Assessing the representativeness of trials of Sodium-glucose Cotransporter-2 inhibitors in type 2 diabetes: a comparison of individual-level trial data and people newly prescribed treatment in a Welsh routine care database

Journal article

Background: Randomised controlled trials are often criticised for excluding people with multiple long-term conditions. This study used individual participant data for 25 trials of sodium glucose co-transporter-2 inhibitors (SGLT2i) to compare baseline characteristics, comorbidities, and event rates between trial participants and community SGLT2i-treated people in routine care. Methods: Trials were identified through systematic review with subsequent application for individual-level data. Community SGLT2i-treated people in routine care were identified from the Secure Anonymised Information Linkage (SAIL) databank (Wales, UK). For each trial, we applied the eligibility criteria to the community SGLT2i-treated populations. We then (i) assessed the proportion eligible/ineligible for each trial, (ii) compared age, sex and number of comorbidities between trial participants and those eligible/ineligible in routine care, (iii) compared rates of serious adverse events in the trials to the expected rate in community SGLT2i-treated participants and (iv) compared the rate of major adverse cardiovascular events (MACE), all-cause mortality, non-cardiovascular mortality, and estimated glomerular filtration rate (eGFR) slope between trial and community participants. Results: The number of comorbidities was consistently lower in trial populations compared to community SGLT2i-treated who met trial eligibility criteria. Compared with other trial populations, in the large cardiovascular outcome trials (CANVAS, CANVAS-R, CREDENCE and EMPA-REG) levels of participant comorbidity were higher; comorbidity differences between trial and community were smaller; and serious adverse event rates were broadly similar to the expected rate based on the community. For the remaining trials, the serious adverse event rate was lower in the trials than the expected rate based on community SGLT2i-treated participants. In the cardiovascular outcome trials, rates of MACE, mortality and decline in eGFR slope were similar or higher in trial populations. Conclusions: While people with comorbidity are under-represented in most trials compared to a Welsh routine care population, the large cardiovascular outcome trials are more representative of SGLT2i-treated patients and have similar rates of serious adverse events. Therefore, while our findings support calls for caution regarding trial representativeness, the criticism that trials are not representative does not apply equally to all trials. Our results broadly support the applicability of cardiovascular outcome trials to people currently treated with SGLT2i within routine clinical practice.

Authors: Hanlon, P; Wightman, H; Sullivan, M; Lees, JS; Butterly, EW

• Publication status: Published
• Peer review status: Peer reviewed
• Publisher: BioMed Central
• Journal: BMC Medicine
• Volume: 23
• Issue: 1
• Article number: 661
• Publication date: 2025-11-26
• Acceptance date: 2025-10-30
• DOI: 10.1186/s12916-025-04492-2
• EISSN: 1741-7015
• ISSN: 1741-7015
• Language: English
• Keywords: Adverse events; Representativeness; Applicability; Comorbidity; Sodium Glucose Co-transporter 2 inhibitors; Randomised controlled trials; Type 2 diabetes; Multimorbidity