Variability in HbA1c and the risk of major clinical outcomes in type 2 diabetes with chronic kidney disease: Post hoc analysis from the CREDENCE trial

Abstract

Glycated hemoglobin (HbA1c) levels, a measure of average glucose levels over approximately 3 months, are widely accepted clinical indicators of glycaemic control and are recommended for ongoing monitoring in accordance with established guidelines. HbA1c variability refers to the fluctuations in a person's HbA1c levels over longer periods of time and reflects changes in glycaemic control over longer periods, for example, months to years. Recent studies have highlighted the importance of HbA1c variability as an independent predictor of microvascular and macrovascular complications in Type 1 and Type 2 diabetes (T1D and T2D). For instance, a meta-analysis by Shen et al. demonstrated a significant association between HbA1c variability and increased cardiovascular risk in T2D patients.¹ A study following 1240 Type 1 diabetics for over 20 years linked higher HbA1c variability to increased microvascular complications.² Studies have suggested that higher HbA1c variability is associated with increased microvascular complications, such as retinopathy, microalbuminuria,^{3, 4} cardiovascular events and mortality,^{1, 5} in people with T1D and with a specifically higher mortality risks⁶ in people with Type 2 diabetes (T2D). Furthermore, recent guidelines from the American Diabetes Association (ADA) emphasize the need to evaluate HbA1c variability in high-risk populations, such as those with chronic kidney disease (CKD).⁷ However, the prospective association between HbA1c variability and significant clinical outcomes, such as cardiovascular and kidney events, in patients with T2D and CKD remains underexplored. This study aims to quantify HbA1c variability in T2D patients with CKD and examine its association with major clinical outcomes, leveraging data from the CREDENCE trial.

Understanding HbA1c variability dynamics could enhance patient management protocols, identify patients at high risk and mitigate the progression of diabetic complications. This study aims to quantify HbA1C variability in T2D patients with CKD and examine the association between HbA1c variability and significant clinical outcomes.

Of the 4401 CREDENCE participants, 3080 (69.98%) were eligible for inclusion in the current study (Figure S2).

The mean participant age was 63.3 years; 1016 (33.0%) were female (Table 1). Across increasing tertiles of HbA1c variability, participants were more likely to be younger, have a shorter duration of diabetes and have higher levels of albuminuria. Other characteristics were broadly similar across the three groups (Table 1).

During a median follow-up of 2.62 years (interquartile range 25th–75th percentile: 2.0 to 3.2), 182 (5.9%) participants experienced a major cardiovascular event, 112 (3.6%) experienced kidney events, 35 (1.1%) experienced a stroke and 102 (3.3%) died of any cause. Increasing variability was associated with higher numbers of kidney events (Table S2).

In unadjusted analysis, greater HbA1c variability was independently associated with a higher risk of kidney events (HR for moderate/high vs. low variability: 1.58 95% CI: 0.88–2.82 and 3.51, 95% CI:2.08–5.94, respectively) (Figure 1A), with no statistically significant associations between greater HbA1c variability and the risk of major macrovascular events, stroke or all-cause mortality. In adjusted models, greater HbA1c variability was independently associated with a higher risk of major macrovascular events (HR for moderate/high vs. low variability: 1.15 95% CI: 0.79–1.67 and 1.47, 95% CI:1.02–2.13, respectively) and kidney events (HR for moderate/high vs. low variability: 1.53, 95% CI: 0.84–2.79 and 2.75, 95% CI:1.57–4.83, respectively) (Figure 1B).

In subgroup analyses, using adjusted cox-regression models, the group with greater mean HbA1c within the high variability group had a lower risk of kidney events (HR for HbA1c ≥ 7.5% compared with HbA1c < 7.5%: 0.43 95% CI: 0.24–0.76) with no statistically significant association between greater HbA1c and the risk of major macrovascular events, stroke or all-cause mortality (Table S3). Sensitivity analyses confirmed the primary findings (Table S4).

Higher HbA1c variability predicts worse cardiovascular and renal outcomes in T2D patients with CKD, independent of mean HbA1c levels. These findings underscore the importance of monitoring glycemic variability as a complementary strategy to traditional HbA1c targets. Future studies should explore interventions targeting HbA1c variability and validate these findings in real-world populations.

YZ, SK, MJ, RF, CA and BN contributed to the concept and rationale for the study and interpretation of the results. YZ conducted a statistical analysis and drafted the manuscript with advice from SK. All authors contributed to the discussion and reviewed and edited the manuscript. YZ and SK are the guarantors of this work and, as such, had full access to all the data in the study and took responsibility for the integrity of the data and the accuracy of the data analysis.

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.