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FEATURED

NEW COPD DRUG APPROVED

Ensifentrine (Ohtuvayre®), a phosphodiesterase 3 and 4 inhibitor (PDE3/4), was recently approved to treat COPD. PDE inhibitors increase pulmonary levels of cAMP, an intracellular signaling molecule that stimulates bronchodilation. In a 24-week trial enrolling 790 moderate-to-severe COPD patients, ensifentrine 3 mg twice daily via nebulizer increased the average post-dose FEV1 over 12 hours by 94 ml compared to placebo. Moderate or severe COPD exacerbations were also lower with ensifentrine (0.24/year vs 0.42/year ); however, daily rescue inhaler use was not significantly different between groups. Ensifentrine side effects were mild and similar to placebo.

Ensifentrine is the second PDE inhibitor approved for COPD. Roflumilast (Daliresp®), which only inhibits PDE4, has been available since 2011. It is an oral tablet and has significant GI effects, including weight loss, nausea, and diarrhea, which have limited its uptake. The 2023 GOLD COPD guidelines list roflumilast as a fourth- or fifth-line agent in patients with severe COPD.

Steroid tapering recommendations
prednisone box
One of the first bits of medical knowledge all providers learn in training is that glucocorticoids should be tapered to prevent hypothalamic-pituitary-adrenal axis suppression. Despite this universal rule, little professional guidance has been published, causing tapering practices to vary widely among clinicians. Finally, this past June, the Endocrine Society published meaningful tapering guidelines available at the link below.
picture of Shield box

BLOOD TEST APPROVED FOR COLON CANCER SCREENING

The Shield test, a blood assay that detects alternations associated with colorectal cancer (CRC) in cell-free DNA, was recently approved to screen for colon cancer in average-risk individuals. In a study of 10,258 adults using colonoscopy as the reference standard, Shield had the following accuracy:
  • Sensitivity (any colorectal cancer): 83.1%
  • Sensitivity (stage 1 colorectal cancer): 54.5%
  • Sensitivity (advanced adenoma✝): 13.2%
  • Specificity (colorectal cancer or advanced adenoma): 89.6%
  • ✝Advanced adenomas are polyps with precancerous features

Shield is actually the second blood test approved for colon cancer screening. The Epi proColon test, which detects a bloodborne marker of CRC called methylated SEPT9 DNA, was approved in 2016. It has a sensitivity of 69% for any CRC and 41% for stage 1 CRC. For comparison, Cologuard, the widely advertised stool DNA test, has sensitivities of 92% and 88%, respectively.

When it comes to DNA-based colon cancer screening, Cologuard is the clear winner; however, none of the assays are particularly good at detecting precancerous adenomas (Shield - 13.2%, Epi proColon - 21.5%, Cologuard - 42%). As far as cost, Shield runs $895, Epi proColon $192, and Cologuard $500. Professional guidelines recommend repeating Cologuard every three years. Epi proColon has never been incorporated into any guidelines, and Shield is too new to have been considered.
Tirzepatide improves nonalcoholic steatohepatitis (NASH)
illustration of fatty liver disease
Tirzepatide, the blockbuster GLP/GIP weight-loss drug marketed as Zepbound, was recently compared to placebo in patients with NASH, also known as metabolic dysfunction–associated steatohepatitis or fatty liver disease. The SYNERGY-NASH trial randomized 190 patients with NASH and F2 or F3 fibrosis to three doses of tirzepatide - 5 mg, 10 mg, and 15 mg - or placebo. After 52 weeks, NASH resolution occurred in 44%, 56%, 62%, and 10%, respectively, while a decrease in fibrosis stage of ≥ 1 was seen in 55%, 51%, 51%, and 30% (all tirzepatide-placebo comparisons were significant). Tirzepatide-treated patients lost 11 - 16% of their body weight, depending on the dose. Drug discontinuations due to side effects were rare in all groups (≤4%).

