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ENDOCRINE SOCIETY PUBLISHES PRIMARY ALDOSTERONISM RECOMMENDATIONS

adrenal gland and aldosterone
Primary aldosteronism (PA), excess aldosterone secretion by the adrenal glands, raises blood pressure and is prevalent in up to 14% of patients with hypertension. Despite this, it is rarely diagnosed. The Endocrine Society recently published guidelines on primary aldosteronism that cover screening, diagnosis, and treatment. Important points from the recommendations include the following:

  • Screening: Screen all patients with hypertension for primary aldosteronism by measuring serum/plasma aldosterone concentration and plasma renin (concentration or activity) to determine the aldosterone to renin ratio (ARR)
  • Diagnosis: If screening is positive, determine the probability of lateralizing disease, which is excess aldosterone from one adrenal gland. Findings consistent with lateralizing disease include hypokalemia, age less than 35 years, a unilateral adrenal mass, and/or very low renin with high aldosterone. If probability is high, proceed directly to adrenal CT scan and adrenal venous sampling. If probability is intermediate, consider an empiric trial of a mineralocorticoid receptor antagonist (MRA) versus proceeding to aldosterone suppression testing. If probability is low, consider a trial of an MRA.
  • Treatment: If disease is lateralizing, offer surgery. Otherwise, treat with an MRA.

There are no controlled trials supporting the cost-effectiveness or benefits of screening all patients with hypertension for primary aldosteronism. Given that 120 million U.S. adults have hypertension, it's unlikely many providers are going to spend their time chasing this diagnosis in every patient. Other issues with screening include: (1) many common medications interfere with testing (e.g., beta blockers, NSAIDs, diuretics, ARBs, ACE inhibitors, SGLT2 inhibitors) and need to be withdrawn before screening, making the process onerous, (2) studies evaluating the accuracy of the ARR for diagnosing primary aldosteronism have found that it performs poorly.

These guidelines are helpful when assessing patients for primary aldosteronism. However, the recommendation to screen all individuals with hypertension is impractical and unlikely to be cost-effective. The American Heart Association recommends a more targeted approach when selecting patients for secondary hypertension screening (see who to evaluate for secondary hypertension).
Third study finds aspirin should not be combined with anticoagulants in stable coronary artery disease
platelets and clot in artery
Patients with coronary artery disease (CAD) and atrial fibrillation (AF) have indications for antiplatelet therapy and anticoagulation. Past guidelines were equivocal about combining these therapies. Then, in 2019, the AFIRE study was published comparing rivaroxaban to rivaroxaban + an antiplatelet agent (combination therapy) in patients with AF and stable CAD. AFIRE found that combination therapy did not improve efficacy outcomes while increasing bleeding events. A similar study, EPIC-CAD, published in 2024, also found that anticoagulant monotherapy was superior to combination therapy. Now, a third study has evaluated the issue. The AQUATIC study randomized 872 patients with a history of PCI (≥ 6 months prior), high atherothrombotic risk, and an indication for long-term anticoagulation (89% had AF) to aspirin 100 mg daily or placebo added to anticoagulation. The trial was stopped early after a median of 2.2 years due to excess deaths in the aspirin group.

A third study has now demonstrated that the combination of antiplatelet therapy and an anticoagulant is harmful in patients with stable CAD and AF. Scenarios where combination therapy may still be indicated include after recent PCI (within 12 months) and certain patients with mechanical heart valves.

FDA APPROVES WEGOVY FOR METABOLIC DYSFUNCTION–ASSOCIATED STEATOHEPATITIS (MASH)

obese woman with weight-loss injection
Metabolic dysfunction–associated steatohepatitis (MASH), formerly known as nonalcoholic steatohepatitis, is a common condition, affecting an estimated 25% of American adults and up to 90% of people with a BMI of 40 or greater. Until recently, the only FDA-approved MASH therapy was Resmetirom (Rezdiffra), a thyroid hormone receptor-beta (THR-β) partial agonist. On August 15, 2025, the FDA approved Wegovy for MASH based on an interim analysis of the ESSENCE study that compared Wegovy to placebo in 1,197 patients with MASH and fibrosis stage 2 or 3. At 72 weeks, resolution of steatohepatitis without worsening of fibrosis was observed in 63% of Wegovy-treated patients and 34% of placebo-treated patients (P<0.001). A reduction in liver fibrosis without worsening of steatohepatitis occurred in 37% and 22%, respectively (P<0.001). The Wegovy group lost 10.5% of their body weight compared to 2% in the placebo group.

