Type 2 diabetes mellitus (T2DM) is highly prevalent among older adults and represents a leading cause of morbidity due to microvascular complications such as diabetic retinopathy, nephropathy, and neuropathy [1,2]. With increasing life expectancy and global population aging, the burden of diabetes in individuals aged ≥65 years continues to rise, posing significant clinical and public health challenges [3].

Glycated hemoglobin (HbA1c) remains the standard indicator of long-term glycemic control and is strongly associated with the risk of diabetic complications [4]. However, emerging evidence suggests that visit-to-visit HbA1c variability, independent of mean HbA1c, may contribute to microvascular damage through mechanisms involving oxidative stress, endothelial dysfunction, and inflammatory activation [5–7]. Glycemic fluctuations have been shown to induce greater cellular injury than sustained hyperglycemia, potentially amplifying vascular complications even when average glycemic control appears adequate [8].

Several observational studies have demonstrated associations between HbA1c variability and the development or progression of diabetic retinopathy, nephropathy, and neuropathy in general adult populations [9–11]. Nevertheless, data specifically focusing on the geriatric population remain limited. Older adults differ from younger individuals in terms of disease duration, comorbidity burden, physiological reserve, and susceptibility to hypoglycemia, all of which may modify the impact of glycemic variability [12].

Given these considerations, a focused synthesis of available evidence is warranted. Therefore, this systematic review and meta-analysis aims to evaluate the association between long-term HbA1c variability and microvascular complications among geriatric patients with T2DM.

This systematic review and meta-analysis was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines [13]. A comprehensive literature search was performed in PubMed/MEDLINE, Embase, Scopus, Web of Science, and the Cochrane Library from database inception to January 2025. The search strategy combined Medical Subject Headings (MeSH) and free-text terms related to type 2 diabetes mellitus, HbA1c variability (including visit-to-visit variability, standard deviation, coefficient of variation, variability independent of the mean, and average real variability), microvascular complications (retinopathy, nephropathy, neuropathy), and geriatric or elderly populations. Reference lists of eligible articles and relevant reviews were manually screened to identify additional studies. Observational cohort and case–control studies were included if they enrolled patients with type 2 diabetes mellitus, reported a mean age of ≥65 years or provided age-stratified data for participants aged ≥65 years, assessed long-term HbA1c variability, and evaluated microvascular outcomes with adjusted effect estimates (hazard ratios, odds ratios, or relative risks) and corresponding 95% confidence intervals. Studies involving type 1 diabetes, cross-sectional designs without follow-up, reviews, editorials, case reports, and those lacking sufficient statistical data were excluded. Two independent reviewers screened titles and abstracts for eligibility, followed by full-text assessment of potentially relevant articles. Discrepancies were resolved by discussion or consultation with a third reviewer. Data were extracted using a standardized form, including study characteristics (author, year, country, design), sample size, mean age, duration of follow-up, HbA1c variability metric used, outcome definitions, adjusted covariates, and the most fully adjusted effect estimates. Methodological quality was assessed using the Newcastle–Ottawa Scale (NOS) for observational studies, which evaluates selection, comparability, and outcome assessment domains. Studies scoring ≥7 points were considered high quality. Statistical analysis was conducted using a random-effects model (DerSimonian–Laird method) to account for anticipated heterogeneity. Pooled effect estimates were calculated separately for diabetic retinopathy, nephropathy, and neuropathy. Heterogeneity was evaluated using Cochran’s Q test and quantified with the I² statistic, with values of 25%, 50%, and 75% representing low, moderate, and high heterogeneity, respectively. Subgroup analyses were performed based on HbA1c variability metrics, duration of diabetes, follow-up period, and geographic region. Publication bias was assessed through funnel plot inspection and Egger’s regression test. Sensitivity analyses were conducted by excluding low-quality studies and performing leave-one-out analyses to evaluate the robustness of the findings. A two-sided p-value <0.05 was considered statistically significant.

