Long-term visit-to-visit glycemic variability as predictor of micro- and macrovascular complications in patients with type 2 diabetes: The Rio de Janeiro Type 2 Diabetes Cohort Study

BackgroundLong-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.Methods654 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.ResultsDuring 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.ConclusionsLong-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.

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title: Direct medical costs of complications of diabetes in the United States: estimates for event-year and annual state costs (USD 2012)
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title: Standards of Medical Care in Diabetes—2012
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title: Glycosylated Hemoglobin in Relationship to Cardiovascular Outcomes and Death in Patients with Type 2 Diabetes: A Systematic Review and Meta-Analysis
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title: 10-year follow-up of intensive glucose control in type 2 diabetes.
abstract: During the United Kingdom Prospective Diabetes Study (UKPDS), patients with type 2 diabetes mellitus who received intensive glucose therapy had a lower risk of microvascular complications than did those receiving conventional dietary therapy. We conducted post-trial monitoring to determine whether this improved glucose control persisted and whether such therapy had a long-term effect on macrovascular outcomes.



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Between-group differences in glycated hemoglobin levels were lost after the first year. In the sulfonylurea-insulin group, relative reductions in risk persisted at 10 years for any diabetes-related end point (9%, P=0.04) and microvascular disease (24%, P=0.001), and risk reductions for myocardial infarction (15%, P=0.01) and death from any cause (13%, P=0.007) emerged over time, as more events occurred. In the metformin group, significant risk reductions persisted for any diabetes-related end point (21%, P=0.01), myocardial infarction (33%, P=0.005), and death from any cause (27%, P=0.002).



Despite an early loss of glycemic differences, a continued reduction in microvascular risk and emergent risk reductions for myocardial infarction and death from any cause were observed during 10 years of post-trial follow-up. A continued benefit after metformin therapy was evident among overweight patients.

title: Follow-up of glycemic control and cardiovascular outcomes in type 2 diabetes.
abstract: The Veterans Affairs Diabetes Trial previously showed that intensive glucose lowering, as compared with standard therapy, did not significantly reduce the rate of major cardiovascular events among 1791 military veterans (median follow-up, 5.6 years). We report the extended follow-up of the study participants.



After the conclusion of the clinical trial, we followed participants, using central databases to identify procedures, hospitalizations, and deaths (complete cohort, with follow-up data for 92.4% of participants). Most participants agreed to additional data collection by means of annual surveys and periodic chart reviews (survey cohort, with 77.7% follow-up). The primary outcome was the time to the first major cardiovascular event (heart attack, stroke, new or worsening congestive heart failure, amputation for ischemic gangrene, or cardiovascular-related death). Secondary outcomes were cardiovascular mortality and all-cause mortality.



The difference in glycated hemoglobin levels between the intensive-therapy group and the standard-therapy group averaged 1.5 percentage points during the trial (median level, 6.9% vs. 8.4%) and declined to 0.2 to 0.3 percentage points by 3 years after the trial ended. Over a median follow-up of 9.8 years, the intensive-therapy group had a significantly lower risk of the primary outcome than did the standard-therapy group (hazard ratio, 0.83; 95% confidence interval [CI], 0.70 to 0.99; P=0.04), with an absolute reduction in risk of 8.6 major cardiovascular events per 1000 person-years, but did not have reduced cardiovascular mortality (hazard ratio, 0.88; 95% CI, 0.64 to 1.20; P=0.42). No reduction in total mortality was evident (hazard ratio in the intensive-therapy group, 1.05; 95% CI, 0.89 to 1.25; P=0.54; median follow-up, 11.8 years).



After nearly 10 years of follow-up, patients with type 2 diabetes who had been randomly assigned to intensive glucose control for 5.6 years had 8.6 fewer major cardiovascular events per 1000 person-years than those assigned to standard therapy, but no improvement was seen in the rate of overall survival.

title: Follow-up of blood-pressure lowering and glucose control in type 2 diabetes.
abstract: In the Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation (ADVANCE) factorial trial, the combination of perindopril and indapamide reduced mortality among patients with type 2 diabetes, but intensive glucose control, targeting a glycated hemoglobin level of less than 6.5%, did not. We now report results of the 6-year post-trial follow-up.



We invited surviving participants, who had previously been assigned to perindopril-indapamide or placebo and to intensive or standard glucose control (with the glucose-control comparison extending for an additional 6 months), to participate in a post-trial follow-up evaluation. The primary end points were death from any cause and major macrovascular events.



The baseline characteristics were similar among the 11,140 patients who originally underwent randomization and the 8494 patients who participated in the post-trial follow-up for a median of 5.9 years (blood-pressure-lowering comparison) or 5.4 years (glucose-control comparison). Between-group differences in blood pressure and glycated hemoglobin levels during the trial were no longer evident by the first post-trial visit. The reductions in the risk of death from any cause and of death from cardiovascular causes that had been observed in the group receiving active blood-pressure-lowering treatment during the trial were attenuated but significant at the end of the post-trial follow-up; the hazard ratios were 0.91 (95% confidence interval [CI], 0.84 to 0.99; P=0.03) and 0.88 (95% CI, 0.77 to 0.99; P=0.04), respectively. No differences were observed during follow-up in the risk of death from any cause or major macrovascular events between the intensive-glucose-control group and the standard-glucose-control group; the hazard ratios were 1.00 (95% CI, 0.92 to 1.08) and 1.00 (95% CI, 0.92 to 1.08), respectively.



The benefits with respect to mortality that had been observed among patients originally assigned to blood-pressure-lowering therapy were attenuated but still evident at the end of follow-up. There was no evidence that intensive glucose control during the trial led to long-term benefits with respect to mortality or macrovascular events. (Funded by the National Health and Medical Research Council of Australia and others; ADVANCE-ON ClinicalTrials.gov number, NCT00949286.).

title: Long-term Glycemic Variability and Risk of Adverse Outcomes: A Systematic Review and Meta-analysis
abstract: Glycemic variability is emerging as a measure of glycemic control, which may be a reliable predictor of complications. This systematic review and meta-analysis evaluates the association between HbA1c variability and micro- and macrovascular complications and mortality in type 1 and type 2 diabetes.  Medline and Embase were searched (2004–2015) for studies describing associations between HbA1c variability and adverse outcomes in patients with type 1 and type 2 diabetes. Data extraction was performed independently by two reviewers. Random-effects meta-analysis was performed with stratification according to the measure of HbA1c variability, method of analysis, and diabetes type.  Seven studies evaluated HbA1c variability among patients with type 1 diabetes and showed an association of HbA1c variability with renal disease (risk ratio 1.56 [95% CI 1.08–2.25], two studies), cardiovascular events (1.98 [1.39–2.82]), and retinopathy (2.11 [1.54–2.89]). Thirteen studies evaluated HbA1c variability among patients with type 2 diabetes. Higher HbA1c variability was associated with higher risk of renal disease (1.34 [1.15–1.57], two studies), macrovascular events (1.21 [1.06–1.38]), ulceration/gangrene (1.50 [1.06–2.12]), cardiovascular disease (1.27 [1.15–1.40]), and mortality (1.34 [1.18–1.53]). Most studies were retrospective with lack of adjustment for potential confounders, and inconsistency existed in the definition of HbA1c variability.  HbA1c variability was positively associated with micro- and macrovascular complications and mortality independently of the HbA1c level and might play a future role in clinical risk assessment.

title: Fasting plasma glucose variability as a risk factor of retinopathy in Type 2 diabetic patients.
abstract: The purpose of this study was to determine whether plasma glucose variability, irrespective of glycated hemoglobin (HbA1c), was able to predict the onset of retinopathy in Type 2 diabetic patients.



The study was based on a cohort of 130 Type 2 diabetic patients without retinopathy recruited from June 1994 to June 1998. The fundus was reexamined between November 2000 and June 2001, with a mean follow-up period of 5.2 years. Fasting plasma glucose (FPG) variability was measured by its variation coefficient (VC). Stratified and multivariate models were used to estimate the effect of FPG variability and mean HbA1c during follow-up on cumulative incidence (IP) of retinopathy.



The IP of retinopathy was 36.2% and increased all along the quartiles of FPG variability (P=.001). In multivariate analyses, only the last quartile of the distribution of VC (OR=3.68; 95% confidence interval (CI) 1.01-13.4; P=.049) was significant. The term of interaction between mean HbA1c and VC was not significant.



FPG variability fulfills criteria to be considered a risk factor for retinopathy: A statistically significant association exists after adjustment for confounders, time sequence, dosage response gradient, and biological plausibility.

title: Is fasting glucose variability a risk factor for retinopathy in people with type 2 diabetes?
abstract: Fasting plasma glucose variability strongly predicts the incidence of cardiovascular events in type 2 diabetic patients. We prospectively assessed whether fasting plasma glucose variability predicts the development/progression of retinopathy in a large cohort of type 2 diabetic outpatients.



In the period 1996-1999, 1019 type 2 diabetic participants (aged 69+/-11 years) in the Verona Diabetes Study underwent at least 3 fasting plasma glucose (FPG) determinations and an eye examination by retinography. Of these, 746 underwent a 2nd eye examination in the period 2000-2004, while 273 did not (102 patients had died before undergoing the 2nd eye examination). For each patient, the mean (M-FPG) and the coefficient of variation of FPG (CV-FPG) were computed.



By the 2nd eye examination, 124 patients had either developed new retinopathy (79 patients) or progressed to a more severe degree of retinopathy (45 patients). In a multivariable logistic regression analysis, the development/progression of retinopathy was independently predicted by average glycaemia over time, expressed as glycated haemoglobin (odds ratio [OR] 1.82, 95%CI 1.40-2.38 for 1 SD increase) or M-FPG (OR 1.88, 1.47-2.41), but not by CV-FPG. Among other independent variables, HDL-cholesterol was inversely associated with the development/progression of retinopathy.



