Current guidelines recommend assessing glycemic control using continuous glucose monitoring (CGM), which provides a comprehensive glycemic profile to supplement HbA1c measurement. However, the association between CGM-derived metrics and risk of adverse kidney outcomes is not entirely clear. This retrospective cohort study included 1274 patients with type 2 diabetes hospitalized from July 2020 to December 2022, with a median follow-up time of 923 days. Monitor using CGM at baseline and evaluate renal function indicators of participants at baseline and end of follow-up. Multiple CGM-derived metrics, particularly time in range (TIR) and glucose coefficient of variation (CV), were calculated from 3-day glucose profiles obtained from CGM. Relevant clinical data was collected from clinical records and/or patient interviews. The primary outcome was chronic-kidney-disease (CKD) progression. Secondary outcomes included worsening of albuminuria and, all-cause mortality and major-adverse-cardiac-events(MACE). Multivariate regression models were employed to analyze the association between CGM-derived indices, particularly TIR and CV, and the risk of adverse kidney outcomes. We demonstrated that the lower TIR categories had a remarkably increased risk of CKD progression, with a HR per 10 % increment of 0.90 (95 %CI:0.83-0.91). Conversely, higher CV was positively related to the subsequent risk of CKD progression, with an HR per 10 % increment of 1.30 (95 %CI:1.07-1.59). These results were consistent across various subgroups and sensitivity analyses. This study found that TIR and CV are significantly associated with CKD progression, proteinuria deterioration, all-cause mortality, and the risk of MACE. These findings have elasticity in adjusting for multiple covariates and have been confirmed in different subgroups and sensitivity analyses.

In this cross-sectional analysis, we explored how fluctuations in glycemic levels impact executive functions and psychosocial outcomes in patients with type 2 diabetes mellitus (T2DM). The goal was to understand the relationship between glycemic control and both neuropsychological and psychosocial health. We stratified participants into well-controlled and poorly controlled groups based on glycated hemoglobin (HbA1c) levels and variability, including a healthy control group for comparison. The study consisted of neuropsychological tests and psychosocial assessments. Results indicated that the poorly controlled T2DM group experienced significant executive dysfunction and scored lower on the Tower of London, Wisconsin Card Sorting, and Digit Span Tests, reflecting a broader impact on quality of life and resilience. These findings support the importance of maintaining stable glycemic levels for better executive and psychosocial outcomes and highlight the need for regular neuropsychological and psychosocial assessments in diabetes care.

The association of haemoglobin A1c (HbA1c) variability with the risk of adverse outcomes in patients with atrial fibrillation (AF) prescribed anticoagulants remains unclear. This study aimed to evaluate the association of HbA1c variability with the risk of ischaemic stroke (IS)/systemic embolism (SE) and all-cause mortality among patients with non-valvular AF prescribed anticoagulants.

Patients newly diagnosed with AF from 2013 to 2018 were included. Variability in HbA1c, indexed by the coefficient of variation (CV), was determined for those with at least three HbA1c measurements available from the time of study enrolment to the end of follow-up. To evaluate whether prevalent diabetes would modify the relationship between HbA1c variability and outcomes, participants were divided into diabetes and non-diabetes groups. The study included 8790 patients (mean age 72.7% and 48.5% female). Over a median follow-up of 5.5 years (interquartile range 5.2, 5.8), the incident rate was 3.74 per 100 person-years for IS/SE and 4.89 for all-cause mortality in the diabetes group. The corresponding incident rates in the non-diabetes group were 2.41 and 2.42 per 100 person-years. In the diabetes group, after adjusting for covariates including mean HbA1c, greater HbA1c variability was significantly associated with increased risk of IS/SE [hazard ratio (HR) = 1.65, 95% confidence interval (CI): 1.27-2.13) and all-cause mortality (HR = 1.24, 95% CI: 1.05-1.47) compared with the lowest CV tertile. A similar pattern was evident in the non-diabetes group (IS/SE: HR = 1.58, 95% CI: 1.23-2.02; all-cause mortality: HR = 1.35, 95% CI: 1.10-1.64).

Greater HbA1c variability was independently associated with increased risk of IS/SE and all-cause mortality among patients with AF, regardless of diabetic status.

Glycemic variability (GV), independently of glycemic control, has emerged as a prognostic marker in patients with type 2 diabetes mellitus (DM). In this study, we assessed the prognostic value of long-term GV for predicting major adverse cardiovascular events (MACE) in our local population. We also assessed its prognostic value for diabetic microvascular complications (DMC) and its relationships with antidiabetic medications. This was a retrospective cohort study that recruited 680 patients with type 2 DM across 2015-2017. MACE were defined as: the composite of; total death, myocardial infarction (MI), stroke, hospitalization due to heart failure, and revascularization. GV was calculated for two glycemic control markers: glycated hemoglobin (G-Hb) and fasting blood sugar (FBS); via three metrics- standard deviation (SD), coefficient of variation (CV), and variability independent from the mean (VIM). Cox proportional hazard models and Kruskal-Wallis tests were used in the statistical analysis. 105 events classified as MACE were identified in 86 patients and 104 DMC in 98 patients in an average follow-up period of 78.43 months. Long-term GV was found to be an independent predictor of MACE, particularly for FBS-CV but not a predictor of DMC. FBS-CV ≥ 17.51% as compared with < 17.51% was a significant and independent predictor of MACE, with HR 1.589 (95% CI; 1.022, 2.472) (P = 0.040). DMC were predicted mainly by the duration of type 2 DM, and by the glycemic control; similarly represented by G-Hb and FBS. Patients on metformin, and dipeptidyl peptidase (DPP) 4 inhibitors, had the lowest GV, as compared with patients whose treatments included insulin/sulphonylureas (P < 0.001). In our population, long-term GV predicted MACE: with FBS-CV superior to the "gold standard" glycemic control marker G-Hb. Further, GV may be explained, partially at least, by the choice of antidiabetic medications: this finding might contribute to the cardiovascular protection attributed to one class rather than another.

This study aimed to determine the relationship between HbA1c variability and foot ulcer healing at 12 weeks and 12 months.

Using National Diabetic Foot Care Audit (NDFA) and hospital records, demographics, baseline ulcer characteristics and healing outcomes for subjects presenting with a foot ulcer between 2017-2022 were collected at 12 weeks and 12 months. Subjects had diabetes duration > 3 years and ≥ 3 HbA1c recordings in the 5 years prior to presentation.

