require intensive insulin therapy, including the use of insulin pumps and continuous glucose monitoring (CGM) devices, as explained by Aoife M. Egan, MB, BCh, BAO, PhD, an endocrinologist at Mayo Clinic in Rochester, Minn.

Over the past few years regulatory approval of the first automated insulin delivery (AID) systems has been granted, which combine an insulin pump and CGM. Used primarily in type 1 diabetes, AID has been shown to improve time in range (70-180mg/dL) and reduce the percentage of time that glucose is <70 mg/dL and >180 mg/dL. AID is also used to improve psychosocial outcomes such as quality of life and fear of hypoglycemia.

Dr. Egan noted that the American Diabetes Association (ADA) recommends that AID systems be offered for diabetes management to individuals with type 1 diabetes A and other types of insulin-deficient diabetes who are able to use it safely. The ADA also recommends insulin pump therapy for individuals with type 2 diabetes who require multiple daily injections.

Also discussed were diabetes-related eye diseases, which are increasing in prevalence and associated with rising health care costs and disability. Anti-vascular endothelial growth factor intravitreal injections combined with panretinal photocoagulation and focal laser treatment remain the cornerstone of current diabetic retinopathy treatment.

“Only 60% of people with diabetes mellitus have [the] recommended annual screening for diabetic retinopathy,” said Brittni A. Scruggs, MD, PhD, Adult & Pediatric Vitreoretinal Surgeon, Mayo Clinic, Rochester, Minn. “Patients should be educated that early treatment works but retinal exams are needed to detect retinopathy at an early stage, and these exams are needed at least annually.”

Early treatment has also been associated with reductions in vision loss, Dr. Scruggs noted. For example, the Early Treatment Diabetic Retinopathy Study (ETDRS) enrolled 3,711 patients with mild-to-severe nonproliferative or early proliferative DR in both eyes. Treatment with focal laser decreased the risk of moderate vision loss by 50% over 3 years, and focal laser led to 2-line gain in visual acuity. For proliferative retinopathy (PDR), early panretinal photocoagulation led to a reduction in severe vision loss.

While new strategies such as gene therapy are currently being developed and in clinical trials, Dr. Scruggs emphasized that “a wealth of evidence-based work supports the current treatment options, and that knowledge of these studies can guide counseling and decision-making.”

Management of Congenital Adrenal Hyperplasia

Congenital adrenal hyperplasia (CAH) is most commonly due to 21-hydroxylase deficiency caused by mutations in the CYP21A2 gene, leading to impaired cortisol synthesis and excess androgen production. It is a monogenic disorder with complex genetic variation and a wide spectrum of disease severity. Approximately 15% of patients have a contiguous gene deletion that results in connective tissue dysplasia.

This disorder can be fatal, as patients are at risk of life-threatening adrenal crises with hypoglycemia, most often triggered by infectious illnesses and exacerbated by adrenaline deficiency. Management of CAH generally involves receiving supraphysiologic doses of glucocorticoids and in adults preservation of fertility and monitoring for long term consequences of glucocorticoid therapy and androgen excess are needed explained Deborah Merkes, MD, MS, Chief, Department of Pediatrics, Head, Section on Congenital Disorders, NIH Clinical Center.

“In CAH, unresolved clinical issues are common, reflecting both disease and treatment-related factors,” said Dr. Merkes. Current interventions aim to reset the multiple hormonal imbalances in classic CAH by replacing deficient cortisol and aldosterone as well as controlling adrenal androgen overproduction. Controlling the levels of cortisol and androgen can be challenging and high amounts of either one can result in varying sets of side effects including early puberty, short stature, infertility, obesity, osteoporosis, and cardiovascular risks.  Standard glucocorticoid formulations are often unable to replicate the circadian rhythm of cortisol and to control efficient adrenocorticotrophic hormone-driven adrenal androgen production. Inadequate hormonal control is common. As previously evidenced in two large patient cohorts, only about one-third of patients had normal serum levels of androstenedione reflecting good hormonal control.

While the approach to CAH management has remained relatively unchanged for several decades, the pace of research into safer, more effective therapies has accelerated. Dr. Merkes explained that current research is investigating novel approaches to physiologic cortisol replacement and non-glucocorticoid agents that specifically target the derangement in the hypothalamic-pituitary-adrenal axis that is responsible for the androgen excess of CAH and gene therapy.

Cushing’s Syndrome

Another rare and challenging-to-treat condition that generated discussion at the conference was Cushing’s syndrome. Two presentations examined the efficacy and safety of osilodrostat, an oral 11β‑hydroxylase inhibitor. Currently approved by the EMA for patients with endogenous Cushing’s syndrome and by the FDA and EMA for patients with Cushing’s disease for whom pituitary surgery is not an option or has not been curative, osilodrostat provided rapid and sustained reductions in cortisol levels in patients with non-pituitary Cushing’s syndrome.

“This type of Cushing’s syndrome is often associated with severe disease, and this is reflected by the fact that almost a third of patients died during the study,” said Arnd Mueller, MD, one of the investigators and Associate Clinical Lead Global Endocrinology at Recordati Rare Diseases, the manufacturer.

A total of 103 patients were enrolled (safety population); 77 patients were included in the ITT population and 52 patients in the mITT population. The primary endpoint was the proportion of patients with mean urinary free cortisol (mUFC) levels ≤ upper limit of normal (ULN) at week 12, based on the mITT population.

At week 12, 44.2% (95% CI 30.5, 58.7) of patients had mUFC ≤ULN, and 64.6% (95% CI 49.5, 77.8) had any cortisol parameter ≤ULN. Overall, the proportion of patients with mUFC ≤ ULN and any cortisol parameter ≤ULN generally increased during the study period. Mean mUFC and serum cortisol levels generally decreased during the study in all subgroups, regardless of hypercortisolism etiology. Dr. Mueller noted that the data are limited due to the small population but shows that osilodrostat was effective and well tolerated in this difficult-to-treat patient population.

“The data is being reviewed by the FDA now, based on the data from these studies.” Dr. Mueller said.

Written by Roxanne Nelson

Roxanne Nelson is a Seattle-based writer, specializing in health and medical subjects. Ms. Nelson is a registered nurse, in addition to her freelance writing for a wide variety of consumer magazines including Scientific American, GQ, Woman’s Day, A & E’s Biography and Good Housekeeping, as well as professional journals such as Hospital Pharmacist Report, RN and Nurseweek.

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