2024 NEJM Journal Watch Audio General Medicine: March Week 2

Educational Objectives

After hearing and assimilating this program, the listener will be better able to:

1. Increase his/her/their basic knowledge of important advances in medicine;
2. Identify a broad range of clinical research reported in the medical literature;
3. Synthesize research findings through one-on-one interviews with authors, editorialists, or experts in the field;
4. Integrate new treatments reviewed in the summaries into current practice;
5. Challenge oneself with thoughtful, clinically relevant questions.

Summary

Guideline Watch: Childhood and Adolescent Immunization Schedule, 2024 Update

The updated 2024 childhood immunization schedule can be viewed on the U.S. Centers for Disease Control and Prevention (CDC) website (https://www.cdc.gov/vaccines/schedules; https://doi.org/10.15585/mmwr.mm7301a2) and in Pediatrics (https://doi.org/10.1542/peds.2023-065044). Footnotes detail each vaccine and provide details regarding administration. Links to parent-friendly vaccine schedules are available, as well as an addendum outlining vaccine administration by medical indication (https://www.cdc.gov/vaccines/schedules/hcp/imz/child-indications.html#addendum-child) and a catch-up immunization schedule (https://www.cdc.gov/vaccines/schedules/hcp/imz/catchup.html).

Key Recommendations

• New inclusions:

  — RSV-mAb (nirsevimab) for infants and young children

  — RSV preF vaccine (trade name: Abrysvo) for pregnant people, with information regarding seasonality and recommended administration

  — Mpox vaccine (trade name: Jynneos) for high-risk adults (age, ≥18)

  — Pentavalent meningococcal vaccine (MenACWY-TT/MenBFHbp [trade name: Penbraya]) with a linked resource to aid in shared clinical decision making regarding MenB vaccine

• Removal of vaccines no longer available:

  — Bivalent COVID‑19 mRNA vaccines

  — 13-valent pneumococcal vaccine (PCV13); replaced with PCV15 and PCV20 for routine use

  — Diphtheria and tetanus toxoid vaccine (DT)

  — Meningococcal vaccine MenACYW-D (trade name: Menactra)

• Updated recommendations:

  — Influenza: People with egg allergies of any severity can receive any appropriate influenza vaccine without special considerations.

  — Polio: Administer a onetime lifetime inactivated poliovirus vaccine (IPV) booster to adults (age, ≥18) who have completed the primary series and are at excess risk for exposure to poliovirus.

Vaccination rates in kindergarteners have not returned to pre–COVID‑19 levels, and immunization exemptions are on the rise, leaving children susceptible to multiple vaccine-preventable illnesses. Although the immunization schedule is complicated enough to require multiple tables and annual updates, it remains a valuable tool for those who care for children and adolescents. Redoubled efforts are critical to combat vaccine hesitancy and misinformation about risks and benefits, as is the focus on communicating successfully with tentative parents. This updated immunization schedule reflects dramatic progress in protection against infectious diseases — still, vaccines must be given to be effective.

Deborah Lehman, MD

Low-Risk Pulmonary Embolism: An Opportunity to Prevent Hospitalizations

More than a decade after randomized trials demonstrated the safety of early discharge after low-risk pulmonary embolism (PE; https://www.jwatch.org/em201107220000001 and Lancet 2011; 378:41), many low-risk patients still are hospitalized for PE. To assess patterns of emergency department (ED) discharge or hospital admission of patients with acute PE in the U.S., investigators conducted serial cross-sectional analyses of data from >1.6 million ED visits (2012-2020). Their findings appear in the Annals of Internal Medicine (https://doi.org/10.7326/M23-2442).