These results suggest that in elderly type 2 diabetic patients the magnitude of hyperglycaemia, but not fasting plasma glucose variability, strongly predicts the development/progression of diabetic retinopathy independently of other known risk factors.

title: The effect of fasting plasma glucose variability on the risk of retinopathy in type 2 diabetic patients: retrospective long-term follow-up.
abstract: This study aimed to determine whether fasting plasma glucose (FPG) variability can predict diabetic retinopathy development and progression independently of glycemic control.



Subjects consisted of 170 type 2 diabetes mellitus patients not showing diabetic retinopathy on their first visit to our hospital between 1966 and 1979, and continuously visited thereafter for 27-40 (mean, 33) years. Plasma glucose and HbA1c data obtained on every hospital visit were collected. As FPG variability parameter, standard deviations (SD) were used.



The investigation in which patients were classified based on the median value of the mean HbA1c or FPG and that of FPG SD have revealed that the risk of retinopathy development and progression were similar between the group showing good control and high variability and that with poor control and low variability. In multivariate analysis models with the mean FPG or HbA1c as a covariate and models using the mean FPG or HbA1c as a time-dependent covariate after adjustment for age, sex, diabetes duration, BMI, hypertension, and hypoglycemia, FPG SD was a significant independent risk factor for retinopathy.



In type 2 diabetic patients, FPG variability is a risk factor for diabetic retinopathy independent of the mean FPG or HbA1c.

title: HbA1c, systolic blood pressure variability and diabetic retinopathy in Asian type 2 diabetics
abstract: The aim of the present study was to examine the association between variability in HbA1c or systolic blood pressure (SBP) and diabetes‐specific moderate retinopathy in Asians with type 2 diabetes (T2D).

title: Predictive ability of visit-to-visit variability in HbA1c and systolic blood pressure for the development of microalbuminuria and retinopathy in people with type 2 diabetes.
abstract: We explored whether visit-to-visit variability in both glycated hemoglobin (HbA1c) and systolic blood pressure (SBP) simultaneously predicted the development of microalbuminuria and retinopathy, and whether the predictive ability of these measurements changed according to mean HbA1c and SBP levels in people with type 2 diabetes.



A retrospective observational cohort study was conducted on 243 type 2 diabetes patients with normoalbuminuria and 486 without retinopathy at the first visit and within 1year thereafter. The two cohorts were followed up from 1995 until 2012. Multivariate and stratified analyses were performed using Cox proportional hazard models.



Microalbuminuria developed in 84 patients and retinopathy in 108. Hazard ratios (HRs) for the development of microalbuminuria associated with the coefficient of variation (CV) and variation independent of mean (VIM) of both HbA1c and SBP significantly increased. In participants with a mean SBP <130mmHg, the HRs for the development of retinopathy associated with CV and VIM of HbA1c were abruptly elevated and significant compared with those with a mean SBP ≥130mmHg.



Visit-to-visit variability in both HbA1c and SBP simultaneously predict the development of microalbuminuria. HbA1c variability may predict the development of retinopathy when the mean SBP is normal (<130mmHg).

title: Glycemic Control Patterns and Kidney Disease Progression among Primary Care Patients with Diabetes Mellitus
abstract: Reducing glycosylated hemoglobin (HbA1c) to near or less than 7% in patients with diabetes is associated with diminished microvascular complications, but this level is not consistently achieved. The purpose of this study was to examine the relationship between fluctuations in HbA1c and changes in estimated glomerular filtration rate (eGFR) and estimated stage of chronic kidney disease (CKD) in an academic primary care practice. We analyzed data from 791 diabetic primary care patients (25% white; 75% African American) enrolled between 1998 to 2002 and followed through 2008 (mean follow-up, 7.6 ± 1.9 years). We calculated baseline and final follow-up eGFR using the Modification of Diet in Renal Disease equation. We examined the relationship between fluctuations in HbA1c and changes in eGFR and stage of CKD using multivariable linear and logistic regression models that controlled for demographic and clinical variables associated with CKD progression. From baseline to follow-up, mean eGFR in African Americans declined to a greater extent and more rapidly than in whites. Age, mean systolic blood pressure, initial HbA1c, initial eGFR, and number of HbA1c values (all P < .01) were significant predictors of change in eGFR. Among HbA1c fluctuation measures, the strongest predictor of change in eGFR was the proportion of HbA1c values >7% (P = .02); however, this contributed little to explaining model variance. These data suggest that traditional demographic and clinical risk factors remain significantly associated with changes in eGFR and that the pattern of variability in HbA1c is only modestly important in contributing to changes in eGFR among African-American and white diabetic patients in primary care.

title: HbA1c variability is associated with microalbuminuria development in type 2 diabetes: a 7-year prospective cohort study
abstract: hypothesisHbA1c variability has been shown to be an independent risk factor for nephropathy in patients with type 1 diabetes. In this study, we aimed to explore the association between HbA1c variability and microalbuminuria development in patients with type 2 diabetes. We also intended to test the applicability of serially measured HbA1c over 2 years for this risk assessment.MethodsBetween 2003 and 2005, we recruited 821 middle-aged normoalbuminuric individuals with type 2 diabetes and followed them through to the end of 2010. The average follow-up time was 6.2 years. We defined microalbuminuria as a urine albumin to creatinine ratio of 30 mg/g (3.4 mg/mmol) or higher. HbA1c variability was calculated by the SD of serially measured HbA1c. The Cox proportional hazards model was used to evaluate the association between HbA1c SD quartile and development of microalbuminuria.ResultsThe incidence of microalbuminuria for the overall population was 58.4, 58.6, 60.8 and 91.9 per 1,000 person-years for Q1- to Q4-adjusted HbA1c SD, respectively (p for trend = 0.042). Compared with patients in Q1, those in Q4 were about 37% more likely to develop microalbuminuria. The HR derived from a series of 2 year HbA1c measurements was similar to that from data collection for longer than 4 years. to mean HbA1c values, HbA1c variability, even measured as early as 2 years, is independently associated with the development of microalbuminuria in patients with type 2 diabetes.

title: HbA1c variability and the development of microalbuminuria in type 2 diabetes: Tsukuba Kawai Diabetes Registry 2
abstract: hypothesisThe aim of this study was to examine the association between HbA1c variability and the development of microalbuminuria as defined by an albumin/creatinine ratio ≥3.4 mg/mmol (≥30 mg/g) in at least two of three consecutive urine samples in Japanese patients with type 2 diabetes.MethodsHbA1c level was measured in 812 serially registered normoalbuminuric adults aged 21–79 years with type 2 diabetes. After registration, a 1-year period to establish baseline values for mean HbA1c and HbA1c variability (measured as the intrapersonal SD of serially collected HbA1c) was decided upon. The association between HbA1c variability and the development of microalbuminuria was determined by Cox regression analysis after adjustment for other risk factors for microalbuminuria.ResultsMicroalbuminuria occurred in 193 patients during the observation period of (mean ± SD) 4.3 ± 2.7 years. Even after adjustment for mean HbA1c, HbA1c variability was a significant predictor of microalbuminuria independently of the mean HbA1c; the HR for every 1% (95% CI) increase in mean HbA1c was 1.22 (1.06, 1.40) (p = 0.005), and that for HbA1c variability was 1.35 (1.05, 1.72) (p = 0.019). The effects of these two variables were quite similar when 1 SD was used; the HR for every 1 SD increase (95% CI) in HbA1c was 1.23 (1.07, 1.43) (p = 0.005), and that for HbA1c variability was 1.20 (1.03, 1.39) (p = 0.019).Conclusions/interpretationHbA1c variability affects the development of microalbuminuria independently of mean HbA1c in type 2 diabetes. Further studies should be performed to evaluate the influence of HbA1c variability on other complications and in individuals of other ethnicities with type 2 diabetes.

title: Intrapersonal HbA1c variability and the risk of progression of nephropathy in patients with Type 2 diabetes
abstract: (2012)

title: Risk association of HbA1c variability with chronic kidney disease and cardiovascular disease in type 2 diabetes: prospective analysis of the Hong Kong Diabetes Registry
abstract: In type 2 diabetes, tight glycaemic control lowers the risk of diabetic complications, but it remains uncertain whether variability of glycaemia influences outcomes. We examined the association of glycated haemoglobin (HbA1c) variability with incident chronic kidney disease and cardiovascular disease in a prospective cohort of 8439 Chinese patients with type 2 diabetes recruited from 1994 to 2007.

title: Risks of diabetic nephropathy with variation in hemoglobin A1c and fasting plasma glucose.
abstract: This study examined whether annual variation in glycosylated hemoglobin A1c (HbA1c) and fasting plasma glucose (FPG), as represented by the coefficient of variation (CV), can predict diabetic nephropathy independently of mean FPG, mean HbA1c, and other risk factors in patients with type 2 diabetes.



A computerized database of patients with type 2 diabetes aged ≥30 years and free of diabetic nephropathy (n = 3220) who were enrolled in the Diabetes Care Management Program of China Medical University Hospital before 2007 was used in a time-dependent Cox proportional hazards regression model.



The incidence rates of diabetic nephropathy were 16.11, 22.95, and 28.86 per 1000 person-years in the first, second, and third tertiles of baseline HbA1c-CV, respectively; the corresponding incidence rates for FPG-CV were 9.46, 21.23, and 37.51 per 1000 person-years, respectively. After multivariate adjustment, the corresponding hazard ratios for the second and third tertiles versus the first tertile of annual HbA1c-CV were 1.18 (95% confidence interval [CI], 0.88-1.58) and 1.58 (95% CI, 1.19-2.11), respectively, and 1.55 (95% CI, 0.99-2.41) and 4.75 (95% CI, 3.22-7.01) for FPG-CV, respectively. The risks of diabetic nephropathy for HbA1c-CV and FPG-CV stratified according to age, gender, renal function, and hypertension status were provided.



