TY - JOUR
T1 - Emulating the GRADE trial using real world data
T2 - Retrospective comparative effectiveness study
AU - Deng, Yihong
AU - Polley, Eric C.
AU - Wallach, Joshua D.
AU - Dhruva, Sanket S.
AU - Herrin, Jeph
AU - Quinto, Kenneth
AU - Gandotra, Charu
AU - Crown, William
AU - Noseworthy, Peter
AU - Yao, Xiaoxi
AU - Lyon, Timothy D.
AU - Shah, Nilay D.
AU - Ross, Joseph S.
AU - McCoy, Rozalina G.
N1 - Funding Information:
Funding : This publication is supported by the Food and Drug Administration of the US Department of Health and Human Services (HHS) as part of a financial assistance (Center of Excellence in Regulatory Science and Innovation grant to Yale University and Mayo Clinic U01FD005938) totaling $250 000 with 100% funded by FDA/HHS. RGM is also supported by the National Institutes of Health (NIH) National Institute of Diabetes and Digestive and Kidney Diseases (grant number K23DK114497). The funders had no role in considering the study design or in the collection, analysis, interpretation of data, writing of the report, or decision to submit the article for publication. The contents are those of the authors and do not necessarily represent the official views of, nor an endorsement, by FDA/HHS, NIH, or the US government.
Funding Information:
Competing interests: All authors have completed the ICMJE uniform disclosure form at www.icmje.org/coi_disclosure.pdf and declare: support from the US Food and Drug Administration (YD, JDW, NDS, JSR, JH, RGM) and the National Institute of Diabetes and Digestive and Kidney Diseases (RGM) for the submitted work. In the previous three years, authors report support from the FDA (SSD), Johnson & Johnson through the Yale Open Data Access project (JDW, JSR), the National Institute on Alcohol Abuse and Alcoholism of the National Institutes of Health (NIH; JDW), AHRQ (JSR), PCORI (RGM), Department of Veterans Affairs Health Services Research and Development (SSD), Department of Veterans Affairs Office of Rural Health (SSD), NIH (SSD), Arnold Ventures (JDW, SSD, JSR), National Evaluation System for Health Technology Coordinating Center (SSD), National Institute for Health Care Management (SSD), Institute for Clinical and Economic Review California Technology Assessment Form (SSD), American College of Cardiology (SSD), National Academy of Medicine (SSD), American Diabetes Association (RGM), Medical Devises Innovation Consortium (JSR), Bristol Myers Squibb (TDL). JSR has served as an expert witness. JDW serves as a consultant for Hagens Berman Sobol Shapiro LLP and Dugan Law Firm APLC. NDS is currently employed by Delta Air Lines; he was an employee of Mayo Clinic when this research was conducted. JSR is a co-founder of medRxiv and an associate research editor for The BMJ. Other declarations are: no other relationships or activities that could appear to have influenced the submitted work; no financial relationships with any organizations that might have an interest in the submitted work in the previous three years; no other relationships or activities that could appear to have influenced the submitted work.
Publisher Copyright:
© Author(s) (or their employer(s)) 2019.