Less than 20% of commercial health insurance plans cover Wegovy for weight loss, so a MASH indication is encouraging since it may increase access. However, a looming question is what criteria will insurance companies require for a MASH diagnosis. In the ESSENCE study, MASH was diagnosed with a liver biopsy, and only patients with stage 2 or 3 fibrosis were enrolled. Prior authorization criteria for Rezdiffra, which has the exact same indication as Wegovy, vary by insurance, but I know some plans require the following: (1) diagnosis by liver biopsy, Fibroscan, or magnetic resonance elastography (MRE), (2) prescribed by a gastroenterologist or hepatologist. Fibroscan is a specialized ultrasound typically found in gastroenterology practices, and MRE is a specific type of MRI that is not widely available. If insurance companies have the same criteria for Wegovy, it will create a significant barrier to access, especially in primary care.

Tirzepatide (Zepbound) has also been shown to improve MASH, and Eli Lilly is in the process of pursuing a MASH indication for it.
Finerenone (Kerendia®) approved for heart failure with preserved ejection fraction
illustration of human heart
In 2021, the SGLT2 inhibitor empagliflozin (Jardiance) became the first drug FDA-approved to treat heart failure with preserved ejection fraction (HFpEF). Several years later, another SGLT2 inhibitor, dapagliflozin (Farxiga), was approved. Now, Finerenone (Kerendia), a nonsteroidal mineralocorticoid receptor antagonist, has become the third drug and the first non-SGLT2 inhibitor to be approved. Approval was based on results from the FINEARTS-HF Study, where 6016 patients with heart failure and an ejection fraction (EF) of 40% or greater (average EF 53%) were randomized to finerenone or placebo. Over a median follow-up of 32 months, the incidence of the primary composite outcome (total worsening heart failure events and death from cardiovascular causes) was 14.9 events per 100 patient-years in the finerenone group and 17.7 events per 100 patient-years in the placebo group (P=0.007). There was no significant difference in overall mortality. Hyperkalemia was more common in the finerenone group (14.3% vs 6.9%) as was hypotension (18.5% vs 12.4%).

Finerenone blocks aldosterone receptors, similar to spironolactone, an inexpensive aldosterone antagonist that has been available for decades. Spironolactone, which is FDA-approved for heart failure with reduced ejection fraction (HFrEF), has also been studied in HFpEF. In the TOPCAT study, which enrolled 3445 patients with heart failure and an EF ≥ 45% (median EF 56%), spironolactone was not superior to placebo for a composite of CVD events; however, it did significantly reduce heart failure hospitalizations. The trial was plagued by discordant data in certain geographic regions (Russia, Georgia), and post-hoc analyses have found that when these regions were excluded, spironolactone significantly improved the primary outcome. The ACC 2023 HFpEF guidelines recommend spironolactone in some patients. Other drugs, including Entresto, Wegovy, and Zepbound, have demonstrated improvements in HFpEF outcomes in clinical trials but have not received FDA approval for the condition.

Finerenone is the third drug and only non-SGLT2 inhibitor approved for HFpEF. Providers should note that finerenone dosing recommendations for HFpEF, which are based on GFR and potassium levels, differ from those used in diabetic kidney disease. For patients who cannot afford finerenone, spironolactone likely offers similar benefits. Potassium levels should be monitored closely with either drug.

IS THE FDA REMOVING ARMOUR THYROID AND SIMILAR PRODUCTS FROM THE MARKET?