Annual FPG and HbA1c variations have a strong association with diabetic nephropathy in patients with type 2 diabetes. Whether intervention for reducing glucose variation should be administered needs to be examined in a future study.

title: HbA1c variability in type 2 diabetes is associated with the occurrence of new-onset albuminuria within three years.
abstract: To evaluate the association between HbA1c coefficient of variation (HbA1c-CV) and 3-year new-onset albuminuria risk.



A retrospective cohort study involving 716 normoalbuminuric type 2 diabetes patients was conducted between 2010 and 2014. HbA1c-CV was used to categorize patients into low, moderate or high variability groups. Multivariate logistic models were constructed and validated. Integrated discrimination (IDI) and net reclassification (NRI) improvement indices were used to quantify the added predictive value of HbA1c-CV.



The mean age of our cohort was 56.1±12.9years with a baseline HbA1c of 8.3±1.3%. Over 3-years of follow-up, 35.2% (n=252) developed albuminuria. An incremental risk of albuminuria was observed with moderate (6.68-13.43%) and high (above 13.44%) HbA1c-CV categories demonstrating adjusted odds ratios of 1.63 (1.12-2.38) and 3.80 (2.10-6.97) for 3-year new-onset albuminuria, respectively. Including HbA1c-CV for 3-year new-onset albuminuria prediction improved model discrimination (IDI: 0.023, NRI: 0.293, p<0.05). The final model had a C-statistic of 0.760±0.018 on validation.



HbA1c-CV improves 3-year prediction of new-onset albuminuria. Together with mean HbA1c, baseline urine albumin-to-creatinine ratio and presence of hypertension, accurate 3-year new-onset albuminuria prediction may be possible.

title: Effect of long‐term glycemic variability on estimated glomerular filtration rate decline among patients with type 2 diabetes mellitus: Insights from the Diabetic Nephropathy Cohort in Singapore
abstract: In the present study, we examined the association between HbA1c variability and renal disease progression based on estimated glomerular filtration rate (eGFR) decline in patients with type 2 diabetes mellitus (T2DM) in Singapore.

title: Glycated albumin and its variability as an indicator of cardiovascular autonomic neuropathy development in type 2 diabetic patients
abstract: BackgroundWe investigated whether glycated albumin (GA) and its variability are associated with cardiovascular autonomic neuropathy (CAN) and further compared their associations with glycated hemoglobin (HbA1c).MethodsThis retrospective longitudinal study included 498 type 2 diabetic patients without CAN. CAN was defined as at least two abnormal results in parasympathetic tests or presence of orthostatic hypotension. The mean, standard deviation (SD), and coefficient of variance (CV) were calculated from consecutively measured GA (median 7 times) and HbA1c levels (median 8 times) over 2 years. Logistic regression analysis was used to compare the associations between CAN and GA- or HbA1c-related parameters. Receiver operating characteristic (ROC) curve analysis was used to compare the predictive power for CAN between GA- and HbA1c-related parameters. total of 53 subjects (10.6%) developed CAN over 2 years. The mean, SD, and CV of GA or HbA1c were significantly higher in subjects with CAN. Higher mean GA and GA variability were associated with the risk of developing CAN, independent of conventional risk factors and HbA1c. In ROC curve analysis, the SD and CV of GA showed higher predictive value for CAN compared to the SD and CV of HbA1c, whereas the predictive value of mean GA did not differ from that of mean HbA1c. The mean, SD, and CV of GA showed additive predictive power to detect CAN development along with mean HbA1c.ConclusionsHigher serum GA and its variability are significantly associated with the risk of developing CAN. Serum GA might be a useful indicator for diabetic complications and can enhance HbA1c’s modest clinical prediction for CAN.

title: Fluctuations in HbA1c are associated with a higher incidence of cardiovascular disease in Japanese patients with type 2 diabetes
abstract: To reveal whether visit‐to‐visit variability in HbA1c is associated with higher risk of cardiovascular disease (CVD) in patients with type 2 diabetes.

title: Impact of Visit-to-Visit Glycemic Variability on the Risks of Macrovascular and Microvascular Events and All-Cause Mortality in Type 2 Diabetes: The ADVANCE Trial
abstract: There is no consensus on the importance of visit-to-visit glycemic variability in diabetes. Therefore, we assessed the effects of visit-to-visit variability (VVV) in HbA1c and fasting glucose on major outcomes in the ADVANCE (Action in Diabetes and Vascular Disease: Preterax and Diamicron MR Controlled Evaluation) trial.  ADVANCE was a factorial randomized controlled trial of intensive glucose control and blood pressure lowering in patients with type 2 diabetes. VVV in the intensive glucose treatment group was defined using the SD of five measurements of HbA1c and glucose taken 3–24 months after randomization. Outcomes were combined macro- and microvascular events and all-cause mortality occurring post 24 months. Sensitivity analyses were performed using other indices of variability and in the standard glucose treatment group.  Among 4,399 patients in the intensive group, an increase in VVV of HbA1c was associated with an increased risk of vascular events (P = 0.01) and with mortality (P < 0.001): highest versus lowest tenth hazard ratio (95% CI) 1.64 (1.05–2.55) and 3.31 (1.57–6.98), respectively, after multivariable adjustment. A clear association was also observed between VVV of fasting glucose and increased risk of vascular events (P < 0.001; 2.70 [1.65–4.42]). HbA1c variability was positively associated with the risk of macrovascular events (P = 0.02 for trend), whereas glucose variability was associated with both macro- and microvascular events (P = 0.005 and P < 0.001 for trend, respectively). Sensitivity analyses using other indices, and patients in the standard glucose treatment group, were broadly consistent with these results.  Consistency of glycemic control is important to reduce the risks of vascular events and death in type 2 diabetes.

title: The combined effect of visit-to-visit variability in HbA1c and systolic blood pressure on the incidence of cardiovascular events in patients with type 2 diabetes
abstract: To investigate the association between long-term visit-to-visit variability in glycated hemoglobin (HbA1c) and systolic blood pressure (SBP) and the incidence of cardiovascular disease (CVD) in patients with type 2 diabetes.  We retrospectively enrolled 632 patients with type 2 diabetes and no history of CVD who first visited our hospital between 1995 and 1996, were followed-up for ≥1 year, attended at least 4 clinic visits and had at least 1 visit per year. Patients were followed until June 2012 at the latest, and mailed questionnaires.  During the median follow-up period (15.4 years), 81 patients developed CVD. Multivariate analysis revealed that the coefficient of variation (CV) and the variation independent of mean (VIM) for HbA1c and SBP were significant predictors of CVD incidence independent of mean HbA1c and SBP. Patients were classified into 4 groups by median HbA1cCV and SBPCV values and by median HbA1cVIM and SBPVIM values. Among these groups, the HRs were highest in the high-HbA1cCV/high-SBPCV and high-HbA1cVIM/high-SBPVIM groups and were significantly higher compared with those in the low-HbA1cCV/low-SBPCV and low-HbA1cVIM/low-SBPVIM groups, respectively. Among patients with mean SBP≥130 mm Hg, the HRs associated with HbA1cCV and HbA1cVIM were drastically elevated compared with those with mean SBP<130 mm Hg (interaction p<0.05).  Long-term visit-to-visit variability in HbA1c and SBP represented a combined and additive risk for CVD incidence in patients with type 2 diabetes. It is suggested that a synergistic effect exists between HbA1c variability and mean SBP levels for CVD incidence.

title: Association of the average rate of change in HbA1c with severe adverse events: a longitudinal evaluation of audit data from the Bavarian Disease Management Program for patients with type 2 diabetes mellitus
abstract: patients with type 2 diabetes mellitus, the effects of HbA1c variability on macrovascular events remain uncertain. The present investigation evaluates the association of HbA1c variability with non-fatal cardiovascular events, emergency admissions and episodes of severe hypoglycaemia in a cohort of patients newly started on insulin therapy.MethodsHbA1c variability was defined as the rate of change in values between observations. The medical records of 406,356 patients enrolled in a disease management programme for type 2 diabetes mellitus were analysed to identify a cohort of 13,777 patients with observed transition to insulin therapy. The cohort was observed for a period of at least 5 years. Cox regression models were applied to quantify the association of HbA1c variability with the events of interest.ResultsThe models reveal a significant non-linear association between HbA1c variability and the risk of experiencing myocardial infarction, stroke and hypoglycaemia. The lowest risk is seen with a variability of approximately 0.5% (5.5 mmol/mol) per quarter. Using Cox models to predict survival curves for the cohort with hypothetical HbA1c variability of 0.5% (5.5 mmol/mol) and 1.5% (16.4 mmol/mol) per quarter, the proportion experiencing myocardial infarction within 2 years increases significantly from 1% to 10%. The proportion experiencing stroke increases from 1% to 29%, hypoglycaemia from 2% to 24% and the risk of emergency admission from 2% to 21%.Conclusions/interpretationIn patients newly started on insulin therapy, rapid and higher HbA1c variability is associated with an increased risk of myocardial infarction, stroke, severe hypoglycaemia and emergency admission.

title: Identifying the independent effect of HbA1c variability on adverse health outcomes in patients with Type 2 diabetes
abstract: To characterize the relationship between HbA1c variability and adverse health outcomes among US military veterans with Type 2 diabetes.

title: Association of variability in hemoglobin A1c with cardiovascular diseases and mortality in Chinese patients with type 2 diabetes mellitus - A retrospective population-based cohort study.
abstract: This study aimed to investigate the association between variability in HbA1c and incidence of cardiovascular disease (CVD) event and mortality among Chinese primary care patients with Type 2 diabetes mellitus (T2DM).



