News Release

Wakefulness-promoting agents effective for excessive daytime sleepiness but patients may discontinue due to side effects

Embargoed News from Annals of Internal Medicine

Peer-Reviewed Publication

American College of Physicians

1. Wakefulness-promoting agents effective for excessive daytime sleepiness but patients may discontinue due to side effects
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A systematic review and analysis of 14 trials found that solriamfetol, armodafinil–modafinil, and pitolisant reduce excessive daytime sleepiness (ESA) for patients with obstructive sleep apnea (OSA) already using conventional therapy. However, patients may be more likely to discontinue the use of these medications due to adverse events including headache, anxiety, and insomnia. The review is published in Annals of Internal Medicine.

Symptoms of EDS are often improved with standard treatment of OSA, but it may persist in up to 18 percent of OSA patients despite ongoing conventional therapy. EDS is associated with neuropsychological impairment and decreased quality of life, and treatment is a continued priority for clinicians. Pharmacological interventions for OSA include solriamfetol and armodafinil–modafinil, which are approved for OSA treatment in the U.S., and pitolisant, which has been studied in previous trials but is not approved for treatment of OSA.

Researchers from McMaster University, Dalhousie University, and the University of Toronto conducted a systematic review and meta-analysis of 14 trials enrolling 3,085 patients and included the use of armodafinil, modafinil, solriamfetol, and pitolisant–H3-autoreceptor antagonist. The authors found that solriamfetol, armodafinil–modafinil and pitolisant reduced daytime sleepiness for patients with OSA already on conventional therapy, and solriamfetol was likely superior in effectiveness. However, adverse events including headache, insomnia, and anxiety were associated with an increased risk for discontinuation in several trials. According to the authors, future research should address potential long-term and rare harms that may be associated with these drugs and potential differential effects of these drugs in patients who are not adherent to conventional OSA treatment.

Media contacts: For an embargoed PDF, please contact Angela Collom at To speak with corresponding author Dena Zeraatkar, PhD, please email Veronica McGuire at
2. GLP1RA, but not SGLT2i, associated with reduced hospitalizations for heart failure, stroke, and death compared with DPP4i
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A cohort study of older persons without heart disease found that the use of glucagon-like peptide-1 receptor agonists (GLP1RA) reduced major adverse cardiac events (MACE) and heart failure (HF) hospitalization compared with dipeptidyl peptidase-4 inhibitors (DPP4i). However, the use of sodium–glucose cotransporter-2 inhibitors (SGLT2i) was not associated with similar reductions. The findings are published in Annals of Internal Medicine.

More than 30 million adults in the United States have diabetes mellitus and it’s a condition that carries a high risk for cardiovascular disease (CVD). Previous trials have demonstrated benefits for using GLP1RA and SGLT2i to reduce MACE risk in persons with diabetes and preexisting CVD, but the use of these medications in preventing complications among persons with CVD remains unclear.

Researchers from Vanderbilt University Medical Center and the Veterans Health Administration Tennessee Valley Healthcare System conducted a retrospective cohort study of older veterans with diabetes and without heart disease who received care between 2001 and 2019. The authors found that compared with DPP4i, the addition of GLP1RA to baseline diabetes therapy was associated with reduced MACE and HF hospitalization events. However, the addition of SGLT2i was not associated with reduced MACE and HF hospitalizations compared with adding DPP4i. According to the authors, their findings in aggregate suggest that GLP1RA may have a role in CVD prevention. Diabetes and its complications represent an enormous health care burden and prevention of heart disease for those who are at highest risk is an important goal of doctors, scientists and patients.

An accompanying editorial by Steven S. Nissen, MD of the Cleveland Clinic discusses the limitations of using observational studies for clinical decision making. This type of research may overemphasize its value or applicability. He highlights that large observational studies can be useful and informative, but the choice of outcomes measured, and the study method must be carefully considered, and the results interpreted within the context of the study’s limitations.

Media contacts: For an embargoed PDF, please contact Angela Collom at To speak with corresponding author Christianne L. Roumie, M.D., MPH, please email Paul Govern at
3. At the right cost, screening for 3 selected genetic disorders could be cost effective

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A cost-effectiveness analysis of screening tests for three common genetic disorders found that conducting these tests in adults under the age of 40 could be cost-effective at a population level if test costs are sufficiently low. The findings are published in Annals of Internal Medicine.

In 2014, the Centers for Disease Control and Prevention (CDC) designated three genetic tests as having evidence-based guidelines and recommendations to prevent morbidity and mortality associated with genetic risk. These genetic conditions include Lynch syndrome (LS), which is associated with a higher risk for colorectal cancer, hereditary breast and ovarian cancer (HBOC), and familial hypercholesterolemia (FH), which is associated with a greater risk for early heart disease and stroke. However, modeling studies to date have suggested that screening for these genetic conditions independently is not cost-effective.

Researchers from the University of Washington, Geisinger, and Vanderbilt University Medical Center conducted a cost-effectiveness analysis of multiple cohorts aged 20 to 60 that reflect the current U.S. population. The authors found that if all three conditions are bundled together in the same test, which was assumed to cost $250 and confirmed with a second test, one-time screening of US adults age 40 and under was cost-effective according to commonly used thresholds. For every 100,000 individuals screened with genomic testing, 101 cancers and 15 cardiovascular events were prevented compared to testing based on family history alone, which translated to 495 quality-of-life-adjusted years of additional survival. To address considerations beyond cost-effectiveness, the authors recommend that a policy analysis be conducted that considers budgetary impact, availability of trained genetic counselors and other resources, longitudinal follow-up in primary care settings, and assessment by clinical guidelines and reimbursement policymakers.

Media contacts: For an embargoed PDF, please contact Angela Collom at To speak with corresponding author Josh F. Peterson, M.D., MPH, please contact

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