Comparative effectiveness of second line oral antidiabetic treatments among people with type 2 diabetes mellitus: emulation of a target trial using routinely collected health data.

Objective: To compare the effectiveness of three commonly prescribed oral antidiabetic drugs added to metformin for people with type 2 diabetes mellitus requiring second line treatment in routine clinical practice.
Design: Cohort study emulating a comparative effectiveness trial (target trial).
Setting: Linked primary care, hospital, and death data in England, 2015-21.
Participants: 75 739 adults with type 2 diabetes mellitus who initiated second line oral antidiabetic treatment with a sulfonylurea, DPP-4 inhibitor, or SGLT-2 inhibitor added to metformin.
Main Outcome Measures: Primary outcome was absolute change in glycated haemoglobin A _1c (HbA _1c ) between baseline and one year follow-up. Secondary outcomes were change in body mass index (BMI), systolic blood pressure, and estimated glomerular filtration rate (eGFR) at one year and two years, change in HbA _1c at two years, and time to ≥40% decline in eGFR, major adverse kidney event, hospital admission for heart failure, major adverse cardiovascular event (MACE), and all cause mortality. Instrumental variable analysis was used to reduce the risk of confounding due to unobserved baseline measures.
Results: 75 739 people initiated second line oral antidiabetic treatment with sulfonylureas (n=25 693, 33.9%), DPP-4 inhibitors (n=34 464 ,45.5%), or SGLT-2 inhibitors (n=15 582, 20.6%). SGLT-2 inhibitors were more effective than DPP-4 inhibitors or sulfonylureas in reducing mean HbA _1c values between baseline and one year. After the instrumental variable analysis, the mean differences in HbA _1c change between baseline and one year were -2.5 mmol/mol (95% confidence interval (CI) -3.7 to -1.3) for SGLT-2 inhibitors versus sulfonylureas and -3.2 mmol/mol (-4.6 to -1.8) for SGLT-2 inhibitors versus DPP-4 inhibitors. SGLT-2 inhibitors were more effective than sulfonylureas or DPP-4 inhibitors in reducing BMI and systolic blood pressure. For some secondary endpoints, evidence for SGLT-2 inhibitors being more effective was lacking-the hazard ratio for MACE, for example, was 0.99 (95% CI 0.61 to 1.62) versus sulfonylureas and 0.91 (0.51 to 1.63) versus DPP-4 inhibitors. SGLT-2 inhibitors had reduced hazards of hospital admission for heart failure compared with DPP-4 inhibitors (0.32, 0.12 to 0.90) and sulfonylureas (0.46, 0.20 to 1.05). The hazard ratio for a ≥40% decline in eGFR indicated a protective effect versus sulfonylureas (0.42, 0.22 to 0.82), with high uncertainty in the estimated hazard ratio versus DPP-4 inhibitors (0.64, 0.29 to 1.43).
Conclusions: This emulation study of a target trial found that SGLT-2 inhibitors were more effective than sulfonylureas or DPP-4 inhibitors in lowering mean HbA _1c , BMI, and systolic blood pressure and in reducing the hazards of hospital admission for heart failure ( v DPP-4 inhibitors) and kidney disease progression ( v sulfonylureas), with no evidence of differences in other clinical endpoints.
Competing Interests: Competing interests: All authors have completed the ICMJE uniform disclosure form at www.icmje.org/disclosure-of-interest/ and declare: support from the National Institute for Health and Care Research (NIHR). AIA receives salary from the NIHR Biomedical Research Centre via the Oxford Centre for Diabetes, Endocrinology and Metabolism. AB is an economic advisor on the DiRECT trial, with ongoing responsibility for economic analysis during the long term follow-up phase. He serves as a consultant to Salutis Consulting on projects not related to diabetes. JWB has acted as a consultant to AstraZeneca, Bayer, Novartis, and Roche. DN is the UK Kidney Association Director of Informatics Research; she previously was involved in two GSK funded studies in sub-Saharan Africa unrelated to this work. PC sat on an NIHR Health Technology Assessment commissioning committee until September 2021. AHB has acted as consultant to several pharmaceutical companies within the past three years: AstraZeneca, Boehringer Ingelheim, Daiichi Sankyo, Eli Lilly, Gilead, Idorsia, Novo Nordisk, Rhythm, Roche, and Sanofi. IJD has unrestricted research grants from and shares in GSK and a research grant from AstraZeneca. KK has acted as a consultant and speaker or received grants for investigator initiated studies for AstraZeneca, Bayer, Novartis, Novo Nordisk, Sanofi-Aventis, Lilly and Merck Sharp and Dohme, Boehringer Ingelheim, Oramed Pharmaceuticals, Roche, and Applied Therapeutics.
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