Armour thyroid and Nature-Throid bottle
Animal-derived thyroid products, including Armour Thyroid, NP Thyroid, WP Thyroid, and Nature-throid, are not FDA-approved to treat hypothyroidism; however, they existed before the Food, Drug, and Cosmetic Act of 1938 and, therefore, were grandfathered into the FDA's list of prescription drug medications without going through the formal approval process. The products are produced from dried, ground thyroid glands, typically from pigs. The FDA contends that due to a lack of safety and efficacy data, these products may be unsafe because of variations in purity and potency and the presence of contaminants. The agency sent letters to manufacturers on August 6, 2025, notifying them of their intent to take action against unapproved animal-derived thyroid medications. The FDA is also encouraging healthcare providers to transition patients from animal-derived products to synthetic levothyroxine.

An estimated 1.5 million Americans receive prescriptions for animal-derived combination products each year. However, all major professional organizations recommend synthetic levothyroxine products (e.g., Synthroid) for treating hypothyroidism. Reasons they are preferred over combination products include:

  • Combination products (e.g. Armour Thyroid) have a T4 to T3 ratio of 4:1, while physiologic ratios secreted by the thyroid gland are around 14:1.
  • Combination therapy leads to supraphysiologic levels of T3, which may lead to symptoms of thyrotoxicosis
  • T3 has a shorter half-life than T4, which can lead to fluctuations in T3 levels, with a peak occurring shortly after dosing
  • There is substantially more data from trials on the use of levothyroxine compared to combination therapy

In my experience, patients who are on animal-derived combination products have already tried synthetic levothyroxine and feel that the combination products control their symptoms better. However, blinded studies comparing levothyroxine to combination products have not found a difference in symptom control. Despite this, it can be difficult to change patient perceptions, especially with regard to subjective symptoms. I anticipate significant pushback when trying to switch these patients to levothyroxine products.
Dapagliflozin evaluated for metabolic dysfunction-associated steatohepatitis in small study
illustration of a liver
Metabolic dysfunction–associated steatohepatitis (MASH), formerly known as nonalcoholic steatohepatitis, is a chronic liver disease strongly associated with obesity and diabetes. Dapagliflozin (Farxiga), an SGLT2 inhibitor approved to treat type 2 diabetes, has been associated with modest weight loss in clinical trials. A small study (N=154) conducted in China evaluated the effects of dapagliflozin on MASH in Chinese adults with or without type 2 diabetes who had biopsy-diagnosed MASH (average BMI 29.2 | type 2 diabetes - 45%). Subjects were randomized to dapagliflozin 10 mg once daily or placebo for 48 weeks. At the end of the trial, the primary outcome, MASH improvement without worsening of liver fibrosis, occurred in 53% of dapagliflozin-treated patients and 30% of placebo-treated patients (p=0.006). Fibrosis improvement without worsening MASH was seen in 45% and 20%, respectively (p=0.001). Over the course of the trial, the dapagliflozin group lost an average of 9.4 lbs, while the placebo group lost 1.7 lbs.

In the small study above, dapagliflozin improved MASH in Chinese people with and without diabetes. An exploratory mediation analysis of the results found that weight loss largely accounted for the higher proportion of MASH improvement and MASH resolution in the dapagliflozin group. However, fibrosis improvement without worsening of MASH was found to be independent of weight loss. Proposed mechanisms by which dapagliflozin may improve MASH independent of weight loss include: (1) modulation of energy homeostasis and improvement of insulin resistance, (2) anti-inflammatory, anti-oxidant, and anti-fibrotic effects, (3) systemic metabolic reprogramming and negative energy balance, and (4) promotion of ketone body synthesis.

Weight loss in the dapagliflozin group was much greater in this trial than what has been observed in diabetes and heart failure trials. Reasons for this are unclear. Larger studies in more diverse populations are needed to further evaluate the effects of SGLT2 inhibitors on MASH.