The systematic search yielded 1,243 records, of which 312 duplicates were removed. After title and abstract screening, 64 full-text articles were assessed for eligibility. Eighteen studies met the inclusion criteria and were included in the final qualitative synthesis and quantitative meta-analysis.

Figure 1. PRISMA flow diagram illustrating the study selection process for the systematic review and meta-analysis on the association between HbA1c variability and microvascular complications in geriatric patients with type 2 diabetes mellitus. A total of 1,243 records were identified through database searching, of which 312 duplicates were removed. After screening 931 titles and abstracts, 64 full-text articles were assessed for eligibility. Forty-six studies were excluded based on predefined criteria, and 18 studies were included in the final qualitative and quantitative synthesis.

Study Characteristics

The 18 included studies comprised approximately 142,000 participants with type 2 diabetes mellitus, with mean ages ranging from 65 to 78 years. Most studies were prospective cohort designs (n = 14), while four were retrospective cohort studies. The duration of follow-up ranged from 3 to 12 years. Geographically, studies were conducted in Asia (n = 10), Europe (n = 4), and North America (n = 4).

HbA1c variability was most commonly assessed using standard deviation (SD) (12 studies) and coefficient of variation (CV) (9 studies); five studies used variability independent of the mean (VIM), and three reported average real variability (ARV). The number of HbA1c measurements used to calculate variability ranged from three to twelve per participant. Most studies adjusted for mean HbA1c, duration of diabetes, age, sex, hypertension, dyslipidemia, smoking status, and baseline renal function. The majority of studies were of high methodological quality (NOS ≥7).

Meta-Analysis Findings

Diabetic Retinopathy

Twelve studies evaluated the association between HbA1c variability and diabetic retinopathy. The pooled analysis demonstrated that higher HbA1c variability was significantly associated with increased risk of retinopathy progression (pooled HR 1.28; 95% CI: 1.15–1.42). Moderate heterogeneity was observed (I² = 58%). The association remained significant after adjustment for mean HbA1c and other confounders.

Diabetic Nephropathy

Fourteen studies assessed nephropathy outcomes, including incident albuminuria, progression of albuminuria, or decline in estimated glomerular filtration rate (eGFR). Higher HbA1c variability was associated with a significantly increased risk of nephropathy (pooled HR 1.34; 95% CI: 1.20–1.50), with moderate heterogeneity (I² = 62%). Subgroup analyses indicated stronger associations in patients with longer diabetes duration (>10 years).

Peripheral Neuropathy

Seven studies examined peripheral neuropathy. The pooled odds ratio showed a significant association between HbA1c variability and neuropathy (pooled OR 1.22; 95% CI: 1.08–1.37), with low-to-moderate heterogeneity (I² = 49%).

Subgroup and Sensitivity Analyses

Subgroup analyses based on HbA1c variability metric demonstrated consistent associations across SD, CV, and VIM measures. Studies with follow-up duration ≥5 years showed slightly stronger effect estimates compared to shorter follow-up periods. Leave-one-out sensitivity analysis did not materially alter pooled effect sizes, indicating robustness of results.

Funnel plot inspection suggested mild asymmetry for nephropathy outcomes; however, Egger’s regression test did not demonstrate statistically significant publication bias (p > 0.05).

Table 1. Summary of Pooled Effect Estimates for Microvascular Complications

Overall, the findings consistently indicate that higher long-term HbA1c variability is independently associated with increased risk of microvascular complications in geriatric patients with type 2 diabetes mellitus.

Figure 2. Forest-style plot showing pooled effect estimates (hazard ratios/odds ratios with 95% confidence intervals) for the association between long-term HbA1c variability and microvascular complications in geriatric patients (≥65 years) with type 2 diabetes mellitus. The vertical reference line represents the null value (HR/OR = 1). Effect sizes greater than 1 indicate increased risk of complications with higher HbA1c variability. Pooled estimates were derived using a random-effects model.