At 12 weeks, factors associated with an active ulcer were presence on hind foot (adjusted odds ratios) (2.1 [95% CI 1.3-3.7]), ischaemia (2.1 [95% CI:1.4-3.2]), area > 1 cm2 (2.7 [95% CI:1.7-4.2]) and diabetes duration > 24 years vs 3-10 (AOR 2.0 [95% CI 1.2-3.5]). After adjustment, HbA1c variability 6-10 mmol/mol and > 14.5 mmol/mol had AOR of 1.76 (95% CI 1.1-2.8; p = 0.0192) and 1.5 (95% CI 0.9-2.6; p = 0.1148) of an active ulcer at 12 weeks vs variability < 6 mmol/mol. At 12 months, ischaemia (AOR 2.4 [95% CI 1.5-3.8]) and diabetes duration > 24 years vs 3-10 years (AOR 3.3 [95% CI 1.7-6.4] were significant factors. HbA1c variability was not significant at 12 months.

In keeping with the national NDFA data, in our cohort ulcer characteristics, but not HbA1c variability, were the key factors associated with ulcer healing at 12 weeks and 12 months.

High glycated hemoglobin (HbA1c) variability has been reported to be linked with cardiovascular events in type 2 diabetes patients. Only a few studies have been carried out on Asian patients. This study aimed to investigate the association of prediabetes and type 2 diabetes in Asian patients by performing a post-hoc analysis of a multicenter, prospective, observational study.

Data for prediabetes and type 2 diabetes patients were retrieved from a multicenter national registry entitled "CORE-Thailand study." The primary outcome was 4P-MACE (major adverse cardiovascular events, including non-fatal myocardial infarction, heart failure hospitalization, non-fatal stroke and all-cause death). Patients were stratified according to quartiles of HbA1c standard deviation. The Cox proportional hazards regression model was used to estimate the association of HbA1c variability with incident cardiovascular disease.

A total of 3,811 patients with prediabetes and type 2 diabetes were included. The median follow-up duration was 54 months. In the fully adjusted model, the highest quartile of HbA1c variability showed a statistically significant association with 4P-MACE (hazard ratio [HR] 2.77, 95% confidence interval [CI] 1.77-4.35), fatal and non-fatal myocardial infarction (HR 6.91, 95% CI 1.90-25.12), hospitalization for heart failure (HR 3.34, 95% CI 1.20-9.26) and all-cause death (HR 3.10, 95% CI 1.72-5.57). All these outcomes were statistically significantly different among four quartiles of HbA1c (log-rank P-value <0.05). Fatal and non-fatal stroke showed no statistically significant association with high HbA1c variability.

High HbA1c variability in the highest quartile showed a statistically significant association with multiple adverse cardiovascular events in an Asian population. Minimizing HbA1c fluctuation during long-term follow up should be another important objective for type 2 diabetes patients.

To characterize associations between long-term visit-to-visit variability of hemoglobin A1c (HbA1c) and risk of adverse kidney outcomes in patients with diabetes.

Observational study.

93,598 adults with diabetes undergoing routine care in Stockholm, Sweden.

Categories of baseline and time-varying HbA1c variability score (HVS, the percentage of total HbA1c measures that vary by>0.5% [5.5mmol/mol] during a 3-year window): 0-20%, 21%-40%, 41%-60%, 61%-80%, and 81%-100%, with 0-20% as the reference group.

Chronic kidney disease (CKD) progression (composite of>50% estimated glomerular filtration rate [eGFR] decline and kidney failure), acute kidney disease (AKI by clinical diagnosis or transient creatinine elevations according to KDIGO criteria), and worsening of albuminuria.

Multivariable Cox proportional hazards regression.

Compared with persons showing low HbA1c variability (HVS 0-20%), any increase in variability was associated with a higher risk of adverse kidney outcomes beyond mean HbA1c. For example, for patients with a baseline HbA1c variability of 81%-100%, the adjusted HR was 1.6 (95% CI, 1.47-1.74) for CKD progression, 1.23 [1.16-1.3] for AKI, and 1.28 [1.21-1.36] for worsening of albuminuria. The results were consistent across subgroups (diabetes subtypes, baseline eGFR, or albuminuria categories), in time-varying analyses and in sensitivity analyses including time-weighted average HbA1c or alternative metrics of variability.

Observational study, limitations of claims data, lack of information on diet, body mass index, medication changes, and diabetes duration.

Higher long-term visit-to-visit HbA1c variability is consistently associated with the risks of CKD progression, AKI, and worsening of albuminuria.

The evidence for current guideline recommendations derives from clinical trials that focus on a single HbA1c as the definitive measure of efficacy of an intervention. However, long-term visit-to-visit fluctuations of HbA1c may provide additional value in the prediction of future kidney complications. We evaluated the long-term fluctuations in glycemic control in almost 100,000 persons with diabetes undergoing routine care in Stockholm, Sweden. We observed that higher long-term HbA1c fluctuation is consistently associated with the risks of chronic kidney disease progression, worsening of albuminuria and acute kidney injury. This finding supports a role for long-term glycemic variability in the development of kidney complications and illustrates the potential usefulness of this metric for risk stratification at the bedside beyond a single HbA1c test.

To investigate the pathogenesis of diabetic kidney disease (DKD) in type 2 diabetes mellitus (T2DM), we evaluated the effects of short-term glycemic variability (GV) on the profile of T cell subpopulations.

A total of 47 T2DM patients with normoalbuminuria, 47 microalbuminuria, and 49 macroalbuminuria were enrolled. The continuous glucose monitoring (CGM) determined the GV of enrolled patients. Flow cytometry was used to determine the proportion of T cell subpopulations.

The frequency of T helper (Th) 17 and Th1 cells significantly increased while regulatory T cells (Tregs) significantly decreased in the macroalbuminuria group compared to normoalbuminuria and microalbuminuria groups (P < 0.01). The suppressive function of Tregs was significantly lower in the macroalbuminuria group than the normoalbuminuria group (P < 0.05). Compared with the normoalbuminuria group, the mean amplitude of glucose excursions (MAGE) of the macroalbuminuria group was significantly higher (P<0.05). Furthermore, there were negative associations between the proportion of Tregs and MAGE.

Increased GV could decrease the proportion of Tregs and may impair their function. This may lead to increases in Th1 and Th17 cells, and some inflammatory cytokines, which might contribute to the development and progression of DKD in T2DM.

Fasting blood glucose (FBG) variability, an emerging marker of glycemic control, has been shown to be related to the risk of cardiovascular events and all-cause mortality in subjects with or without diabetes. However, whether FBG variability is independently associated with a higher all-cause mortality in heart transplant recipients remains unknown.

We performed a retrospective cohort study including 373 adult recipients who survived for at least 1 year after heart transplantation with a functioning graft and measured FBG more than three times within first year after transplantation. Multivariable adjusted Cox regression analyses were performed to assess the association between FBG variability and all-cause mortality.

