Long-term Glucose Variability Research Articles

Fasting glucose variability and risk of dementia in Parkinson's disease: a 9-year longitudinal follow-up study of a nationwide cohort.

Diabetes is associated with an increased risk of Parkinson's disease dementia (PDD); however, it is unknown whether this association is dependent on continuous hyperglycemia, hypoglycemic events, or glycemic variability. We aimed to investigate the relationship between visit-to-visit fasting glucose variability and PDD development in patients with Parkinson's disease (PD). Using data from the Korean National Health Insurance Service, we examined 9,264 patients aged ≥40 years with de novo Parkinson's disease (PD) who underwent ≥3 health examinations and were followed up until December 2019. Glucose variability was measured using the coefficient of variation, variability independent of the mean, and average real variability. Fine and Gray competing regression analysis was performed to determine the effect of glucose variability on incident PDD. During the 9.5-year follow-up period, 1,757 of 9,264 (19.0%) patients developed PDD. Patients with a higher visit-to-visit glucose variability had a higher risk of future PDD. In the multivariable adjusted model, patients with PD in the highest quartile (subdistribution hazard ratio [SHR] = 1.50, 95% CI 1.19 to 1.88), quartile 3 (SHR = 1.29, 95% CI 1.02 to 1.62), and quartile 2 (SHR = 1.30, 95% CI 1.04 to 1.63) were independently associated with a higher risk of PDD than those in the lowest quartile. We highlighted the effect of long-term glucose variability on the development of PDD in patients with PD. Furthermore, our findings suggest that preventive measures for constant glucose control may be necessary to prevent PDD.

A prospective cohort study of long-term fasting blood glucose variability and risk of mortality in patients with type 2 diabetes

Objective: To investigate the association between long-term fasting blood glucose (FPG) variability and all-cause mortality in patients with type 2 diabetes. Methods: A total of 7 174 type 2 diabetic patients included in National Basic Public Health Service Program in Changshu of Jiangsu Province were recruited as participants. Long-term glucose variability was assessed using standard deviation (SD), coefficient of variation (CV), average real variability (ARV), and variability independent of the mean (VIM) across FPG measurements at the more than three visits. Death information were mainly obtained from the death registry system in Jiangsu. Then Cox proportional hazards regression models were used to estimate the associations of four variability indicators and all-cause mortality's hazard ratios (HRs) and their 95%CIs. Results: Among 55 058.50 person-years of the follow-up, the mean follow-up time was 7.67 years, and 898 deaths occurred during the follow-up period. After adjustment, compared with T1 group, the Cox regression model showed that HRs of T3 group in SD, CV, ARV and VIM were 1.24 (95%CI: 1.03-1.49), 1.20 (95%CI: 1.01-1.43), 1.28 (95%CI: 1.07-1.55) and 1.20 (95%CI:1.01-1.41), respectively. HRs of per 1 SD higher SD, CV, ARV and VIM were 1.13 (95%CI: 1.06-1.21), 1.08 (95%CI: 1.01-1.15), 1.05 (95%CI: 1.00-1.12) and 1.09 (95%CI: 1.02-1.16) for all-cause mortality, respectively. In the stratified analysis, age, gender, hypoglycemic agent and insulin uses had no effect on the above associations (all P for interaction >0.05). Conclusion: Long-term FPG glycemic variability was positively associated with the risk of all-cause mortality in type 2 diabetes patients.