This systematic review and meta-analysis demonstrates that long-term HbA1c variability is significantly associated with an increased risk of microvascular complications—including diabetic retinopathy, nephropathy, and peripheral neuropathy—among geriatric patients with type 2 diabetes mellitus (T2DM). These findings extend previous observations in general adult populations by confirming that the association persists in individuals aged ≥65 years, even after adjustment for mean HbA1c and traditional risk factors [14,15].

The pooled estimates indicate a 28% increased risk of retinopathy, a 34% increased risk of nephropathy, and a 22% increased risk of neuropathy in patients with higher HbA1c variability. Prior cohort studies have reported similar magnitudes of association, suggesting that visit-to-visit variability contributes independently to microvascular damage beyond sustained hyperglycemia [16,17]. Notably, nephropathy demonstrated the strongest association in our analysis, consistent with evidence that renal microvasculature is particularly sensitive to glycemic fluctuations and oxidative stress [18].

The biological plausibility of these findings is supported by experimental and clinical data. Glucose variability induces greater oxidative stress compared to constant hyperglycemia, leading to activation of protein kinase C pathways, increased formation of advanced glycation end-products (AGEs), and endothelial dysfunction [19,20]. Repeated glycemic excursions may also trigger inflammatory cascades and mitochondrial dysfunction, mechanisms implicated in microvascular injury [21]. The concept of “metabolic memory” further suggests that intermittent hyperglycemia can induce persistent epigenetic modifications that sustain vascular damage even after glycemic stabilization [22].

In older adults, age-related endothelial impairment, diminished antioxidant capacity, and reduced renal functional reserve may amplify the detrimental effects of glycemic variability [23]. Additionally, geriatric patients often have longer disease duration and multiple comorbidities, which may interact synergistically with glycemic instability to accelerate complication progression [24]. These factors underscore the importance of evaluating variability specifically within this population rather than extrapolating findings from younger cohorts.

From a clinical perspective, our findings suggest that focusing solely on achieving target mean HbA1c levels may be insufficient in geriatric diabetes care. Several studies have highlighted that stable glycemic control may reduce complication risk more effectively than aggressive HbA1c lowering strategies that increase variability and hypoglycemia risk [25,26]. Current geriatric diabetes guidelines emphasize individualized glycemic targets; our results support incorporating measures of HbA1c variability into routine assessment and therapeutic decision-making [27].

This study has several strengths, including a large pooled sample size, inclusion of adjusted effect estimates, and consistent associations across different variability metrics. However, limitations should be acknowledged. All included studies were observational, precluding causal inference [28]. Heterogeneity in variability measurements (SD, CV, VIM, ARV) and outcome definitions may influence effect estimates. Furthermore, some studies included mixed-age cohorts with subgroup analyses rather than exclusively geriatric populations, which may introduce residual confounding [29]. Publication bias, although not statistically significant, cannot be completely excluded.

Future research should prioritize prospective studies exclusively enrolling older adults, standardization of HbA1c variability metrics, and incorporation of continuous glucose monitoring–derived indices to better capture glycemic fluctuations [30]. Randomized controlled trials evaluating interventions aimed at reducing glycemic variability in geriatric patients would provide more definitive evidence regarding causality and clinical benefit.

In summary, this meta-analysis indicates that HbA1c variability is an independent predictor of microvascular complications in geriatric patients with T2DM. Beyond mean HbA1c, maintaining stable glycemic control may represent a critical component of complication prevention strategies in older adults.

In the era of precision geriatric diabetology, it is no longer sufficient to focus solely on average glycemic control. This systematic review and meta-analysis highlights that HbA1c variability is independently associated with an increased risk of microvascular complications in older adults with type 2 diabetes. The findings reinforce the concept that glycemic stability—not just glycemic targets—matters in preventing retinopathy, nephropathy, and neuropathy in the geriatric population. For clinicians, this underscores a shift in therapeutic emphasis: minimizing fluctuations while individualizing HbA1c goals to balance efficacy and safety. For researchers, it calls for standardized metrics and prospective trials specifically designed for older adults. Ultimately, stabilizing glucose patterns may prove as important as lowering them in safeguarding microvascular health in aging individuals with diabetes.

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