Comparative effectiveness of alternative second-line oral glucose-lowering therapies for type 2 diabetes: a precision medicine approach applied to routine data.

Aims/hypothesis: National clinical guidelines recommend that second-line treatment for type 2 diabetes mellitus is chosen according to individuals' characteristics but there is limited evidence available to inform this choice. This paper's aim is to compare the effects on HbA of sulfonylureas (SU), dipeptidyl peptidase-4 inhibitors (DPP4i) or sodium-glucose cotransporter-2 inhibitors (SGLT2i) added to metformin as second-line oral glucose-lowering treatments according to an individual's age, baseline HbA and presence of multiple long-term conditions (MLTCs).

Methods: We accessed primary care-hospital linked data for 41,790 individuals from the Clinical Practice Research Datalink (CPRD) in England who initiated second-line treatment after metformin between 2015 and 2021. We combined target trial emulation with instrumental variable analysis to reduce the risk of confounding. The outcome was change in HbA between baseline and 1 year follow-up. We reported results stratified by age (18-49 years, 50-69 years and ≥70 years), baseline HbA (<67 mmol/mol [<8.3%], 67-77 mmol/mol [8.3-9.2%] and >77 mmol/mol [>9.2%]) and presence of MLTCs.

Results: The mean (95% CI) difference in HbA change for SGLT2i vs SU was larger for people aged 18-49 years (-5.74 mmol/mol [-7.47, -4.01]) (-0.5% [-0.7, -0.4]) than for those aged 50-69 years (-4.03 mmol/mol [-5.61, -2.44]) (-0.4% [-0.5, -0.2]) and for those aged 70 years or over (-2.68 mmol/mol [-4.50, -0.86]) (-0.3% [-0.4, -0.07]). The mean (95% CI) difference in HbA change for SGLT2i vs DPP4i was -5.80 mmol/mol (-7.60, -4.00) (-0.5% [-0.7, -0.4]) for those aged 18-49 years, -4.13 mmol/mol (-5.82, -2.45) (-0.4% [-0.5, -0.2]) for those aged 50-69 years and -3.13 mmol/mol (-5.01, -1.24) (-0.3% [-0.4, -0.1]) for those aged ≥70 years. The mean difference (improvement) in HbA was similar across subgroups defined by baseline HbA or presence of MLTCs. For SGLT2i vs SU, the mean (95% CI) difference was -5.37 mmol/mol (-7.13, -3.62) (-0.5% [-0.6, -0.3]) for people without MLTC and -3.72 mmol/mol (-5.34, -2.10]) (-0.3% [-0.5, -0.2]) for people with MLTC. For SGLT2i vs DPP4i the corresponding estimated differences (95% CI) were -5.44 mmol/mol (-7.27, -3.61) (-0.5% [-0.7, -0.3]) for those without MLTC and -3.93 mmol/mol (-5.64, -2.21) (-0.3% [-0.5, -0.2]) for those with MLTC.

Conclusions/interpretation: Second-line treatment with SGLT2i is more effective than SU or DPP4i in reducing HbA across subgroups of people defined by age, baseline HbA and presence of MLTCs. Our evidence complements RCTs in using routinely available information on demographic characteristics, biomarkers and comorbidities to inform an individualised approach.