Long-term glucose variability and incident cardiovascular diseases and all-cause mortality events in subjects with and without diabetes: Tehran Lipid and Glucose Study

AimTo examine whether visit to visit variability (VVV) of fasting plasma glucose (FPG) is associated with incident cardiovascular diseases (CVD) and all-cause mortality in individuals with and without type 2 diabetes (T2D). MethodsA total of 4756 participants aged ≥30 years entered the study in 2002–2005 and underwent two subsequent examinations in 2005–2008 and 2008–2011. FPG variability measures included standard deviation (SD), coefficient of variation (CV), average real variability (ARV), and variability independent of mean (VIM). Multivariate Cox proportional hazard models were used to assess the risk of incident CVD and all-cause mortality for each unit increase in different FPG variability measures. ResultsDuring a median follow-up of 18.14 years after baseline recruitment, 492 incident cardiovascular diseases and 338 all-cause mortality were recorded. Among individuals without T2D, the multivariate-adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) for incident CVD were 1.02 (1.01–1.04), 1.02 (1.01–1.04), 1.01 (1.00–1.02), and 1.01 (1.00–1.01) for SD, CV, ARV, and VIM, respectively (all P-values <0.05). Among individuals with T2D, the corresponding HRs and 95% CIs for all-cause mortality were 1.01 (1.00–1.02), 1.02 (1.01–1.03), 1.01 (1.00–1.02), and 1.01 (1.00–1.01), respectively (all P-values <0.05). ConclusionLong-term (VVV) of FPG is significantly associated with increased risk of CVD among participants without T2D, and all-cause mortality among participants with T2D.

Association Between Visit-to-Visit Fasting Plasma Glucose Variability and Osteoporotic Fractures in Nondiabetic Subjects

Although long-term glucose variability has been reported to be a risk factor associated with osteoporosis, there have been no previous studies between the relationship of glucose variability and fractures in people without diabetes. We assessed visit-to-visit variations in fasting plasma glucose (FPG) as a prognostic factor in predicting osteoporotic fractures in individuals without diabetes. Using a nationwide cohort database, we examined the impact of FPG on the development of osteoporotic fractures in men and women (aged ≥50 years). The primary outcomes were the number of total fractures and vertebral fractures. FPG variability was measured using standard deviation (FPG-SD), coefficient of variation (FPG-CV), and variation independent of the mean (FPG-VIM). Of the 92,929 participants, 5,262 (5.7%) developed osteoporotic fractures during the mean follow-up of 8.4 years. Individuals in the highest quartile of FPG-SD showed an 11% and 16% increase in risk of total and vertebral fractures, respectively, compared with those in the lowest quartile after adjustment for mean FPG and other risk factors. Analyses using FPG-CV and FPG-VIM demonstrated similar results. Subgroup analyses and sensitivity analyses to explore potential heterogeneity showed consistent results. FPG variability may be a novel risk factor for osteoporotic fractures independent of risk factors in the general population without diabetes.

Long-term HbA1c variability and the development and progression of diabetic retinopathy in subjects with type 2 diabetes

This study aimed to investigate whether long-term HbA1c variability is associated with the development and progression of diabetic retinopathy (DR) in subjects with type 2 diabetes. We retrospectively reviewed 434 type 2 diabetes subjects without DR who underwent regular DR screening. We reviewed fundus findings, collected HbA1c levels, and calculated the coefficient of variation (CV) and average real variability (ARV) of each subject’s HbA1c level. DR was developed in 55 subjects and progressed to moderate nonproliferative DR or worse DR in 23 subjects. On Cox proportional hazards regression analysis, HbA1c ARV, but not HbA1c CV, was significantly associated with DR development. However, the association between HbA1c variability and the DR progression rate to moderate nonproliferative DR or worse DR was not significant. The inter-visit HbA1c difference value on consecutive examination predicted DR development well and more careful screening for DR is needed for those with an absolute value change of 2.05%, an absolute increase of 1.75%, and an absolute decrease of 1.45% in HbA1c levels on consecutive examination. These results indicate that long-term glucose variability measured by HbA1c ARV might be an independent risk factor for DR development in addition to the mean HbA1c level in early diabetic subjects.

