ENDO 2019: 101st Annual Meeting of the Endocrine Society:

Treatment Insights for Hypothyroidism, Adult GHD Testing, and HbA1c

With Jacqueline Jonklaas, MD, Elena Christofides, MD, and Derek LeRoith, MD, PhD

Thyroid Hormone Preparations—When to Deviate from T4

If, when, and why might it be appropriate to consider going beyond levothyroxine (LT4) monotherapy in patients who are dissatisfied with their current hypothyroid therapy?  It's not unusual for a patient to present with complaints of not feeling well despite a thyroid stimulating hormone (TSH) level in the normal range.

However, requests for combination therapy including either liothyronine (LT3) or thyroid extract require due consideration,1 according to Jacqueline Jonklaas, MD, professor of medicine at Georgetown University, in Washington, DC, who discussed this common clinical quandary, in a session at ENDO 2019, the 101st Annual Meeting of the Endocrine Society, in New Orleans, Louisiana. 

While prescriptions for synthetic levothyroxine (LT4) are up, scripts for the so-called natural LT3 has declined, and there's been a slight rise in thyroxin extract. Interestingly, approximately 15% more patients who are taking levothyroxine (LT4) report impaired quality of life compared to controls.

Yet, findings of a meta-analysis of combination therapy offered no support for its benefit in hypothyroid management; in addition, reports on preferred thyroid supplementation from general well-being questionnaires have been inconclusive.

This discrepancy, Dr. Jonklaas said, may be explained by other diagnoses that were independently affecting quality of life and complicating assignment of causation.1 More likely, unexplained variations in patient contentedness with her thyroid replacement regime may be attributed to an individual TSH setpoint. "The difficulty is that often we don’t know what the setpoint is, so we simply titrate the levothyroxine to get the patient's TSH into the normal lab range," she said.

While there is usually no treatment preference in the majority of patients, it is important to at least consider this request when the patient raises it, without the benefit of guidance from much needed, blinded crossover studies.

Should your patients ask about adding LT3 for better weight control, "you can explain that thyroid extract achieved only modest weight loss of three pounds in clinical studies." It is likely helpful to note that in one such trial, the percent of patients taking LT4 who don't feel well or were dissatisfied were those who tended to have comorbid conditions, such as obesity, depression, hypertension, and hyperlipidemia.

Talk to your patients—those who were aware of their diagnoses felt better about their treatment, said Dr. Jonklass.. What patients were asked how they felt in the moment and eight weeks earlier, they usually answered better now. (Peterson 2018) 

What about CombinationThyroid Replacement Therapy—LT4 and LT3?

There has been an increase in the willingness of physicians to prescribe combination therapy in specific circumstances based on a survey of 389 endocrinologists who are members of the American Thyroid Association. This openness to respond to patients may be necessary since treatment trials have produced very heterogeneous results, including variability in doses and biochemical endpoints. Of the 13 trials evaluating quality of life, only two showed superiority with combination therapy. [Medici]

"We also know that after years of monotherapy, some patients continue to experience impaired quality of life, fatigue, and other such symptoms suggesting poorly managed hypothyroidism despite normal TSH values," she said. However, combination LT4 and synthetic liothyronine (LT3) therapy or the use of desiccated thyroid extract (DTE), have not been recommended for this indication based on short-duration studies suggesting no significant benefits, and other data indicating that 40% of patients receiving combination therapy were overtreated.

While still in early stages of animal testing, a sustained release T4 may prove more effective in achieving a TSH to match the patient's setpoint more closely, Dr. Jonklaas said. T3 sulfate has produced consistent TSH levels for 15 years, and therefore, may be a potential long-acting preparation for some patients who do not feel well on LT4. While the studies support a regimen of three doses or an extended release formula, the 3 times daily dosing would be too hard for most patients to follow consistently.

“When patients ask for T3, many clinicians are willing to comply because they wonder if they may otherwise be missing something,” Dr. Jauklaus told EncocrineWeb. There is no right answer, at present, so trialing variations in thyroid replacement based on the patient's stated sense of wellbeing is reasonable.

It has become apparent that a robust study is needed to better inform clinicians about the benefits of prescribing T3 extract. However, the European guidelines endorse trying combinations therapy.

"Another reason to consider varying from standard therapy—Polymorphisms adversely impact LT4 treatment although may not explain complaints of reduced quality of life and cognitive dysfunction," she said. "As such, it would be reasonable to try introducing T3 with reduced T4 rather than initiating T3 at the current T4 dose. View the T3 as augmentation therapy, particularly in patients who express symptoms of depression and concerns about bone loss."

In the only retrospective study to date, patients who received combination thyroid replacement therapy with both natural and synthetic formulations extending to a mean of 27 months reported more than 90% favorable response to the therapy. The majority described feeling “excellent, very good, or good” when taking combination therapy based on responses to the Medical Outcomes Study short form-20 questionnaire versus monotherapy, and there were no noted adverse side effects.

