Paxlovid, an antiviral containing nirmatrelvir and ritonavir, received an emergency use authorization to treat COVID-19 in December 2021 based on results of the EPIC-HR trial, where it lowered the absolute risk of COVID-19-related hospitalization or death by 5.54% in unvaccinated patients with risk factors for severe COVD. Since then, a large portion of the population has been vaccinated, and the virus has evolved, raising questions about its effects on newer strains in vaccinated patients. To address these issues, the drug's manufacturer conducted the EPIC-SR study (N=1296) that compared Paxlovid to placebo in vaccinated subjects with risk factors for severe disease and unvaccinated subjects without risk factors (57% of participants had been vaccinated). At the study's conclusion, the primary outcome, median days to symptom resolution, was not significantly different between Paxlovid and placebo (12 vs 13 days, respectively, p=0.60). A secondary outcome that included COVID-19 hospitalizations and overall mortality was also nonsignificant.

The EPIC-SR study found that Paxlovid was not beneficial in a mostly vaccinated population. Notedly, vaccinated was defined as having received a complete primary series with or without boosters. Half of the subjects had one or more risk factors for severe COVID, although this designation is soft, considering BMI > 25 and hypertension were two of the top qualifying conditions. According to the Pfizer website, 75% of Americans have one or more "severe" risk factors. Obese patients (18%) and those older than 65 (5%) were underrepresented, so it was not possible to judge its effects in the most susceptible patients.

In summary, Paxlovid does not improve outcomes in vaccinated and unvaccinated subjects with mostly modest risk factors for severe disease. Providers can safely reserve its use for patients with significant comorbidities, including morbid obesity, elderly (> 70), marked respiratory disease, and immunosuppression.

• Paxlovid for Vaccinated and Unvaccinated Adults with COVID-19, NEJM [PubMed abstract]

On April 23rd, the Federal Trade Commission (FTC) announced it plans to ban noncompete clauses, agreements many healthcare providers practice under. According to federal law, the ban will take effect 120 days after it is published in the Federal Register. However, the final say will not likely come for some time, as it's unclear whether the FTC has the authority to do this, and legal challenges have already been filed. I found myself under one in my last job, and foolishly, I didn't read it until I was unhappy and thinking of leaving. It was very restrictive, prohibiting me from working within a 25-mile radius for two years, essentially leaving me unemployed unless I was willing to drive hours every day. Fortunately, my employer had already broken other parts of the contract, so I was able to get out of it.

As far as healthcare is concerned, I can see arguments on both sides. A medical group doesn't want to fund a practice startup just so the provider can leave and open a clinic across the street once he acquires a full slate of patients. Conversely, a business threatening an employee with a lawsuit if they try to work in the same city after quitting seems draconian and undemocratic.

Even though I was miffed by my clause (truthfully, at myself for not reading it), at the end of the day, this is America, and I believe an individual and a business should be allowed to enter into an agreement and be bound by its terms. Since my ordeal, I've quizzed other providers about their contracts and have yet to find one who could tell me what their noncompete says. I suspect this is probably a big reason employers are able to impose them, as many healthcare providers, including myself, are not good at reading their contracts and considering the long-term consequences.

• FTC Noncompete Ban Announcement (ftc.gov)

Resmetirom, a thyroid hormone receptor-beta (THR-β) agonist, received accelerated FDA approval to treat nonalcoholic steatohepatitis (NASH) in patients with moderate to advanced liver fibrosis. In NASH, hepatic THRs are impaired, leading to fatty acid accumulation and fibrosis. Resmetirom stimulates THR receptors, promoting triglyceride metabolism and reducing hepatic adiposity. The effects of resmetirom on NASH-induced liver disease were evaluated in the ongoing MAESTRO-NASH trial (N=966), where 52-week interim results showed that it was superior to placebo for the two primary outcomes, NASH resolution (30% vs 9.7%) and fibrosis improvement (26% vs 14.2%). The full trial is planned for 54 months and will include the following endpoints: mortality, hepatic decompensation (e.g., ascites, hepatic encephalopathy, variceal bleeding), and liver transplant.

Resmetirom is given as a once-daily tablet with weight-based dosing. Common side effects are diarrhea (33%), nausea (15%), pruritus (10%), vomiting (8%), and constipation (8%). Notable drug interactions requiring dose adjustments include certain statins and CYP2C8 inhibitors.

