
Will Mifepristone Prove a CATALYST for Change?
I must be honest, the role of hypercortisolism in T2D was not hitherto on my radar. Whilst the phrase is somewhat of a cliche these days, the CATALYST trial is practice-changing for me.
I'm sure we can all immediately recall patients with suboptimally managed T2D despite their positive lifestyle choices and adherence to multiple medications. We should consider whether underlying hypercortisolism is driving these patients' hyperglycemia. In the opening session of the ADA symposium, Ralph DeFronzo, MD, chief of the Diabetes Division at the University of Texas Health Science Center in San Antonio, Texas, reminded us that in T2D — which is a heterogeneous disorder — hypercortisolism plays an important role and contributes to refractory disease.
In fact, DeFronzo suggested that his 'ominous octet' of core pathophysiological defects in T2D should be expanded to the 'noxious nine' to include hypercortisolism.
DeFronzo made an analogy with resistant hypertension and hyperaldosteronism. Hyperaldosteronism is an etiological factor in 10%-30% of patients with resistant hypertension, and around one-third of these patients have a solitary adrenal adenoma. Yet we do not routinely screen for hyperaldosteronism in resistant hypertension. But we do commonly prescribe mineralocorticoid (primarily aldosterone) receptor antagonists such as spironolactone for these patients. This approach has proven to be an effective strategy for resistant hypertension, as demonstrated in trials such PATHWAY-2.
DeFronzo also reminded us that many patients with hypercortisolism do not present with the classic phenotypic features of Cushing syndrome (ie, moon face, buffalo hump, etc). Instead, most patients with hypercortisolism present with the following 'big 4':
Difficult-to-control T2D
Difficult-to-control hypertension
Visceral or centripetal obesity
Osteoporosis or fractures.
Again, I am sure we can all recall such patients.
So, how does hypercortisolism cause hyperglycemia? Hypercortisolism reduces insulin secretion, increases glucagon secretion, and, interestingly, increases GLP-1 resistance, which generally results in severe insulin resistance. Hypercortisolism is a recognized contributor to T2D, metabolic syndrome, and cardiometabolic risk.
The CATALYST trial sought to explore the prevalence of hypercortisolism in difficult-to-control T2D and whether treatment with mifepristone (a competitive glucocorticoid receptor antagonist) improved glycemia in patients with difficult-to-control T2D. The FDA has already approved mifepristone for the treatment of hyperglycemia secondary to hypercortisolism in adults with endogenous Cushing syndrome who have T2D or glucose intolerance.
The CATALYST trial's prevalence phase recruited 1057 patients with difficult-to-control T2D (mean HbA1c, 8.8%). Eligible participants were taking multiple glucose-lowering therapies or antihypertensive therapies or had microvascular and macrovascular complications of diabetes. Nearly a quarter of participants had hypercortisolism by overnight 1 mg dexamethasone suppression test with a cortisol cutoff of 50 nmol/L. Around one-third of individuals had an adrenal imaging abnormality.
Notably, about 27% of CATALYST participants were taking three or more antihypertensive agents, and the prevalence of hypercortisolism among these patients was about 38%. Moreover, patients with hypercortisolism had more cardiovascular disease (eg, coronary artery disease, atrial fibrillation, and heart failure) and higher overall medication burden.
The CATALYST trial's treatment phase investigated 136 patients with difficult-to-control T2D and hypercortisolism. Ninety-one participants were randomly assigned to receive mifepristone, and 45 participants were randomly assigned to receive placebo. The primary endpoint was change in HbA1c at 24 weeks. Secondary endpoints included changes in glucose-lowering medications, changes in hypercortisolism-related comorbidities, and improvements in cardiometabolic risk factors such as waist circumference, blood pressure, and lipid profile.
Mifepristone was associated with a 1.47% reduction in HbA1c, compared with a 0.15% reduction with placebo, at 24 weeks. Differences in HbA1c were observed even after 12 weeks. Importantly, there was no difference in effect in patients with or without adrenal abnormalities.
Glycemic improvements were accompanied by clinically meaningful reductions in glucose-lowering medications, weight (mean reduction, 4.4 kg), BMI (mean reduction, 1.47), and waist circumference (mean reduction, 5.2 cm). Mean blood pressure in participants taking mifepristone remained at or near the recommended target (< 130/80 mm Hg), but a mean increase of 8 mm Hg in systolic blood pressure was observed in the mifepristone group. The placebo group, however, had a reduction of 2 mm Hg. Reassuringly, in patients on mifepristone with baseline systolic blood pressure ≥ 130 mm Hg, no increases in blood pressure were observed. There were only small numerical changes in lipid profile with mifepristone.
With regard to mifepristone's safety profile, 42 patients (46%) discontinued the treatment, compared with eight patients (18%) receiving placebo. Adverse events with mifepristone were mostly mild to moderate and consistent with the drug's known safety profile; no new safety signals were identified. Adverse events included hypokalemia and fatigue, nausea, vomiting, headache, and dizziness consistent with glucocorticoid withdrawal. Three participants on mifepristone experienced euglycemic ketoacidosis, and all three were receiving SGLT2 inhibitors.
In conclusion, the CATALYST trial is the next evolution in personalized diabetes care. We should consider screening for hypercortisolism in patients with difficult-to-control T2D.
The overnight dexamethasone suppression test can be conducted in primary care, but I am mindful of the considerable pressures we currently face in the community. Patients should take 1 mg of dexamethasone around 11 pm or midnight and have their serum cortisol levels checked at around 8 or 9 am. A morning cortisol level of < 50 nmol/L excludes hypercortisolism. We should be aware of common causes of false positive results, including use of the combined oral contraceptive pill; use of exogenous steroids; severe psychiatric, medical, or surgical illness; night shift work; excess alcohol intake; severe untreated sleep apnea; and hemodialysis or end-stage renal disease.
CT scans should also be performed to establish whether the disease could be surgically remediable. Access to CT is challenging, given the current climate in primary care, but improvements in HbA1c were seen irrespective of adrenal abnormalities.
Treatment with mifepristone must be individualized to maintain the drug's risk-benefit ratio; the compelling benefits in HbA1c and overall cardiometabolic risk reduction must be balanced against the side effects of hypokalemia and glucocorticoid withdrawal. Counseling about sick day guidance remains pivotal for patients on SGLT2 inhibitors, and blood pressure will also need to be monitored regularly.
To paraphrase Paracelsus (1493-1541), the Swiss physician and founder of toxicology, 'No drug is without poison; the dosage makes it a poison or a remedy.'
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