logo
Will Mifepristone Prove a CATALYST for Change?

Will Mifepristone Prove a CATALYST for Change?

Medscape6 days ago
Expanding evidence for the impact of hypercortisolism in patients with difficult-to-control type 2 diabetes (T2D) and key insights from the CATALYST study were discussed during the final symposium at the American Diabetes Association (ADA) 85th Scientific Sessions in Chicago, which I was fortunate to attend.
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.'
Orange background

Try Our AI Features

Explore what Daily8 AI can do for you:

Comments

No comments yet...

Related Articles

If You're Not Doing This One Thing, You May Not Be Pooping Correctly
If You're Not Doing This One Thing, You May Not Be Pooping Correctly

Yahoo

time28 minutes ago

  • Yahoo

If You're Not Doing This One Thing, You May Not Be Pooping Correctly

Among the current wave of wellness obsessions, fibermaxxing is gaining major traction. This more-is-more approach to fiber is touted on TikTok as a way to boost digestion, satiety and overall gut health while also addressing the fact that most Americans aren't getting enough. But while increasing your fiber intake has clear benefits, nutrition experts say there's a right way to do it if you want to see results. Related: What is fibermaxxing? The TikTok trend is all about maximizing fiber intake by loading up every meal and snack with fiber-rich foods, and sometimes supplements, to support gut health, satiety, cholesterol levels, blood sugar stability and even cancer prevention. It reflects a growing shift away from protein-obsessed diets toward a stronger focus on digestive and colon health. But Jennifer House, a registered dietitian and owner of First Step Nutrition in Calgary, Alberta, cautions that if you have IBS or an inflammatory bowel condition like Crohn's disease or ulcerative colitis, a high-fiber diet might not be ideal. 'And if you suffer from constipation, increasing fiber all at once could temporarily make the situation worse.' How much fiber do we actually need? Related: For women ages 18 to 50, the general recommendation is 25 grams of fiber per day, and 21 grams for those 51 and older, House said. For men, it's 30 grams daily. 'Most people only get about half of the recommended amount of fiber each day,' she added. Fiber is found only in plant-based foods, and there are five main groups that provide it: vegetables, fruits, legumes, whole grains, and nuts and seeds. Of these, legumes pack the biggest punch. Just one cup of beans contains 10 to 19 grams of fiber, which can get you more than halfway to your daily target. 'Animal foods don't contain fiber, so an eating pattern that's disproportionately high in meat, dairy and eggs is more likely to fall short on fiber,' said registered dietitian Avery Zenker. The health benefits of fiber: Related: Fiber supports healthy digestion, helps regulate blood sugar and cholesterol levels, and promotes a sense of fullness that can aid in appetite and weight management. It's also linked to a lower risk of heart disease, type 2 diabetes and certain cancers, including colorectal and colon, Zenker noted. 'Low fiber diets are linked to microbiome imbalances and lower microbial diversity, both of which are associated with increased risk of inflammatory diseases.' Different types of fiber offer different benefits. 'Soluble fiber helps regulate blood sugar and lower cholesterol — great for patients with diabetes or heart disease risk,' said Dr. Michael Ednie, founder of Bespoke Concierge MD based in Scottsdale, Arizona. This type of fiber dissolves in water to form a gel that helps lower cholesterol and regulate blood sugar. 'Insoluble fiber promotes regularity and helps prevent constipation, which is crucial for colon health,' Ednie said. Then there's prebiotic fiber, which serves as food for the beneficial bacteria in your gut. 