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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.
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.

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.
Zepbound beats Wegovy in battle of weight-loss drug titans
woman injection weight-loss drug
Three GLP-1 drugs, Zepbound (tirzepatide), Wegovy (semaglutide), and Saxenda (liraglutide), are currently approved for weight loss. Zepbound and Wegovy have demonstrated superior weight loss (16% to 22%) compared to Saxenda (8%), making them two of the most discussed medications in decades. Now, they have been compared head-to-head in an open-label trial, where 751 overweight, nondiabetic adults were randomized to Zepbound (target dose 10 mg or 15 mg/week) or Wegovy (target dose of 1.7 mg or 2.4 mg/week). The primary outcome, percent change in weight from baseline to week 72, was -20.2% with Zepbound and -13.7% with Wegovy (p<0.001). Key secondary outcomes, including average weight loss (50 lbs vs 33 lbs) and the proportion of participants achieving a weight reduction of 20% or more (48% vs 27%), also favored Zepbound. Side effects, including nausea (44% vs 44%), constipation (28% vs 29%), diarrhea (24% vs 23%), and vomiting (15% vs 21%), were similar between groups and mainly occurred during the therapy titration phase. Drug discontinuation due to adverse events was slightly higher in the Wegovy group (6.1% vs 8%).

These results corroborate findings from placebo-controlled studies, which showed that both drugs are highly effective, but Zepbound is superior. Patients sometimes ask me if one of the two has fewer side effects, and I can now confidently say they are similar in that regard. For those who are unaware, current cash pricing for both drugs is detailed below.

Zepbound Cash pay: Eli Lilly offers Zepbound in two forms: pens and vials. The pens are pressed against the skin, and the medication is injected when a button is pushed. The vials require the patient to draw the medication into a syringe and inject it themselves. Pens cost $650/month with the Zepbound savings card (see Zepbound coverage and cost). The vials are available in 4 doses from LillyDirect at the following prices:
  • 2.5 mg: $349 per month
  • 5 mg: $499 per month
  • 7.5 mg: $499 per month
  • 10 mg: $499 per month

Wegovy cash pay: Novo Nordisk now offers all doses of Wegovy for $499/month through their online mail-order pharmacy NovoCare Pharmacy. Wegovy is available from other pharmacies for $650/month with the Wegovy savings card.

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.


Gepotidacin (blujepa): a new antibiotic approved for female UTIs
petri dish with antibiotic discs
Gepotidacin (Blujepa) is a new antibiotic approved for uncomplicated female UTIs in adult and pediatric patients 12 years of age and older weighing at least 88 lbs (40 kg). It is a first-in-class triazaacenaphthylene antibiotic that works by inhibiting bacterial DNA gyrase and topoisomerase IV, essential enzymes for bacterial DNA replication. Its efficacy was evaluated in two randomized, noninferiority trials comparing gepotidacin (1500 mg BID for 5 days) to nitrofurantoin (100 mg BID for 5 days) in females with uncomplicated UTIs. In Trial 1 (N=634), the composite response rate (clinical cure and microbiological eradication at Day 10 to 13) was 51.8% for gepotidacin and 47.0% for nitrofurantoin, with a treatment difference of 5.3% (95% CI: -2.4, 13.0). In Trial 2 (N=567), the composite response rates were 58.9% and 44.0%, respectively, with a treatment difference of 14.4% (95% CI: 6.4, 22.4). Common side effects include diarrhea (16%), nausea (9%), and abdominal pain (4%). Gepotidacin is a sensitive CYP3A4 substrate and should not be taken with strong CYP3A4 inhibitors or inducers. It also inhibits acetylcholinesterase, which may cause it to potentiate the effects of other acetylcholinesterase inhibitors (e.g., donepezil) and reduce the efficacy of anticholinergics (e.g., benztropine, oxybutynin). It comes in a 750 mg tablet, and the recommended dosing is 1500 mg (two 750 mg tablets) twice daily for 5 days, taken after a meal.

