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.

• Semaglutide vs Placebo for MASH, NEJM (2025)
• Tirzepatide vs Placebo for MASH, NEJM (2024)
• Resmetirom (Rezdiffra®) review
• Article on webpage

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.

• 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.

• Zepbound vs Wegovy for Weight Loss in Obese Adults, NEJM (2025)
• Zepbound review
• Wegovy review
• Article on webpage

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.

• Gepotidacin (Blujepa) review
• Gepotidacin vs Nitrofurantoin for Female UTI, Lancet (2024)
• Gepotidacin vs Ceftriaxone + Azithromycin for Gonorrhea, Lancet (2024)
• Article on webpage

The American College of Physicians (ACP) recently published migraine prevention guidelines. The recommendations are based on a systematic review and network meta-analysis that they performed and are intended for nonpregnant adults with episodic migraine (defined as 1 to 14 headache days per month). Key recommendations include:

• First-line therapies: Beta-blocker (metoprolol or propranolol), valproate, venlafaxine, amitriptyline
• Second-line therapies: CGRP receptor antagonists (atogepant, rimegepant) or CGRP antibodies (eptinezumab, erenumab, fremanezumab, or galcanezumab)
• Third-line therapy: Topiramate

All of the guidelines are based on low-certainty evidence, as there are few meaningful head-to-head trials comparing migraine drugs. Their reasoning for recommending CGRP drugs over topiramate is that topiramate has a less favorable side effect profile.

Migraine prevention has always been the Wild West of pharmacotherapy, as a broad range of medications with seemingly unrelated mechanisms are used for treatment. Fortunately, most recommended drugs are affordable. The newer CGRP drugs are expensive and have modest efficacy in trials, reducing average migraine days per month by 1 - 2 compared to placebo. Notably, placebo typically performs well in migraine trials, likely reflecting overdiagnosis, as patients and some providers tend to label all headache syndromes as migraines.

• Migraine headache review
• Migraine headache medications
• Article on webpage

Bacterial vaginosis (BV), affecting up to 30% of young women, has a high recurrence rate, with over 50% of women experiencing reinfection within 12 weeks. The cause of BV is poorly understood, but women who report sex with a regular partner have twice the risk of those who are not sexually active. This observation has led to speculation that the condition is sexually transmitted. However, previous studies where females and their male partners were treated with oral therapy have not demonstrated a reduction in recurrence. One possible explanation for these findings is that oral therapies alone may not be sufficient to clear cutaneous penile carriage of bacterial vaginosis–associated organisms. To test this theory, Australian researchers randomized monogamous couples in which the woman had BV to female-only treatment (female-only group) or female and male partner treatment (partner-treatment group). In both groups, females received metronidazole 400 mg twice daily for 7 days or intravaginal metronidazole or clindamycin if contraindicated. In the partner-treatment group, males received the same metronidazole regimen along with 2% clindamycin cream applied to the penile skin twice daily for 7 days. During follow-up, females were tested for BV at day 8, week 4, week 8, week 12, and as needed for symptoms. At study conclusion, the primary outcome, BV recurrence within 12 weeks, was significantly lower in the partner-treatment group compared to the female-only group (35% vs 63%, p<0.001)

This study provides some insight into BV and sexual transmission. It also raises the question of whether topical therapy alone in male partners, including over-the-counter creams like Neosporin, could reduce recurrence. Lastly, it's important to note that 35% of women in the partner-treatment group had a recurrence, suggesting that some type of underlying predisposition plays a significant role in BV susceptibility.

• Male-Partner Treatment to Prevent Recurrence of Bacterial Vaginosis, NEJM (2025)
• Genitourinary infections
• Article on webpage