'As those bacteria ferment prebiotic fibers, they produce short-chain fatty acids like butyrate, which have anti-inflammatory effects and support gut barrier function. Prebiotics have also been linked to improved mineral absorption and even mood regulation via the gut-brain connection,' Ednie said. Garlic, onions, bananas and asparagus are all excellent sources. Just like variety in your overall diet supports better nutrition, eating different types of fiber helps build a healthier, more resilient gut microbiome. 'Different fibers feed different strains of beneficial bacteria, which leads to better gut health, stronger immune function and lower inflammation overall,' Ednie explained. While there's no strict formula for how much of each fiber type you need, he suggests aiming for about two-thirds insoluble fiber and one-third soluble fiber. Fibermaxxing can backfire on your digestive system. While there's no official upper limit for fiber intake, increasing it too quickly can cause gas, bloating and other digestive issues like cramping, constipation and diarrhea. 'The gut bacteria essentially go into overdrive trying to process the sudden influx of fiber, producing excess gas as a byproduct,' Ednie explained. 'In rare cases, if someone dramatically increases fiber without proper hydration or pacing, it can even lead to intestinal blockages that require medical attention.' The type of fiber you're increasing also affects the symptoms you may experience. 'Soluble fiber — found in foods like oats, apples and beans — tends to be gentler at first but often causes more gas because it's fermented by gut bacteria,' Ednie said. 'Insoluble fiber — from whole grains, vegetable skins and nuts — adds bulk and moves things along but can lead to more bloating and cramping if increased too quickly without enough water.' Zenker also notes that for some people, especially older adults and young children, the satiating effect of fiber may reduce overall food intake, potentially leading to unintended weight loss or nutrient gaps. Additionally, consuming too much fiber can interfere with the absorption of important minerals like iron, zinc and calcium by binding to them in the gut and preventing their absorption. Increasing your fluid intake is key. Related: Hydration is essential when increasing fiber intake to help it do its job effectively. 'Soluble fiber needs water to form the gel that helps regulate blood sugar and cholesterol,' Ednie explained. 'Insoluble fiber needs water to add bulk and move stool efficiently through the digestive tract.' He recommends aiming for at least eight to 10 cups of water a day when boosting your fiber intake, and more if you're active or in a hot climate, and pairing every fiber-rich meal or snack with a full glass of water to support digestion. How to safely increase your fiber intake. Nutrition experts agree that it's important to increase fiber gradually to give your digestive system time to adjust and minimize the risk of bloating or discomfort. 'Instead of jumping from 10 grams a day to 30 overnight, add just 3 to 5 grams of fiber per week,' Ednie said. He also recommends spreading your fiber intake throughout the day, like enjoying oatmeal with berries in the morning, veggies or legumes at lunch and dinner, and snacks like fruit with nuts or popcorn in between. 'Consistency makes it much easier for the body to adapt and helps create sustainable habits that support long-term gut health,' he added. Ednie also emphasizes prioritizing whole foods as your main fiber source to support digestive, metabolic and cardiovascular health. These foods naturally contain a mix of soluble and insoluble fiber, along with vitamins, minerals and phytonutrients that fiber supplements don't offer. 'Supplements can be helpful for people who struggle to meet their fiber needs through diet alone, but they should be viewed as an addition, not a replacement,' he article originally appeared on HuffPost. Also in Goodful: Also in Goodful: Also in Goodful:

