Food And Drug Administration Safety Research Articles

Longitudinal Patterns in Testosterone Prescribing After US FDA Safety Communication in 2014.

The objective of this study was to describe changes in testosterone prescribing following a 2014 US Food and Drug Administration (FDA) safety communication and how changes varied by physician characteristics. Data were extracted from a 20% random sample of Medicare fee-for-service administrative claims data from 2011 through 2019. The sample included 1,544,604 unique male beneficiaries who received evaluation and management (E&M) services from 58,819 unique physicians that prescribed testosterone between 2011 and 2013. Patients were categorized based on presence of coronary artery disease (CAD) and non-age-related hypogonadism. Physician characteristics were identified in the OneKey database and included specialty and affiliations with teaching hospitals, for-profit hospitals, hospitals in integrated delivery networks, and hospitals in the top decile of case mix index. Linear segmented models described how testosterone prescriptions changed following a 2014 FDA safety communication and how changes were associated with physician and organizational characteristics. Among 65,089,560 physician-patient-quarter-year observations, mean (standard deviation) age ranged from 72.16 (5.84) years for observations without CAD or non-age-related hypogonadism to 75.73 (6.92) years with CAD and without non-age-related hypogonadism. Following the safety communication, immediate changes in off-label testosterone prescription levels fell by 0.22 percentage points (pp) (95% confidence interval [CI] -0.33 to -0.11) for patients with CAD and by -0.16 pp (95% CI -0.19 to -0.16) for patients without CAD. A similar change was noticed in on-label prescribing levels. Off-label testosterone prescription quarterly trend, however, increased for patients with CAD and without CAD; on-label testosterone prescription trends declined for both groups. Declines in off-label prescribing were larger when treated by primary care physicians vs. non-primary care physicians, and physicians affiliated with teaching compared to nonteaching hospitals. Physician and organizational characteristics were not associated with changes in on-label prescribing. On-label and off-label testosterone therapy declined following the FDA safety communication. Certain physician characteristics were associated with changes in off-label, but not on-label, prescribing.

A Comparative Assessment of Approvals and Discontinuations of Systemic Antibiotics and Other Therapeutic Areas.

Since 1980, the US Congress has passed legislation providing several incentives to encourage the development and regulatory approval of new drugs, particularly antibiotics. We assessed long-term trends and characteristics of approvals and discontinuations of all new molecular entities, new therapeutic biologics, and gene and cell therapies approved by the US Food and Drug Administration (FDA), as well as reasons for discontinuations by therapeutic class, in the context of laws and regulations implemented over the past four decades. In the period 1980-2021, the FDA approved 1310 new drugs, of which 210 (16.0%) had been discontinued as of 31 December 2021, including 38 (2.9%) withdrawn for safety reasons. The FDA approved 77 (5.9%) new systemic antibiotics, of which 32 (41.6%) had been discontinued at the end of the observation period, including 6 (7.8%) safety withdrawals. Since the enactment of the FDA Safety and Innovation Act in 2012, which created the Qualified Infectious Disease Product designation for antiinfectives to treat serious or life-threatening diseases due to resistant or potentially resistant bacteria, the FDA has approved 15 new systemic antibiotics, all using non-inferiority trials, for 22 indications and five different infections. Only one of the infections had labeled indications for patients with drug-resistant pathogens.

US Food and Drug Administration regulatory reviewer disagreements and postmarket safety actions among new therapeutics

ObjectivesTo examine the association between regulatory reviewer disagreements and postmarket safety actions among novel therapeutics approved by the US Food and Drug Administration (FDA) between 2011 and 2015. Disagreements among...

Narrative Review: The FDA's Perfunctory Approach of Dietary Supplement Regulations Giving Rise to Copious Reports of Adverse Events.