A retrospective cohort study was conducted on 91,866 T2DM patients aged ≥18years without any history of CVD. Variability in HbA1c, was measured by standard deviation (SD), associated with the risks of CVD and all-cause mortality were evaluated using Cox proportional hazards regression analysis by age groups ( 65 and ≥ 65 years old)." to "Variability in HbA1c was measured by standard deviation (SD) The association between Variability in HbA1c and the incidence of CVD and all-cause mortality were evaluated using Cox proportional hazards regression analysis by age groups ( 65 and ≥ 65 years old).



Over a median follow-up of 58.5months, our study identified a positive linear relationship between variability in HbA1c and incidence of CVD and all-cause mortality in the younger and older groups. For every 1-SD increase in HbA1c, the risk of CVD events in the older group only increased by 15.2% (95% CI: 1.026-1.293), and the risks of all-cause mortality in both age groups increased by 49.5% (95% CI: 1.154-1.936) and 77.8% (95% CI: 1.563-2.024), respectively.



The HbA1c variability independently of the mean HbA1c level may provide additional valuable information as a potential predictor for the development of CVD and all-cause mortality in diabetic patients, particularly for the elderly patients.

title: Ten-year hemoglobin A1c trajectories and outcomes in type 2 diabetes mellitus: The Diabetes & Aging Study.
abstract: To classify trajectories of long term HbA1c values in patients after diagnosis of type 2 diabetes and examine each trajectory's associations with subsequent microvascular and macrovascular events and mortality.



A longitudinal follow-up of 28,016 patients newly diagnosed with type 2 diabetes was conducted. Latent growth mixture modeling was used to identify ten-year HbA1c trajectories. Cox proportional hazards models were used to assess how HbA1c trajectories were associated with events (microvascular and macrovascular) and mortality.



We identified 5 HbA1c trajectories: "low stable" (82.5%), "moderate increasing late" (5.1%), "high decreasing early" (4.9%), "moderate peaking late" (4.1%) and "moderate peaking early" (3.3%). After adjusting for average HbA1c, compared to the low stable trajectory, all non-stable trajectories were associated with higher incidences of microvascular events (hazard ratio (HR) range, 1.28 (95% CI, 1.08-1.53) (high decreasing early) to 1.45 (95% CI, 1.20-1.75) (moderate peaking early)). The high decreasing early trajectory was associated with an increased mortality risk (HR, 1.27 (95% CI, 1.03-1.58)). Trajectories were not associated with macrovascular events.



Non-stable HbA1c trajectories were associated with greater risk of microvascular events and mortality. These findings suggest a potential benefit of early diabetes detection, prioritizing good glycemic control, and maintaining control over time.

title: Greater HbA1c variability is associated with increased cardiovascular events in type 2 diabetes patients with preserved renal function, but not in moderate to advanced chronic kidney disease
abstract: Emerging evidence suggests that glycemic variability may be a more reliable measure of glycemic control than mean HbA1c in type 2 diabetes mellitus. This study aimed to determine if HbA1c variability is associated with cardiovascular events in type 2 diabetic patients and if different renal functions affect such association. This longitudinal study enrolled 8259 diabetic patients from the Kaohsiung Medical University Research Database in 2009 and were followed-up until 2015. Intra-individual HbA1C variability was defined as the standard deviation (SD) of HbA1c and cardiovascular events were defined as hospitalization for coronary artery disease, unstable angina, myocardial infarction, stroke, peripheral artery disease, and cardiovascular death. The patients were grouped into two based on their estimated glomerular filtration rate (eGFR) ≥ 60 or < 60 min/ml/1.73m2. In a mean follow-up period of 6.3 years, cardiovascular events were recorded in 8.9% of the patients. In an adjusted Cox model, high HbA1c SD (hazard ratio, 1.290; 95% confidence interval, 1.008–1.650; p = 0.043), but not mean HbA1c, was associated with significantly increased risk of cardiovascular events in patients with eGFR ≥ 60 min/ml/1.73m2. This association was not seen in patients with eGFR < 60 min/ml/1.73m2. In this study, greater HbA1c variability is associated with increased risk of cardiovascular among patients with preserved renal function, but not in those with moderate to advanced chronic kidney disease.

title: Day-to-day fasting glycaemic variability in DEVOTE: associations with severe hypoglycaemia and cardiovascular outcomes (DEVOTE 2)
abstract: Patients with Type 2 Diabetes at High Risk of Cardiovascular Events (DEVOTE) was a double-blind, randomised, event-driven, treat-to-target prospective trial comparing the cardiovascular safety of insulin degludec with that of insulin glargine U100 (100 units/ml) in patients with type 2 diabetes at high risk of cardiovascular events. This paper reports a secondary analysis investigating associations of day-to-day fasting glycaemic variability (pre-breakfast self-measured blood glucose [SMBG]) with severe hypoglycaemia and cardiovascular outcomes.MethodsIn DEVOTE, patients with type 2 diabetes were randomised to receive insulin degludec or insulin glargine U100 once daily. The primary outcome was the first occurrence of an adjudicated major adverse cardiovascular event (MACE). Adjudicated severe hypoglycaemia was the pre-specified secondary outcome. In this article, day-to-day fasting glycaemic variability was based on the standard deviation of the pre-breakfast SMBG measurements. The variability measure was calculated as follows. Each month, only the three pre-breakfast SMBG measurements recorded before contact with the site were used to determine a day-to-day fasting glycaemic variability measure for each patient. For each patient, the variance of the three log-transformed pre-breakfast SMBG measurements each month was determined. The standard deviation was determined as the square root of the mean of these monthly variances and was defined as day-to-day fasting glycaemic variability. The associations between day-to-day fasting glycaemic variability and severe hypoglycaemia, MACE and all-cause mortality were analysed for the pooled trial population with Cox proportional hazards models. Several sensitivity analyses were conducted, including adjustments for baseline characteristics and most recent HbA1c.ResultsDay-to-day fasting glycaemic variability was significantly associated with severe hypoglycaemia (HR 4.11, 95% CI 3.15, 5.35), MACE (HR 1.36, 95% CI 1.12, 1.65) and all-cause mortality (HR 1.58, 95% CI 1.23, 2.03) before adjustments. The increased risks of severe hypoglycaemia, MACE and all-cause mortality translate into 2.7-, 1.2- and 1.4-fold risk, respectively, when a patient’s day-to-day fasting glycaemic variability measure is doubled. The significant relationships of day-to-day fasting glycaemic variability with severe hypoglycaemia and all-cause mortality were maintained after adjustments. However, the significant association with MACE was not maintained following adjustment for baseline characteristics with either baseline HbA1c (HR 1.19, 95% CI 0.96, 1.47) or the most recent HbA1c measurement throughout the trial (HR 1.21, 95% CI 0.98, 1.49).Conclusions/interpretationHigher day-to-day fasting glycaemic variability is associated with increased risks of severe hypoglycaemia and all-cause mortality.

title: Fasting plasma glucose variability predicts 10-year survival of type 2 diabetic patients: the Verona Diabetes Study.
abstract: In the present study, we evaluated whether the coefficient of variation (CV) of fasting plasma glucose (FPG) over a 3-year period was a significant predictor of mortality in type 2 diabetic patients aged 56-74 years.



All type 2 diabetic patients (n = 1,409) aged 56-74 years attending the Verona Diabetes Clinic and having at least two FPG determinations in each of the years 1984-1986 were followed for 10 years (1987-1996) to assess total and cause-specific mortality Patients were grouped into tertiles of mean and CV of FPG during 1984-1986. These parameters as well as sex, age, diabetes duration, insulin treatment, smoking, hypertension, and hypercholesterolemia were included in multivariate survival analyses.



During the follow-up, 468 patients died. The CV of FPG was an independent predictor of total, cardiovascular, and cancer mortality. Mean FPG was a predictor of total mortality only when the CV of FPG was not included in the analyses.



Long-term variability of fasting glucose is an independent predictor of mortality in patients with type 2 diabetes. The CV of FPG might be considered a useful additional parameter in the management of these patients.

title: Variation of fasting plasma glucose: a predictor of mortality in patients with type 2 diabetes.
abstract: The aim of this study was to examine whether time-dependent annual fasting plasma glucose (FPG) variation, as represented by coefficient of variation (CV), can predict mortality in subsequent all-cause, expanded, and nonexpanded cardiovascular disease-related mortality independent of mean FPG, renal function, mean hemoglobin A(1)C (HbA(1C)), HbA(1C) variation, and other risk factors in patients with type 2 diabetes.



A computerized database of all patients with type 2 diabetes aged 30 years and over (n = 5008) enrolled in the Diabetes Care Management Program of China Medical University Hospital before 2007 was used in a time-dependent Cox proportional hazard regression model.



The mortality rates were 8.64, 12.71, and 30.82 per 1000 person-years in groups of first, second, and third tertiles of baseline FPG-CV, respectively. Among these patients with type 2 diabetes, 336, 1191, 914, 585, and 1979 patients provided 1, 2, 3, 4, and 5 or more years of annual FPG-CV measurements, respectively. After adjusting for mean FPG, mean HbA(1C), HbA(1C) variation, and other risk factors, annual FPG-CV was independently associated with all-cause mortality and mortality due to expanded and nonexpanded cardiovascular disease, and the corresponding hazard ratios for third versus first tertile of annual FPG-CV were 5.53 (95% confidence interval [CI], 3.85-7.94), 3.21 (95% CI, 2.00-5.15), and 9.45 (95% CI, 5.37-16.63), respectively.



