News Release 

Potentiall fatal infection of genitals identified as rare side effect of SGLT2 Inhibitors

Embargoed news from Annals of Internal Medicine

American College of Physicians

1. Serious and potentially fatal infection of the genitals identified as a rare side-effect of SGLT2 inhibitors

Awareness of this potential issue can inform prescriber-patient discussions about appropriate diabetes therapy

Abstract: http://annals.org/aim/article/doi/10.7326/M19-0085

URLs go live when the embargo lifts

Physicians prescribing a sodium-glucose cotransporter-2 (SGLT2) inhibitor for type 2 diabetes should be on alert for symptoms of Fournier gangrene, a rare form of the necrotizing bacterial infection that affects soft tissue in the genitals. Fournier gangrene is a newly identified safety concern in patients receiving SGLT2 inhibitors that should receive immediate attention, if suspected. Findings from a review of spontaneous postmarketing cases is published in Annals of Internal Medicine.

Fournier gangrene is a rare urologic emergency characterized by a rapidly progressive necrotizing infection of the external genitalia, perineum, and perianal region requiring broad-spectrum antibiotics and immediate surgical intervention. Diabetes is a comorbid condition in 32 to 66 percent of cases. SGLT2 inhibitors are a newer medication prescribed to improve glycemic control by inhibiting reabsorption of filtered glucose in the proximal tubules of the kidney, which increases urinary glucose excretion. The most common adverse reactions identified with SGLT2 inhibitors in clinical trials were genital mycotic and urinary tract infections, but the SGLT2 inhibitor class can also be associated with Fournier gangrene.

Researchers from the U.S. Food and Drug Administration reviewed adverse event reports to describe and compare reported cases of Fournier gangrene in patients receiving SGLT2 inhibitors versus other antiglycemic agents. The researchers identified 55 cases among patients receiving SGLT2 inhibitors during the 6 years since canagliflozin received U.S. marketing approval in March 2013. Serious complications and death are likely if Fournier gangrene is not recognized immediately and surgical intervention is not carried out within the first few hours of diagnosis. All patients in the case series were hospitalized, some required several surgeries, some had complications, and three died as a result of Fournier gangrene. The researchers found only 19 Fournier gangrene cases in 35 years among patients receiving other classes of antiglycemic agents. According to the researchers, awareness of the association between Fournier gangrene and SGLT2 inhibitor use may be an important factor in an informed prescriber-patient discussion regarding appropriate diabetes therapy.

Media contacts: For an embargoed PDF, please contact Angela Collom at acollom@acponline.org. To interview the lead author, Susan J. Bersoff-Matcha, MD, please contact Kristofer Baumgartner at CDERTradePress@fda.hhs.gov.

2. PFO associated with four-fold increased risk for ischemic stroke in patients with PE

Abstract: http://annals.org/aim/article/doi/10.7326/M18-3485

Editorial: http://annals.org/aim/article/doi/10.7326/M19-1089

URLs go live when the embargo lifts

The presence of patent foramen ovale (PFO) was associated with a four-fold increase in risk for ischemic stroke in patients admitted for symptomatic pulmonary embolism (PE). Findings from a prospective cohort study are published in Annals of Internal Medicine.

PE is associated with increased risk for ischemic stroke, but the underlying mechanism remains unclear. Researchers hypothesized that paradoxical embolism through PFO could be the cause.

Researchers for the French Department of Health studied 361 consecutive patients with symptomatic acute PE from November 2009 through December 2015 at four French hospital centers to determine the frequency of recent ischemic stroke according to whether PFO was detected. All of the patients underwent predefined and standardized MRI within 7 days of admission to identify the presence of a recent ischemic cerebral injury and contrast transthoracic echocardiography to detect the presence of PFO with each of the two examinations being interpreted without knowledge of the result of the other. They found that recent ischemic stroke was significantly more frequent in the PFO group than in the non-PFO group. According to the authors, this finding supports the hypothesis that paradoxical embolism is an important mechanism of ischemic stroke in patients with concomitant PFO and PE. Nevertheless, whether patients with PE should be screened for PFO in daily practice remains to be determined.

Media contacts: For an embargoed PDF, please contact Angela Collom at acollom@acponline.org. The lead author, Emmanuelle Le Moigne, MD, PhD, can be contacted directly at emmanuelle.lemoigne@chu-brest.fr.

3. Supplement to Annals offers resources to help physicians talk with their patients about cost of care

Eight articles and several support tools were funded by a grant from Robert Wood Johnson Foundation's Cost Conversation Projects

Editorial: http://annals.org/aim/article/doi/10.7326/M19-0537

Editorial: http://annals.org/aim/article/doi/10.7326/M19-0778

Tools: http://www.acponline.org/costofcare

URLs go live when the embargo lifts

The findings of 8 projects published in a supplement to Annals of Internal Medicine suggest strategies for discussing the cost of care during clinical encounters. Funded by a grant from Robert Wood Johnson Foundation's (RWJF) Cost Conversation Projects, the supplement includes links to tools designed to overcome barriers that may impede such conversations. The supplement and related resources are available for free at http://www.Annals.org.

Out-of-pocket costs associated with health care are rising and many Americans find themselves paying higher deductibles or foregoing care altogether. For example, 35 percent of American adults under the age of 64 reported not getting needed medical care because of out-of-pocket costs. While patients and physicians have expressed a desire to talk about the cost of medical care, evidence shows that these conversations seldom occur.

The American College of Physicians (ACP) partnered with RWJF, America's Essential Hospitals, the National Patient Advocate Foundation, Avalere Health and 8 research grantees to develop resources for clinicians to support conversations with patients about the expected costs of their care. The research grantees present their work in the following supplement articles:

Notes and media contacts: For an embargoed PDF of any or all of the articles, or for author contact information, please contact Angela Collom at acollom@acponline.org with specific requests.

4. A substantial share of clinical trials go unreported

Abstract: http://annals.org/aim/article/doi/10.7326/M19-0440

Editorial: http://annals.org/aim/article/doi/10.7326/M19-1273

URLs go live when the embargo lifts

A substantial share of randomized clinical trials (RCTs) go unpublished and their results go unreported. The loss of evidence from these trials pertained to nearly 90,000 participants and affects the quality of data of available, published research. Results from a brief research report are published in Annals of Internal Medicine.

Researchers from Stanford University searched ClinicalTrials.gov for studies with a start date after June 2, 2007 and completed before June 1 2012 to assess the preregistered RCTs that were still both unpublished and lacked reported results more than 46 months after completion. The researchers evaluated whether the trials or any of their results subsequently were published. Of 146 large RCTs without main publications listed or results posted on ClinicalTrials.gov, 60 had in fact been published by that time. Two additional trials had duplicate records, and 84 were unreported, meaning they had neither been published nor were their results posted. Seventy of them remained unpublished after another 30 months of follow up by early 2019.

The authors noted that in fields with several available treatments, unreported large trials may represent a substantial share of the evidence. According to the researchers, this lost evidence threatens the credibility of the evidence that has been published. The authors of an accompanying editorial agreed and further said that not reporting results of clinical trials is academic misconduct.

Media contacts: For an embargoed PDF, please contact Angela Collom at acollom@acponline.org. To interview the lead author, John P.A. Ioannidis, MD, DSc, please contact him directly at jioannid@stanford.edu.

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Also New in this issue:

Cases in Precision Medicine: Concerns About Privacy and Discrimination After Genomic Sequencing

Deborah Stiles, JD; Paul S. Appelbaum, MD

Precision Medicine

Abstract: http://annals.org/aim/article/doi/10.7326/M18-2666

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