Another possible use for gepotidacin, treatment of Neisseria gonorrhea, was evaluated in a randomized trial. The EAGLE-1 study (N=628) compared gepotidacin (two 3000 mg doses 10-12 hours apart) to intramuscular ceftriaxone 500 mg plus oral azithromycin 1 g for uncomplicated urogenital gonorrhea in patients 12 years of age and older weighing at least 88 lbs (40 kg). Microbiological cure rates at Days 4 - 8 were 92.6% for gepotidacin and 91.2% for ceftriaxone/azithromycin, demonstrating noninferiority of gepotidacin. Gastrointestinal side effects were more common in the gepotidacin group.

Like all new drugs, gepotidacin will be too expensive to be considered first-line for UTIs. However, its efficacy in gonorrhea is intriguing, given the increasing resistance of this bacterium to available therapies. A study of its effects in drug-resistant gonorrhea would be informative.

NEWS IN BRIEF

Dietary sodium restriction lowers blood pressure in small trial

salt shaker
Sodium reabsorption in the nephron promotes fluid retention, thereby raising blood pressure. Reduced dietary sodium reverses this effect. A recent crossover study (N=102) compared the effects of a diet with 1500 mg/day of sodium to one with 3700 mg/day in diabetics. Participants crossed over between diets every 5 weeks and were provided all of their food with instructions not to eat outside food. At the end of the 5-week period, systolic blood pressure (SBP) was lower by 4.6 mmHg on the 1500 mg diet compared to the 3700 mg one, while diastolic blood pressure (DBP) was 2.3 mmHg lower.

These results are consistent with a 2023 study (N=213), which found that one week of a low sodium diet (500 mg/day) lowered SBP and DBP by 8 and 3 mmHg, respectively, compared to a high sodium diet (> 5000 mg/day).

Dietary sodium restriction has a modest effect on BP. Average sodium consumption in the U.S. is between 3600 and 4800 mg per day, so achieving these reductions would require significant dietary adjustments for most people.

Third large trial compares bedtime vs morning antihypertensive dosing

blood pressure machine with pills
Cardiovascular disease (CVD) events are more common in the morning when blood pressure (BP) rises due to the morning cortisol surge. Morning BP medication dosing causes trough levels in the AM, leading some researchers to speculate that evening dosing (with peak levels in the morning) may be more protective. A 2019 study (N=19,084) caused a small stir when it found that bedtime dosing of BP medications lowered the risk of a composite of CVD events compared to morning dosing. However, a subsequent 2022 study (N=21,104) did not find a benefit with evening dosing. A third trial (N=3357) examining the issue was recently published, and like the 2022 study, it also found no benefit with evening dosing.

The effects of bedtime versus morning dosing of antihypertensives on CVD events were mixed in three large trials, with one showing a benefit and the other two finding none. Patients should be advised to take their medications at a time that optimizes their compliance.

Amiloride for resistant hypertension?

nurse measureing blood pressure
Amiloride, a potassium-sparing diuretic in the epithelial sodium channel (ENaC) inhibitor class, is typically added to hydrochlorothiazide to help prevent potassium loss. Its effects on blood pressure have not been studied extensively, and small trials have found it does not enhance blood pressure lowering when added to hydrochlorothiazide. Furthermore, it is not FDA-approved to lower blood pressure. Given these caveats, results from a recent open-label trial comparing amiloride to spironolactone for resistant hypertension are surprising. In the study, amiloride (5 - 10 mg) was noninferior to spironolactone (12.5 - 25 mg) for blood pressure lowering (-13.6 mmHg vs -14.7 mmHg) over 12 weeks in 118 patients with home SBP of 130 mmHg or higher despite receiving an angiotensin receptor blocker, calcium channel blocker, and thiazide diuretic.

Amiloride's prescribing information states that it "has weak (compared with thiazides) diuretic and antihypertensive effects." However, this study seems to contradict that. Larger, placebo-controlled studies are needed to confirm these findings, as previous open-label antihypertensive trials have been biased by the Hawthorne effect.