Background: The Food and Drug Administration (FDA) originated from the passage of the 1906 Pure Food and Drugs act aimed to rein in the long-standing abuse in the consumer product marketplace. The act was passed to prohibit interstate commerce of misbranded and adulterated foods, drinks, drugs. Thus, promoting the FDA's mission to protect the public health by regulating human and veterinary drugs, biological products, medical devices, food supply, cosmetics, and tobacco to ensure safety, efficacy, and security. Progressing further in 1994, the Dietary Supplement Health and Education Act (DSHEA) was established designating specific label requirements, providing regulatory framework, and authorizing the FDA to promulgate good manufacturing practices for dietary supplements. This act defined and classified "dietary supplements" and "dietary ingredients" as food requiring all over the counter products (OTC) products to consist of labeling that is easy to understand and meets the FDA quality, effectiveness, and safety standards. However, under the umbrella of OTC products, the FDA fell short in its regulation of the expansive dietary supplement market. The objective of this study is to discern how the lack of efficacy in the FDA's regulations of OTC dietary supplements inevitably inspired more harm than benefit. Methods: This review comprised of case studies including young adolescents and adult consumers who experienced adverse events from the use of dietary supplements. Products which showed highest prevalence in adverse event reports through the Food and Drug Administration CFSAN Adverse Event Reporting System (CAERS) included but not limited to; Vitamin E (vitamin derivative), Beta-sitosterol (plant sterol) Yohimbine, Kava Kava Kratom, Garcinia Cambogia, (herbal products) and OxyElite Pro (marketed weight loss product). The primary endpoint was evaluating the FDA's regulations on dietary supplement safety protocols. The secondary endpoint was assessing the actions of the FDA in response to these case events. Results: Overall, between 2004 to 2021, a total of 79,071 adverse events related to the use of dietary supplements were reported to the Center for Food Safety and Applied Nutrition. Vitamin E products for example, marketed for decades for their antioxidant benefits in turn have shown significant evidence of toxicity and an increased risk of bleeding outweighing its potential benefit. The FDA's response was simply implementing a label guideline update, yet this update had evidence of minimal effect as the number of cases gradually continued to increase. Likewise, herbal products such as Kava Kava, Yohimbine, Kratom, and Garcinia Cambogia, in addition to weight regulating products, such as OxyElite Pro and HydroxyCut, have been linked to organ failure, hepatic, renal, cardiac toxicity, and death respectively. The FDA merely responded through instating public consumer warnings of their effects with consumption and limited recalls of certain products. Conclusion: With the easy accessibility of these products, the general public is more inclined to its use without proper guidance and monitoring from their healthcare team, posing as a major concern for possible interactions, contraindications and unfavorable outcomes. With proper implementation of stringent regulations post findings from increased studies on efficacy and safety, cases of adverse events could have been reduced significantly or averted completely. The FDA's minimalistic efforts consisting of only post-marketing monitoring and retrospective actions of label modifying have time and time again shown flaws as seen in the growing series of reports. By emending the over-the-counter supplement review process to reflect that of prescription medication, the magnitude of adverse events can be diminished. The process should include preclinical research in addition to clinical research, FDA thorough examination of data prior approval and post marketing surveillance.

Updated Trends in Inferior Vena Cava Filter Use by Indication in the United States After Food and Drug Administration Safety Warnings: A Decade Analysis From 2010 to 2019.

