Author + information
- Published online December 17, 2018.
- Muthiah Vaduganathan, MD, MPH,
- Vasanth Sathiyakumar, MD,
- Avinainder Singh, MBBS, MMSc,
- Cian P. McCarthy, MB, BCh, BAO,
- Arman Qamar, MD,
- James L. Januzzi Jr., MD,
- Benjamin M. Scirica, MD, MPH,
- Javed Butler, MD, MPH, MBA,
- Christopher P. Cannon, MD and
- Deepak L. Bhatt, MD, MPH∗ (, )@DLBHATTMD
- ↵∗Brigham and Women’s Hospital Heart & Vascular Center, Harvard Medical School, 75 Francis Street, Boston, Massachusetts 02115
Sodium glucose cotransporter-2 inhibitors (SGLT2i) are glucose-lowering therapies with distinct cardiometabolic health benefits. Empagliflozin was shown to reduce risk of cardiovascular death among high-risk patients with type 2 diabetes mellitus (1), which led to the U.S. Food and Drug Administration (FDA) expanding its labeling in December 2016 for reducing cardiovascular risk. Canagliflozin was also demonstrated to reduce major adverse cardiovascular events (2) and FDA evaluation for potential change in its labeling is currently pending.
Despite initial regulatory approval of the first SGLT2i >5 years ago, SGLT2i use remains limited in the United States (3). It is uncertain whether use of these therapies has increased among cardiologists following availability of cardiovascular outcomes trial data. Therefore, we sought to determine specialty-specific prescriber trends of SGLT2i in a large U.S. tertiary care system over the last 5 years.
We retrospectively identified all first-time outpatient prescriptions of FDA-approved SGLT2i (canagliflozin, dapagliflozin, empagliflozin, and ertugliflozin) and marketed combinations with other glucose-lowering therapies from March 2013 (first SGLT2i FDA approval) to December 2017 (1 year after expanded FDA labeling of empagliflozin) across the multicenter Partners HealthCare system (Boston, Massachusetts), which includes Brigham and Women’s Hospital and Massachusetts General Hospital. Statistical analyses were performed with STATA 14.1 (StataCorp, College Station, Texas). The study was approved by the Partners HealthCare Institutional Review Board.
Overall, 1,874 patients received 1,991 SGLT2i prescriptions (117 patients were switched from one SGLT2i to another). An additional 2,143 patients had mentions of SGLT2i in the medical record, but were not prescribed therapy. Median age was 62 (interquartile range: 54 to 69) years, 59.1% were men, and 76.5% were white.
By specialty, prescription rates were the following: cardiology (5.1%), endocrinology (40%), primary care physicians (PCPs) (23.1%), other specialties (18.6%), and unclassified (13.2%) during the study period (Figure 1A). Of prescribers, endocrinologists most commonly (67.5%) initiated a switch to another SGLT2i. In the year after addition of the cardiovascular indication for empagliflozin, endocrinologists continued to prescribe the highest proportion of prescriptions (45.4%), followed by PCPs (22.7%), while cardiologists prescribed 4.5% of annual prescriptions.
Median number of background glucose-lowering therapies in the year before SGLT2i prescription was 2 (interquartile range: 1 to 3) and did not differ by major prescriber specialty. Glucagon-like peptide-1 receptor agonists were co-prescribed in 17.8%, most frequently by endocrinologists (53.8%) and least frequently by cardiologists (4.5%).
Canagliflozin was the most prescribed (61.4%), followed by empagliflozin (32.4%) and dapagliflozin (6.1%) (Figure 1B). Ertugliflozin was approved in December 2017, and no patients had yet been prescribed this agent. Canagliflozin comprised 78.9% to 100% of all prescriptions across quarters in 2013 to 2015. However, canagliflozin prescription rates decreased after 2016. Empagliflozin was the most prescribed agent (57.5%) in 2017, while canagliflozin accounted for 37% of prescriptions.
In this retrospective, tertiary care center “real world” experience, we tracked prescriber patterns of SGLT2i from 2013 to 2017. Cardiologists prescribed only ∼5% of all SGLT2i, while endocrinologists and PCPs represent major prescribers of these agents (accounting for nearly two-thirds of prescriptions). These prescription practices did not appreciably change 1 year after broadening of the FDA labeling of empagliflozin. SGLT2i are often prescribed on the background of 2 other glucose-lowering therapies, but are infrequently co-prescribed with glucagon-like peptide-1 receptor agonists. Given that nearly 1 in 3 patients with cardiovascular disease has comorbid type 2 diabetes mellitus, there remains an unmet need for prompt identification of potential treatment candidates and development of implementation pathways in cardiology practices (4).
