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    Original Investigation
    Diabetes and Endocrinology
    February 7, 2020

    Differences Between Randomized Clinical Trial Participants and Real-World Empagliflozin Users and the Changes in Their Glycated Hemoglobin Levels

    Author Affiliations
    • 1Department of Clinical Epidemiology, Institute of Clinical Medicine, Aarhus University Hospital, Aarhus, Denmark
    • 2Clinical Pharmacology and Pharmacy, University of Southern Denmark, Odense, Denmark
    • 3Department of Public Health, Aarhus University, Aarhus, Denmark
    • 4Danish Diabetes Academy, Odense, Denmark
    • 5Steno Diabetes Center Aarhus, Aarhus, Denmark
    JAMA Netw Open. 2020;3(2):e1920949. doi:10.1001/jamanetworkopen.2019.20949
    Key Points español 中文 (chinese)

    Question  To what extent do real-world initiators of empagliflozin and the changes in their glycated hemoglobin (HbA1c) levels associated with empagliflozin use differ from participants and outcomes in randomized clinical trials?

    Findings  In this cross-sectional study of 7034 empagliflozin initiators, more than half would have been ineligible for the randomized clinical trials leading to the approval of empagliflozin, primarily because of baseline comedications, comorbidities, and HbA1c levels. Overall, reductions in HbA1c levels were similar between real-world patients and trial participants.

    Meaning  These findings suggest that the efficacy of empagliflozin in reducing HbA1c in trials translates into real-world effectiveness, but they also underscore the importance of conducting studies after drug approval, given that real-world patients differ from randomized clinical trial participants.


    Importance  Use of the sodium-glucose cotransporter 2 inhibitor empagliflozin has increased substantially since 2015. Little is known about characteristics of real-world patients who use empagliflozin or about empagliflozin’s effectiveness in reducing glycated hemoglobin (HbA1c) levels in routine clinical care.

    Objectives  To characterize real-world initiators of empagliflozin, to examine the proportion of initiators who would have been eligible for participation in phase 3 randomized clinical trials (RCTs) of empagliflozin, and to assess changes in HbA1c levels after empagliflozin initiation.

    Design, Setting, and Participants  This cross-sectional study used linked population-based medical databases containing complete information on redeemed prescriptions, laboratory tests, and diagnoses for all residents in Northern Denmark. A total of 7034 residents of Denmark who filled a first-time empagliflozin prescription from January 2014 to December 2018 were included. Data analysis was performed in August 2019.

    Exposure  Empagliflozin initiation.

    Main Outcomes and Measures  Proportion of real-world users ineligible for RCT inclusion and absolute reduction in HbA1c level 6 months after empagliflozin initiation.

    Results  Of 7034 first-time empagliflozin initiators (median [interquartile range] age, 61.50 [53.30-69.38] years; 4475 [63.6%] men), 3878 (55.1%) would have been ineligible for phase 3 RCT participation; frequent reasons were concurrent use of specific glucose-lowering drugs (1955 initiators [27.8%]), baseline HbA1c level outside the eligibility range (1772 [25.2%]), or presence of comorbidities (1067 initiators [15.3%]). Initiation of empagliflozin was associated with a mean HbA1c reduction of −0.91% (95% CI, −0.94% to −0.87%) after 6 months, similar to phase 3 RCT results. Real-world empagliflozin initiators who would have been eligible for RCT participation experienced slightly lower mean HbA1c reductions (−0.78%; 95% CI, −0.82% to −0.74%) compared with patients who would have been ineligible (−1.01%; 95% CI, −1.07% to −0.95%). Ineligible initiators had higher median (interquartile range) baseline HbA1c values than eligible initiators (8.5% [7.4% to 10.1%] vs 8.2% [7.6% to 9.8%]).

    Conclusions and Relevance  In this cross-sectional study, more than half of empagliflozin initiators exhibited clinical characteristics that would have led to ineligibility for the RCTs leading to the drug’s approval. While the findings suggest that the efficacy of empagliflozin in reducing HbA1c levels translates into real-world effectiveness, further studies should examine clinical outcome effectiveness and drug safety in routine clinical care.