Among patients with acute PE, 43% had dyspnea, 25% had chest pain, 33% had tachycardia, 34% had tachypnea, and only 6.5% had oxygen desaturation. ED discharge rates remained relatively constant (about one third of patients) during the 9-year period. Similarly, among the half or more of patients who were considered to be low-risk based on hemodynamic stability or validated risk-stratification tools (e.g., Pulmonary Embolism Severity Index (PESI) score (https://www.mdcalc.com/calc/1304/pulmonary-embolism-severity-index-pesi) or simplified-PESI (https://www.mdcalc.com/calc/1247/simplified-pesi-pulmonary-embolism-severity-index), only one third were discharged directly from the ED.

The 2016 CHEST guidelines and their 2021 update (https://www.jwatch.org/na54097 and Chest 2021; 160:545) recommend outpatient management over hospitalization for patients with low-risk PE (if access to medications and outpatient care is available). Although the current study has some limitations (e.g., use of administrative diagnosis codes), the findings suggest that better adherence to those guidelines could reduce costs and prevent unnecessary use of limited hospital beds.

Daniel D. Dressler, MD, MSc, MHM, FACP

In a Real-World Study, Most Patients with Severe Asthma Had Good Response to Biologics

Asthma biologics are an effective, but very expensive, treatment for patients with severe asthma. For a study in Chest (https://doi.org/10.1016/j.chest.2023.10.046), Danish researchers used a national registry to see how many patients achieve “remission” and which patient characteristics predict better responses.

About 500 patients who were starting biologic agents (targeting IgE, interleukin-5, or IL-4/13) for severe asthma were included. Clinical response was defined as a ≥50% reduction in annualized exacerbation rate and ≥50% reduction in maintenance oral corticosteroid doses. Clinical remission was defined as no exacerbations, no maintenance oral steroids, normal lung function, and good asthma control based on questionnaires.

After 12 months, 79% of patients had clinical response, and 24% of those patients achieved clinical remission. Nonresponders were more likely to be obese and to have been taking maintenance oral steroids at baseline. Responders were more likely to be male and to have better baseline lung function, higher levels of type 2 markers of inflammation (i.e., eosinophil counts, IgE levels, and exhaled nitric oxide levels), shorter duration of disease, and more acute exacerbations before starting biologics.

Six biologic agents currently are available in the U.S. Most primary care providers don’t start biologics in their asthma patients, but knowing this information will help with counseling. Most patients have good responses to biologics, and about one fifth will achieve complete control of their asthma. Because these medications are very expensive, understanding the characteristics that predict response is important.

David J. Amrol, MD

Pneumocystis Pneumonia: Characteristics and Prognostic Factors

Pneumocystis jirovecii pneumonia (PJP) is a common complication in patients who are immunocompromised because of HIV infection, solid organ transplantation, or treatment for hematologic malignancies or immune-mediated inflammatory diseases (IMID). To examine the influences of these underlying conditions on the characteristics and outcomes of PJP, French researchers conducted a retrospective study of 481 patients with proven or probable PJP seen at three centers. Findings appear in Chest (https://doi.org/10.1016/j.chest.2024.01.015).

Immunocompromising conditions included hematologic malignancy (25%), HIV infection (24%), solid organ transplantation (21%), IMID (18%), and solid tumors (12%). Mean CD4 T-cell counts were decreased at the time of PJP diagnosis but were significantly higher in patients who were HIV negative compared with those who were HIV positive (292 cells/mm³ vs 64 cells/mm³). Only 10% of patients had received PJP prophylaxis prior to diagnosis.

Overall, 90-day mortality was 26%; it was lowest among patients with HIV infection (10%) and highest among those with IMID (37%) or solid tumors (48%). In multivariate analysis, 90-day mortality was associated independently with solid tumor disease (odds ratio, 5.7), long-term corticosteroid therapy (OR, 2.3), and SOFA score at admission (OR, 1.6).

According to these findings, the prognosis of a PJP episode varies considerably depending on the underlying immunocompromising condition, and long-term steroid therapy is a major risk factor for developing PJP. CD4 T-cell counts might be less reliable as PJP-risk predictors in HIV-negative immunocompromised patients. Finally, PJP prophylaxis appears to be underused considerably in patients at risk.