Impact of long-term glucose variability on coronary atherosclerosis progression in patients with type 2 diabetes: a 2.3\xa0year follow-up study

BackgroundGlycemic variability (GV) confers a risk of cardiovascular events. In this study, we aimed to investigate whether long-term GV has an impact on coronary atherosclerosis progression in patients with type 2 diabetes mellitus (T2DM).MethodsA total of 396 patients with T2DM who had coronary computed tomography angiography and laboratory data available at baseline and for follow-up evaluations [median 2.3 (1.8–3.1) years] were included. Fasting plasma glucose (FPG) was measured every 1–3 months, and HbA1c was measured quarterly. The coefficient of variation (CV) of HbA1c and FPG were calculated as measures of GV. Quantitative assessment of coronary plaques was performed by measuring the annual change and progression rate of total plaque volume (TPV). Significant progression was defined as annual TPV progression ≥ 15%. Multivariable regression analyses were used to assess the effects of GV on atherosclerosis progression.ResultsIn the 396 patients, the annual change in TPV was 12.35 ± 14.23 mm3, and annual progression rate was 13.36 ± 12.69%. There were 143 (36.11%) patients with significant progression, and they had a significantly higher CV-HbA1c (P < 0.001) and CV-FPG (P < 0.001) than those without significant progression. In multivariable regression analyses, both CV-HbA1c and CV-FPG were independent predictors of annual change in TPV [CV-HbA1c: β = 0.241 (0.019–0.462), P = 0.034; CV-FPG: β = 0.265 (0.060–0.465), P = 0.012], annual TPV progression [CV-HbA1c: β = 0.214 (0.023–0.405), P = 0.029; CV-FPG: β = 0.218 (0.037–0.399), P = 0.019], and significant atherosclerosis progression [CV-HbA1c: odds ratio [OR] = 1.367 (1.149–1.650), P = 0.010; CV-FPG: OR = 1.321 (1.127–1.634), P = 0.013].ConclusionsLong-term GV is associated with accelerated progression of coronary atherosclerosis independent of conventional risk factors in patients with T2DM.Trial registration ClinicalTrials.gov (NCT02587741), October 27, 2015; retrospectively registered

Glucose variability and the risks of stroke, myocardial infarction, and all-cause mortality in individuals with diabetes: retrospective cohort study

BackgroundPrevious research regarding long-term glucose variability over several years which is an emerging indicator of glycemic control in diabetes showed several limitations. We investigated whether variability in long-term fasting plasma glucose (FG) can predict the development of stroke, myocardial infarction (MI), and all-cause mortality in patients with diabetes.MethodsThis is a retrospective cohort study using the data provided by the Korean National Health Insurance Corporation. A total of 624,237 Koreans ≥ 20 years old with diabetes who had undergone health examinations at least twice from 2005 to 2008 and simultaneously more than once from 2009 to 2010 (baseline) without previous histories of stroke or MI. As a parameter of variability of FG, variability independent of mean (VIM) was calculated using FG levels measured at least three times during the 5 years until the baseline. Study endpoints were incident stroke, MI, and all-cause mortality through December 31, 2017.ResultsDuring follow-up, 25,038 cases of stroke, 15,832 cases of MI, and 44,716 deaths were identified. As the quartile of FG VIM increased, the risk of clinical outcomes serially increased after adjustment for confounding factors including duration and medications of diabetes and the mean FG. Adjusted hazard ratios (95% confidence intervals) of FG VIM quartile 4 compared with quartile 1 were 1.20 (1.16–1.24), 1.20 (1.15–1.25), and 1.32 (1.29–1.36) for stroke, MI and all-cause mortality, respectively. The impact of FG variability was higher in the elderly and those with a longer duration of diabetes and lower FG levels.ConclusionsIn diabetes, long-term glucose variability showed a dose–response relationship with the risk of stroke, MI, and all-cause mortality in this nationwide observational study.