Patients were categorized into three groups according to the coefficient of variation of FBG level: ≤7.0%, 7.0%-13.5%, and >13.5%. During a median follow-up of 44.4 months (interquartile range [IQR], 22.6-63.3 months), 31 (8.3%) participants died. In univariate analyses, FBG variability was associated with an increased all-cause mortality (hazard ratio [HR]: 3.00, 95% confidence interval [CI]: 1.67, 5.38; p < .001). This association remained materially unchanged in the multivariable model adjusted for components of demographics, cardiovascular history and lifestyle, hospital information, immunosuppressive therapy, and post-transplant renal function (HR: 2.75, 95% CI: 1.43, 5.28; p = .004).

After heart transplantation, high FBG variability is strongly and independently associated with an increased risk of all-cause mortality. Our findings suggest that FBG variability is a novel risk factor and prognostic marker for heart transplantation recipients in outpatient clinic.

Previous studies suggest that the complexity of glucose time series may serve as a novel marker of glucose homeostasis.

We aimed to investigate the relationship between the complexity of glucose time series and all-cause mortality in patients with type 2 diabetes.

Prospective data of 6000 adult inpatients with type 2 diabetes from a single center was analyzed. The complexity of glucose time series index (CGI) based on continuous glucose monitoring (CGM) was measured at baseline with refined composite multi-scale entropy. Participants were stratified by the tertiles of CGI: < 2.15, 2.15-2.99, and ≥ 3.00. Cox proportional hazards regression models were used to assess the relationship between CGI and all-cause mortality.

During a median follow-up of 9.4 years, 1217 deaths were identified. A significant interaction between glycated hemoglobin A1c (HbA1c) and CGI in relation to all-cause mortality was noted (P for interaction = 0.016). The multivariable-adjusted hazard ratios for all-cause mortality at different CGI levels [≥ 3.00 (reference group), 2.15-2.99, and < 2.15] were 1.00, 0.76 (95% CI 0.52-1.12), and 1.47 (95% CI 1.03-2.09) in patients with HbA1c < 7.0%, while the association was nonsignificant in those with HbA1c ≥ 7.0%. The restricted cubic spline regression revealed a non-linear (P for non-linearity = 0.041) relationship between CGI and all-cause mortality in subjects with HbA1c < 7.0% only.

Lower CGI is associated with an increased risk of all-cause mortality among patients with type 2 diabetes achieving the HbA1c target. CGI may be a new indicator for the identification of residual risk of death in well-controlled type 2 diabetes.

To quantify associations of different metrics of long-term glycemic variability (GV) with multiple adverse diabetes-related outcomes.

We searched PubMed and Embase from database inception to 23 August 2021. GV was based on measurements of HbA1c or fasting plasma glucose (FPG) and calculated by standard deviation (SD), coefficient of variance (CV) or other metrics. Outcomes included mortality, cardiovascular disease (CVD), renal disease, peripheral neuropathy, retinopathy, dementia and cancer. Random-effects meta-analyses were adopted to pool the relative risks (RRs).

Seventy-five articles with 2,051,701 participants were included. When comparing top with bottom quartiles, HbA1c variabilities were associated with all-cause mortality (RR_CV = 1.63, 95 % CI 1.37-1.92; RR_SD = 1.87, 1.55-2.26), CVD (RR_CV = 1.38, 1.07-1.78; RR_SD = 1.34, 1.12-1.59), renal disease (RR_CV = 1.43, 1.18-1.74; RR_SD = 1.44, 1.24-1.67), and peripheral neuropathy (RR_CV = 1.84, 1.40-2.43; RR_SD = 1.98, 1.51-2.61), but not retinopathy. FPG variabilities were associated with all-cause mortality (RR_CV = 1.59, 1.43-1.78; RR_SD = 1.67, 1.26-2.20), renal disease (RR_CV = 1.77, 1.32-2.38), and retinopathy (RR_CV = 1.92, 1.10-3.35), but not CVD and peripheral neuropathy. Associations of GV with Alzheimer's disease (RR_HbA1c-CV = 1.38, 1.13-1.70; RR_FPG-CV = 1.32, 1.07-1.63) and cancer (RR_HbA1c-SD = 2.19, 1.52-3.17; RR_FPG-CV = 3.64, 2.21-5.98) were each found significant in one study.

Long-term GV was associated with multiple adverse diabetes-related outcomes, while the strength of associations varied. The findings support the use of long-term GV for diabetes management in clinical practice.

Glycated hemoglobin (HbA1c) variability is emerging as an indicator of long-term glycemic control, which may play a significant role during vascular complications. We conducted a systematic review and meta-analysis to assess the association between the scope of HbA1c variability and vascular complications in patients with type 2 diabetes mellitus. PubMed and Embase were searched for studies that evaluated the association of HbA1c variability with vascular complications in patients with type 2 diabetes. Two reviewers independently completed data extraction. Random-effects meta-analysis was conducted with stratification according to the type of vascular complications. Nine studies were eligible for inclusion in our systematic review and meta-analysis. Six studies evaluated the impact of the standard deviation of HbA1c (HbA1c-SD) on cardiovascular events and showed an association of HbA1c-SD with cardiovascular events (HR: 1.25, 95% CI 1.18-1.32, 5 studies). Six studies evaluated renal disease associated with HbA1c-SD and showed that HbA1c-SD was correlated with an increased risk of renal disease (HR: 1.19, 95% CI 1.13-1.24). Two studies evaluated HbA1c-SD and the risk of retinopathy and showed that no significant association was found between retinopathy and HbA1c-SD (HR 1.08, 95% CI 0.92-125). For HbA1c-SD ranging from 0.6 to 0.8%, HbA1c-SD was associated with an increased risk of cardiovascular events (HR: 1.25, 95% CI 1.15-1.35) and renal disease (HR: 1.16, 95% CI 1.11-1.22). For individuals with index HbA1c variability greater than or equal to 0.6%, HbA1c variability was significantly associated with vascular complications in patients with type 2 diabetes mellitus.

The goal of diabetes treatment is to maintain good glycemic control, prevent the development and progression of diabetic complications, and ensure the same quality of life and life expectancy as healthy people. Hemoglobin A1c (HbA1c) is used as an index of glycemic control, but strict glycemic control using HbA1c as an index may lead to severe hypoglycemia and cardiovascular death. Glycemic variability (GV), such as excessive hyperglycemia and hypoglycemia, is associated with diabetic vascular complications and has been recognized as an important index of glycemic control. Here, we reviewed the definition and evaluated the clinical usefulness of GV, and its relationship with diabetic complications and therapeutic strategies to reduce GV.

This study is aimed at clarifying the relationship between visit-to-visit variability of glycated hemoglobin (HbA1c) and the risk of diabetic kidney disease (DKD) and to identifying the most useful index of visit-to-visit variability of HbA1c.