NEWS IN BRIEF

FDA approves vagus nerve stimulation device for rheumatoid arthritis

woman with rheumatoid arthritis
The FDA recently approved an implantable device for the treatment of rheumatoid arthritis (RA). The SetPoint System, a first-of-its-kind neuroimmune modulation device, is implanted in the neck, where it delivers once-daily electrical stimulation to the left cervical vagus nerve. In theory, vagal nerve stimulation activates anti-inflammatory pathways that inhibit the production of TNF, IL-1, IL-6, and other proinflammatory cytokines in immune cells within the reticuloendothelial system. In its pivotal study, 242 adults with difficult-to-treat RA (incomplete responders to or intolerant to at least one biologic or targeted synthetic disease-modifying anti-rheumatic drug [DMARD]) were randomized to the SetPoint System or a sham device. At 12 weeks, the primary outcome (ACR20 response) was observed in 35.2% of the SetPoint group and 24.2% of the sham group (P=0.0209). An unblinded extension phase (Weeks 12 to 24), during which all patients (SetPoint and sham groups) received SetPoint therapy, found that through Week 24, 81% of patients were managed on SetPoint therapy without the addition of adjunctive steroids or DMARDs.

This is an interesting approach to treating autoimmune diseases. Larger and longer studies are needed to validate its efficacy and define its place in therapy.

Cancer study shows profound effect of exercise

woman exercising
The benefits of exercise on a wide range of conditions, including everything from ADHD to osteoporosis, have long been known. Now, a randomized controlled trial published in the New England Journal of Medicine has found that exercise improves survival in patients with colorectal cancer. The CHALLENGE study randomized 889 patients with resected colon cancer (stage III or high-risk stage II) who had completed adjuvant chemotherapy to a structured exercise program with required visits over 3 years (exercise group) or general health-education materials (control group). After a median follow-up of 7.9 years, the primary endpoint, 5-year disease-free survival, was 80.3% in the exercise group and 73.9% in the control group (difference, 6.4 percentage points; 95% CI 0.6 to 12.2). Eight-year overall survival was 90.3% and 83.2%, respectively. Notably, weight loss did not differ significantly between groups, so it does not explain the observed effect.

Exercise improved overall survival among colorectal cancer patients by 7%. The study authors note that this effect size is similar to what is observed with many approved drug therapies, minus the side effects and costs. This study provides yet another reason for people to exercise.

Twice-yearly injection approved for HIV pre-exposure prophylaxis (PrEP)

red hiv awareness ribbon
The FDA recently approved lenacapavir (Yeztugo), a twice-yearly subcutaneous injection, for the prevention of HIV. In a study enrolling 5338 African women, no new HIV infections were observed over 104 weeks in the lenacapavir group (N=2134), compared to 39 in the Descovy group (N=2136) and 16 in the Truvada group (N=1068). In another study among 3265 high-risk men and women, the incidence of HIV infection was 0.10%/year in the lenacapavir group and 0.93%/year in the Truvada group. The most common side effect reported was injection site reactions (e.g., nodule, pain, erythema), which occurred in 69% of patients. Upon initiation, it is recommended that patients take 2 days of oral lenacapavir to achieve therapeutic levels more quickly.

While oral and injectable forms of HIV PrEP are highly effective, studies have found that up to 70% of PrEP users discontinue therapy or exhibit suboptimal adherence within six months of initiation. Yeztugo's twice-yearly dosing schedule will likely improve compliance and lower infection rates compared to other approved therapies, which include daily oral pills Descovy and Truvada, and the every-two-month IM injection Apretude (cabotegravir).

Combination of finerenone and empagliflozin improves proteinuria in DKD more than either drug alone

illustration of the kidneys
Finerenone, a nonsteroidal mineralocorticoid receptor antagonist, has been shown to improve outcomes in diabetic kidney disease (DKD). Empagliflozin, an SGLT2 inhibitor, has also been proven to improve DKD outcomes. A recent study compared a combination of the two drugs to either one alone in diabetics with DKD.

In the CONFIDENCE trial, 818 diabetics with DKD and a median urinary albumin-to-creatinine ratio (UACR) of 579 were randomized to finerenone (10 or 20 mg/day), empagliflozin (10 mg/day), or a combination of finerenone and empagliflozin. After 180 days, the average UACR reduction in the combination group was 29% greater than with finerenone alone and 32% greater than with empagliflozin alone.

Longer studies evaluating hard clinical outcomes are needed to fully elucidate the effects of this combination regimen.

