Response of 1,5-anhydroglucitol level to intensive glucose- and blood-pressure lowering interventions, and its associations with clinical outcomes in the ADVANCE trial.
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SUBMITTER: Selvin E
PROVIDER: S-EPMC6620118 | biostudies-literature | 2019 Aug
REPOSITORIES: biostudies-literature
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Response of 1,5-anhydroglucitol level to intensive glucose- and blood-pressure lowering interventions, and its associations with clinical outcomes in the ADVANCE trial.
Selvin Elizabeth E Wang Dan D McEvoy John William JW Juraschek Stephen P SP Lazo Mariana M Hamet Pavel P Cooper Mark E ME Marre Michel M Williams Bryan B Harrap Stephen S Chalmers John J Woodward Mark M
Diabetes, obesity & metabolism 20190529 8
<h4>Aims</h4>To evaluate 1,5-anhydroglucitol (1,5-AG) according to clinical outcomes and assess the effects of glucose- and blood pressure-lowering interventions on change in 1,5-AG levels in people with type 2 diabetes.<h4>Methods</h4>We measured 1,5-AG in 6826 stored samples at baseline and in a random subsample of 684 participants at the 1-year follow-up visit in the ADVANCE trial. We examined baseline 1,5-AG [< 39.7, 39.7-66.2, ≥ 66.2 μmol/L (<6, 6-10, ≥10 μg/mL)] and microvascular and macro ...[more]
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Project description:Our previous studies identified an increase in the levels of the metabolite 1,5-anhydroglucitol (1,5-AG) in the plasma of patients with newly diagnosed B-ALL by untargeted metabolomics detection.Except for the direct influence of 1,5-AG on leukemia cells, the effect on macrophages is still unclear.We reported the application of RNA sequencing to determine the transcriptional response of murine macrophage Raw 264.7 cells in response to stimulate with 1,5-AG conditions.
2023-01-03 | GSE221889 | GEO
Project description:Background1,5-Anhydroglucitol (1,5-AG) is a novel biomarker of glycemic control proposed to monitor recent hyperglycemic excursions in persons with diabetes. The clinical utility of 1,5-AG outside of diagnosed diabetes is unclear, but it may identify people at high risk for diabetes and its complications. We compared associations of 1,5-AG with 2-h glucose for risk of major clinical complications.Research design and methodsWe prospectively followed 6644 Atherosclerosis Risk in Communities (ARIC) Study participants without diagnosed diabetes for incident diagnosed diabetes, chronic kidney disease, cardiovascular disease, and all-cause mortality for ∼20 years. We assessed associations of 1,5-AG and 2-h glucose (modeled categorically and continuously with restricted cubic splines) with adverse outcomes using Cox models and evaluated improvement in risk discrimination using Harrell's c-statistic.Results1,5-AG <10 µg/mL was statistically significantly associated with incident diabetes (HR: 2.70, 95% CI 2.31, 3.15), and showed suggestion of association with the other outcomes compared to 1,5-AG ≥10 µg/mL. Continuous associations of 1,5-AG with outcomes displayed a clear threshold effect, with risk associations generally observed only <10 µg/mL. Comparing associations of 1,5-AG and 2-h glucose with outcomes resulted in larger c-statistics for 2-h glucose than 1,5-AG for all outcomes (difference in c-statistic [2-h glucose -1,5-AG] for diagnosed diabetes: 0.17 [95%CI, 0.15, 0.19]; chronic kidney disease 0.02 [95%CI 0.00, 0.05]; cardiovascular disease 0.03 [95%CI, 0.00, 0.06]; and all-cause mortality 0.04 [95%CI, 0.02, 0.06]).ConclusionsIn this community-based population without diagnosed diabetes, low 1,5-AG was modestly associated with major clinical outcomes and did not outperform 2-h glucose.
| S-EPMC7648735 | biostudies-literature
Project description:1,5-anhydroglucitol (1,5-AG) is a biomarker of hyperglycemic excursions associated with diabetic complications. Because of its structural similarity to glucose, genetic studies of 1,5-AG can deliver complementary insights into glucose metabolism. We conducted genome-wide association studies of serum 1,5-AG concentrations in 7,550 European ancestry (EA) and 2,030 African American participants (AA) free of diagnosed diabetes from the ARIC Study. Seven loci in/near EFNA1/SLC50A1, MCM6/LCT, SI, MGAM, MGAM2, SLC5A10, and SLC5A1 showed genome-wide significant associations (P < 5 × 10-8) among EA participants, five of which were novel. Six of the seven loci were successfully replicated in 8,790 independent EA individuals, and MCM6/LCT and SLC5A10 were also associated among AA. Most of 1,5-AG-associated index SNPs were not associated with the clinical glycemic markers fasting glucose or the HbA1c, and vice versa. Only the index variant in SLC5A1 showed a significant association with fasting glucose in the expected opposing direction. Products of genes in all 1,5-AG-associated loci have known roles in carbohydrate digestion and enteral or renal glucose transport, suggesting that genetic variants associated with 1,5-AG influence its concentration via effects on glucose metabolism and handling.