This clinic-based retrospective longitudinal study included 699 Japanese type 2 diabetes mellitus patients. Visit-to-visit variability of HbA1c was calculated as the internal standard deviation of HbA1c (HbA1c-SD), the coefficient of variation of HbA1c (HbA1c-CV), the HbA1c change score (HbA1c-HVS), and the area under the HbA1c curve (HbA1c-AUC) with 3-year serial HbA1c measurement data, and the associations between these indices and the development/progression of DKD were examined.

Cox proportional hazards models showed that the HbA1c-SD and HbA1c-AUC were associated with the incidence of microalbuminuria, independently of the HbA1c level. These results were verified and replicated in propensity score (PS) matching and bootstrap analyses. Moreover, the HbA1c-SD and HbA1c-AUC were also associated with oxidized human serum albumin (HSA), an oxidative stress marker.

Visit-to-visit variability of HbA1c was an independent risk factor of microalbuminuria in association with oxidative stress among type 2 diabetes mellitus patients. HbA1c-AUC, a novel index of HbA1c variability, may be a potent prognostic indicator in predicting the risk of microalbuminuria.

Clinical data of esaxerenone in hypertensive patients with diabetic kidney disease (DKD) are lacking. We evaluated the efficacy and safety of esaxerenone in patients with DKD and an inadequate response to blood pressure (BP)-lowering treatment.

In this multicenter, open-label, prospective study, patients were divided into urinary albumin-to-creatinine ratio subcohorts (UACR < 30, 30 to < 300, and 300 to < 1000 mg/gCr). Esaxerenone was initiated at 1.25 mg/day and followed by incremental dose escalation based on BP and serum potassium level monitoring. The treatment period was 12 weeks. The primary endpoint was change in morning home systolic BP/diastolic BP (SBP/DBP) from baseline to end of treatment (EOT). Secondary endpoints included achievement rate of target BP, change in UACR from baseline, and safety.

In total, 113 patients were enrolled. Morning home SBP/DBP significantly decreased from baseline to EOT in the total population (- 11.6/- 5.2 mmHg, both p < 0.001) and in all UACR subcohorts (all p < 0.001). The target BP achievement rate was 38.5%. Significant reductions in bedtime home and office BPs were also shown in the total population and all UACR subcohorts. UACR significantly improved from baseline to EOT in the total (- 50.9%, p < 0.001) and all UACR subcohorts (all p < 0.001). Incidence of serum potassium elevation as drug-related treatment emergent adverse events was 2.7%. The change from baseline in estimated glomerular filtration rate (eGFR) was - 4.8 mL/min/1.73 m².

Esaxerenone demonstrated a BP-lowering effect and improved albuminuria. The effects were consistent regardless of the severity of albuminuria without clinically relevant serum potassium elevation and eGFR reduction.

jRCTs06119002.

Diabetic kidney disease (DKD) is a critical microvascular complication of diabetes. With the continuous increase in the prevalence of diabetes since 2000, the prevalence of DKD has also been increasing in past years. The prevalence of DKD among individuals with type 2 diabetes in Taiwan increased from 13.32% in 2000 to 17.92% in 2014. The cumulative incidence of DKD among individuals with type 1 diabetes in Taiwan was higher than 30% during 1999-2012. DKD is the leading cause of end-stage renal disease (ESRD), with a prevalence of approximately 45% in a population on chronic dialysis in Taiwan. Among individuals with type 2 diabetes, the prevalence of ESRD in the receipt of dialysis also increased from 1.32% in 2005 to 1.47% in 2014. Risk factors for DKD development are age, race, family history, hyperglycemia, hypertension, dyslipidemia, dietary patterns, and lifestyles. Prognostic factors that aggravate DKD progression include age, family history, sex, glycemic control, blood pressure (BP), microvascular complications, and atherosclerosis. This review summarizes updated information on the onset and progression of DKD, particularly in the Taiwanese population. Translating these epidemiological features is essential to optimizing the kidney care and improving the prognosis of DKD in Asian populations.

Aim: Glycated hemoglobin (HbA1c) is an efficient and easy test to evaluate glycemic control of patients with type 2 diabetes (T2DM). This study aims to evaluate HbA1c variability and associated factors in patients with T2DM. Methods: Four hundred four consecutive patients with T2DM who gave consent to participate and who were eligible were included. The inclusion criterion was presence of three or more HbA1c levels in 1 year. A change ≥0.5% in HbA1c was identified as a significant variability in HbA1c in 1 year. Primary endpoint of the study was to identify the factors associated with HbA1c variability. Patients were grouped as (1) without variability, (2) one variability, and (3) more than one variability. Variability frequency and associated factors such as body mass index, smoking, and c-peptide value were assessed. Results: There were 404 patients (45.3% male) with mean age 58.91 ± 10.8 years. Thirty-four patients (8.4%) had no variability, 19 patients (4.7%) had one variability, and 351 patients (86.9%) had more than one variability. Patients only on insulin treatment and patients on both oral antidiabetic agents (OAD) and insulin had higher variability than patients only on OAD (P = 0.002; P < 0.01). Patients with variability had higher HbA1c levels than patients without variability (P < 0.01). A 1% increase in HbA1c had a 4.864-fold (95% confidence interval: 2.360-10.023) increased variability risk. Conclusions: HbA1c variability is seen in 9 of 10 patients with T2DM and higher HbA1c values and poor glycemic control are associated with a higher risk of HbA1c variability.

The association of glycemic variability with microvascular disease complications in type 2 diabetes (T2D) has been under-studied and remains unclear. We investigated this relationship using both Action to Control Cardiovascular Risk in Diabetes (ACCORD) and the Veteran Affairs Diabetes Trial (VADT).

In ACCORD, fasting plasma glucose (FPG) was measured 1 to 3 times/year for up to 84 months in 10 251 individuals. In the VADT, FPG was measured every 3 months for up to 87 months in 1791 individuals. Variability measures included coefficient of variation (CV) and average real variability (ARV) for fasting glucose. The primary composite outcome was time to either severe nephropathy or retinopathy event and secondary outcomes included each outcome individually. To assess the association, we considered variability measures as time-dependent covariates in Cox proportional hazard models. We conducted a meta-analysis across the 2 trials to estimate the risk of fasting glucose variability as well as to assess the heterogenous effects of FPG variability across treatment arms.

In both ACCORD and the VADT, the CV and ARV of FPG were associated with development of future microvascular outcomes even after adjusting for other risk factors, including measures of average glycemic control (ie, cumulative average of HbA1c). Meta-analyses of these 2 trials confirmed these findings and indicated FPG variation may be more harmful in those with less intensive glucose control.

This post hoc analysis indicates that variability of FPG plays a role in, and/or is an independent and readily available marker of, development of microvascular complications in T2D.