Diagnostic Testing Advance for Adult Growth Hormone Deficiency

Elena Christofides, MD, a private practice endocrinologist in Columbus, Ohio, presented an overview of a new oral solution, macimorelin (Macrilen), that introduces a much-needed simplification in the ability to ease in-office testing for growth hormone deficiency (GHD) in adults.1

Macimorelin, a growth hormone secretagogue receptor agonist, represents the first and only oral test available to assess patients suspected of having a growth hormone deficiency, having gained Food and Drug Administration approval for use in adults at the end of 2017.2

“This new diagnostic approach affords clinicians the ability to expand our reach and to more readily identify growth hormone deficient patients without the onerous testing that took place before the introduction of macimorelin,” Dr. Christofies told EndocrineWeb.

For the past 35 years, the insulin tolerance test (ITT) has been regarded as the gold standard in evaluating the integrity of the adrenal hypothalamic-pituitary-adrenal axis relied on as a guide in making a clinical diagnosis of adult GHD and adrenal insufficiency.3

Stimulation testing is very problematic. Not only does the ITT introduce significant intra- and inter-individual variability,1 “this [standard] testing method is time intensive for both the patient and physician,” Dr. Christofides told EndocrineWeb. She elaborated saying, ”The ITT methodology requires multiple blood draws and insulin challenges occurring over the course of two to four hours, which leaves patients sick with discomfort and symptoms from induced hypoglycemia following the procedure,” including dizziness, headache, sweating, weakness, mental fog, and heart palpitations.2

“This oral preparation— an orally available ghrelin agonist—represents a great advance in our opportunity to be able to identify and treat growth hormone deficiency patients,” she said. “Because it is an oral solution, it offers a new way to address these patients’ needs in a way that’s less invasive, less time consuming, and less resource intensive.”

“Given the heavy time and supervision required during the testing period with the existing challenge tests, having an alternative that simplifies the process and cuts down on time and bypassing the onerous side effects is very beneficial,” Dr. Christofides said.

FDA approval was granted after reviewing data obtained from a randomized, open-label, single-dose, crossover trial conducted to compare the efficacy and safety of the macimorelin test against the insulin tolerance test in adults.3

The study findings were drawn from the experience of 154 patients who were divided into four groups: adults at high risk for GHD, adults deemed at modest risk for GHD, adults considered at low risk for GHD, and a matched cohort of healthy adults (ie, adults with no likelihood of having a growth hormone deficiency). The control group was matched for age, body mass index, and in estrogen status in the women.3

Changes in growth hormone levels from baseline were measured in 15-minute increments (30, 45, 60 and 90 minutes) following ingestion of the oral preparation. The treatment group also had the insulin tolerance test; agreement between the two tests represented the primary efficacy outcome of the study.3

The findings indicated an overall agreement of 84% between the two tests: macimorelin and ITT.3 Among patients at highest risk for GHD, the agreement was 89%. Results were reliable in greater than 99% of first testing as compared to 83% for the ITT. Reproducibility of results was confirmed in 91.2% of the patients (n=34) who underwent two tests.4

When tested in both men (n=90) and women (n=64), the outcomes were similar. The study group was comprised of primarily younger ((98% under age 65 years), white (86%) subjects so any differences in effectiveness in older, non-white adults is not available.4

The recommended dose is a single oral dose of 0.5 mg/kg of macimorelin.  The dose is administered as a reconstituted solution. Use of this test has not yet been tested in children and so is not approved for use in the pediatric population.

This test was purchased by Novo Nordick from Strongbridge.

Controversy Regarding Reliance on HbA1c Continues

Derek LeRoith, MD, PhD, professor of Medicine at the Icahn School of Medicine at Mount Sinai in New York, offered his perspective on the ongoing controversy regarding reliance on HbA1c as the guidepost for diabetes disease management to EndocrineWeb.

"Clinicians should take into account that there are problems, such as diluting effects including hemolytic and renal changes that should be considered in making a differential diagnosis," Dr. LeRoith said.

There are many reasons for the ongoing debate about the best level of hemoglobin A1c (HBA1c) to be achieved for the most favorable glucose control. There are some organizations that suggest 6.5  while others suggest that 7.0 is adequate, and still others that believe a loosening of these strict levels should be allowed for certain subgroups, he said.

"In the older patient, for example, who has cardiovascular disease and other comorbidities, most agree that we should not try to intensify therapy to bring the HbA1c too low given concerns about hypoglycemia, which raises the patients' risk of falls and fractures, and other outcomes. So I think, again, when it comes to determining the right HbA1c level to aim for, the best determination is one that relies on a personalized patient-centered approach that has taken been made in consultation with the caregivers or the family," said Dr. LeRoith.

Next Summary:
Focus Turns to Need for Better Diabetes Management in Older Adults
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