Lowering HbA1c Variability: Key to Reduced Major Clinical Events with DPP4 Inhibitors, study finds

The study, published in Diabetes, Obesity and Metabolism, showed that initiating DPP4 inhibitors at HbA1c <7.5% significantly reduced risks of severe hypoglycemia, insulin initiation, heart failure, CV events, kidney disease progression & mortality compared to starting at ≥7.5%.

"Lower HbA1c variability largely accounted for these improvements, indicating that early DPP4i initiation can combat therapeutic inertia, minimize HbA1c fluctuations, and delay insulin requirement," the researchers reported.

In recent years, DPP-4 inhibitors, a class of oral antidiabetic medications, have gained prominence for their efficacy in improving glycemic control while exhibiting favorable safety profiles. However, the timing of DPP-4 inhibitor initiation relative to HbA1c levels and its impact on clinical outcomes have remained areas of active investigation within the medical community.

Therapeutic inertia, poor treatment persistence, and hypoglycemia can lead to glycaemic fluctuation and poor outcomes in type 2 diabetes (T2D). Juliana C. N. Chan, Prince of Wales Hospital, Hong Kong Special Administrative Region, China, and colleagues compared insulin initiation, glycated hemoglobin (HbA1c) variability, severe hypoglycemia, and clinical events in patients with T2D-initiated DPP4 inhibitors at low versus high HbA1c thresholds.

For this purpose, the researchers curated a propensity score-matched cohort of patients who initiated DPP4i at HbA1c <7.5% versus ≥7.5% in 2007-2019 using territory-wide electronic medical records in Hong Kong. HbA1c variability score (HVS) was expressed as a proportion of HbA1c varied by ≥0.5% compared with preceding values.

The Cox model was used to compare the risks of insulin initiation and clinical outcomes, adjusted for time-varying variables between the two groups. The effects of HbA1c variability on outcomes were also estimated.

The researchers reported the following findings:

• 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 of insulin initiation (0.35), major adverse cardiovascular endpoints (0.76), heart failure (0.42), severe hypoglycemia (0.38), mortality (0.45), and end-stage kidney disease (0.65).
• Reduced HbA1c variability explained 31.1%-81.2% of the effect size of DPP4i initiation at HbA1c <7.5% versus ≥7.5% on outcomes.

In conclusion, the study showed that in Chinese patients with type 2 diabetes, avoiding therapeutic inertia with intensified glycaemic control at HbA1c <7.5% using drugs with low hypoglycemia risk and good tolerability, such as DPP4i, reduced HbA1c variability, delayed insulin treatment, and improved clinical events.

The implications of this research extend beyond the realm of diabetes management, shedding light on the broader principles of individualized medicine and preventive care. As healthcare providers strive to tailor treatment strategies to each patient's unique needs of each patient, the findings from this study offer a compelling rationale for early intervention and proactive glycemic management in optimizing health outcomes for individuals with diabetes.

Reference:

DOI: https://doi.org/10.1111/dom.15662