Chronic hyperglycemia is an established risk factor for the development of complications in both type 1 and type 2 diabetes, but glycemic variability has emerged as a possible independent risk factor for diabetes complications, possibly through oxidative stress. In this review, methods to access glycemic variability and oxidative stress, as well as their correlations, are discussed. Non-pharmacological and pharmacological strategies are also debated to achieve better glycemic control, not only by HbA1c target but also with reduced glycemic fluctuations, possibly minimizing the risk of diabetes complications.

Diabetic kidney disease (DKD) is a kind of common microvascular complication of diabetes. This study aims to explore the possible links between blood sugar level and albuminuria, providing the exact cut point of the "risk threshold" for blood glucose with DKD.

The relationship between blood glucose and albuminuria was modeled using linear and logistic regression in the REACTION study cohorts (N= 8932). Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated by logistic regression model. Two-slope linear regression was used to simulate associations between blood glucose and ACR.

We found that the increase in ACR was accompanied by increased HbA1c, with a turning point at 5.5%. The positive correlation remained highly significant (P<0.001) when adjusted for age, sex, marital status, education, smoking status, drinking status, BMI, waistline, SBP and DBP. In subgroup analyses including gender, obesity, hypertension, and smoking habits, the relationship was significant and stable.

We determined a risk threshold for HbA1c associated with albuminuria in a Chinese population over the age of 40. HbA1c ≥ 5.5% was positively and independently associated with ACR. These results suggest the necessity of early blood glucose control and renal function screening for DKD in at-risk populations.

Glycated hemoglobin (HbA1c) has proven to be indicative in the development of microvascular complications. In this study, the contribution of HbA1c variability to microvascular complications was evaluated.

Twenty-one cases with type 1 diabetes mellitus (T1DM) who developed microvascular complications and 39 cases without complications, that were similar in terms of gender, age of diagnosis, insulin treatment, insulin doses (U/kg), and mean HbA1c levels were included.

Mean age of T1DM diagnosis was 5.87 ± 3.93 years in the complication group and 4.63 ± 3.33 years in the control group. Nephropathy was detected in 17 cases, neuropathy in 8 cases, and retinopathy in 1 case. Nephropathy occurred at a mean age of 11.52 ± 4.12 years and neuropathy at 14.13 ± 5.68 years. The mean HbA1c during follow-up was similar in the group with complications and the control group (8.60 ± 0.63 vs. 8.84 ± 1.32). Adjusted HbA1c-standard deviation (SD) and HbA1c-variation coefficient (CV) values were 1.30 ± 0.65 and 14.36 ± 6.23 in the group with complications (p=0.014), and 0.91 ± 0.37 and 10.59 ± 4.01 in the control group (p=0.013). In the Receiver Operating Characteristic (ROC)-analysis for microvascular complications, the limit value HbA1c-CV was 11.99 (sensitivity: 61.9%, specificity: 71.9%). This value for HbA1c-SD was 0.9699 (sensitivity: 71.43%, specificity: 66.67%).

This study has shown that long-term fluctuations in HbA1c are associated with the development of microvascular complications in type 1 diabetes.

To investigate whether long-term glycemic variability (GV) is associated with vascular complication development in type 2 diabetes.

In a post hoc FIELD trial analysis, GV was calculated as the standard deviation and coefficient of variation (CV) of glycated hemoglobin A1c (HbA1c) and fasting plasma glucose. Baseline variables were compared across quartiles of on-study variability by chi square and ANOVA. Prospective associations between baseline to 2-year GV and subsequent vascular and mortality outcomes were analyzed using landmark logistic and Cox proportional hazards regression.

Baseline factors associated with higher on-study GV included younger age, male gender, longer diabetes duration, and higher pharmacological therapies usage. Both HbA1c and fasting glucose CV were associated with increased risk of microvascular complications (HR 1.02 [95% CI, 1.01-1.03] P < 0.01; and HR 1.01 [95% CI, 1.00-1.01] P < 0.001, respectively). HbA1c and fasting glucose CV were associated with increased cardiovascular disease (HR 1.02 [95% CI, 1.00-1.04]; and HR 1.01 [95% CI, 1.00-1.02], both P < 0.05). HbA1c CV associated with increased stroke (HR 1.03 [95% CI, 1.01-1.06) P < 0.01). Glucose CV associated with increased coronary events (HR 1.01 [95% CI, 1.00-1.02] P < 0.05). Both HbA1c and glucose CV associated with increased total mortality (HR 1.04 [95% CI, 1.02-1.06]; and HR 1.01 [95% CI, 1.01-1.02], both P < 0.001) and noncardiovascular mortality (HR 1.05 [95% CI, (1.03-1.07]; and HR 1.02 [95% CI, 1.01-1.03], both P < 0.001). HbA1c CV associated with coronary mortality (HR 1.04 [95% CI, 1.01-1.07] P < 0.05).

Long-term GV was associated with increased risk of vascular outcomes in type 2 diabetes.

To investigate the associations of increased variability in glycated haemoglobin (HbA1c) with cardiovascular disease (CVD) and mortality risk in patients with diabetes.

This prospective cohort study included 147 811 patients aged 45 to 84 years with type 2 diabetes mellitus, without CVD and with at least three HbA1c values recorded before baseline in the period 2008 to 2010. HbA1c variability was evaluated using a mixed effects model to reduce regression dilution bias. Age-specific associations (45- 54, 55- 64, 65- 74 and 75- 84 years) between HbA1c variability and risk of CVD and mortality were assessed by Cox regression, adjusted for patient characteristics and usual HbA1c.

After a median follow-up of 7.4 years(1.02 million person-years), an overall incidence of 40 785 events including CVD (incidence 27  793) and all-cause mortalities (incidence 23 175) were identified. Positive log-linear associations between HbA1c variability and CVD and mortality were identified in all age groups. The hazard ratios (HRs) for the composite of CVD and all-cause mortality showed that age was inversely associated with HbA1c variability, with a 28% higher risk per 1% increase in HbA1c variability in the age group 45 to 54 years (all composite outcomes: HR 1.28, 95% confidence interval [CI] 1.21, 1.35), whereas only a 14% higher risk in the 75- 84 age group (all composite outcomes: HR 1.14, 95% CI 1.11, 1.17). Subgroup analysis showed the risk in patients with usual HbA1c <53mmol/mol was about eight times higher than in those with usual HbA1c ≥64mmol/mol.

HbA1c variability was strongly related to CVD and mortality in patients with diabetes across all age groups. Whilst pursuing optimal HbA1c targets, attention should be given to patients with high HbA1c variability, especially younger patients with good HbA1c control.

The associations between sociodemographic factors and HbA1c variability in type 2 diabetes are not yet established. Examining group differences in HbA1c variability may help identify patient characteristics related to diabetes management. The present study examined differences in baseline HbA1c and HbA1c variability between groups with regard to sex, level of education, civil status, age, and BMI, in a sample of individuals with type 2 diabetes.