Overall inferior vena cava filter (IVCF) utilization has decreased in the United States since the 2010 US Food and Drug Administration (FDA) safety communication. The FDA renewed this safety warning in 2014 with additional mandates on reporting IVCF-related adverse events. We evaluated the impact of the FDA recommendations on IVCF placements for different indications from 2010 to 2019 and further assessed utilization trends by region and hospital teaching status. Inferior vena cava filter placements between 2010 and 2019 were identified in the Nationwide Inpatient Sample database using the associated International Classification of Diseases, Ninth Revision, Clinical Modification, and Tenth Revision codes. Inferior vena cava filter placements were categorized by indication for venous thromboembolism (VTE) "treatment" in patients with VTE diagnosis and contraindication to anticoagulation and "prophylaxis" in patients without VTE. Generalized linear regression was used to analyze utilization trends. A total of 823 717 IVCFs were placed over the study period, of which 644 663 (78.3%) were for VTE treatment and 179 054 (21.7%) were for prophylaxis indications. The median age for both categories of patients was 68 years. The total number of IVCFs placed for all indications decreased from 129 616 in 2010 to 58 465 in 2019, with an aggregate decline rate of -8.4%. The decline rate was higher between 2014 and 2019 than between 2010 and 2014 (-11.6% vs -7.2%). From 2010 to 2019, IVCF placement for VTE treatment and prophylaxis trended downward at rates of -7.9% and -10.2%, respectively. Urban nonteaching hospitals saw the highest decline for both VTE treatment (-17.2%) and prophylactic indications (-18.0%). Hospitals located in the Northeast region had the highest decline rates for VTE treatment (-10.3%) and prophylactic indications (-12.5%). The higher decline rate in IVCF placements between 2014 and 2019 compared with 2010 and 2014 suggests an additional impact of the renewed 2014 FDA safety indications on national IVCF utilization. Variations in IVCF use for VTE treatment and prophylactic indications existed across hospital teaching types, locations, and regions. Inferior vena cava filters (IVCF) are associated with medical complications. The 2010 and 2014 FDA safety warnings appeared to have synergistically contributed to a significant decline in IVCF utilization rates from 2010 - 2019 in the US. IVC filter placements in patients without venous thromboembolism (VTE) declined at a higher rate than VTE. However, IVCF utilization varied across hospitals and geographical locations, likely due to the absence of universally accepted clinical guidelines on IVCF indications and use. Harmonization of IVCF placement guidelines is needed to standardize clinical practice, thereby reducing the observed regional and hospital variations and potential IVC filter overutilization.

Characteristics of pivotal clinical trials of FDA-approved endovascular devices between 2000 and 2018: An interrupted time series analysis.

The Food and Drug Administration (FDA) reviews safety, efficacy, and the quality of medical devices through its regulatory process. The FDA Safety and Innovation Act (FDASIA) of 2012 was aimed at accelerating the regulatory process for medical devices. The purpose of our study was to (1) quantify characteristics of pivotal clinical trials (PCTs) supporting the premarket approval of endovascular medical devices and (2) analyze trends over the last two decades in light of the FDASIA. We surveyed the study designs of endovascular devices with PCTs from the US FDA pre-market approval medical devices database. The effect of FDASIA on key design parameters (e.g., randomization, masking, and number of enrolled patients) was estimated using an interrupted time series analysis (segmented regression). We identified 117 devices between 2000-2018. FDASIA was associated with a decrease in double blinding (p < 0.0001) and a decrease in historical comparators (p < 0.0001). Our results reveal an overall trend of decreased regulatory requirements as it relates to clinical trial characteristics, but a compensatory increased rate of post-approval across device classes. Furthermore, there was an emphasis on proving equivalence or non-inferiority rather than more use of active comparators in clinical trials. Medical device stakeholders, notably clinicians, must be aware of the shifting regulatory landscape in order to play an active role in promoting patient safety.

Clinical Consensus Statement: Vaginal Energy-Based Devices

(Abstracted from Urogynecology 2022;28:633–648) The US Food and Drug Administration (FDA) announced a July 2018 public warning for using energy-based devices (EBDs) for performing vaginal cosmetic procedures or vaginal rejuvenation, based on both the imprecision of the term “vaginal rejuvenation” and the lack of FDA approval of the use of any devices such as lasers for any specific gynecologic indication. Some health care providers subspecializing in female reconstructive surgery and pelvic medicine deliver patient services via the EBDs discussed in the FDA Safety Communication.

