Higher Doses of ‘Abortion Pill’ Safe in Cushing’s?

Reviewed by Zalman S. Agus, MD; Emeritus Professor, Perelman School of Medicine at the University of Pennsylvania

LAS VEGAS — Higher doses of mifepristone for Cushing’s disease (Korlym) weren’t associated with increases in serious adverse events, researchers reported here.

Korlym is a glucocorticoid receptor antagonist better known as RU-486, or the “abortion pill.” It was approved for treating hyperglycemia associated with Cushing’s disease in 2012.

In an analysis of data from the SEISMIC trial, Dat Nguyen, MD, and colleagues found that similar percentages of patients had serious adverse events across all doses of the drug, reported.

They also reported at the American Association of Clinical Endocrinologists meeting here, that the proportion of the four most common adverse events — headache, fatigue, nausea, and hypokalemia — fell off after 10 weeks of the 24-week trial.

“Recent prescription data indicate that many physicians are not titrating beyond 300 mg per day, potentially limiting patients’ clinical response,” the researchers said.

The 2012 approval was based on the SEISMIC study, which followed 50 Cushing’s disease patients over 24-weeks in an open-label format. It found that daily doses improved blood sugar control and reduced insulin requirements.

Clinicians participating in the trial were told they could titrate beyond the starting dose of 300 mg a day. To look at the relationship between dose and safety, as well as response, Nguyen and colleagues looked at data on 40 of the patients who responded to therapy.

Most of them (90%) were taking at least 600 mg a day, 68% were taking at least 900 mg per day, and 44% took 1,200 mg daily.

Most of the responders (85%) had their initial clinical response at a dose of at least 600 mg daily.

Overall, there were 26 serious adverse events:

  • 10 at the 300 mg dose
  • 8 at the 600 mg dose
  • 3 at the 900 mg dose
  • 3 at the 1200 mg dose
  • 2 while off drug

 

When the researchers adjusted for the number of patients who had ever reached a given dose, the frequency of serious adverse events was similar across doses:

  • 10% of patients at 300 mg
  • 16% of patients at 600 mg
  • 15% of patients at 900 mg
  • 14% of patients at 1200 mg

 

The four most common adverse events decreased after week 10 – although that tracked an increase in dose (mean 588 mg/day before week 10 versus 895 mg/day thereafter).

Nguyen and colleagues concluded that higher doses of mifepristone weren’t associated with increases in serious adverse events or in the most common adverse events – and that better response was seen with higher doses.

Korlym was developed by Corcept Therapeutics of Menlo Park, Calif., as an orphan drug given that it is is believed only 5,000 patients are eligible for treatment. That gave the company 7 years of exclusive rights to market the agent for Cushing’s disease.

The label limits the drug’s indication to patients with endogenous Cushing’s disease who have type 2 diabetes or glucose intolerance and aren’t candidates for surgery, or failed to respond to surgical intervention.

The drug doesn’t reduce cortisol production but prevents it from binding to its receptor – an action separate from its blockade of the progesterone receptor, which makes it an effective agent in abortion.

Since the daily doses are in the same range as those used to induce abortion, the drug is contraindicated in pregnant women. It also carries a boxed warning that the drug will terminate a pregnancy.

From http://www.medpagetoday.com/MeetingCoverage/AACE/45790

Interview May 7 with Kathy C, Pituitary Patient

My name is Kathy Casey. I am a 63 year old retired school nurse. I am married with two wonderful sons and a grandson. My husband and I live in the mountain town of Mt. Shasta in northern California. I have always been athletic.

In 1995, I was diagnosed with a pituitary tumor. At the time the only symptom I was aware of was a severe headache. I had a transphenoidal resection by Dr. Wilson at UCSF Medical Center followed by radiation therapy for 23 days. At the time they said they could not remove all of the tumor.

In 2008/2009. I exhibited symptoms of Cushing’s and my cortisol level was outrageous, and I had to be hospitalized initially for a potassium level of 2. I returned to UCSF and Dr. Anwar Sandeep operated . By removing part of the tumor. My Cushing symptoms resolved. However, he said that the tumor was not encapsulated and was invading the cavernous sinus and stella turcica so it was still not possible to remove it all.

I was OK until December 2013 when I began exhibiting the symptoms of Cushings. One of my 24 hr. urines was 14,000. I had to be hospitalized for a potassium level of 1.9. Dr. Heaney said he has never seen a cortisol level that high. This time I decided to go to the UCLA Pituitary Tumor and Endocrinology Program where they were more oriented to follow-up and treating this disorder. Dr. Bergsneider decided that surgery was not an option. He and Dr. Heaney decided radiation was not an option. So now I am being followed by Dr. Heaney to see if medication can help.

I am now on Cabergoline 0.5 mg three tabs twice a week and Signifor 0.9 mg subcutaneosly twice a day. I think they are alleviating some of the symptoms. However, the Signifor caused my blood sugar to rise, and I had to go on Metformin which is causing nausea to a point where I have a hard time eating.

Anyway, this whole situation is depressing and overwhelming. I am tryng to stay positive, but I wonder how it will turn out. I am fortunate to have a supportive and helpful husband.

I am interested in communicating with people who may be going through a similar experience and learning more about this rare condition.