The study was a prospective exploratory cohort study. Differences in HbA1c variability between sociodemographic groups were analyzed in 158 individuals. HbA1c variability was assessed as the standard deviation (SD) and coefficient of variation (CV) over five measured points, and a questionnaire was used to assess sociodemographic factors.

The results showed significantly higher HbA1c variability in men compared to women (mean difference 1.44 mmol/mol [95% CI: 0.58 to 2.31]), and significantly higher HbA1c variability in individuals with a BMI characterized as obese compared to individuals with a BMI characterized as normal weight (mean difference 1.56 mmol/mol [95% CI: 0.25 to 2.88]). There were no significant associations between HbA1c variability and civil status or education.

Men and individuals with obesity may be more vulnerable to future diabetic complications than other groups, since they have greater long-term glycemic variability.

To assess the associations of various HbA1c measures, including a single baseline HbA1c value, overall mean, yearly updated means, standard deviation (HbA1c-SD), coefficient of variation (HbA1c-CV), and HbA1c variability score (HVS), with microvascular disease (MVD) risk in patients with type 2 diabetes.

Linked data between National Cheng Kung University Hospital and Taiwan's National Health Insurance Research Database were utilized to identify the study cohort. The primary outcome was the composite MVD events (retinopathy, nephropathy, or neuropathy) occurring during the study follow-up. Cox model analyses were performed to assess the associations between HbA1c measures and MVD risk, with adjustment for patients' baseline HbA1c, demographics, comorbidities/complications, and treatments.

In the models without adjustment for baseline HbA1c, all HbA1c variability and mean measures were significantly associated with MVD risk, except HVS. With adjustment for baseline HbA1c, HbA1c-CV had the strongest association with MVD risk. For every unit of increase in HbA1c-CV, the MVD risk significantly increased by 3.42- and 2.81-fold based on the models without and with adjustment for baseline HbA1c, respectively. The associations of HbA1c variability and mean measures with MVD risk in patients with baseline HbA1c < 7.5% (58 mmol/mol) were stronger compared with those in patients with baseline HbA1c ≥ 7.5% (58 mmol/mol).

HbA1c variability, especially HbA1c-CV, can supplement conventional baseline HbA1c measure for explaining MVD risk. HbA1c variability may play a greater role in MVD outcomes among patients with relatively optimal baseline glycemic control compared to those with relatively poor baseline glycemic control.

To evaluate the effect of mean HbA1c on the correlation between HbA1c variability and all-cause mortality, and the risks associated with different levels of HbA1c and glycaemic control status in patients with type 2 diabetes.

Patients with type 2 diabetes and at least three HbA1c measurements within 12-24 months were included. HbA1c variability score, coefficient of variation (CV) and standard deviation (SD) were used to evaluate variability. A variability score of 50 was set as a cutoff to define low and high variability.

A total of 4216 patients were included, of whom 1196 died during the observation period (11.1 ± 3.2 years). All-cause mortality increased with HbA1c variability score and the quartiles of HbA1c CV and SD. The strength of this association was attenuated after adjustment for mean HbA1c, and the risks associated with HbA1c variability and glycaemic control status were similar. The highest associated risk was observed with an HbA1c variability score of >50 and mean HbA1c of ≥7.5%. Mortality risk was significantly higher with a mean HbA1c of ≤6.0% and >8.5% and of ≤6.0% and >8.0% for low and high HbA1c variability, respectively.

Mean HbA1c contributed to the correlation between HbA1c variability and all-cause mortality. The risks associated with HbA1c variability and glycaemic control status were similar. The relationship between mean HbA1c and mortality presented a J-shaped distribution for both low and high HbA1c variability.

Glycemic variation has been suggested to be a risk factor for diabetes-related complications. Previous studies did not address confounding of diabetes duration, number of visits and length of follow-up. Here, we characterize glycemic variability over time and whether its relation to diabetes-related complications and mortality is independent from diabetes- and follow-up duration.

Individuals with type 2 diabetes (n = 6770) from the Hoorn Diabetes Care System cohort were included in this study. The coefficient of variation (CV) was calculated over 5-year sliding intervals. People divided in quintiles based on their CV. Cox proportional hazard models were used to investigate the role of glycemic CV as risk factor in diabetes-related complications and mortality.

The coefficient of variation of glucose (FG-CV) increased with time, in contrast to HbA1c (HbA1c-CV). People with a high FG-CV were those with an early age of diabetes onset (Δ_Q5-Q1 = - 2.39 years), a higher BMI (Δ_Q5-Q1 = + 0.92 kg/m²), an unfavorable lipid profile, i.e. lower levels of HDL-C (Δ_Q5-Q1 = - 0.06 mmol/mol) and higher triglycerides (Δ_Q5-Q1 =+ 1.20 mmol/mol). People with the highest FG-CV in the first 5-year interval showed an increased risk of insulin initiation, retinopathy, macrovascular complications and mortality independent of mean glycemia, classical risk factors and medication use. For HbA1c, the associations were weaker and less consistent.

Individuals with a higher FG-CV have an unfavorable metabolic profile and have an increased risk of developing micro- and macrovascular complications and mortality. The association of HbA1c-CV with metabolic outcomes and complications was less consistent in comparison to FG-CV.

Nutrition is an integral part of type 2 diabetes (T2DM) treatment, but the optimal macronutrient composition is still debated and previous studies have not addressed the role of ethnicity in dietary response. The current study aims were to compare the effect of short-term glycemic response to low-carbohydrate high-fat (LC-HF) diet vs. high-carbohydrate low-fat (HC-LF) diet using continuous glucose monitoring (CGM) and to evaluate the response of individuals with T2DM of Yemenite (Y-DM) and non-Yemenite origin (NY-DM).

Twenty T2DM males, ten Y-DM and ten NY-DM underwent meal tolerance test and indexes of insulin resistance and secretion were calculated. Subsequently, patients were connected to CGM to assess daily glycemic control and glucose variability in response to isocaloric HC-LF or LC-HF diet, receiving each diet for 2 days by providing prepared meals. Daily glucose levels, area under the glucose curve (G-AUC) and parameters of glucose variability [standard deviation (SD), mean amplitude of glycemic excursions (MAGE) and mean absolute glucose (MAG)] were evaluated.

The LC-HF resulted in a significantly lower G-AUC (p < 0.001) and in lower variability parameters (p < 0.001) vs. the HC-LF diet. However, Y-DM showed less reduction in glucose variability indices upon diet-switching vs. NY-DM; MAGE decreased, respectively, by 69% vs. 89%, p = 0.043 and MAG by 34% vs. 45%, p = 0.007 in Y-DM compared to NY-DM.

These results suggest that LC-HF diet is effective in reducing glycemic fluctuation in T2DM and that ethnicity may have a role in the response to dietary regime.