Considerations for the Over-the-Counter Hearing Aid Delivery Model

Purpose: The U.S. Food and Drug Administration (FDA) introduced the Reauthorization Act that included provisions for self-fitting hearing aids to be sold over the counter in 2017, and in August 2022, the FDA published the final regulatory guidelines for the safety and efficacy of the devices. The American Speech-Language-Hearing Association and other professional organizations provided feedback to proposed regulations before they were finalized. This article updates hearing health care and related professionals on the history and state of hearing aid delivery models and addresses considerations for clinicians, physicians, and consumers. Conclusions: Direct-to-consumer (DTC) hearing devices can vary largely in quality and performance capability. Some might meet the finalized FDA safety and performance criteria for over-the-counter hearing aids and be able to provide accurate amplification for mild-to-moderate hearing loss but most likely cannot meet the needs of more severe hearing losses, for which they are not approved. Other DTC devices may not meet the FDA criteria and may not provide accurate amplification for many degrees of hearing loss. It is important that these devices are correctly advertised and marketed to those with hearing loss no worse than mild to moderate. Consumers and health care providers also need to know how to identify quality devices that can meet patients' hearing needs. The DTC hearing devices may be difficult to program; thus, manufacturers should provide support for consumers to properly fit these devices. Lastly, hearing health care professionals should take the time to verify that any current and soon-to-come DTC hearing devices can be useful for a given patient population.

Safe Technical Innovation: Development and Implementation of a Robotic Breast Operation Program.

Safe Technical Innovation: Development and Implementation of a Robotic Breast Operation Program.

Diversity and Inclusion in Pancreatic Cancer Clinical Trials

Diversity and Inclusion in Pancreatic Cancer Clinical Trials

Mycobacterium abscessus Surgical Site Infections Due to Modular Cooler-Heater Units in Cardiac Surgery

Background: In the spring of 2020, we identified 3 patients with organ-space surgical site infections (SSIs) secondary to Mycobacterium abscessus (Table 1). All 3 patients underwent cardiac surgery in the same operating room (OR) during which the CardioQuip Modular Cooler-Heaters (MCHs) were used. We describe key aspects of our cluster investigation, which ultimately led to release of a national safety alert by the Food and Drug Administration (FDA). Methods: For environmental cultures, we obtained samples from 9 MCHs in circulation; 2 scrub sink samples; ice from the OR ice machine; water samples from sinks in the cardiovascular critical care unit, and water samples from floors above the cardiac ORs. All samples were sent for molecular genotyping. For pathway studies, an external environmental engineering team was consulted who conducted smoke pathway tests in 3 different ORs. The team also conducted a particle generator experiment, simulating the set-up of a cardiac bypass surgery case. To assess disinfection practices, we reviewed the manufacturer instructions for use (IFU) protocol of the MCHs and audited our own policies and procedures to ensure compliance. Results: For environmental cultures, molecular typing from 5 of 9 MCHs and all 3 patient SSI isolates returned positive for the identical hybrid species M. abscessus bolleti. All other samples with mycobacterial growth returned with different species. For pathway studies, the particle-generator experiment demonstrated particle movement from the MCH to the sterile field with facilities-guidelines–compliant OR ventilation and despite MCH manufacturing design. For disinfection practices, despite compliance with the stated IFU, and in consultation with experts, we implemented disinfection of associated Quick-connect devices (otherwise not stated in the IFU), and we also initiated a precleaning step prior to disinfection. Conclusions: Our investigation concluded that 3 patients developed SSIs with Mycobacterium abscessus that was aerosolized from the CardioQuip MCH. This finding led to the national FDA safety report alerting providers to risks associated with the device and the need for continued vigilance around disinfection. In addition, we implemented other control measures including placement of MCHs outside all ORs; creation of a separate MCH fleet for non-OR use; and use of modified disinfection protocols. To date, no additional cases have been identified.Funding: NoDisclosures: None

Updated Experience of Mycobacterium chimaera Infection: Diagnosis and Management in a Tertiary Care Center.