| S-EPMC5460207 | biostudies-literature
Project description:OBJECTIVE:1,5-Anhydroglucitol (1,5-AG) is a biomarker of glucose peaks and has been associated with clinical cardiovascular disease. However, the association between 1,5-AG and subclinical cardiovascular disease is unknown. We investigated the association of 1,5-AG with subclinical myocardial damage (assessed by high-sensitivity cardiac troponin T [hs-cTnT]) and atherosclerosis (assessed by carotid intima-media thickness [CIMT] and carotid plaque). RESEARCH DESIGN AND METHODS:We measured 1,5-AG, hs-cTnT, CIMT, and carotid plaque among 10,072 people without diabetes and 681 with diabetes who attended the second examination of the Atherosclerosis Risk in Communities (ARIC) Study (baseline, 1990-1992). We used Poisson regression to characterize the associations between 1,5-AG and prevalent elevated hs-cTnT, thick CIMT, or carotid plaque. Among 9,145 people with a second hs-cTnT measurement 6 years later, we used multinomial logistic regression to assess associations with incident elevation in hs-cTnT. RESULTS:We found that in people with diabetes, lower 1,5-AG (<6 μg/mL) was cross-sectionally associated with elevated hs-cTnT (prevalence ratio 2.06, 95% CI 1.23-3.46) compared with higher 1,5-AG (≥10 μg/mL). Associations in people without diabetes and with thick CIMT or the presence of carotid plaque were less robust. Low 1,5-AG was prospectively associated with the 6-year incident elevation in hs-cTnT (relative risk 2.90, 95% CI 1.23-6.85) in people with diabetes. All associations were strongly attenuated with further adjustment for HbA1c. CONCLUSIONS:In people with diabetes, 1,5-AG was associated with subclinical cardiovascular disease, particularly chronic subclinical myocardial damage. Nonetheless, whether observed associations are truly independent of average glycemia is unclear.
| S-EPMC5033083 | biostudies-other
Project description:OBJECTIVE:To assess the magnitude and independence of the effects of routine blood pressure lowering and intensive glucose control on clinical outcomes in patients with long-standing type 2 diabetes. RESEARCH DESIGN AND METHODS:This was a multicenter, factorial randomized trial of perindopril-indapamide versus placebo (double-blind comparison) and intensive glucose control with a gliclazide MR-based regimen (target A1C <or=6.5%) versus standard glucose control (open comparison) in 11,140 participants with type 2 diabetes who participated in the Action in Diabetes and Vascular Disease: Preterax and Diamicron MR Controlled Evaluation (ADVANCE) trial. Annual event rates and risks of major macrovascular and microvascular events considered jointly and separately, renal events, and death during an average 4.3 years of follow-up were assessed, using Cox proportional hazards models. RESULTS:There was no interaction between the effects of routine blood pressure lowering and intensive glucose control for any of the prespecified clinical outcomes (all P > 0.1): the separate effects of the two interventions for the renal outcomes and death appeared to be additive on the log scale. Compared with neither intervention, combination treatment reduced the risk of new or worsening nephropathy by 33% (95% CI 12-50%, P = 0.005), new onset of macroalbuminuria by 54% (35-68%, P < 0.0001), and new onset of microalbuminuria by 26% (17-34%). Combination treatment was associated with an 18% reduction in the risk of all-cause death (1-32%, P = 0.04). CONCLUSIONS:The effects of routine blood pressure lowering and intensive glucose control were independent of one another. When combined, they produced additional reductions in clinically relevant outcomes.