We aimed to investigate whether there are differences in the risk factors or markers for the progression of diabetic retinopathy (DR) and diabetic nephropathy (DN) in type 2 diabetes mellitus.

We carried out a 3-year retrospective cohort study of 604 patients with type 2 diabetes mellitus. The outcomes were the progression of DR (worsening of the DR stage) and DN (an estimated glomerular filtration rate decline >12%) at the 3-year follow up. The mean hemoglobin A1c (HbA1c) level and HbA1c variability (HbA1c-VAR) were calculated.

The mean HbA1c and HbA1c-VAR levels were higher in the DR progressors (n = 67) than in the DR non-progressors (n = 537). The mean HbA1c was a significant predictor for DR progression independent of the duration of diabetes and HbA1c-VAR levels. The urine albumin-to-creatinine ratio at baseline and HbA1c-VAR levels were higher in the DN progressors (n = 34) than in the DN non-progressors (n = 570). The triglyceride to high-density lipoprotein cholesterol ratio at baseline tended to be higher in the DN progressors than in the DN non-progressors. HbA1c-VAR levels and the triglyceride-to-high-density lipoprotein cholesterol ratio were significant predictors for DN progression independent of estimated glomerular filtration rate and the urine albumin-to-creatinine ratio.

Average glycemia was significantly associated with progression of DR, whereas glycemic variability and dyslipidemia were significantly associated with progression of DN in type 2 diabetes mellitus.

This study aimed to investigate the association between the presence and severity of cardiovascular autonomic neuropathy (CAN) and development of long-term glucose fluctuation in subjects with type 2 diabetes mellitus.

In this retrospective cohort study, subjects with type 2 diabetes mellitus who received cardiovascular autonomic reflex tests (CARTs) at baseline and at least 4-year of follow-up with ≥6 measures of glycosylated hemoglobin (HbA1c) were included. The severity of CAN was categorized as normal, early, or severe CAN according to the CARTs score. HbA1c variability was measured as the standard deviation (SD), coefficient of variation, and adjusted SD of serial HbA1c measurements.

A total of 681 subjects were analyzed (294 normal, 318 early, and 69 severe CAN). The HbA1c variability index values showed a positive relationship with the severity of CAN. Multivariable logistic regression analysis showed that CAN was significantly associated with the risk of developing higher HbA1c variability (SD) after adjusting for age, sex, body mass index, diabetes duration, mean HbA1c, heart rate, glomerular filtration rate, diabetic retinopathy, coronary artery disease, insulin use, and anti-hypertensive medication (early CAN: odds ratio [OR], 1.65; 95% confidence interval [CI], 1.12 to 2.43) (severe CAN: OR, 2.86; 95% CI, 1.47 to 5.56). This association was more prominent in subjects who had a longer duration of diabetes (>10 years) and lower mean HbA1c (<7%).

CAN is an independent risk factor for future higher HbA1c variability in subjects with type 2 diabetes mellitus. Tailored therapy for stabilizing glucose fluctuation should be emphasized in subjects with CAN.

Fluctuation of kidney function may signify intra-glomerular microvascular hemodynamic instability. We aim to examine the association of long-term serum creatinine and estimated glomerular filtration rate variability with diabetic retinopathy.

We included type 2 diabetes mellitus patients who attended the Diabetes Centre in 2011-2014 and were followed up (median = 3.2 years). Digital colour fundus photographs were assessed for diabetic retinopathy at follow-up. Diabetic retinopathy severity was categorized into non-proliferative diabetic retinopathy and proliferative diabetic retinopathy. We conducted a nested case-control study involving 177 diabetic retinopathy (118 non-proliferative diabetic retinopathy, 50 proliferative diabetic retinopathy) and 327 age- and gender-matched non-diabetic retinopathy. Serum creatinine measured before follow-up visit was obtained (⩾3 readings/patient). Variability was calculated as intra-individual standard deviation/√ n/( n - 1).

Diabetic retinopathy have higher adjusted-serum creatinine-standard deviation than non-diabetic retinopathy [9.1 (4.9-21.6) vs 5.4 (3.4-10.1) µM, p < 0.001]. After multivariable adjustment, adjusted-serum creatinine-standard deviation was associated with diabetic retinopathy [odds ratio = 1.47, 95% confidence interval (1.02-2.10), p = 0.04]. The area under the curve increased significantly after adding adjusted-serum creatinine-standard deviation [0.70 (0.65-0.75) vs 0.72 (0.68-0.77), p < 0.03]. Proliferative diabetic retinopathy have higher adjusted-serum creatinine-standard deviation than non-proliferative diabetic retinopathy [15.5 (6.6-39.7) vs 7.47 (4.52-17.8) µM, p < 0.001]. After adjustment, adjusted-serum creatinine-standard deviation remained associated with non-proliferative diabetic retinopathy [1.48 (1.04-2.12), p = 0.03] and proliferative diabetic retinopathy [2.43 (1.34-4.39), p = 0.003; p-trend = 0.002]. Similar findings were observed for estimated glomerular filtration rate variability.

Serum creatinine and estimated glomerular filtration rate variability is associated with the presence and severity of diabetic retinopathy independent of intra-individual means. This may inform novel therapeutic strategies aiming to achieve stable renal function in type 2 diabetes mellitus.

In type 2 diabetes, we aimed at clarifying the role of glycated haemoglobin variability and other risk factors in the development of the main micro-vascular complications: peripheral neuropathy, nephropathy and retinopathy.

In a single-centre cohort of 900 patients, glycated haemoglobin variability was evaluated as intra-individual standard deviation, adjusted standard deviation and coefficient of variation of serially measured glycated haemoglobin in the 2-year period before a randomly selected index visit. We devised four models considering different aspects of glycated haemoglobin evolution. Multivariate stepwise logistic regression analysis was performed including the following covariates at the index visit: age, disease duration, body mass index, total cholesterol, high-density lipoprotein cholesterol, triglycerides, sex, smoking habit, hypertension, dyslipidemia, treatment with anti-diabetic drugs, occurrence of macro-vascular events and the presence of another micro-vascular complication.

Males with high mean glycated haemoglobin, long duration of diabetes, presence of macro-vascular events and retinopathy emerged at higher risk for peripheral neuropathy. Development of nephropathy was independently associated with higher glycated haemoglobin variability, older age, male sex, current smoking status, presence of retinopathy, of peripheral neuropathy and of hypertension. Higher mean glycated haemoglobin, younger age, longer duration of diabetes, reduced estimated glomerular filtration rate and the presence of peripheral neuropathy were significantly associated with increased incidence of retinopathy.