1225-P: The Association between Long-Term Glucose Variability (GV), Cardiovascular (CV) Death, and Heart Failure (HF) Outcomes in the EMPA-REG OUTCOME Trial

Markers of GV have been associated with CV outcomes in type 2 diabetes (T2D), however, the association of GV with HF outcomes remains unclear. In EMPA-REG OUTCOME, empagliflozin reduced the risk of CV death by 38% and HF hospitalizations (HHF) by 35%. Here we explore the association between GV and CV death/HHF outcomes. In EMPA-REG OUTCOME, 7,020 patients with T2D and established CV disease received placebo (PBO), empagliflozin (EMPA) 10 mg or 25 mg and were observed for a median period of 3.1 years. We defined within-patient GV as range and standard deviation of HbA1c measurements on-treatment until week 28. The associations with CV death, first HHF, and HHF or CV death were explored in PBO and pooled EMPA arms separately with landmark (LM) analyses at week 28 by Cox regression models adjusted for baseline risk factors including changes in HbA1c from baseline to week 12. GV levels were lower with EMPA (Table). In the LM analysis, higher GV increased the risk for CV death and CV death or HHF in both treatment arms. For HHF, no significant association could be shown (Table). In EMPA-REG OUTCOME, EMPA reduced GV. An increase in GV correlated with increased risk of subsequent CV death and CV death or HHF. The association with HHF alone was not significant maybe due to a lower numbers of HHF events, or the assumption that the effects of EMPA on HHF are largely glucose-independent. Disclosure A. Ceriello: Advisory Panel; Self; Abbott Laboratories, Eli Lilly and Company, Janssen Pharmaceuticals, Inc., Novo Nordisk A/S, Vifor Pharma. Research Support; Self; Mitsubishi Tanabe Pharma Corporation. Speaker's Bureau; Self; A. Menarini Diagnostics, AstraZeneca, Berlin-Chemie AG, Boehringer Ingelheim Pharmaceuticals, Inc. A. Ofstad: Employee; Self; Boehringer Ingelheim International GmbH. I. Zwiener: Employee; Self; Boehringer Ingelheim Pharma GmbH &amp; Co KG, Merck KGaA. S. Kaspers: Employee; Self; Boehringer Ingelheim International GmbH. J. George: Employee; Self; Boehringer Ingelheim International GmbH. A. Nicolucci: Consultant; Self; AstraZeneca, Eli Lilly and Company, Medtronic, Novo Nordisk A/S. Research Support; Self; Artsana S.p.A., Dexcom, Inc., Novo Nordisk A/S, Sanofi-Aventis. Funding Boehringer Ingelheim; Eli Lilly and Company

Fasting glucose variability in young adulthood and incident diabetes, cardiovascular disease and all-cause mortality.

The aim of this study was to determine whether long-term intra-individual variability in fasting glucose (FG) during young adulthood is associated with incident diabetes, cardiovascular disease (CVD) and mortality. We included participants from the Coronary Artery Risk Development in Young Adults (CARDIA) study, ages 18-30years at baseline (1985-1986) and followed with eight examinations for up to 30years. Long-term glucose variability was assessed using the CV (CV-FG) and the absolute difference between successive FG measurements (average real variability; ARV-FG). For participants who developed any event (diabetes, CVD or mortality), FG variability measurement was censored at the examination prior to event ascertainment. We estimated HRs for incident diabetes, CVD and mortality with adjustment for demographics, baseline FG, change in FG (censor - baseline) and time-varying education, smoking, alcohol consumption, BMI, physical activity, systolic BP, BP medications, LDL-cholesterol and cholesterol medications (and incident diabetes and diabetes medications for CVD and mortality outcomes). Among 3769 black and white participants, there were 317 incident diabetes cases (102,677 person-years), 159 incident CVD events (110,314 person-years) and 174 deaths (111,390 person-years). After adjustment, HRs per 1 SD higher ARV-FG were 1.64 (95% CI 1.52, 1.78) for diabetes, 1.15 (95% CI 1.01, 1.31) for CVD and 1.25 (95% CI 1.11, 1.40) for mortality. The HRs per 1 SD higher CV-FG were 1.39 (95% CI 1.21, 1.58) for diabetes, 1.32 (95% CI 1.13, 1.54) for CVD and 1.08 (95% CI 0.92, 1.27) for mortality, after adjustment. The cause-specific HRs per 1 SD higher ARV-FG were 1.29 (95% CI 1.14, 1.47) for non-CVD death and 1.05 (95% CI 0.76, 1.45) for CVD death. We did not observe evidence for effect modification of any association by sex or race. Our results suggest that higher intra-individual FG variability during young adulthood before the onset of diabetes is associated with incident diabetes, CVD and mortality.