NASH is driven by hepatocellular adiposity, so it is not surprising that tirzepatide-induced weight loss improved liver pathology. In a previous trial, semaglutide was significantly better than placebo for NASH resolution but not fibrosis improvement. [PMID 33185364]

Resmetirom is the only medication currently FDA-approved to treat NASH, and while results from different studies are not comparable linearly, nothing in resmetirom's pivotal trial suggests that it is superior to tirzepatide. Furthermore, it does not cause weight loss, giving it no benefit in other obesity-related conditions.
Paxlovid box

PAXLOVID DOES NOT PREVENT COVID IN EXPOSED PATIENTS

Some patients and providers assume Paxlovid helps to prevent COVID in exposed patients, and it is often prescribed for this purpose. To evaluate this use, researchers randomized 2736 asymptomatic adults who had been exposed to a household contact with COVID within 96 hours to Paxlovid for 5 or 10 days or matching placebo. Other inclusion criteria included no known history of COVID and a negative baseline COVID antigen test. Only 13% of participants had received one or more COVID vaccines, and 73% had at least one risk factor for severe COVID. At the end of the trial, the primary outcome, symptomatic COVID confirmed by PCR or antigen testing through 14 days, occurred in 2.6% of the Paxlovid 5-day group, 2.4% of the 10-day group, and 3.9% of the placebo group. All Paxlovid-placebo comparisons were nonsignificant.

This is the second negative Paxlovid study Pfizer has funded. A study published in April found that Paxlovid did not shorten the time to symptom resolution, compared to placebo, in a mix of vaccinated and unvaccinated adults with new-onset COVID. For COVID protection, vaccination continues to be the clear winner.
Updated vitamin D guidelines still miss the mark
doctor with vitamin D bottle
In 2011, the Endocrine Society (ES) published vitamin D guidelines that recommended widespread screening and defined normal serum values as > 30 ng/ml. The guidance was harshly criticized for its lack of supporting evidence. Nonetheless, many providers adopted universal screening and recommended supplementation, including large weekly doses, to many patients. Since then, numerous studies have found that vitamin D does not improve outcomes across a broad array of conditions. In response to the new data, the ES recently published updated guidelines, and while they improve on the previous ones, their recommendation for empiric supplementation in certain groups flies in the face of evidence from randomized trials. Significant new recommendations, including links to contradictory evidence, are presented below.
  • Screening: Routine vitamin D screening is not recommended in generally healthy adults
  • Target levels: There is no clear evidence supporting an optimal vitamin D level
  • Supplementation: Empiric supplementation, defined as daily intake of fortified foods and/or supplements containing vitamin D, is recommended in the following groups:
    • Ages 1 - 18 years: to prevent nutritional rickets and potentially lower the risk of respiratory tract infections. [Contradictory studies: PMID 32706534, PMID 29813149, PMID 28719693, PMID 22494826]
    • Age ≥ 75 years: may lower the risk of mortality [Contradictory study: PMID 35026158]
    • Prediabetics: to reduce the risk of progression to diabetes [Contradictory studies: PMID 31173679, PMID 26829443]
    • Pregnancy: to lower the risk of preeclampsia, intra-uterine mortality, preterm birth, small-for-gestational-age (SGA) birth, and neonatal mortality [Contradictory studies: PMID 30089075, PMID 26944421]

After years of rampant vitamin D testing and unwarranted treatment, the updated recommendations are welcome. However, the empiric supplementation guidance is not supported by randomized trials and is unlikely to have a meaningful effect.

NEWS IN BRIEF

Atopic dermatitis (AD) recommendations

atopic dermatitis on elbow
AD treatment has traditionally been straightforward, with topical steroids and calcineurin inhibitors being the primary options. In recent years, new therapies, including Janus kinase inhibitors, biologics, and PDE-4 inhibitors, have been approved, expanding treatment options. The AAAAI recently published guidelines for AD treatment, and we have consolidated them into easy-to-follow steps available at the link below.

PCOS recommendations

uterus and ovary illustration
Most providers don't want to read an encyclopedia on polycystic ovary syndrome (PCOS), but concise and up-to-date diagnostic criteria and treatment recommendations can come in handy, so we added straightforward PCOS algorithms to our female hormone physiology page.

Platelet-rich plasma (PRP) injections ineffective in yet another study

platelet-rich plasma knee injection
Despite negative studies, providers who give PRP injections continue to promote them as miracle treatments for all things joint- and tendon-related. In a recent study, researchers randomized 120 patients undergoing ACL reconstruction to post-op PRP knee injections once monthly for 3 months or no injection. At 12 months post-op, there was no difference between groups in knee pain or function. Study participants were not blinded, favoring a placebo effect in the PRP group. Even so, PRP showed no benefit.

CDC recommends doxycycline PEP in some patients

cdc
The DoxyPEP Study (N=501) found that one 200 mg dose of doxycycline within 72 hours of condomless intercourse reduced the absolute risk of gonorrhea, chlamydia, or syphilis by 20% compared to usual care in men who have sex with men and transgender women (Infection rate: Doxycycline - 11%, Usual care - 31%). Based on these findings, the CDC issued a recommendation that doxycycline postexposure prophylaxis (PEP) be offered to this patient population for self-administration within 72 hours of oral, vaginal, or anal sex.