Thomas Glück, MD

Important Cause of Nausea and Vomiting in Pregnancy Has Been Identified

Nausea and vomiting of pregnancy (NVP) occurs in most women to some degree. As many as 3% of women develop severe NVP, known as hyperemesis gravidarum (HG). Previous studies have indicated that a hormone called growth differentiation factor 15 (GDF15) might play a role in NVP.

Using a combination of genomics, studies of pregnant and nonpregnant women, and studies in mice, researchers showed that, during pregnancy, most of this hormone is produced by the placenta and fetus. Details appear in Nature (https://doi.org/10.1038/s41586-023-06921-9 and https://doi.org/10.1038/d41586-023-03940-4). They also confirmed earlier reports that levels of GDF15 are higher in women with NVP and HG than in women without NVP and that a center in the brainstem that causes nausea and vomiting has a specific receptor for GDF15. More interesting, they show that women with higher levels of GDF15 before pregnancy — seemingly paradoxically — are less likely to develop NVP or HG during pregnancy. The mouse studies helped to explain the paradox: Mice became desensitized to GDF15 after receiving bolus doses. Thus, high levels of GDF15 prior to pregnancy might desensitize its brainstem receptor, making the rising levels of the hormone that naturally occur in pregnancy less likely to produce nausea.

This study confirms the importance of a particular hormone, GDF15, in causing NVP and HG. It also suggests that we might be able to develop targeted interventions to prevent or treat NVP and HG.

Anthony L. Komaroff, MD

Congenital Malformations and Choice of Treatment for Opioid Use Disorder in Pregnancy

Untreated opioid use disorder (OUD) during pregnancy is associated with substantial perinatal morbidity and mortality. Opioid agonist medication (buprenorphine or methadone) is recommended management for pregnant patients with OUD (https://www.acog.org/clinical/clinical-guidance/committee-opinion/articles/2017/08/opioid-use-and-opioid-use-disorder-in-pregnancy) although limited pregnancy safety data exist for either medication. Using a U.S. Medicaid database covering the years from 2000 to 2018, researchers identified almost 14,000 live births in which the mother received either a methadone (29%) or a buprenorphine (71%) prescription during the first trimester. Details appear in JAMA Internal Medicine (https://doi.org/10.1001/jamainternmed.2023.6986).

The rate of major congenital malformations was 51 per 1000 pregnancies with buprenorphine and 61 per 1000 pregnancies with methadone. In comparisons that were adjusted for baseline differences between the two groups, buprenorphine-exposed infants had lower rates of cardiac malformations, oral clefts, and clubfoot, but had a higher rate of gastrointestinal malformations (mainly pyloric stenosis).

These rates of major congenital malformations associated with exposure to both methadone and buprenorphine indicate excess risk above population-level risk (reportedly ≈2%–4% of live births). However, despite small excess risks for major congenital malformations, opioid agonist treatment with either methadone or buprenorphine remains crucial to optimizing outcomes in pregnancies affected by OUD.

Marie Claire O’Dwyer, MB BCh BAO, MPH

Testosterone Replacement Doesn’t Improve Glycemia in Men with Prediabetes or Diabetes

Observational evidence suggests that testosterone replacement therapy lowers glycosylated hemoglobin (HbA_1c). In a substudy of the randomized, placebo-controlled TRAVERSE trial (https://www.jwatch.org/na56264 and N Engl J Med 2023; 389:107) in JAMA Internal Medicine (https://doi.org/10.1001/jamainternmed.2023.7862), researchers determined whether testosterone replacement in men (age range, 45-80) with hypogonadism prevents progression from prediabetes to diabetes and induces glycemic remission in diabetes.

Among 1200 participants with prediabetes, risk for progression to diabetes (i.e., HbA_1c level ≥6.5%) was similar in the testosterone-replacement and placebo groups at all follow-up times through 48 months. Among 3900 participants with diabetes, the testosterone replacement and placebo groups had similar rates of glycemic remission (i.e., HbA_1c level <6.5% or two measurements of fasting glucose <126 mg/dL) through 48 months.