In the past, I've been reluctant to pursue extensive NASH workups since the only real treatment was weight loss. Now, I have to give it more consideration. The main challenge is identifying patients who will benefit the most from resmetirom, as it is expensive, and the majority of NASH patients do not progress to cirrhosis. For primary care doctors, selecting appropriate candidates may follow the following sequence: (1) Calculate a FIB-4 score; (2) If FIB-4 is > 1.3, order an ELF test; (3) If ELF is > 7.7, order a liver biopsy; (4) if F2 or F3 fibrosis is present, start resmetirom. Given its projected cost of $47,400 per year, it's likely insurance companies will require prior authorization that includes proof of liver fibrosis.

• Resmetirom (Rezdiffra) review
• Liver tests and diseases

Over the last eight years, three new classes of migraine medications have emerged. Two classes target calcitonin gene-related peptide (CGRP), a chemical mediator involved in eliciting migraine headaches, and the third is a serotonin agonist selective for receptor 5-HT1F, which differs from the nonselective triptans. Each class is summarized below.

• CGRP antibodies (Emgality, Aimovig, Ajovy, and Vyepti) - monoclonal antibodies that bind CGRP and block it from stimulating its receptor. All drugs are given parenterally and approved for migraine prevention. In studies, the placebo-subtracted reduction in monthly migraine days was 1 - 2 with CGRP antibodies.
• CGRP receptor antagonists (Qulipta, Nurtec, Ubrelvy, Zavzpret) - these drugs block the CGRP receptor. They are taken orally, except for Zavzpret, which is a nose spray. Qulipta is approved for migraine prevention, Ubrelvy and Zavzpret are approved for acute migraine, and Nurtec is approved for both. In studies, the placebo-subtracted reduction in monthly migraine days was 1 - 2 with Nurtec and Qulipta, while acute migraine response rates were 2 - 10% higher with Ubrelvy, Zavzpret, and Nurtec compared to placebo.
• Lasmiditan (Reyvow) - Lasmiditan is a non-triptan serotonin agonist selective for the 5-HT1F receptor, which theoretically makes it safer in patients with cardiovascular disease. It comes in a tablet and is approved for acute migraine. In one study (N=3005), 38.8% of lasmiditan-treated patients (200 mg) were pain-free two hours after dosing compared to 21.3% of placebo-treated patients.

The upside of these medications is that they have few side effects, precautions, and drug interactions. The downside is their high cost and modest efficacy. Of note, placebo always does well in migraine trials, which may be because other headache syndromes that are more responsive to psychological persuasion are often misdiagnosed as migraines.

• Migraine headache medications

The TRAVERSE Study, a randomized controlled trial comparing TRT to placebo in hypogonadal men, found that TRT did not increase the risk of cardiovascular events over 33 months, albeit average treatment length was only 22 months and testosterone levels in the TRT group were below typical targets (median of 371 ng/dl). The large size of the trial (N=5246) made it a desirable setting to evaluate other TRT outcomes, spurring a number of recently published substudies. Findings from those analyses are summarized below.

• Erectile function and libido - TRT did not improve ED, while daily libido events (e.g., sexual activity, sexual thoughts, flirting, sexual daydreams, spontaneous erections), which had a baseline average of 1.8 per day in both groups, improved to 2.8 in the TRT group and 2.3 in the placebo group, yielding a difference of 0.47 that was statistically significant (p=0.011)
• Bone health - small studies have found that TRT increases BMD, so it was surprising that TRT-treated subjects had a significantly higher fracture risk over a median of 3.19 years (3.5% vs 2.46%, HR 1.43, 95%CI [1.04 to 1.97])
• Diabetes and insulin resistance - TRT did not reduce progression to diabetes among prediabetics, nor did it improve glucose control in diabetics
• Cognition, sleep, mood, energy - TRT had a modest but significant effect on mood and energy but no effect on cognition or sleep
• Prostate events - TRT did not increase the risk of prostate events (e.g., prostate cancer, acute urinary retention, prostate biopsy)

TRT proponents often tout it as a fountain of youth, and defining its true effects has been difficult, as past studies have been mostly small and heterogeneous. TRAVERSE helps close the knowledge gap and dispel some myths, but its short treatment duration and modest testosterone levels in the TRT group are significant weaknesses.

• Low testosterone review
• TRAVERSE Study
• Testosterone replacement therapies