Abstract MP46: Fasting Glucose Variability in Young Adulthood and Incident Diabetes, Cardiovascular Disease, and Mortality: The Coronary Artery Risk Development in Young Adults (CARDIA) Study

Introduction: Whether long-term variability in fasting glucose (FG) independent of incident diabetes mellitus (DM) is associated with incident cardiovascular disease (CVD) and mortality is unclear. Hypothesis: Higher variability of FG would be associated with higher risk for incident CVD and mortality as compared with lower FG variability, independent of increases in FG over time and the development of DM. Methods: We studied 4210 black and white CARDIA participants, ages 18 to 30 years (1985-1986) at baseline and calculated 2 measures of long-term glucose variability, the coefficient of variation about the mean (CV-FG) and the absolute difference between successive FG measurements (average real variability; ARV-FG) before the onset of DM. We estimated hazard ratios (HR) for incident CVD and mortality over 30 years of follow-up with adjustment for time-varying CVD risk factors. Results: There were 417 incident cases of DM, 195 incident CVD events (122,279 person-years) and 237 deaths (123,505 person-years). The HR for incident CVD per 1-standard deviation (1-SD) higher CV-FG was 1.24 (95% confidence interval [CI]: 1.08, 1.42) and for ARV-FG was 1.14 (95% CI: 1.01, 1.28) after adjustment for demographics, baseline FG, change in FG, and time-varying education, smoking, alcohol consumption, body mass index, physical activity, systolic blood pressure (BP), BP medications, low-density lipoprotein cholesterol, cholesterol medications, incident DM, and DM medications (Figure 1A and 1B). HRs for mortality were similar in magnitude for 1-SD ARV-FG (HR: 1.22, 95% CI: 1.10, 1.35) and slightly weaker for CV-FG (HR: 1.12, 95% CI:0.98, 1.27) after adjustment for time-varying CVD risk factors. The majority of mortality and the variability-mortality association was due to non-CVD mortality. Associations were similar in magnitude when restricted to individuals without incident DM. Conclusion: Higher intra-individual FG variability during young adulthood before the onset of DM was associated with incident CVD and mortality.

Fasting Glucose Variability in Young Adulthood and Cognitive Function in Middle Age: The Coronary Artery Risk Development in Young Adults (CARDIA) Study

To determine whether intraindividual variability in fasting glucose (FG) below the threshold of diabetes is associated with cognitive function in middle adulthood beyond increasing FG. We studied 3,307 CARDIA (Coronary Artery Risk Development in Young Adults) Study participants (age range 18-30 years and enrolled in 1985-1986) at baseline and calculated two measures of long-term glucose variability: the coefficient of variation about the mean FG (CV-FG) and the absolute difference between successive FG measurements (average real variability [ARV-FG]) before the onset of diabetes over 25 and 30 years of follow-up. Cognitive function was assessed at years 25 (2010-2011) and 30 (2015-2016) with the Digit Symbol Substitution Test (DSST), Rey-Auditory Verbal Learning Test (RAVLT), Stroop Test, Montreal Cognitive Assessment, and category and letter fluency tests. We estimated the association between glucose variability and cognitive function test score with adjustment for clinical and behavioral risk factors, mean FG level, change in FG level, and diabetes development, medication use, and duration. After multivariable adjustment, 1-SD increment of CV-FG was associated with worse cognitive scores at year 25: DSST, standardized regression coefficient -0.95 (95% CI -1.54, -0.36); RAVLT, -0.14 (95% CI -0.27, -0.02); and Stroop Test, 0.49 (95% CI 0.04, 0.94). Findings were similar between CV-FG with each cognitive test score at year 30 and when we used an alternative measure of variability (ARV-FG) that captures variability in successive FG values. Higher intraindividual FG variability during young adulthood below the threshold of diabetes was associated with worse processing speed, memory, and language fluency in midlife independent of FG levels.