Previously published observations that testosterone therapy might prevent progression from prediabetes to diabetes (e.g., https://doi.org/10.2337/dc18-2388) are not supported by the findings in this randomized trial. As editorialists note (https://doi.org/10.1001/jamainternmed.2023.8079), “the only indication for [testosterone replacement] in men with hypogonadism remains treatment of bothersome symptoms of hypogonadism, generally sexual dysfunction.”

Paul S. Mueller, MD, MPH, FACP

Which GLP-1 Agonist Is Most Effective for Glycemic Control and Weight Loss?

Six glucagon-like peptide-1 (GLP-1) receptor agonists are U.S. FDA approved for managing diabetes; three of these also have been approved for obesity and overweight. However, few trials have compared different GLP-1 receptor agonists. Now, researchers have conducted a network meta-analysis of 76 randomized trials of approved and investigational GLP-1 receptor agonists compared with placebo or each other; 39,000 adults with type 2 diabetes, followed for ≥12 weeks, were included in their systematic review, which appears in The BMJ (https://doi.org/10.1136/bmj-2023-076410).

• Tirzepatide, a combined GLP-1 and glucose-dependent insulinotropic polypeptide (GIP) receptor agonist, was the most-effective approved agent for both indications, with mean differences of −2.1% in glycosylated hemoglobin (HbA_1c), −56 mg/dL in fasting blood glucose, and −8.5 kg in body weight compared with placebo.

• Semaglutide was second most effective for both indications, with mean differences of −1.4% in HbA_1c, −36 mg/dL in fasting blood glucose, and −3.1 kg in body weight.

• The most-effective agent for weight loss overall was an investigational combination of semaglutide and the amylin analog cagrilintide, which yielded a mean 14.0 kg lower body weight than placebo.

• Most available agents had similar adverse effect profiles, with gastrointestinal effects predominating.

Tirzepatide is the most effective currently available GLP-1 receptor agonist for both glycemic control and weight loss in the short and intermediate term; long-term efficacy and safety are still open questions. Future agents in this class might leverage additional mechanisms of action for greater efficacy.

Bruce Soloway, MD

SGLT-2 Inhibitors Lower Risk for Kidney Stones in Patients with Type 2 Diabetes

Type 2 diabetes is associated with excess risk for kidney stones. Sodium–glucose cotransporter-2 (SGLT‑2) inhibitors increase urine output and alter urine composition in ways that might lower risk for kidney stones. In a U.S. study in JAMA Internal Medicine (https://doi.org/10.1001/jamainternmed.2023.7660), researchers compared risks for kidney stones among 600,000 adults with type 2 diabetes who were new users of SGLT‑2 inhibitors vs 600,000 propensity score–matched patients who initiated glucagon-like peptide-1 (GLP-1) receptor agonists and dipeptidyl peptidase-4 (DPP-4) inhibitors, which do not have the same renal effects.

During median follow-up of 6 months, risk for kidney stones was significantly lower in patients who began using SGLT‑2 inhibitors than in patients who began using GLP-1 receptor agonists (15 vs 22 events/1000 person-years) or DPP-4 inhibitors (15 vs 20 events/1000 person-years). The effect was larger for younger patients (age, <70).

This study suggests that initiating SGLT‑2 inhibitors, compared with GLP-1 receptor agonists or DPP-4 inhibitors, is associated with lower risk for kidney stones in the short term; whether this effect will persist long term is unknown. For a patient in whom the decision to start an SGLT‑2 inhibitor (vs another diabetes drug) is otherwise a toss-up, a history of recurrent kidney stones might tip the balance toward the SGLT‑2 inhibitor.