Prazosin + cyproheptadine for alcohol use disorder

shots of liquor
Animal studies have suggested that alcohol addiction may be caused in part by abnormal regulation of noradrenergic and serotonergic regions of the brain. The combination of prazosin, a noradrenergic alpha blocker used to treat hypertension, and cyproheptadine, an antihistamine with antiserotonergic activity, has been shown to reduce alcohol cravings in mice. To evaluate their effects in humans, researchers randomized 154 people with a baseline average alcohol consumption of 7.8 drinks/day to cyproheptadine + prazosin (2 different doses) or placebo. After 3 months, patients receiving cyproheptadine 12/prazosin 10 mg (high dose group) reduced their daily alcohol intake by 3.4 drinks compared to 2.4 in the placebo group.

POPULAR PAGES

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POPULAR BUT UNPROVEN

  • Meniscal surgery - It's one of the most common orthopedic procedures performed, but does it do anything?
  • CPAP for sleep apnea - Sleep doctors are on every corner it seems, but what are the benefits of diagnosing and treating sleep apnea?
  • Knee injections - these treatments are popular among orthopedists and primary care doctors, but are they effective?
  • Pneumonia vaccines in adults - vaccine manufacturers, the CDC, and Medicare want everyone to get a pneumonia vaccine, so they must be highly effective, right?
Vonoprazan (Voquezna®), first in class GERD drug
Voquezna advertisement
Vonoprazan (Voquezna®), a new stomach acid-reducing drug with a novel mechanism, recently became available. It works by competing with potassium ions at gastric H+/K+-ATPase proton pumps; this differs from traditional PPIs that inhibit the pump through covalent binding. Proposed advantages of vonoprazan over PPIs include: (1) longer half-life (9 hours vs 1 - 2 hours); (2) acid stable, which gives it a more rapid onset of action; and (3) food-independent effects. A study (N=1024) comparing vonoprazan 20 mg daily to lansoprazole 30 mg in patients with erosive esophagitis found that vonoprazan was superior for endoscopic healing at 8 weeks (92.9% vs 84.6%, p<0.0001). Maintenance of healing at 24 weeks also favored vonoprazan (79.2% vs 72%), but heartburn-free days did not differ significantly between groups. Side effects are mild and similar to placebo. One notable drug interaction is clopidogrel, whose conversion to the active form may be blocked by vonoprazan through CYP2C19 inhibition, also a known effect of omeprazole and esomeprazole.

Voquezna TV commercials are starting to air so patients may be asking about it. In short, it appears to be slightly better than PPIs at healing erosive esophagitis, but its effects on reflux symptoms, the reason most people take these drugs, are no better than PPIs. Given that PPIs are cheap and ubiquitous, insurance companies will not be inclined to cover Voquezna, making prior authorizations and formulary exclusions likely.

Beta blockers in COPD and asthma
Beta-2 receptors are present in lung airways, where they facilitate smooth muscle relaxation and bronchodilation when stimulated. Nonselective beta blockers, which block beta-1 and beta-2 receptors, can theoretically worsen asthma and COPD; selective beta blockers, which primarily inhibit beta-1 receptors, also block beta-2 receptors to a small degree. Observational studies evaluating the effects of beta blockers in patients with COPD and asthma have found no evidence of adverse effects, and in some COPD studies, a potential benefit was observed. To examine the issue, researchers randomized 519 patients with COPD to bisoprolol, a selective beta blocker, or placebo and compared the number of patient-reported COPD exacerbations between groups. After one year, there was no significant difference between bisoprolol and placebo (2.03 events/year vs 2.01 events/year, respectively; HR 0.97 95%CI [0.84-1.13])

All beta blockers carry warnings about their use in patients with COPD or asthma. Despite this, they are frequently prescribed to these patients to treat hypertension, heart failure, and angina. Some observational studies have suggested a beneficial effect in COPD patients; however, the study above did not find one, nor did a previous study that evaluated metoprolol. [PMID 31633896] Bisoprolol did not worsen COPD symptoms, while in the metoprolol study, COPD hospitalizations were more common in the metoprolol group.

Overall, the potential benefits of selective beta blockers likely outweigh the risks in COPD patients with indications for their use.

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.