Association of dipeptidyl peptidase‐4 inhibitor initiation at glycated haemoglobin <7.5% with reduced major clinical events mediated by low glycated haemoglobin variability

Abstract Aim Therapeutic inertia, hypoglycaemia and poor treatment persistence can lead to glycaemic fluctuation and poor outcomes in type 2 diabetes (T2D). We compared glycated haemoglobin (HbA1c) variability, insulin initiation, severe hypoglycaemia and clinical events in patients with T2D initiated dipeptidyl peptidase‐4 inhibitors (DPP4is) at low versus high HbA1c thresholds. Methods Using territory‐wide electronic medical records in Hong Kong, we curated a propensity score‐matched cohort of patients initiated DPP4i at HbA1c <7.5% versus ≥7.5% in 2007‐2019. We expressed the HbA1c variability score (HVS) as a proportion of HbA1c varied by ≥0.5% compared with preceding values. We used the Cox model to compare the risks of insulin initiation and clinical outcomes, adjusted for time‐varying variables between the two groups. Mediation analysis estimated the effects of HbA1c variability on outcomes. Results Among 6874 insulin‐naïve patients who initiated DPP4i, 88.7% were treated with metformin and 79.6% with sulphonylureas at baseline (54.9% men; mean age 65.2 ± 11.4 years). After a median follow‐up of 4.6 years, compared with the high‐threshold plus high‐HVS group (≥50%), the low‐threshold plus low‐HVS (<50%) group had reduced hazard ratios (95% confidence interval) of insulin initiation (0.35, 0.31‐0.40), severe hypoglycaemia (0.38, 0.34‐0.44), major adverse cardiovascular endpoints (0.76, 0.66‐0.88), heart failure (0.42, 0.36‐0.49), end‐stage kidney disease (0.65, 0.36‐0.49) and mortality (0.45, 0.35‐0.57). Reduced HbA1c variability explained 31.1%‐81.2% of the effect size of DPP4i initiation at HbA1c <7.5% versus ≥7.5% on outcomes. Conclusions In Chinese patients with T2D, avoiding therapeutic inertia with intensified glycaemic control at HbA1c <7.5% using drugs with low risk of hypoglycaemia and good tolerability, such as DPP4i, delayed insulin treatment, reduced HbA1c variability and improved clinical events.