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Corrected calcium levels in hypoalbuminemia are misleading and inaccurate
tube of blood
In plasma, approximately 50% of calcium circulates in the active ionized form, 10% is complexed with anions, and the remaining 40% is bound to protein, mainly albumin. If albumin levels are low, total calcium levels may not accurately reflect the amount of ionized calcium. In medical training, providers are often taught to correct calcium levels in the setting of hypoalbuminemia using formulas that incorporate albumin and total calcium levels. The most widely used formula is the simplified Payne formula: Corrected calcium (mg/dL) = measured total Ca (mg/dL) + 0.8 (4.0 - serum albumin [g/dL]). Despite this widely accepted practice, studies have not found these corrections to be accurate. To further evaluate the issue, a recent cross-sectional study published in the JAMA Network evaluated lab results from 22,658 patients who had their total calcium and ionized calcium levels measured simultaneously. The accuracy of 10 adjustment formulas for correcting total calcium levels was then measured. The results showed that unadjusted total calcium levels correlated as well and sometimes better with ionized calcium levels than the formula-adjusted values. For example, unadjusted total calcium showed a correlation (on a continuous numerical scale) with ionized calcium of 71.7% compared to 68.9% with the simplified Payne formula. When classifying patients into calcium status categories (hypocalcemia, normocalcemia, hypercalcemia), unadjusted total calcium agreed 74.5% of the time with ionized calcium compared to 63% with the simplified Payne formula. Furthermore, subgroup analysis in patients with concomitant hypoalbuminemia showed that formula-adjusted values were even less accurate than unadjusted levels in these subjects.

Corrected calcium levels are a cautionary tale on how easily some practices can become widely accepted in medicine despite a lack of rigorous scientific evaluation. Providers concerned about the accuracy of total calcium levels in the setting of hypoalbuminemia should check ionized levels directly and avoid using correction formulas.
Semaglutide (Wegovy) improves MASH in ongoing study
illustration of a fatty liver
Currently, resmetirom (Rezdiffra®), a thyroid hormone receptor beta partial agonist, is the only FDA-approved medication for the treatment of metabolic dysfunction-associated steatohepatitis (MASH), formally known as nonalcoholic steatohepatitis or fatty liver disease. MASH is a progressive liver condition with an estimated global prevalence of 4 to 6%. Its strong association with obesity has prompted researchers to evaluate the effects of weight-loss GLP therapies, specifically semaglutide and tirzepatide, on MASH pathology. A 72-week interim analysis from a placebo-controlled semaglutide study (N=800) in MASH patients with stage 2 or 3 fibrosis was recently published. The analysis found that semaglutide (2.4 mg) caused resolution of steatohepatitis without worsening of fibrosis in 62.9% of patients, compared to 34.3% in the placebo group (p<0.001). A reduction in liver fibrosis without worsening of steatohepatitis occurred in 36.8% and 22.4%, respectively (p<0.001). Semaglutide-treated patients lost 10.5% of their body weight compared to 2.0% with placebo (p<0.001). As expected, gastrointestinal adverse events were more frequent in the semaglutide group.

These results are consistent with a previous 52-week study (N=190) involving tirzepatide, where MASH resolution without worsening of fibrosis was observed in 62% of tirzepatide-treated patients (15 mg) and 10% of placebo-treated patients (p<0.001). Weight loss in this study was 15.6% and 0.8%, respectively.

While results from different studies are not comparable linearly, nothing in resmetirom's pivotal trial suggests that it is superior to semaglutide or tirzepatide. Furthermore, it does not cause weight loss, giving it no benefit in other obesity-related conditions. Resmetirom also has drug interactions and requires lab monitoring, while GLP-1 therapies generally do not. The effects of these drugs on long-term clinical outcomes like cirrhosis and liver failure are being evaluated in ongoing studies. MASH indications for semaglutide and tirzepatide are likely forthcoming.


CLINICAL CHALLENGE

A 45-year-old female comes to see you for her annual physical. She reports having gastric bypass surgery three years ago and says she followed up with her surgeon once and never went back. She asks you to order her routine lab work.

Given her history of gastric bypass, what lab work is recommended? Are any other studies indicated? Find out at the link below.