BackgroundDespite safety communications from the Food and Drug Administration (FDA) regarding the outbreak of Mycobacterium chimaera infections (MCIs) from contaminated heater-cooler devices, new cases continue to be identified.MethodsWe retrospectively reviewed confirmed cases of MCI that were managed at Mayo Clinic sites (Arizona, Florida, and Minnesota) from 09/2015 to 01/2021. Clinical histories including prior cardiovascular surgery were recorded. Diagnostic workup including ophthalmologic examination, imaging, and laboratory testing was reviewed. Treatment and survival outcomes on follow-up were obtained.ResultsTwelve patients with MCI were included. All patients had aortic valve or graft replacement. Five patients had their surgical procedures following the 10/15/2015 FDA safety communication. The mean time from surgery to symptom onset (range) was 32 (13–73) months. Ten of 11 patients who underwent ophthalmologic examination had chorioretinal abnormalities. Three patients who underwent microbial cell-free deoxyribonucleic acid sequencing tested positive for M. chimaera, which was subsequently confirmed with blood culture growth. Echocardiography and positron emission tomography/computed tomography (PET/CT) revealed evidence of prosthetic valve/graft infection in 7/12 (58.3%) and 6/10 (60.0%) of cases, respectively. Seven patients (58.3%) underwent redo cardiovascular surgery. Of these, 1 patient died 2 days postdischarge, 1 experienced spinal osteomyelitis relapse, and another had interval prosthetic valve fluorodeoxyglucose (FDG) uptake on PET/CT suspicious for recurrent infection. Among 4 patients on medical therapy only, 3 expired or transitioned to hospice during follow-up.ConclusionsMCI continues to occur despite the FDA communications. Incorporation of ophthalmologic examination and use of advanced tools may improve MCI diagnosis. The mortality in these patients is high even with aggressive surgical/medical management.

Outpatient Fluoroquinolone Prescription Fills in the United States, 2014 to 2020: Assessing the Impact of Food and Drug Administration Safety Warnings.

The impact of United States Food and Drug Administration (FDA) safety warnings on outpatient fluoroquinolone use is unclear. Annual changes in outpatient ciprofloxacin, levofloxacin, and moxifloxacin prescription fills (IQVIA National Prescription Audit databases) were assessed using a regression model. Monthly fills during baseline (August 2014 to April 2016) and first (May 2016 to June 2018) and second FDA warning periods (July 2018 to February 2020) were compared by interrupted time series analysis. From 2015 through 2019, total fluoroquinolone fills decreased from 35,616,786 (111.1/1,000 persons) to 21,100,050 (64.3/1,000 persons) annually (10.8% annually [P = 0.001]). Ciprofloxacin, levofloxacin, and moxifloxacin fills decreased annually by 10.4% (P = 0.001), 11.2% (P < 0.001), and 17.7% (P = 0.008), respectively. During the baseline period, there was no significant change in monthly fluoroquinolone fills. In May 2016 and during the first warning period, monthly fluoroquinolone fills decreased significantly (P < 0.001); the trend of decreased fills was significantly greater than that of the baseline period (P = 0.02). There was no change in fluoroquinolone fills in July 2018. Monthly fills decreased significantly throughout the second warning period (P < 0.001), but the trend did not differ from that of the first warning period. Trends for ciprofloxacin, the most commonly prescribed fluoroquinolone, were similar to those for the class. Fills of prescriptions by infectious diseases specialists (P < 0.005) and nurse practitioners (P = 0.04) significantly increased during the study. U.S. outpatient fluoroquinolone prescription fills significantly decreased from August 2014 to February 2020, most strongly in association with May 2016 FDA warnings. FDA safety warnings are useful tools for leveraging outpatient antimicrobial stewardship.

FDA safety warning on the cardiac effects of lamotrigine: An advisory from the Ad Hoc ILAE/AES Task Force.