PY - 2022/10/3
Y1 - 2022/10/3
N2 - Objective: To emulate the GRADE (Glycemia Reduction Approaches in Diabetes: A Comparative Effectiveness Study) trial using real world data before its publication. GRADE directly compared second line glucose lowering drugs for their ability to lower glycated hemoglobin A1c (HbA1c). Design: Observational study. Setting: OptumLabs® Data Warehouse (OLDW), a nationwide claims database in the US, 25 January 2010 to 30 June 2019. Participants: Adults with type 2 diabetes and HbA1c 6.8-8.5% while using metformin monotherapy, identified according to the GRADE trial specifications, who also used glimepiride, liraglutide, sitagliptin, or insulin glargine. Main outcome measures: The primary outcome was time to HbA1c ≥7.0%. Secondary outcomes were time to HbA1c >7.5%, incident microvascular complications, incident macrovascular complications, adverse events, all cause hospital admissions, and all cause mortality. Propensity scores were estimated using the gradient boosting machine method, and inverse propensity score weighting was used to emulate randomization of the treatment groups, which were then compared using Cox proportional hazards regression. Results: 8252 people were identified (19.7% of adults starting the study drugs in OLDW) who met eligibility criteria for the GRADE trial (glimepiride arm=4318, liraglutide arm=690, sitagliptin arm=2993, glargine arm=251). The glargine arm was excluded from analyses owing to small sample size. Median times to HbA1c ≥7.0% were 442 days (95% confidence interval 394 to 480 days) for glimepiride, 764 (741 to not calculable) days for liraglutide, and 427 (380 to 483) days for sitagliptin. Liraglutide was associated with lower risk of reaching HbA1c ≥7.0% compared with glimepiride (hazard ratio 0.57, 95% confidence interval 0.43 to 0.75) and sitagliptin (0.55, 0.41 to 0.73). Results were consistent for the secondary outcome of time to HbA1c >7.5%. No significant differences were observed among treatment groups for the remaining secondary outcomes. Conclusions: In this emulation of the GRADE trial, liraglutide was statistically significantly more effective at maintaining glycemic control than glimepiride or sitagliptin when added to metformin monotherapy. Generating timely evidence on medical treatments using real world data as a complement to prospective trials is of value.
AB - Objective: To emulate the GRADE (Glycemia Reduction Approaches in Diabetes: A Comparative Effectiveness Study) trial using real world data before its publication. GRADE directly compared second line glucose lowering drugs for their ability to lower glycated hemoglobin A1c (HbA1c). Design: Observational study. Setting: OptumLabs® Data Warehouse (OLDW), a nationwide claims database in the US, 25 January 2010 to 30 June 2019. Participants: Adults with type 2 diabetes and HbA1c 6.8-8.5% while using metformin monotherapy, identified according to the GRADE trial specifications, who also used glimepiride, liraglutide, sitagliptin, or insulin glargine. Main outcome measures: The primary outcome was time to HbA1c ≥7.0%. Secondary outcomes were time to HbA1c >7.5%, incident microvascular complications, incident macrovascular complications, adverse events, all cause hospital admissions, and all cause mortality. Propensity scores were estimated using the gradient boosting machine method, and inverse propensity score weighting was used to emulate randomization of the treatment groups, which were then compared using Cox proportional hazards regression. Results: 8252 people were identified (19.7% of adults starting the study drugs in OLDW) who met eligibility criteria for the GRADE trial (glimepiride arm=4318, liraglutide arm=690, sitagliptin arm=2993, glargine arm=251). The glargine arm was excluded from analyses owing to small sample size. Median times to HbA1c ≥7.0% were 442 days (95% confidence interval 394 to 480 days) for glimepiride, 764 (741 to not calculable) days for liraglutide, and 427 (380 to 483) days for sitagliptin. Liraglutide was associated with lower risk of reaching HbA1c ≥7.0% compared with glimepiride (hazard ratio 0.57, 95% confidence interval 0.43 to 0.75) and sitagliptin (0.55, 0.41 to 0.73). Results were consistent for the secondary outcome of time to HbA1c >7.5%. No significant differences were observed among treatment groups for the remaining secondary outcomes. Conclusions: In this emulation of the GRADE trial, liraglutide was statistically significantly more effective at maintaining glycemic control than glimepiride or sitagliptin when added to metformin monotherapy. Generating timely evidence on medical treatments using real world data as a complement to prospective trials is of value.
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U2 - 10.1136/bmj-2022-070717
DO - 10.1136/bmj-2022-070717
M3 - Article
C2 - 36191949
AN - SCOPUS:85139125768
SN - 0959-8146
JO - The BMJ
JF - The BMJ
M1 - e070717
ER -