Time-dependent variation of FPG was a strong predictor of all-cause, expanded, and nonexpanded cardiovascular disease-related mortality in patients with type 2 diabetes, suggesting that glucose variation may become a measure in clinical practice for the goal in the management of these patients.

title: Variability in hemoglobin A1c predicts all-cause mortality in patients with type 2 diabetes.
abstract: To evaluate the relationship between hemoglobin A1c variability and all-cause mortality in type 2 diabetic patients.



This was a retrospective cohort study in type 2 diabetic patients followed for at least 2 years between 2003 and 2009. A1C variability was determined from the standard deviation or coefficient of variation of serial A1C values (A1C(SD) or A1C(CV)). Subjects were categorized into either the high or low A1C variability group according to their A1C(CV) median. Hazard ratios (HRs) of various factors for all-cause mortality were determined from Cox's proportional hazard models.



A total of 881 subjects (422 men, 459 women) were included and 73 (8.3%) died during follow-up. The follow-up period was 4.7 ± 2.3 years. All-cause mortality was higher in subjects with high A1C(CV) (11.0% vs. 5.4%, p=0.002). In the Kaplan-Meier failure curve, subjects with higher A1C(CV) demonstrated a trend of higher mortality (p=0.1). In multivariate Cox's proportional hazards models, A1C(SD) and A1C(CV) significantly predicted all-cause mortality with an HR of 1.987 (p=0.02) and 1.062 (p=0.013), respectively, after adjusting for age, gender, body mass index, duration of diabetes, mean systolic blood pressure, use of antihypertensives and statins, mean LDL-cholesterol, smoking status, chronic kidney disease, and mean A1C values (A1C(MEAN)). The ability of A1C(SD) and A1C(CV) to predict all-cause mortality was more evident in subjects with relatively low A1C(MEAN.)



A1C variability is an important risk factor for all-cause mortality in type 2 diabetic patients.

title: Association between HbA1c variability and mortality in patients with type 2 diabetes.
abstract: We aimed to evaluate the association between HbA1c variability and mortality due to all causes, cancer, and non-cancer in patients with type 2 diabetes independently of mean HbA1c levels.



We enrolled 754 patients with type 2 diabetes who first visited our hospital between 1995 and 1996, had been followed for at least 2years, and had undergone four or more HbA1c determinations. Patients were followed through June 2012. The standard deviation (SD) or coefficient of variation (CV) was used as a measure of HbA1c variability. Risk of death was evaluated by multivariate Cox proportional hazard models.



Through June 2012, 63 patients died. Hazard ratios (HRs) for all-cause mortality and non-cancer mortality including cardiovascular diseases (CVD) increased across tertiles of both HbA1cSD and HbA1cCV. HRs for cancer mortality did not increase across tertiles of either HbA1cSD or HbA1cCV. Using a stepwise regression method, both HbA1cSD and HbA1cCV predicted all-cause mortality, especially non-cancer mortality. In contrast, mean HbA1c predicted cancer mortality.



HbA1c variability is a predictor of all-cause mortality, especially non-cancer mortality including CVD, in patients with type 2 diabetes, independent of mean HbA1c level. In contrast, mean HbA1c, but not HbA1c variability, might predict cancer mortality.

title: Relationship of HbA1c variability, absolute changes in HbA1c, and all-cause mortality in type 2 diabetes: a Danish population-based prospective observational study
abstract: We assessed the relationship of mortality with glycated hemoglobin (HbA1c) variability and with absolute change in HbA1c.  A population-based prospective observational study with a median follow-up time of 6 years.  Based on a validated algorithm, 11 205 Danish individuals with type 2 diabetes during 2001–2006 were identified from public data files, with at least three HbA1c measurements: one index measure, one closing measure 22–26 months later, and one measurement in-between. Medium index HbA1c was 7.3%, median age was 63.9 years, and 48% were women. HbA1c variability was defined as the mean absolute residual around the line connecting index value with closing value. Cox proportional hazard models with restricted cubic splines were used, with all-cause mortality as the outcome.  Variability between 0 and 0.5 HbA1c percentage point was not associated with mortality, but for index HbA1c ≤8% (64 mmol/mol), a variability above 0.5 was associated with increased mortality (HR of 1 HbA1c percentage point variability was 1.3 (95% CI 1.1 to 1.5) for index HbA1c 6.6–7.4%). For index HbA1c≤8%, mortality increased when HbA1c declined, but was stable when HbA1c rose. For index HbA1c>8%, change in HbA1c was associated with mortality, with the lowest mortality for greatest decline (HR=0.9 (95% CI 0.80 to 0.98) for a 2-percentage point decrease).  For individuals with an index HbA1c below 8%, both high HbA1c variability and a decline in HbA1c were associated with increased mortality. For individuals with index HbA1c above 8%, change in HbA1c was associated with mortality, whereas variability was not.

title: Glycemic Variability and Diabetes Complications: Does It Matter? Of Course It Does!
abstract: There is no argument that improving mean levels of glycemic control as judged by assays for glycated hemoglobin (HbA1c) reduces the risks of microvascular complications and cardiovascular disease events in patients with type 1 and type 2 diabetes. However, observations in some trials have suggested that targeting HbA1c to suggested targets may not always result in improved outcomes for people with long-standing type 2 diabetes. The reasons why the glycemic control strategies that primarily use HbA1c in these studies did not have predicted outcomes are not clear. Thus, controversy remains as to whether there are glycemic metrics beyond HbA1c that can be defined as effective measures that can be used in addition to HbA1c to help in assessing the risk of an individual developing diabetes complications. In this regard, the concept of “glycemic variability” (GV) is one metric that has attracted a lot of attention. GV can be simply defined as the degree to which a patient’s blood glucose level fluctuates between high (peaks) and low (nadir) levels. The best and most precise way to assess GV is also one that is still debated. Thus, while there is universal agreement that HbA1c is the current gold standard for the primary clinical target, there is no consensus as to whether other proposed glycemic metrics hold promise to provide additional clinical data or whether there should be additional targets beyond HbA1c. Therefore, given the current controversy, we provide a Point-Counterpoint debate on this issue. In the point narrative below, Dr. Hirsch provides his argument that fluctuations in blood glucose as assessed by GV metrics are deleterious and control of GV should be a primary treatment target. In the following counterpoint narrative, Dr. Bergenstal argues that there are better markers to assess the risk of diabetes than GV and provides his consideration of other concepts. —William T. Cefalu Editor in Chief, Diabetes Care

title: Glycemic Variability and Diabetes Complications: Does It Matter? Simply Put, There Are Better Glycemic Markers!
abstract: There is no argument that improving mean levels of glycemic control as judged by assays for glycated hemoglobin (HbA1c) reduces the risks of microvascular complications and cardiovascular disease events in patients with type 1 and type 2 diabetes. However, observations in some trials have suggested that targeting HbA1c to suggested targets may not always result in improved outcomes for people with long-standing type 2 diabetes. The reasons why the glycemic control strategies that primarily use HbA1c in these studies did not have predicted outcomes are not clear. Thus, controversy remains as to whether there are glycemic metrics beyond HbA1c that can be defined as effective measures that can be used in addition to HbA1c to help in assessing the risk of an individual developing diabetes complications. In this regard, the concept of “glycemic variability” (GV) is one metric that has attracted a lot of attention. GV can be simply defined as the degree to which a patient’s blood glucose level fluctuates between high (peaks) and low (nadir) levels. The best and most precise way to assess GV is also one that is still debated. Thus, while there is universal agreement that HbA1c is the current gold standard for the primary clinical target, there is no consensus as to whether other proposed glycemic metrics hold promise to provide additional clinical data or whether there should be additional targets beyond HbA1c. Therefore, given the current controversy, we provide a Point-Counterpoint debate on this issue. In the preceding point narrative, Dr. Hirsch provides his argument that fluctuations in blood glucose as assessed by GV metrics are deleterious and control of GV should be a primary treatment target. In the counterpoint narrative below, Dr. Bergenstal argues that there are better markers to assess the risk of diabetes than GV and provides his consideration of other concepts. —William T. Cefalu Editor in Chief, Diabetes Care

title: Prognostic importance of baseline and serial glycated hemoglobin levels in high-risk patients with type 2 diabetes: the Rio de Janeiro Type 2 Diabetes Cohort Study
abstract: The prognostic importance of baseline and serial glycated hemoglobin (HbA1c) changes for cardiovascular outcomes is still debated. We aimed to evaluate it in 620 high-risk individuals with type 2 diabetes (mean age 60.4 years, 37 % males, 55 % Caucasians). Patients had HbA1c levels measured at study entry and serially during follow-up. Primary end points were total cardiovascular events (CVEs), major CVEs (non-fatal myocardial infarctions and strokes plus cardiovascular deaths) and all-cause mortality. Cardiovascular and non-cardiovascular mortalities were secondary end points. HbA1c was evaluated either as a continuous variable and categorized at clinically relevant cutoffs. Multivariate Cox regressions assessed the associations with end points. After a median follow-up of 6.6 years, 125 total CVEs occurred (90 major CVEs), and 111 patients died (64 from cardiovascular diseases). After statistical adjustments for other cardiovascular risk factors, baseline and mean first-year HbA1c predicted all end points, except non-cardiovascular deaths; and hazard ratios tended to be higher for mean first year than for baseline HbA1c. Each 1 % (10.9 mmol/mol) increase in mean first-year HbA1c increased 27 % the risk of major CVEs occurrence (95 % CI 11–45 %). Updating HbA1c for values obtained beyond the second year of follow-up did not improve its predictive performance. The cardiovascular protection was observed until HbA1c values lower than 6.5 % (48 mmol/mol). Moreover, the magnitude of HbA1c reduction during the first year of follow-up was predictive of better cardiovascular outcomes, independent of baseline HbA1c levels. In conclusion, better glycemic control, especially during the first year of follow-up, is determinant of better cardiovascular outcomes in high-risk patients with type 2 diabetes, without any detectable lower threshold level of HbA1c.