Glycated haemoglobin variability was associated with increased incidence of nephropathy, while mean glycated haemoglobin emerged as independent risk factor for the development of retinopathy and peripheral neuropathy. The presence of macro-vascular events was positively correlated with peripheral neuropathy. Finally, the occurrence of another micro-vascular complication was found to be a stronger risk factor for developing another micro-vascular complication than the mean or variability of glycated haemoglobin.

This study aimed to review studies that identified patterns of longitudinal HbA1c trends in patients with diabetes and to summarize factors and outcomes associated with distinct trajectory patterns.

PubMed and Web of Science were systematically searched for studies examining HbA1c trends among patients with diabetes from database inception through September 2017. Articles were included if they met the following inclusion criteria: (a) longitudinal study of subjects with diabetes only, (b) use of serial measurements of HbA1c , and (c) analysis of the trend of HbA1c using group-based trajectory approaches.

Twenty studies were included, 11 on type 1 diabetes and 9 on type 2 diabetes. These studies identified 2 to 6 HbA1c trajectory patterns. The most commonly identified patterns included stable HbA1c around 7.0% and at levels between 8.0% and 9.9%, which usually captured the HbA1c pattern among the majority of subjects in the study population. Unstable patterns identified included increasing HbA1c trend, decreasing HbA1c trend, and non-linear patterns. These patterns were associated with differential risk of disease outcomes, over and beyond single-point HbA1c measures. Age, gender, ethnicity, diabetes duration, disease management frequency, cardiovascular risk factors, insulin treatment, family environment, and psychosocial factors were the most frequently reported factors associated with membership of specific HbA1c pattern groups.

Common patterns of longitudinal HbA1c trends were identified despite heterogeneity among the studies. A better understanding of what underlies these different patterns may provide opportunities to tailor therapies and care for these patients to reduce adverse outcomes.

To evaluate various measures of haemoglobin (Hb) A1c variability, compared with average HbA1c, as independent predictors of mortality.

The Renal Insufficiency And Cardiovascular Events Italian multicentre study enroled 15 733 patients with type 2 diabetes from 19 diabetes clinics during 2006-2008. A total of 3 to 5 HbA1c measures, obtained during the 2-year period before enrolment, were available from 9 centres (8290 patients) and were used to calculate average HbA1c (HbA1c -MEAN) and HbA1c variability, measured as intra-individual standard deviation (HbA1c-SD), SD adjusted for the number of HbA1c assessments (HbA1c-AdjSD) and coefficient of variation (HbA1c-CV), that is, the HbA1c-SD to HbA1c-MEAN ratio. Vital status on October 31, 2015 was retrieved for 8252 patients (99.5%).

The measures of HbA1c variability increased according to quartiles of HbA1c-MEAN and vice versa. HbA1c-MEAN and measures of HbA1c variability were associated with all-cause mortality; however, the strength of association of HbA1c-MEAN was lower than that of HbA1c -SD, HbA1c-CV or HbA1c-AdjSD, and disappeared after adjusting for confounders and any of the measures of HbA1c variability. Mortality increased with quartiles of HbA1c-MEAN, HbA1c -SD, HbA1c-CV and HbA1c-AdjSD, but only the association with HbA1c variability measures remained after adjustment for confounders and/or each other measure. In the fully adjusted model, mortality risk was lower for HbA1c-SD below the median and higher for HbA1c-SD above the median, regardless of whether HbA1c-MEAN was below or above the median. Conclusions HbA1c variability is a strong, independent predictor of all-cause mortality in type 2 diabetes and appears to be even more powerful than average HbA1c in predicting mortality.

Long-term visit-to-visit glycemic variability is an additional measure of glycemic control. We aimed to evaluate the prognostic value of several measures of glycemic variability for the occurrence of micro- and macrovascular complications, and all-cause mortality in patients with type 2 diabetes.

654 individuals were followed-up over a median of 9.3 years. Glycemic variability (SDs and coefficients of variation of HbA1c and fasting glycaemia) was measured during the first 12- and 24-months. Multivariate Cox analysis, adjusted for risk factors and mean HbA1c and fasting glycaemia levels, examined the associations between glycemic variability and the occurrence of microvascular (retinopathy, microalbuminuria, renal function deterioration, peripheral neuropathy) and macrovascular complications [total cardiovascular events (CVE), major adverse CVEs (MACE) and cardiovascular mortality], and of all-cause mortality.

During follow-up, 128 patients had a CVE (96 MACE), and 158 patients died (67 from cardiovascular diseases); 152 newly-developed or worsened diabetic retinopathy, 183 achieved the renal composite outcome (89 newly developed microalbuminuria and 91 deteriorated renal function), and 96 newly-developed or worsened peripheral neuropathy. Glycemic variability, particularly the 24-month parameters either estimated by HbA1c or by fasting glycemia, predicted all endpoints, except for retinopathy and peripheral neuropathy development/progression, and was a better predictor than mean HbA1c. Glycemic variability predicted retinopathy development/progression in patients with good glycemic control (HbA1c ≤ 7.5%, 58 mmol/mol) and predicted new-incident peripheral neuropathy.

Long-term visit-to-visit glycemic variability is an additional and frequently a better glycemic parameter than mean HbA1c levels for assessing the risk of future development of micro- and macrovascular complications in patients with type 2 diabetes.

Variability in HbA1c and blood pressure is associated with the risk of diabetic kidney disease (DKD). No evidence exists on the role of variability in lipids or serum uric acid (UA), or the interplay between the variability of different parameters, in renal outcomes.

Within the AMD Annals database, we identified patients with ≥5 measurements of HbA1c, systolic blood pressure (SBP) and diastolic blood pressure (DBP), total-, high-density lipoprotein (HDL)- and low-density lipoprotein (LDL)-cholesterol, triglycerides, and UA. Patients were followed-up for up to 5 years. The impact of measures of variability on the risk of DKD was investigated by Cox regression analysis and recursive partitioning techniques.

Four-thousand, two-hundred and thirty-one patients were evaluated for development of albuminuria, and 7560 for decreased estimated glomerular filtration rate (eGFR; <60 mL/min/1.73 m² ). A significantly higher risk of developing albuminuria was associated with variability in HbA1c [upper quartile hazard ratio (HR) = 1.3; 95% confidence interval (CI) 1.1-1.6]. Variability in SBP, DBP, HDL-C, LDL-C and UA predicted the decline in eGFR, the association with UA variability being particularly strong (upper quartile HR = 1.8; 95% CI 1.3-2.4). The concomitance of high variability in HbA1c and HDL-C conferred the highest risk of developing albuminuria (HR = 1.47; 95% CI 1.17-1.84), while a high variability in UA (HR = 1.54; 95% CI 1.19-1.99) or DBP (HR = 1.47; 95% CI 1.11-1.94) conferred the highest risk of decline in eGFR.

The variability of several parameters influences the development of DKD, having a different impact on albuminuria development and on the decline in GFR.