12 Gut-Healthy Diabetes-Friendly Breakfast Recipes
12 Gut-Healthy Diabetes-Friendly Breakfast Recipes

Yahoo

timean hour ago

  • Yahoo

12 Gut-Healthy Diabetes-Friendly Breakfast Recipes

Reviewed by Dietitian Jessica Ball, M.S., RD Start the day with a focus on your gut health by trying these breakfast recipes. With fiber-rich, prebiotic-packed ingredients like raspberries, bananas and beans these dishes can help improve digestion and support healthy immunity. Plus, complex carbs like yogurt and oats paired with sodium-conscious ingredients and low amounts of saturated fats make these meals well-suited for a diabetes-friendly eating pattern. Recipes like our Anti-Inflammatory Breakfast Bowl and our Tropical Gut-Healthy Smoothie are delicious, gut-friendly ways to kick off the any of these recipes? Tap "Save" to add them to MyRecipes, your new, free recipe box for colorful, satisfying breakfast grain bowl is a nutritional powerhouse, packed with ingredients like black beans, roasted broccoli and beets that fight inflammation to start your day. The egg is cooked just right—firm egg whites with a slightly jammy yolk. If you want the yolk fully cooked, cook it an extra two minutes. This grain bowl is vibrant and interesting with plenty of textural contrast, and we know you won't be able to stop making it. View Recipe This dairy-free gut-healthy smoothie features kiwi (a prebiotic) and coconut-milk yogurt (a probiotic) working together to support a healthy gut. Golden kiwis add a lovely golden hue to the smoothie, but green kiwis work just as well. View Recipe For this healthy smoothie bowl recipe, be sure to use frozen fruit (not fresh) to keep the texture thick, creamy and frosty. View Recipe While eggs offer plenty of protein, you can make a satisfying, high-protein breakfast without them. This breakfast bowl includes black beans, yogurt and Monterey Jack cheese, providing 15 grams of protein to keep you feeling full and energized throughout the morning. View Recipe Salad for breakfast? Don't knock it until you've tried it. We love how this meal gives you 3 whole cups of vegetables to start your day. View Recipe This breakfast is great when you have leftover ricotta cheese--plus it comes together in just 5 minutes. View Recipe Eggs in Purgatory, an Italian favorite, involves gently cooking eggs in tomato sauce (with some regional variations) and can fit neatly into breakfast, lunch or dinner. Our rendition features anchovies for an infusion of savory flavor, and baby spinach to pack in extra veggies. Cracking the eggs in a bowl before you slide them into the pan will ensure that you don't get unwanted shells in the dish and helps keep the yolks from breaking so they remain soft and runny when they blend with the sauce. View Recipe This baked oatmeal gets crunchiness from walnuts and natural sweetness from banana and dates with bursts of juicy blueberries. This hearty dish is perfect for meal prep or sharing at brunch, offering a nutritious start to your day. Serve it warm with a dollop of yogurt. View Recipe Peanut butter and banana are the original power couple. Top a simple toasted English muffin with the duo, then sprinkle everything with a hit of ground cinnamon for a healthy breakfast of champions. View Recipe Strawberry and watermelon combine in this easy, four-ingredient healthy fruit smoothie recipe. View Recipe These delicious and unbelievably simple pancakes are best enjoyed right after cooking. With just eggs and a banana, you can have healthy grain-free pancakes with no added sugar. View Recipe Switch up your morning oatmeal routine with this so-easy chia pudding recipe. This healthy breakfast recipe has all the warm, spicy flavors of chai topped with creamy bananas and crunchy pistachios for added flavor and texture. View Recipe Read the original article on EATINGWELL

One of the Best Meteor Showers of the Year Is About to Begin—and It Can Be Seen Across the U.S.
One of the Best Meteor Showers of the Year Is About to Begin—and It Can Be Seen Across the U.S.

Travel + Leisure

timean hour ago

  • Travel + Leisure

One of the Best Meteor Showers of the Year Is About to Begin—and It Can Be Seen Across the U.S.

The Perseid meteor shower peaks the night of Aug. 12 into the early hours of Aug. 13, with up to 100 meteors per hour visible, especially in dark-sky areas across the U.S. One of the best shooting star displays of the year is coming to a sky near you. The annual Perseid meteor shower is visible across most of the U.S. from mid-July to late August. This year, the meteor shower is expected to peak on the night of Aug. 12 and before dawn on Aug. 13. According to to catch the shower's peak, you should start observing the night skies around 11 p.m. local time on Aug. 12 when the rates of shooting stars increase. The peak display will continue until dawn on Aug. 13. During this viewing window, you can expect to see an average of up to 100 meteors per hour. The Perseids meteor shower occurs when Earth passes through debris (bits of ice and rock) left behind by Comet Swift-Tuttle, a comet that is also the largest known object to repeatedly pass by Earth. The comet debris moves at around 133,200 mph in space and is typically the size of a grain of sand. The fragments become visible when they enter the atmosphere and burn up in a bright burst of light, streaking through the sky. Although the debris enters the Earth's atmosphere, it rarely hits the ground. The Perseid meteor shower is most easily seen from the Northern Hemisphere, but is also visible in the mid-southern latitudes. Although it can technically be viewed from anywhere in the U.S., the meteor shower is much easier to see in dark-sky destinations where there is less light pollution. It is also helpful to find somewhere where the sky is wide and open since buildings and mountains can obscure the view. No telescopes or binoculars are needed to see the Persied meteor shower, but recommends giving your eyes 30 minutes to adjust to the dark. It also helps to know where the meteors will come from. According to NASA, the meteor shower radiates from the Perseus constellation, which follows the easier-to-find Cassiopeia constellation across the night sky. If you can find Perseus, you'll know where the meteors will streak across the sky during the celestial event's peak. The Perseid meteor shower occurs annually in August, however in 2028, the shower is expected to evolve into a storm that will be even more spectacular than the standard, annual event.

DOWNLOAD THE APP

Get Started Now: Download the App

Ready to dive into a world of global content with local flavor? Download Daily8 app today from your preferred app store and start exploring.
app-storeplay-store