Paul S. Mueller, MD, MPH, FACP

SGLT-2 Inhibitors and Nonalcoholic Fatty Liver Disease

Many patients with type 2 diabetes also have nonalcoholic fatty liver disease (NAFLD), which can progress to fibrosis, cirrhosis, and cancer. In a retrospective study in JAMA Internal Medicine (https://doi.org/10.1001/jamainternmed.2023.8029) of 80,000 people (mean age, 59) with diabetes and presumed NAFLD, Korean researchers examined associations between liver-related outcomes and use of several oral diabetes drug classes, added to metformin. NAFLD was identified indirectly, using the Fatty Liver Index (FLI; https://www.mdcalc.com/calc/10001/fatty-liver-index) — a calculated score based on body-mass index, waist circumference, triglycerides, and serum γ-glutamyl transpeptidase level. At baseline, all patients had FLI scores ≥60 on a 100-point scale (considered to have high sensitivity for identifying NAFLD) and were taking metformin.

After a median 2.6 years of follow-up, 4100 patients had FLI scores <30 (considered to represent NAFLD regression). In adjusted analyses, sodium–glucose cotransporter-2 (SGLT‑2) inhibitors, thiazolidinediones, and dipeptidyl peptidase-4 (DPP-4) inhibitors were associated with 99%, 70%, and 45% higher probabilities of NAFLD regression than were sulfonylureas. Additionally, NAFLD regression was significantly more likely with SGLT‑2 inhibitors than with thiazolidinediones and DPP-4 inhibitors. Also, only SGLT‑2 inhibitors were associated with lower risk for a composite of adverse liver outcomes (i.e., liver-related hospitalization, liver-related death, liver transplant, or liver cancer) compared with sulfonylureas.

In this observational study of metformin-treated patients with type 2 diabetes, favorable liver outcomes were more likely with SGLT‑2 inhibitors than with other oral diabetes drug classes. However, keep in mind that no diabetes drug is U.S. FDA-approved specifically for treating patients with NAFLD and that the comparisons in this trial did not include glucagon-like peptide-1 (GLP-1) agonists (which have demonstrated improvement of steatohepatitis on liver biopsy in small studies).

Paul S. Mueller, MD, MPH, FACP

On The Horizon: Potential New Treatment Options for NASH with Fibrosis

Although several available medications have favorable effects on liver histology in selected patients with nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH), no drugs are U.S. FDA-approved for this purpose. Researchers are examining novel pharmacological approaches, two of which were reported in the New England Journal of Medicine.

Agonists of the thyroid hormone receptor-beta (THR-β) in the liver improve hepatic histology in NASH. In a manufacturer-sponsored, phase 3 trial (https://doi.org/10.1056/NEJMoa2309000), researchers randomized nearly 1000 patients with biopsy-proven NASH (most with fibrosis stage 2 or 3) to receive the THR-β agonist resmetirom or placebo. On repeat biopsy at 1 year, NASH had resolved (with no worsening of fibrosis) in 28% of resmetirom recipients and in 10% of placebo recipients (P<0.001). Additionally, fibrosis was significantly more likely to improve by ≥1 stage (with no worsening of NAFLD activity) with resmetirom than with placebo (25% vs 14%). Self-limited diarrhea and nausea were the most common side effects. This trial will continue for several more years to assess clinical endpoints.

Fibroblast growth factor 21 (FGF21) is a hormone with favorable metabolic effects in the liver. In a manufacturer-sponsored, phase 2b randomized trial (https://doi.org/10.1056/NEJMoa2304286), 192 patients with biopsy-proven NASH (nearly all with fibrosis stages 2 or 3) received either the FGF21 analogue pegozafermin or placebo. On repeat biopsy at 24 weeks, NASH had resolved (with no worsening of fibrosis) in 23% to 37% of pegozafermin recipients and in 2% of placebo recipients (the 23%–37% pegozafermin range represents several different doses). Fibrosis was more likely to improve by ≥1 stage (with no worsening of NAFLD activity) with pegozafermin than with placebo (22%–27% vs 7%). Again, diarrhea and nausea were the most common side effects.