Clinical outcomes data and FDA regulatory labeling represent potentially important drivers influencing selection of specific drugs within a class (4). Canagliflozin, the first SGLT2i to receive FDA approval, was the most prescribed agent during our study period. However, following publication of the EMPA-REG OUTCOME trial, subsequent addition of a cardiovascular indication for empagliflozin, and communication of potential amputation risks with canagliflozin by the FDA (5), prescription rates for empagliflozin increased while canagliflozin prescription rates decreased. The influence of recently completed and ongoing cardiovascular outcomes trials of SGLT2i on prescriber patterns remains to be seen.
We were unable to query patients eligible for SGLT2i due to limitations of our electronic health record system. Only new prescriptions for SGLT2i within Partners HealthCare were studied, potentially misidentifying original prescribers if prescriptions were initiated externally. We were not able to ascertain prescription fill or adherence rates. Finally, these data from an integrated tertiary care system may not be generalizable to all settings.
Increasing familiarity and utilization of SGLT2i by cardiologists provides an additional avenue to improve cardiovascular health in this high-risk population.
Please note: Drs. Vaduganathan and Qamar are supported by National Heart, Lung, and Blood Institute T32 postdoctoral training grants (T32HL007604). Dr. Vaduganathan has served on advisory boards for Bayer AG and Baxter Healthcare. Dr. Januzzi is supported in part by the Hutter Family Professorship; has received grant support from Abbott, Cleveland Heart Labs, Singulex, and Prevencio; has received consulting income from Roche Diagnostics, Critical Diagnostics, and Novartis; and has participated in clinical endpoint committees or data or safety monitoring boards for Novartis, Amgen, GE, Janssen, Pfizer, and Boehringer Ingelheim. Dr. Butler has received research support from the National Institutes of Health and European Union; and has served as a consultant for Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, CVRx, Janssen, Luitpold Pharmaceuticals, Medtronic, Merck, Novartis, Relypsa, Vifor Pharma, and ZS Pharma. Dr. Scirica has received research grant support from AstraZeneca, Eisai, Novartis, and Merck; has received consulting fees from AstraZeneca, Biogen Idec, Boehringer Ingelheim, Covance, Dr. Reddy’s Laboratory, Eisai, Elsevier Practice Update Cardiology, GlaxoSmithKline, Lexicon, Merck, Novo Nordisk, Sanofi, and St. Jude Medical; and owns equity in Health [at] Scale. Dr. Cannon has received research grant support from Amgen, Arisaph, Boehringer Ingelheim, Bristol-Myers Squibb, Daiichi Sankyo, Janssen, Merck, and Takeda; and consulting fees from Alnylam, Amgen, Arisaph, AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, GlaxoSmithKline, Kowa, Lipimedix, Merck, Pfizer, Regeneron, Sanofi, and Takeda. Dr. Bhatt has served on the advisory board for Cardax, Elsevier Practice Update Cardiology, Medscape Cardiology, and Regado Biosciences; has served on the board of directors for Boston VA Research Institute, Society of Cardiovascular Patient Care, and TobeSoft; has served as the Chair of the American Heart Association Quality Oversight Committee, NCDR-ACTION Registry Steering Committee, and VA CART Research and Publications Committee; has served on the data monitoring committees for the Baim Institute for Clinical Research (formerly Harvard Clinical Research Institute, for the PORTICO trial, funded by St. Jude Medical, now Abbott), Cleveland Clinic, Duke Clinical Research Institute, Mayo Clinic, Mount Sinai School of Medicine, and Population Health Research Institute; has received honoraria from the American College of Cardiology (Senior Associate Editor, Clinical Trials and News, ACC.org; Vice-Chair, ACC Accreditation Committee), Baim Institute for Clinical Research (formerly Harvard Clinical Research Institute; RE-DUAL PCI clinical trial steering committee funded by Boehringer Ingelheim), Belvoir Publications (Editor in Chief, Harvard Heart Letter), Duke Clinical Research Institute (clinical trial steering committees), HMP Global (Editor in Chief, Journal of Invasive Cardiology), Journal of the American College of Cardiology (Guest Editor; Associate Editor), Population Health Research Institute (COMPASS clinical trial steering committee funded by Bayer), Slack Publications (Chief Medical Editor, Cardiology Today’s Intervention), Society of Cardiovascular Patient Care (Secretary/Treasurer), WebMD (CME steering committees); has served as the Deputy Editor for Clinical Cardiology; has received research funding from Abbott, Amarin, Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Chiesi, Eisai, Ethicon, Forest Laboratories, Idorsia, Ironwood, Ischemix, Lilly, Medtronic, PhaseBio, Pfizer, Regeneron, Roche, Sanofi, Synaptic, and The Medicines Company; has received royalties from Elsevier (Editor, Cardiovascular Intervention: A Companion to Braunwald’s Heart Disease); has served as a site co-investigator for Biotronik, Boston Scientific, St. Jude Medical (now Abbott), and Svelte; has served as a trustee for the American College of Cardiology; and has conducted unfunded research for FlowCo, Merck, Novo Nordisk, PLx Pharma, and Takeda. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose. Drs. Vaduganathan and Sathiyakumar contributed equally to this work.
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