Kathy will be interviewed May 7, 2014 in BlogTalkRadio

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Subclinical Cushing’s syndrome and cardiovascular disease

Guido Di Dalmazi and colleagues1 reported that in patients with adrenal incidentalomas and either stable mild hypercortisolism or worsening of cortisol hypersecretion, all-cause and cardiovascular disease-specific mortality was higher compared with in those with adrenal incidentalomas that did not secrete cortisol, after a mean follow-up of 7·5 years. Moreover, cortisol concentrations measured after dexamethasone-suppression test were associated with all-cause mortality independent of the presence of traditional cardiovascular disease risk factors.
Subclinical Cushing’s syndrome is the most common hormonal abnormality in patients with adrenal incidentalomas (prevalence 1—29%).2 The proportion of adrenal incidentalomas that progress to subclinical Cushing’s syndrome is low (1·7%) and most are lesions of 3 cm or larger.2 Progression to overt Cushing’s syndrome is controversial (because both spontaneous normalisation of hypersecretion and stable disease have been reported during follow-up) and spontaneous normalisation of hypersecretion has been reported in 50% of cases.2 Results of the study by Di Dalmazi and co-workers1 are important because they show, for the first time, that patients with subclinical Cushing’s syndrome are at increased risk of cardiovascular disease and all-cause mortality (mainly attributable to cardiovascular disease). The association of cortisol with all-cause mortality might also be attributable to its potential role in the pathogenesis of metabolic syndrome.3
Findings of previous studies have shown an increased prevalence of cardiovascular disease risk factors in patients with subclinical Cushing’s syndrome, but data for optimum management are conflicting. Some criteria—such as large (>4—6 cm) adrenal incidentalomas, features suggestive of malignancy (eg, heterogeneity, irregular shape, calcification or necrosis, invasion to adjacent tissues), or potentially lethal hormonal hypersecretion (ie, pheochromocytomas)—support the need for adrenalectomy. However, universal surgical management of patients with subclinical Cushing’s syndrome has not been accepted.2, 4 Uncertainty about the most effective management strategy for subclinical Cushing’s syndrome is attributable to the variable definitions used, and the small sample size and retrospective nature of most studies.4 Only one prospective study has been published so far showing that laparoscopic adrenalectomy is more beneficial than is conservative management for the normalisation or improvement of cardiovascular disease risk factors, such as diabetes, dyslipidaemia, hypertension, and obesity.5
Prospective studies and registries are needed to document the effect of different approaches on the incidence of cardiovascular disease events and mortality in patients with adrenal incidentalomas and subclinical Cushing’s syndrome. Until then, individualised treatment seems prudent. Surgical management of subclinical Cushing’s syndrome can be suggested in young patients (age <50 years) and in those with cardiovascular disease risk factors or bone disease associated with hypercortisolism that are of recent onset, difficult to control with drugs, or show progression over time.4
Another message from Di Dalmazi’s study1 is that hormonal deterioration might develop even after 4—5 years, which most studies reported as a reasonable and safe follow-up.2 This possibility should be kept in mind for the management of patients with adrenal incidentalomas, especially if clinical signs of Cushing’s syndrome develop or if cardiovascular disease risk factors become evident or increase in severity (ie, hormonal hypersecretion).
We declare that we have no competing interests.

References

1 Di Dalmazi G, Vicennati V, Garelli S, et al. Cardiovascular events and mortality in patients with adrenal incidentalomas that are either non-secreting or associated with intermediate phenotype or subclinical Cushing’s syndrome: a 15-year retrospective study. Lancet Diabetes Endocrinol 2014. published online Jan 29 http://dx.doi.org/10.1016/S2213-8587(13)70211-0.
2 Anagnostis P, Karagiannis A, Tziomalos K, Kakafika AI, Athyros VG, Mikhailidis DP. Adrenal incidentaloma: a diagnostic challenge. Hormones (Athens) 2009; 8: 163-184. PubMed
3 Anagnostis P, Athyros VG, Tziomalos K, Karagiannis A, Mikhailidis DP. Clinical review: The pathogenetic role of cortisol in the metabolic syndrome: a hypothesis. J Clin Endocrinol Metab 2009; 94:2692-2701. PubMed
4 Terzolo M, Pia A, Reimondo G. Subclinical Cushing’s syndrome: definition and management. Clin Endocrinol (Oxf) 2012; 76: 12-18. PubMed
5 Toniato A, Merante-Boschin I, Opocher G, Pelizzo MR, Schiavi F, Ballotta E. Surgical versus conservative management for subclinical Cushing syndrome in adrenal incidentalomas: a prospective randomized study. Ann Surg 2009; 249: 388-391. PubMed
a Division of Endocrinology, Police Medical Centre, Thessaloniki, 54 640, Greece
b Department of Endocrinology and Metabolism, Agios Pavlos General Hospital, Thessaloniki, Greece
c Second Propedeutic Department of Internal Medicine, Medical School, Aristotle University of Thessaloniki, Hippokration Hospital, Thessaloniki, Greece
d Department of Clinical Biochemistry (Vascular Prevention Clinic) Royal Free Hospital Campus, University College London Medical School, University College London, London, UK
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