title: Increased aortic stiffness predicts future development and progression of peripheral neuropathy in patients with type 2 diabetes: the Rio de Janeiro Type 2 Diabetes Cohort Study
abstract: peripheral neuropathy (DPN) is a chronic microvascular complication that is strongly associated with poor glycaemic control and also with a worse prognosis. We aimed to evaluate the predictors of the development and progression of DPN in a cohort of high-risk patients with type 2 diabetes.MethodsIn a prospective study, 477 patients with type 2 diabetes were clinically assessed for the presence of DPN at baseline and after a median follow-up of 6.2 years (range 2–10 years). Clinical laboratory data were obtained at study entry and throughout the follow-up. Aortic stiffness was assessed by the carotid–femoral pulse wave velocity (cf-PWV) at baseline. Multivariate Poisson regression analysis was used to examine independent predictors of the development/progression of DPN.ResultsAt baseline, 135 patients (28%) had DPN, and during follow-up 97 patients (20%) had either a new development or a worsening of DPN. Patients who showed a development or progression of DPN were taller and had a longer duration of diabetes, a greater prevalence of other microvascular complications and hypertension, greater aortic stiffness and poorer glycaemic control than patients who did not have new or progressive neuropathy. After adjustments for the baseline prevalence of DPN, the patient’s age and sex, and the time interval between DPN assessments; an increased aortic stiffness (cf-PWV >10 m/s) were predictive of new/progressive DPN (incidence rate ratio 2.04, 95% CI 1.28, 3.23; p = 0.002). Other independent predictors were the mean first-year HbA1c level (p = 0.05), nephropathy (p = 0.006), arterial hypertension (p = 0.06) and height (p = 0.03).Conclusions/interpretationIncreased aortic stiffness at baseline predicts the future development or progression of peripheral neuropathy, independent of diabetic metabolic control, suggesting a physiopathological link between macrovascular and microvascular abnormalities in type 2 diabetes.

title: Predictors of Development and Progression of Retinopathy in Patients with Type 2 Diabetes: Importance of Blood Pressure Parameters
abstract: Diabetic retinopathy (DR) is a chronic microvascular complication associated a worse prognosis. We aimed to evaluate the predictors of development/progression of DR in a cohort of 544 high-risk patients with type 2 diabetes who had annual ophthalmologic examinations over a median follow-up of 6 years. Ambulatory blood pressure (BP) monitoring and aortic stiffness by carotid-femoral pulse wave velocity were performed. Multivariate Cox survival analysis examined the independent predictors of development or progression of DR. During follow-up, 156 patients either newly-developed or worsened DR. Patients who developed/progressed DR had longer diabetes duration, higher ambulatory and clinic BP levels, higher aortic stiffness, and poorer glycemic control than patients who did not developed/progressed DR. After adjustments for baseline retinopathy prevalence, age and sex, a longer diabetes duration (p < 0.001), higher baseline ambulatory BPs (p = 0.013, for 24-hour diastolic BP), and higher mean cumulative exposure of HbA1c (p < 0.001), clinic diastolic BP (p < 0.001) and LDL-cholesterol (p = 0.05) during follow-up were the independent predictors of development/progression of DR. BP parameters were only predictors of DR development. In conclusion, a longer diabetes duration, poorer glycemic and lipid control, and higher BPs were the main predictors of development/progression of DR. Mean cumulative clinic diastolic BP was the strongest BP-related predictor.

title: Aortic stiffness and ambulatory blood pressure as predictors of diabetic kidney disease: a competing risks analysis from the Rio de Janeiro Type 2 Diabetes Cohort Study
abstract: kidney disease (DKD) is a microvascular complication associated with poor control of blood glucose and BP. We aimed to evaluate the predictors of development and progression of DKD in a cohort of high-risk individuals with type 2 diabetes, placing emphasis on ambulatory BP and arterial stiffness.MethodsIn a prospective study, 629 individuals without advanced renal failure had their renal function evaluated annually over a median follow-up period of 7.8 years. Ambulatory BP was monitored and aortic stiffness was assessed by carotid–femoral pulse wave velocity at baseline. Multivariate competing risks analysis with all-cause mortality, using the Fine and Gray approach, was used to examine the independent predictors of development and progression of DKD, a composite of development or progression of abnormal albuminuria and worsening of renal function (doubling of serum creatinine or progression to end-stage renal disease).ResultsAt baseline, 197 individuals had DKD. During follow-up, DKD developed or progressed in 195 individuals, abnormal albuminuria developed or progressed in 125 individuals and renal function deteriorated in 91. After adjustments for baseline albuminuria and renal function, age, sex, diabetes duration and use of renin–angiotensin antagonists, poorer control of blood glucose (HR 1.17; 95% CI 0.98, 1.40; p = 0.09 for each 1 SD increment in mean first-year HbA1c), higher ambulatory systolic BP (HR 1.28; 95% CI 1.09, 1.50; p = 0.003, for each 1 SD increase in daytime systolic BP [SBP]) and increased aortic stiffness (HR 1.16; 95% CI 1.00, 1.34; p = 0.05) were independent predictors of development or progression of DKD. At baseline, ambulatory BP was a stronger predictor than BP measured in the clinic. Aortic stiffness predicted abnormal albuminuria development or progression (HR 1.26; 95% CI 1.02, 1.56; p = 0.036) whereas ambulatory BP was a stronger predictor of renal function deterioration (HR 1.32; 95% CI 1.09, 1.60; p = 0.005 for daytime SBP).Conclusions/interpretationPoor blood glucose and BP control and increased aortic stiffness were the main predictors of development or progression of DKD; ambulatory SBP was a better predictor than BP measured in the clinic. Ambulatory BP monitoring and assessment of aortic stiffness should be more widely used in clinical type 2 diabetes management.

title: Fasting plasma glucose variability as a marker of nocturnal hypoglycemia in diabetes: evidence from the PREDICTIVE study.
abstract: The relationship between fasting glucose (FG) variability and nocturnal hypoglycemia was assessed using longitudinal data from PREDICTIVE, the large-scale observational study of insulin detemir. An HbA(1c)-corrected correlation was found between these endpoints, suggesting FG variability can serve as a useful marker for this risk in clinical practice.

title: DEVOTE 3: temporal relationships between severe hypoglycaemia, cardiovascular outcomes and mortality
abstract: hypothesisThe double-blind Trial Comparing Cardiovascular Safety of Insulin Degludec vs Insulin Glargine in Patients with Type 2 Diabetes at High Risk of Cardiovascular Events (DEVOTE) assessed the cardiovascular safety of insulin degludec. The incidence and rates of adjudicated severe hypoglycaemia, and all-cause mortality were also determined. This paper reports a secondary analysis investigating associations of severe hypoglycaemia with cardiovascular outcomes and mortality.MethodsIn DEVOTE, patients with type 2 diabetes were randomised to receive either insulin degludec or insulin glargine U100 (100 units/ml) once daily (between dinner and bedtime) in an event-driven, double-blind, treat-to-target cardiovascular outcomes trial. The primary outcome was the first occurrence of an adjudicated major adverse cardiovascular event (MACE; cardiovascular death, non-fatal myocardial infarction or non-fatal stroke). Adjudicated severe hypoglycaemia was the pre-specified secondary outcome. In the present analysis, the associations of severe hypoglycaemia with both MACE and all-cause mortality was evaluated in the pooled trial population using time-to-event analyses, with severe hypoglycaemia as a time-dependent variable and randomised treatment as a fixed factor. An investigation with interaction terms indicated that the effect of severe hypoglycaemia on the risk of MACE and all-cause mortality were the same for both treatment arms, and so the temporal association for severe hypoglycaemia with subsequent MACE and all-cause mortality is reported for the pooled population.ResultsThere was a non-significant difference in the risk of MACE for individuals who had vs those who had not experienced severe hypoglycaemia during the trial (HR 1.38, 95% CI 0.96, 1.96; p = 0.080) and therefore there was no temporal relationship between severe hypoglycaemia and MACE. There was a significantly higher risk of all-cause mortality for patients who had vs those who had not experienced severe hypoglycaemia during the trial (HR 2.51, 95% CI 1.79, 3.50; p < 0.001). There was a higher risk of all-cause mortality 15, 30, 60, 90, 180 and 365 days after experiencing severe hypoglycaemia compared with not experiencing severe hypoglycaemia in the same time interval. The association between severe hypoglycaemia and all-cause mortality was maintained after adjustment for the following baseline characteristics: age, sex, HbA1c, BMI, diabetes duration, insulin regimen, hepatic impairment, renal status and cardiovascular risk group.interpretationThe results from these analyses demonstrate an association between severe hypoglycaemia and all-cause mortality. Furthermore, they indicate that patients who experienced severe hypoglycaemia were particularly at greater risk of death in the short term after the hypoglycaemic episode. These findings indicate that severe hypoglycaemia is associated with higher subsequent mortality; however, they cannot answer the question as to whether severe hypoglycaemia serves as a risk marker for adverse outcomes or whether there is a direct causal effect.