The impact of basal insulin analogues on glucose variability in patients with type 2 diabetes undergoing renal replacement therapy for end-stage renal disease.

We aimed to analyze the impact of basal insulin analogues on glucose variability (GV) in patients with type 2 diabetes (DM) undergoing renal replacement therapy. Fourteen subjects on insulin therapy for at least 6months (detemir, n=7 vs. glargine, n=7) were sequentially enrolled in this prospective study. Continuous glucose monitoring system (CGMS Gold, Dex Com 7+) was applied for 5days, over 3 consecutive sessions of hemodialysis (HD). Various glycemic profiles (coefficient of variation-CV of mean glucose) were compared between the day on (HD-on) and the day off (HD-off) dialysis. The CV of at least 3 values of HbA1c (HPLC) since replacement therapy has been applied to assay the long-term GV. Endogenous insulin and insulin resistance (HOMA using fasting glucose and C-peptide levels), fasting lipid profile, quantitative C-reactive protein (CRP) and ferritin (values adjusted for Hb) were measured in serum at inclusion. The overnight HD-off and HD-on short-term (CV CGMS) GV, overall long-term (CV of HbA1c) GV, CRP and ferritin were reduced in subjects treated with detemir (paired t test, p=0.0001, 0.0011, 0.036, <0.001, and <0.001 between groups). All participants were insulin-resistant (HOMA-IR>3). Insulin-resistant patients with type 2 diabetes undergoing hemodialysis for end-stage renal disease on insulin detemir exhibit lower glycemic variability and pro-inflammatory profile than with insulin glargine.

Poincaré Plot Quantification for Assessing Glucose Variability from Continuous Glucose Monitoring Systems and a New Risk Marker for Hypoglycemia: Application to Type 1 Diabetes Patients Switching to Continuous Subcutaneous Insulin Infusion

The Poincaré plot (PCP) is a valuable tool for describing glucose variability (GV) from continuous glucose monitoring (CGM) but remains only visual and qualitative. The aim of this work was to validate metrics for the geometry of the PCP in type 1 diabetes and to apply them to the study of a series of patients switching to continuous subcutaneous insulin infusion (CSII). We reviewed the CGM profiles of 44 patients with type 1 diabetes. A subgroup (n=13) used CGM before and after 6 months on CSII. Additionally, we prospectively collected seven recordings from healthy controls. The new PCP metrics were correlated with hypoglycemia and classical GV indices and were compared between groups. SDs related to the PCP fitting ellipse (SD1, SD2) and area and shape of the fitting ellipse (SFE) were all higher in diabetes patients than in the controls and decreased significantly on CSII. SD1 represented short-term GV and was equivalent to continuous overlapping net glycemic action (CONGA). SD2 represented long-term GV and correlated with the SD of glucose levels (r ≥ 0.98), mean of daily differences (r ≥ 0.91), and mean amplitude of glycemic excursions (r ≥ 0.88). SFE correlated positively with CONGA at 1 h but not with the other indices and was inversely correlated with hypoglycemic episodes (Spearman's ρ=-0.42), independently of the coefficient of variation and the Low Blood Glucose Index in a multivariate analysis (partial r=-0.34). PCP metrics are correlated with known GV indices and may be used for the study of CGM recording series in type 1 diabetes. SFE is a new risk marker for hypoglycemia.