Neither of these drugs is FDA-approved, but the FDA has granted priority review for resmetirom and a “breakthrough therapy” designation for pegozafermin. These developments are designed to speed up the review process and seem appropriate, given the prevalence and seriousness of NASH. We obviously need longer-term information on clinical outcomes and safety, but initial results of these trials appear promising.

Allan S. Brett, MD

Clinical and Epidemiological Features of Hyperosmolar Hyperglycemic State

Lack of clinician familiarity and nonspecific symptoms can hinder prompt recognition of hyperosmolar hyperglycemic state (HHS). In a study in Diabetes Care (https://doi.org/10.2337/dc23-0988), researchers used data from a nationwide registry in Denmark to report renal function and acid/base status among 634 patients (median age, 69) who were hospitalized with HHS from 2016 to 2018 and to estimate population incidence rates of HHS among patients with known diabetes. HHS was defined as an admission blood glucose of >600 mg/dL with plasma osmolarity of >320 mOsm/kg H₂O. Patients with concomitant HHS and diabetic ketoacidosis (DKA) were identified using administrative data. Clinical information (e.g., presence of hypovolemia or encephalopathy) was not captured in the registry.

Key findings were as follows:

• 62% of patients had pure HHS; the remaining 38% had HHS-DKA overlap.

• Among all patients, 33% of HHS cases represented new diagnoses of diabetes.

• Among patients with pure HHS, 39% had acidosis (pH <7.35), 65% had acute kidney injury, and inpatient mortality was 17%.

• Among patients with previously identified type 1 and type 2 diabetes, incidence rates of HHS were 16.5 and 3.9 cases per 10,000 person-years, respectively.

Although HHS once was thought to occur primarily in people with type 2 diabetes, these results suggest that the incidence is roughly four times greater among patients with type 1 diabetes. In addition, in one third of cases, HHS was the first presentation of diabetes. Given these findings, the absence of a diabetes diagnosis should not preclude checking plasma osmolarity in a patient with marked hyperglycemia and clinical presentation compatible with HHS.

Rahul B. Ganatra, MD, MPH

These summaries are presented to facilitate your understanding of ongoing medical research. They aren’t intended for use as the sole basis for clinical treatment nor as a substitute for reading the original research. Journal Watch is a registered trademark of the Massachusetts Medical Society, publishers of the New England Journal of Medicine.

Access additional content, included with your subscription, at jwatch.org.

Readings

Disclosures

In adherence to the ACCME Standards for Commercial Support, Audio Digest requires all faculty and members of the planning committee to disclose relevant financial relationships within the past 12 months that might create any personal conflicts of interest. Any identified conflicts were resolved to ensure that this educational activity promotes quality in health care and not a proprietary business or commercial interest. The planning committee members reported that they had nothing to disclose.

Acknowledgements

CME/CE INFO

Accreditation:

The Audio- Digest Foundation is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians.

The Audio- Digest Foundation designates this enduring material for a maximum of 1.00 AMA PRA Category 1 Credits™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.

Audio Digest Foundation is accredited as a provider of continuing nursing education by the American Nurses Credentialing Center's (ANCC's) Commission on Accreditation. Audio Digest Foundation designates this activity for 1.00 CE contact hours.

Lecture ID:

JW350502

Expiration:

This CME course qualifies for AMA PRA Category 1 Credits™ for 3 years from the date of publication.

Instructions:

To earn CME/CE credit for this course, you must complete all the following components in the order recommended: (1) Review introductory course content, including Educational Objectives and Faculty/Planner Disclosures; (2) Listen to the audio program and review accompanying learning materials; (3) Complete posttest (only after completing Step 2) and earn a passing score of at least 80%. Taking the course Pretest and completing the Evaluation Survey are strongly recommended (but not mandatory) components of completing this CME/CE course.

Estimated time to complete this CME/CE course:

Approximately 2x the length of the recorded lecture to account for time spent studying accompanying learning materials and completing tests.

More Details - Certification & Accreditation