Oral semaglutide (Wegovy) coming soon

woman placing tablet on her tongue
In May 2025, Novo Nordisk applied for FDA approval of an oral version of semaglutide (Wegovy). In a 64-week trial enrolling 307 overweight adults, oral semaglutide 25 mg once daily caused 13.6% weight loss compared to 2.2% with placebo. Common side effects in the semaglutide group included nausea (47%), vomiting (31%), and constipation (20%). A previous trial using a 50 mg dose of oral semaglutide showed similar results. Given that efficacy was not significantly better at 50 mg, it appears Novo Nordisk will only pursue the 25 mg dose. The FDA anticipates a decision on approval in the fourth quarter of 2025. If approved, this medication will become the first oral GLP-1 receptor agonist approved for weight loss. Eli Lilly is also developing an oral GLP-1 therapy called Orforglipron, which caused 14.7% weight loss over 36 weeks in a study enrolling 272 overweight adults.

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Clopidogrel bests aspirin in chronic coronary disease (CCD)
bottle of aspirin and clopidogrel
Low-dose aspirin is currently recommended as monotherapy to reduce atherosclerotic events in patients with chronic coronary disease (CCD). To explore the effects of other antiplatelet agents, researchers in South Korea performed SMART-CHOICE 3, a randomized, open-label study that compared clopidogrel 75 mg daily to aspirin 100 mg daily in 5506 high-risk CCD patients who had completed standard dual antiplatelet therapy after PCI. Over a median follow-up of 2.3 years, the primary outcome, a composite of death from any cause, myocardial infarction, or stroke, occurred in 4.4% of the clopidogrel group and 6.6% of the aspirin group (hazard ratio 0.71 [95% CI 0.54-0.93]; p=0.013). There was no significant difference in bleeding risk. 

These findings align with a previous 2021 study, HOST-EXAM (N=5438), which similarly found clopidogrel monotherapy superior to aspirin for preventing a composite of CVD events in South Korean patients (5.7% vs 7.7%, p=0.003). Despite these results favoring clopidogrel, the 2023 AHA CCD guidelines, published after HOST-EXAM but before SMART-CHOICE 3, still recommend aspirin as first-line therapy. The authors cite weaknesses in HOST-EXAM, including its open-label design, homogenous South Korean population (high CYP2C19 loss-of-function allele prevalence), and low event rate, as reasons for sticking with aspirin. Until updated guidelines are published, it is unclear if SMART-CHOICE 3 will change this position.


Study finds Rybelsus lowers cardiovascular events in type 2 diabetes
doctor holding heart
Semaglutide, a GLP-1 analog, is available in two injectable forms (Wegovy and Ozempic) and an oral tablet (Rybelsus). Wegovy and Ozempic have been proven to reduce cardiovascular events in trials, leading to FDA-approved indications for cardiovascular disease (CVD) reduction in obesity and diabetes, respectively. The effects of Rybelsus on cardiovascular events were evaluated in the 2019 PIONEER-6 Trial (N=3183), where the absolute risk of a composite CVD outcome over 16 months was 3.8% with Rybelsus and 4.8% with placebo, a 1% difference that was noninferior to placebo (p<0.001) but not superior (p=0.17). Hoping to achieve a trifecta, Novo Nordisk funded another Rybelsus trial (SOUL Study) that enrolled 9650 diabetics with an A1C between 6.5% and 10% and a history of CVD or eGFR < 60 ml/min. Participants were randomized to Rybelsus with a target dose of 14 mg/day or placebo. After 48 months, a composite of CVD events (death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke) was lower in the Rybelsus group than the placebo group (12% vs 13.8%, p=0.006). HgA1c reduction at Week 104 was 0.71% in the Rybelsus group and 0.15% with placebo, while weight loss was 9.3 lbs and 2.8 lbs, respectively.

After missing statistical significance in the PIONEER-6 study, Novo Nordisk performed the larger and longer SOUL study, where Rybelsus was found to be superior to placebo for a composite of CVD events. Larger sample sizes and longer study durations, leading to more outcome events, help to narrow confidence intervals and increase the chance of a significant result (to learn more about these concepts, take our Medical Study Analysis CME). An analysis adjusting for changes in HgA1c and weight would be informative to see if Rybelsus has a benefit independent of its glucose-lowering and weight-loss effects.

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.