The International League Against Epilepsy (ILAE) / American Epilepsy Society (AES) Task Force on the cardiac effects of lamotrigine was convened in response to a recent addition to the lamotrigine label by the US Food and Drug Administration (FDA). 1 Lamotrigine is the nonproprietary name for a medicine that is sold under its generic name and several brand names including Lamictal™. The present advisory is based on an assessment of currently available evidence. It is not intended to replace regulatory requirements, nor is it intended to be an exhaustive review. Its purpose is to advise healthcare professionals worldwide on how to minimize cardiac safety risks associated with lamotrigine use.

Vaginal laser treatment of genitourinary syndrome of menopause: does the evidence support the FDA safety communication?

Genitourinary syndrome of menopause (GSM) is a chronic, progressive condition frequently manifesting as vaginal dryness and pain with intercourse. Survey data indicate this is a highly prevalent, likely underreported, condition that profoundly affects quality of life for millions of women. Vaginal lasers demonstrate promise as an effective, nonhormone therapeutic alternative for GSM; however, the risks associated with them may have been overstated. Despite reports of improved sexual and vaginal comfort without serious safety concerns, the Food and Drug Administration (FDA) issued a 2018 safety communication warning against it. We conducted a systematic literature review and surveyed both the FDA Manufacturer and User Facility Device Experience (MAUDE) and Bloomberg Law Databases to evaluate risks associated with laser treatment for GSM. A systematic literature review identified articles published before September 2019. The MAUDE database was searched by name from 2009 to 2019 for safety claims for 24 vaginal laser devices. The Bloomberg Law database was searched for product liability claims against any vaginal laser device manufacturer before July 2019. Literature review revealed 3 publications detailing 29 presumptive laser-associated complications, only 5 of which (17.2%) reported worsening symptoms after treatment. The MAUDE database contained 120 complaints; only 30 (25%) detailed potential adverse patient events, most frequently pain (n = 12) and burning (n = 10). The Bloomberg law database contained no claims asserting harm from device use. Lacking strong evidence indicating significant patient risk for vaginal laser treatment of GSM, the FDA safety communication appears unsubstantiated and implies gender bias. Identified complications suggest most reported "adverse events" represent lack of treatment effect. The well-documented benefits and low risk of adverse event suggest laser therapy for GSM is reasonable with appropriate pretreatment counseling. Additional randomized, well-controlled clinical trials are needed to further elucidate both the safety and efficacy of this nonhormone therapy.

Occult Uterine Malignancy at the Time of Sacrocolpopexy in the Context of the Safety Communication on Power Morcellation by the FDA

The objective of this study was to determine the incidence of occult uterine malignancy at the time of sacrocolpopexy with concurrent hysterectomy, in the context of practice pattern changes as a result of the 2014 Food and Drug Administration (FDA) power morcellation safety communication. Retrospective chart review. Tertiary care referral center in the United States. A total of 839 patients who underwent sacrocolpopexy from January 2004 to December 2018. All patients received a concurrent hysterectomy without a diagnosis of suspected or confirmed gynecologic malignancy before surgery. Trends of surgeries were compared before and after the 2014 FDA power morcellation safety communication. Demographic and perioperative data were collected from the system-wide electronic medical record. Operative and pathology reports were reviewed to determine the method of specimen retrieval and specimen pathology results. A total of 238 patients (28.4%) had a hysterectomy at the time of sacrocolpopexy. There were no cases of occult uterine malignancy (0%, 95% CI 0%-1.6%). There was 1 case of borderline tumor of the ovary. The most common mode of hysterectomy over the 15-year period was laparoscopic hysterectomy (n = 84, 35.3%), followed by vaginal hysterectomy (n = 63, 26.5%). After the FDA communication, the most common form of hysterectomy changed significantly to vaginal hysterectomy (n = 35, 55.6%; p <.001). When comparing the first 2 years after the announcement (2014-2016) to the subsequent 2 years (2017-2018), there was again a significant increase in the use of laparoscopic hysterectomy in the latter time period (7.3% vs 40.9%; p <.001). In this cohort of patients undergoing sacrocolpopexy with concurrent hysterectomy, the incidence of occult uterine malignancy was low. After the FDA safety communication, practice patterns with regard to the mode of hysterectomy changed, but the magnitude of these changes were transient.