title: Devoting attention to glucose variability and hypoglycaemia in type 2 diabetes
abstract: In the Trial Comparing Cardiovascular Safety of Insulin Degludec vs Insulin Glargine in Patients with Type 2 Diabetes at High Risk of Cardiovascular Events (DEVOTE), insulin degludec was non-inferior to insulin glargine in terms of cardiovascular events and mortality. However, there were lower rates of severe hypoglycaemia with insulin degludec. DEVOTE investigators now extend these findings by presenting the results of two observational epidemiological analyses based on trial data. In the first of these analyses (DEVOTE 2), Zinman et al (Diabetologia DOI: 10.1007/s00125-017-4423-z) demonstrate that, compared with individuals with lower day-to-day fasting glycaemic variability, those with higher day-to-day fasting glycaemic variability had a similar risk of major adverse cardiovascular events (MACE) but a higher risk of severe hypoglycaemia and all-cause mortality. In the second analysis (DEVOTE 3), Pieber et al (Diabetologia DOI: 10.1007/s00125-017-4422-0) found that individuals who experienced severe hypoglycaemia had a similar risk of MACE compared with those who never experienced severe hypoglycaemia, but had a more than twofold higher risk of subsequent total mortality and cardiovascular disease (CVD) mortality. The strengths of these studies relate to the availability of high-quality prospective data on adjudicated severe hypoglycaemia, MACE and mortality events in a large number of high-risk insulin-treated individuals with type 2 diabetes. Limitations include the observational nature of the data and thus residual confounding remains possible. Furthermore, the short duration of the trial resulted in limited statistical power for some analyses. Therefore, whilst DEVOTE 2 and DEVOTE 3 raise awareness of the mortality risks associated with glucose variability and severe hypoglycaemia in high-risk, insulin-treated patients with type 2 diabetes, they cannot clarify causal relationships. Preventing severe hypoglycaemia in those with type 2 diabetes should already be a priority in clinical practice. However, findings from future clinical trials are needed to guide physicians on whether it is beneficial to target glucose variability, and risk for severe hypoglycaemia, to reduce the risks for CVD events and mortality in these individuals.

title: Low 1,5-anhydroglucitol levels are associated with long-term cardiac mortality in acute coronary syndrome patients with hemoglobin A1c levels less than 7.0%
abstract: BackgroundDiabetes mellitus is considered an important risk factor for cardiovascular diseases. High hemoglobin A1c (HbA1c) levels, which indicate poor glycemic control, have been associated with occurrence of cardiovascular diseases. There are few parameters which can predict cardiovascular risk in patients with well-controlled diabetes. Low 1,5-anhydroglucitol (1,5-AG) levels are considered a clinical marker of postprandial hyperglycemia. We hypothesized that low 1,5-AG levels could predict long-term mortality in acute coronary syndrome (ACS) patients with relatively low HbA1c levels.MethodsThe present study followed a retrospective observational study design. We enrolled 388 consecutive patients with ACS admitted to the cardiac intensive care unit at the Juntendo University Hospital from January 2011 to December 2013. Levels of 1,5-AG were measured immediately before emergency coronary angiography. Patients with early stent thrombosis, no significant coronary artery stenosis, malignancy, liver cirrhosis, a history of gastrectomy, current steroid treatment, moderately to severely reduced kidney function (estimated glomerular filtration rate < 45 ml/min/1.73 m2; chronic kidney disease stage 3B, 4, and 5), HbA1c levels ≥ 7.0%, and those who received sodium glucose co-transporter 2 inhibitor therapy were excluded.ResultsDuring the 46.9-month mean follow-up period, nine patients (4.5%) died of cardiovascular disease. The 1,5-AG level was significantly lower in the cardiac death group compared with that in the survivor group (12.3 ± 5.3 vs. 19.2 ± 7.7 µg/ml, p < 0.01). Kaplan–Meier survival analysis showed that low 1,5-AG levels were associated with cardiac mortality (p = 0.02). Multivariable Cox regression analysis showed that 1,5-AG levels were an independent predictor of cardiac mortality (hazard ratio 0.76; 95% confidence interval 0.41–0.98; p = 0.03).ConclusionLow 1,5-AG levels, which indicate postprandial hyperglycemia, predict long-term cardiac mortality even in ACS patients with HbA1c levels < 7.0%.

title: Low and exacerbated levels of 1,5-anhydroglucitol are associated with cardiovascular events in patients after first-time elective percutaneous coronary intervention
abstract: BackgroundPostprandial hyperglycemia plays an important role in the pathogenesis of coronary artery disease and cardiovascular events. Serum 1,5-anhydroglucitol (1,5-AG) levels are known to be a clinical marker of postprandial hyperglycemia. However, the impact of 1,5-AG level on cardiovascular events has not been fully investigated.MethodsWe enrolled 240 consecutive patients who had undergone first-time elective percutaneous coronary intervention (PCI) with follow-up angiography within 1 year. We excluded patients with a history of acute coronary syndrome, advanced chronic kidney disease (estimated glomerular filtration rate <30 mL/min/1.73 m2), or uncontrolled diabetes mellitus (HbA1c ≥7.0%). Fasting blood glucose (FBS), HbA1c, and 1,5-AG levels were measured prior to PCI and at the time of follow-up angiography. Clinical events, including target lesion revascularization, target vessel revascularization, and revascularization of new lesions, were evaluated.ResultsSubjects were divided into two groups according to clinical outcomes: the Event (+) group (n = 40) and the Event (−) group (n = 200). No significant differences were observed, except for the number of diseased vessels and the prevalence of statin use, in baseline clinical characteristics between the two groups. Serum levels of 1,5-AG at follow-up were significantly lower in the Event (+) group than in the Event (−) group (P = 0.02). A significant reduction in 1,5-AG level from baseline to follow-up was observed in the Event (+) group compared with the Event (−) group (P = 0.04). The association between 1,5-AG levels at follow-up and clinical events remained significant after adjustment for independent variables, including FBS and HbA1c levels (P = 0.04).ConclusionsLow and exacerbated levels of 1,5-AG were associated with cardiovascular events in the present study, indicating that postprandial hyperglycemia is an important risk factor for adverse clinical events even in patients with HbA1c < 7.0%, following first-time elective PCI.

title: Activation of oxidative stress by acute glucose fluctuations compared with sustained chronic hyperglycemia in patients with type 2 diabetes.
abstract: Glycemic disorders, one of the main risk factors for cardiovascular disease, are associated with activation of oxidative stress.



To assess the respective contributions of sustained chronic hyperglycemia and of acute glucose fluctuations to oxidative stress in type 2 diabetes.



Case-control study of 21 patients with type 2 diabetes (studied 2003-2005) compared with 21 age- and sex-matched controls (studied in 2001) 
Oxidative stress, estimated from 24-hour urinary excretion rates of free 8-iso prostaglandin F2alpha (8-iso PGF2alpha). Assessment of glucose fluctuations was obtained from continuous glucose monitoring system data by calculating the mean amplitude of glycemic excursions (MAGE). Postprandial contribution to glycemic instability was assessed by determining the postprandial increment of glucose level above preprandial values (mean postprandial incremental area under the curve [AUCpp]). Long-term exposure to glucose was estimated from hemoglobin A1c, from fasting glucose levels, and from mean glucose concentrations over a 24-hour period.



Mean (SD) urinary 8-iso PGF2alpha excretion rates were higher in the 21 patients with diabetes (482 [206] pg/mg of creatinine) compared with controls (275 [85] pg/mg of creatinine). In univariate analysis, only MAGE (r = 0.86; P<.001) and AUCpp (r = 0.55; P = .009) showed significant correlations with urinary 8-iso PGF2alpha excretion rates. Relationships between 8-iso PGF2alpha excretion rates and either MAGE or AUCpp remained significant after adjustment for the other markers of diabetic control in multiple linear regression analysis (multiple R2 = 0.72 for the model including MAGE and multiple R2 = 0.41 for the model including AUCpp). Standardized regression coefficients were 0.830 (P<.001) for MAGE and 0.700 (P = .003) for AUCpp.



Glucose fluctuations during postprandial periods and, more generally, during glucose swings exhibited a more specific triggering effect on oxidative stress than chronic sustained hyperglycemia. The present data suggest that interventional trials in type 2 diabetes should target not only hemoglobin A1c and mean glucose concentrations but also acute glucose swings.

title: Oscillating Glucose Is More Deleterious to Endothelial Function and Oxidative Stress Than Mean Glucose in Normal and Type 2 Diabetic Patients
abstract: To explore the possibility that oscillating glucose may outweigh A1C levels in determining the risk for cardiovascular diabetes complications. A euinsulinemic hyperglycemic clamp at 5, 10, and 15 mmol/l glucose was given in increasing steps as a single “spike” or oscillating between basal and high levels over 24 h in normal subjects and type 2 diabetic patients. Flow-mediated dilatation, a marker of endothelial function, and plasma 3-nitrotyrosine and 24-h urinary excretion rates of free 8-iso PGF2α, two markers of oxidative stress, were measured over 48 h postclamp. Glucose at two different levels (10 and 15 mmol/l) resulted in a concentration-dependent fasting blood glucose–independent induction of both endothelial dysfunction and oxidative stress in both normal and type 2 diabetic patients. Oscillating glucose between 5 and 15 mmol/l every 6 h for 24 h resulted in further significant increases in endothelial dysfunction and oxidative stress compared with either continuous 10 or 15 mmol/l glucose. These data suggest that oscillating glucose can have more deleterious effects than constant high glucose on endothelial function and oxidative stress, two key players in favoring cardiovascular complications in diabetes. Concomitant vitamin C infusion can reverse this impairment.