AORN Position Statement on Environmental Responsibility

<scp>AORN</scp> Position Statement on Environmental Responsibility

Biotin interference in routine laboratory tests: A bibliometric analysis

Biotin interference in routine laboratory tests: A bibliometric analysis

Food and Drug Administration Safety Communication on the Use of Transvaginal Mesh in Pelvic Organ Prolapse Repair Surgery: The Impact of Social Determinants of Health.

This study was to examine the impact of the July 2011 Food and Drug Administration (FDA) safety communication on the use of transvaginal mesh in pelvic organ prolapse (POP) repair by patients' race and ethnicity. We conducted an observational cohort study of women undergoing POP repairs in 2008 to 2015 in New York State. We examined the changes in transvaginal mesh use in POP repairs before and after the FDA communication by patients' race and ethnicity. Piecewise logistic regression models were used to assess the trends of mesh use, adjusting for patient characteristics. We performed a subgroup analysis of the trends of transvaginal mesh use by racial groups, stratifying by patients' neighborhood socioeconomic status. We included 49,848 women (78% white, 7% black, and 15% Hispanic) with an average ± SD age of 60.2 ± 13.0 years. After the safety communication, the use of transvaginal mesh in POP repairs decreased among white women (odds ratio [OR], 0.45; 95% confidence interval [CI], 0.41-0.50) and African Americans (OR, 0.48; 95% CI, 0.35-0.67) but remained stable among Hispanic women (OR, 0.88; 95% CI, 0.70-1.11). Only in the subgroup of patients from high-income areas, there was a trend toward decreasing mesh use among Hispanic patients after 2011 (OR, 0.71; 95% CI, 0.49-1.04). The communications related to the safety of transvaginal mesh did not have an equal impact across racial groups. Mesh use decreased among white and African American women but not among Hispanic women after the 2011 FDA safety communication. Particular attention is warranted for patients from disadvantaged groups, especially low-income minorities, when disseminating medical device safety messages.

Contemporary Trends in Prescription of Dipeptidyl Peptidase-4 Inhibitors in the Context of US Food and Drug Administration Warnings of Heart Failure Risk

Dipeptidyl peptidase-4 inhibitors (DPP-4i) are one of the most widely used antihyperglycemic therapeutic classes in type 2 diabetes mellitus management. In April 2016 and August 2017, the US Food and Drug Administration (FDA) introduced sequential labelling requirements regarding heart failure risk related to DPP-4i. We explored longitudinal trends in prescription of DPP-4i before and after these FDA warnings in a multicenter health system. We identified all first-time prescriptions of DPP4i or their combinations across the Partners HealthCare system (Boston, MA) from October 2006 (FDA approval of first DPP-4i) to December 2018. Overall, 11,830 patients were newly prescribed DPP-4i during the study period. Primary care physicians (31.5%) were the most common prescribing specialty. Overall, 8.4%, 20.4%, and 11.6% had heart failure, atherosclerotic cardiovascular disease, and chronic kidney disease, respectively. Median number of background antihyperglycemic therapies was 2 [25th to 75th percentiles 1 to 2], commonly metformin (65.4%) and/or insulin (36.4%). The vast majority of prescriptions were sitagliptin (85.7%), followed by linagliptin (9.5%), saxagliptin (4.7%), and alogliptin (0.2%). Quarterly prescriptions rose gradually from 2006 to mid-2016, and have decreased consistently since then for each of the 4 DPP-4i. Declines in DPP-4i among high-risk groups and those initiated by endocrinologists were most pronounced. In conclusion, although DPP-4i remain a dominant oral antihyperglycemic therapy in clinical practice, new prescriptions have declined recently. These data may reflect relatively swift health system response to broad FDA safety communications regarding heart failure risk, which appeared to impact the entire DPP-4i class, including specific drugs that have not demonstrated any increased risk of heart failure.