title: Effects of daily glucose fluctuations on the healing response to everolimus-eluting stent implantation as assessed using continuous glucose monitoring and optical coherence tomography
abstract: BackgroundSeveral studies have revealed that glucose fluctuations provoke oxidative stress that leads to endothelial cell dysfunction, progression of coronary atherosclerosis, and plaque vulnerability. However, little is known regarding their effect on neointimal growth after stenting in patients with coronary artery disease (CAD). We aimed to investigate the effects of glucose fluctuations on neointimal growth after everolimus-eluting stent (EES) implantation.MethodsThis study examined 50 patients who underwent a 9-month follow-up using optical coherence tomography (OCT) after EES implantation. Glucose fluctuation was expressed as the mean amplitude of glycemic excursion (MAGE), and was determined via continuous glucose monitoring before stenting. At the OCT follow-up, we evaluated the percentage of uncovered struts and three-dimensional uniformity of neointimal distribution by calculating the mean neointimal thickness (NIT) within 360 equally-spaced radial sectors for every 1-mm cross-sectional OCT analysis, and assessed the incidence of major adverse cardiovascular events (MACE).ResultsWe evaluated 60 lesions in 50 patients. Linear mixed effect models were used to explore the influence of different variables on variability in NIT and the percentage of uncovered struts and to adjust for covariates. Univariate analysis showed that MAGE was most strongly correlated with the previously mentioned OCT measurements (coefficient β ± standard error = 0.267 ± 0.073 and 0.016 ± 0.003, t = 3.668 and 6.092, both P < 0.001, respectively). In multivariate analysis, MAGE had the strongest effect on variability in NIT (coefficient β ± standard error = 0.239 ± 0.093, P = 0.014) and the percentage of uncovered struts (coefficient β ± standard error = 0.019 ± 0.004, P < 0.001). Five lesions in four patients required target lesion revascularization (10.0 %) at a mean duration of 9 months after EES implantation. Compared to non-MACE cases, cases of MACE exhibited a significantly higher MAGE (99 vs. 68; P = 0.004), maximum NIT (580 vs. 330 µm; P = 0.002), and variability in NIT (100 vs. 65; P = 0.007), although there was no significant difference in these groups’ HbA1c levels.ConclusionsGlucose fluctuation may affect vessel healing after EES implantation in patients with CAD who are receiving lipid-lowering therapy. Therefore, glucose fluctuations may be an important target for secondary prevention after coronary stenting, which is independent of dyslipidemia control.

title: Effect of glycemic variability on short term prognosis in acute myocardial infarction subjects undergoing primary percutaneous coronary interventions
abstract: ObjectiveGlycemic variability (GV) still remains unclear whether acute glycemic excursion has the important prognostic significance in ST-segment elevation myocardial infarction (STEMI) patients undergoing p-PCI. So our aim is to assess the prognostic value of GV in STEMI patients undergoing p-PCI.MethodsWe studied 237 STEMI patients undergoing p-PCI, whose clinical and laboratory data were collected. We used a continuous glucose monitoring system (CGMS) to measure the fluctuations of blood glucose. Participants were grouped into diabetes group and non-diabetes group, and grouped into tertiles of mean amplitude of glycemic excursions (MAGE). The major adverse cardiac events (MACE) of patients was documented during in-hospital and 30-day follow-up. The relationship of MAGE and the incidence of MACE were analyzed.ResultsData from 237 subjects were incorporated into the statistical analysis, a higher MAGE level was associated with the higher peak CK-MB values (r = 0.374, P <0.01), and the higher peak cTnI values (r = 0.410, P <0.01). The rate of composite MACE by MAGE tertiles (<2.37 mmol/l, 2.37-3.65 mmol/l and >3.65 mmol/l) was 7.5% vs. 14.1% vs. 22.8%, respectively (P = 0.025); STEMI patients with a higher MAGE level had a significantly higher non-IRA revascularization compared with those with lower MAGE levels (32% vs. 15% vs. 21%, P = 0.037). Moreover, diabetic patients with higher MAGE level had significantly higher incidence of composite MACE and non-IRA revascularization, non-diabetic subjects did not show the similar results. In multivariable logistic analysis, the independent predictors of MACE were: MBG, MAGE and LVEF in diabetic subjects and were MBG and MAGE in nondiabetic subjects. Other factors were not significantly associated with MACE.ConclusionsGreater GV is associated with composite MACE and non-IRA revascularization during in-hospital and 30-day follow-up in unadjusted analyses, especially for diabetic subjects. After multivariable logistic analysis, GV remains an independent prognostic factor for composite MACE in STEMI patients undergoing p-PCI.

title: Impact of glycemic variability on the occurrence of periprocedural myocardial infarction and major adverse cardiovascular events (MACE) after coronary intervention in patients with stable angina pectoris at 6months follow-up.
abstract: We explored the impact of glycemic variability on the occurrence of periprocedural myocardial infarction and major adverse cardiovascular events (MACE) after coronary intervention in patients with stable angina pectoris (SAP) at 6months follow-up.



From May 2015 to April 2016, a total of 746 patients with SAP were divided to high glycemic variability group (H group) (n=261) and low glycemic variability group (L group) (n=485). The primary end point was incidence of periprocedural myocardial infarction and MACE at 6months follow-up.



The occurrence of periprocedural myocardial infarction occurred in 18.8% of patients in H group and in 12.4% in L group (P=0.03). The incidence of MACE at 6months follow-up was 9.6% in H group and 4.5% in L group (P=0.01). Multivariable analysis suggested that high glycemic variability conferred a 53% risk increment of 6months follow-up MACE (odds ratio 2.13, 95% confidence interval 1.85-5.38; P=0.01).



The trial shows that higher blood glucose variability was correlated with higher incidence of periprocedural myocardial infarction and MACE at 6months follow-up.

title: Glucose oscillations, more than constant high glucose, induce p53 activation and a metabolic memory in human endothelial cells
abstract: persists in HUVECs exposed to a constant high glucose concentration long after glucose normalisation, a phenomenon termed ‘metabolic memory’. Evaluation of the effects of exposure of HUVECs to oscillating high glucose on the induction of markers of oxidative stress and DNA damage (phospho-γ-histone H2AX and PKCδ) and onset of metabolic memory, and the possible role of the tumour suppressor transcriptional factor p53 is of pivotal interest.MethodsHUVECs were incubated for 3 weeks in 5 or 25 mmol/l glucose or oscillating glucose (24 h in 5 mmol/l glucose followed by 24 h in 25 mmol/l glucose) or for 1 week in constant 5 mmol/l glucose after being exposed for 2 weeks to continuous 25 mmol/l high glucose or oscillating glucose. Transcriptional activity of p53 was also evaluated in the first 24 h after high glucose exposure.ResultsHigh constant glucose upregulated phospho-γ-histone H2AX and protein kinase C (PKC)δ compared with control. Oscillating glucose was even more effective than both normal and constant high glucose. Both constant and oscillating glucose resulted in a memory effect, which was more pronounced in the oscillating condition. Transcriptional activity of p53 peaked 6 h after glucose exposure, showing a predicted oscillatory behaviour. to oscillating glucose was more deleterious than constant high glucose and induced a metabolic memory after glucose normalisation. Hyperactivation of p53 during glucose oscillation might be due to the absence of consistent feedback inhibition during each glucose spike and might account for the worse outcome of this condition.

title: Glycemic Memories and the Epigenetic Component of Diabetic Nephropathy
abstract: A strong case for the deregulation of epigenetic chromatin modifications in the development and progression of various chronic complications of diabetes has emerged from recent experimental observations. Clinical trials of type 1 and type 2 diabetes patients highlight the importance of early and intensive treatment and the prolonged damage of hyperglycemia on organs such as the kidney. The functional relationship between the regulation of chromatin architecture and persistent gene expression changes conferred by prior hyperglycemia represents an important avenue of investigation for explaining diabetic nephropathy. While several studies implicate epigenetic changes at the chromatin template in the deregulated gene expression associated with diabetic nephropathy, the molecular determinants of metabolic memory in renal cells remain poorly understood. There is now strong evidence from experimental animals and cell culture of persistent glucose-driven changes in vascular endothelial gene expression that may also have relevance for the microvasculature of the kidney. Exploration of epigenetic mechanisms underlying the hyperglycemic cue mediating persistent transcriptional changes in renal cells holds novel therapeutic potential for diabetic nephropathy.

title: Mechanisms of Disease: pathway-selective insulin resistance and microvascular complications of diabetes
abstract: Resistance to the actions of insulin is strongly associated with the microvascular complications of diabetes. To the extent that insulin resistance leads to hyperglycemia, dyslipidemia and hypertension, this association is not surprising. It is now clear that insulin also has direct actions in the microvasculature that influence the development and progression of microvascular disease. In the healthy state, insulin appears to have only minor effects on vascular function, because of the activation of opposing mediators such as nitric oxide and endothelin-1. Diabetes and obesity, however, are associated with selective insulin resistance in the phosphatidylinositol-3-kinase signaling pathway, which leads to reduced synthesis of nitric oxide, impaired metabolic control and compensatory hyperinsulinemia. By contrast, insulin signaling via extracellular signal-regulated kinase dependent pathways is relatively unaffected in diabetes, tipping the balance of insulin's actions so that they favor abnormal vasoreactivity, angiogenesis, and other pathways implicated in microvascular complications and hypertension. In addition, preferential impairment of nonoxidative glucose metabolism leads to increased intracellular formation of advanced glycation end products, oxidative stress and activation of other pathogenic mediators. Despite a strong temporal association, a causal link between pathway-selective insulin resistance and microvascular damage remains to be established. It is possible that this association reflects a common genotype or phenotype. Nonetheless, insulin resistance remains an important marker of risk and a key target for intervention, because those patients who achieve a greater improvement of insulin sensitivity achieve better microvascular outcomes.

title: Gliclazide protects human islet beta‐cells from apoptosis induced by intermittent high glucose
abstract: Decreased beta‐cell mass, mainly due to apoptosis, is crucial for the development and progression of type 2 diabetes. Chronic exposure to high glucose levels is a probable underlying mechanism, whereas the role of oral anti‐diabetic agents (sulphonylureas in particular) is still unsettled.