| S-EPMC2768202 | biostudies-literature
Project description:ObjectiveTo develop a frailty index (FI) and explore the relationship of frailty to subsequent adverse outcomes on the effectiveness and safety of more intensive control of both blood glucose and blood pressure (BP), among participants with type 2 diabetes in the Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation (ADVANCE) trial.Research design and methodsCox proportional hazard models were used to estimate the effectiveness and safety of intensive glucose control and BP intervention according to frailty (defined as FI >0.21) status. The primary outcomes were macro- and microvascular events. The secondary outcomes were all-cause mortality, cardiovascular mortality, severe hypoglycemia, and discontinuation of BP treatment due to hypotension/dizziness.ResultsThere were 11,140 participants (mean age, 65.8 years; 42.5% women, 25.7% frail). Frailty was an independent predictor of all primary outcomes and secondary outcomes. The effect of intensive glucose treatment on primary outcomes showed some evidence of attenuation in the frail: hazard ratios for combined major macro- and microvascular events 1.03 (95% CI 0.90-1.19) in the frail versus 0.84 (95% CI 0.74-0.94) in the nonfrail (P = 0.02). A similar trend was observed with BP intervention. Severe hypoglycemia rates (per 1,000 person-years) were higher in the frail: 8.39 (6.15-10.63) vs. 4.80 (3.84-5.76) in nonfrail (P < 0.001). There was no significant difference in discontinuation of BP treatment between frailty groups.ConclusionsIt was possible to retrospectively estimate frailty in a trial population, and this FI identified those at higher risk of poor outcomes. Participants with frailty had some attenuation of benefit from intensive glucose-lowering and BP-lowering treatments.
| S-EPMC8323181 | biostudies-literature
Project description:1,5 anhydroglucitol (1,5-AG), is a nonmetabolized 1-deoxy form of glucose, originate mainly from the diet. 1,5-AG is a biomarker to detect and magnify hyperglycemic excursions (postprandial hyperglycemia) in diabetic patients. Concentrations of 1,5-AG has been applied as supporting biomarker to diagnosis of the major forms of diabetes (type 1, type 2, and gestational). The serum 1,5-AG reference interval is relevant to the appropriate clinical application of this biomarker. This article contains data regards to serum concentration of the biomarker primarily for healthy subjects, capture from the literature, in different populations. Correlation analysis between 1,5-AG and markers associated with diabetes and its complication were presented. The data was complementary to the study "Reference intervals for serum 1,5-anhydroglucitol in children, adolescents, adults, and pregnant women" (Welter et al., 2018). The data present in this article improve the comparisons for 1,5-AG in different conditions and methodologies.
| S-EPMC6129696 | biostudies-literature
Project description:Background1,5-Anhydroglucitol (1,5-AG) is inversely related to hyperglycemia and may be a useful indicator of short-term (1-2 weeks) hyperglycemia and glycemic excursions, but its prognostic value is unclear. We sought to evaluate the associations of 1,5-AG with risk of diabetes and microvascular disease.MethodsWe measured 1,5-AG in blood samples from over 10 000 participants in the ARIC (Atherosclerosis Risk in Communities) Study (baseline, 1990-1992) and characterized the independent associations with prevalent retinopathy and with incident chronic kidney disease and incident diabetes during approximately 20 years of follow-up.ResultsWe found that 1,5-AG was associated with prevalent retinopathy, driven primarily by the strong association in persons with diagnosed diabetes: adjusted odds ratio (OR) 11.26 (95% CI, 6.17-20.53) for <6 μg/mL compared to 1,5-AG ≥10 μg/mL. This result remained significant after further adjustment for hemoglobin A(1c) (Hb A(1c)) (OR, 4.85; 95% CI, 2.42-9.74). In persons with diagnosed diabetes, low 1,5-AG (<6 μg/mL vs ≥10 μg/mL) was also associated with a >2-fold increased risk of incident chronic kidney disease [adjusted hazard ratio (HR), 2.83; 95% CI, 2.15-3.74] and remained significant after adjustment for Hb A(1c) (HR, 1.43; 95% CI, 1.02-2.00). Nondiabetic participants with high 1,5-AG (≥10 μg/mL) had the lowest prevalence of retinopathy and lowest risk of kidney disease. In persons without diagnosed diabetes at baseline, 1,5-AG <10 μg/mL was also associated with incident diabetes (adjusted HR, 2.29; 95% CI, 2.03-2.58).Conclusions1,5-AG was associated with long-term risk of important microvascular outcomes, particularly in persons with diagnosed diabetes and even after adjustment for Hb A(1c). Our results suggest 1,5-AG may capture risk information associated with hyperglycemic excursions.
| S-EPMC4215646 | biostudies-literature
Project description:BackgroundEpidemiologic studies have shown a relationship between glycated hemoglobin levels and cardiovascular events in patients with type 2 diabetes. We investigated whether intensive therapy to target normal glycated hemoglobin levels would reduce cardiovascular events in patients with type 2 diabetes who had either established cardiovascular disease or additional cardiovascular risk factors.MethodsIn this randomized study, 10,251 patients (mean age, 62.2 years) with a median glycated hemoglobin level of 8.1% were assigned to receive intensive therapy (targeting a glycated hemoglobin level below 6.0%) or standard therapy (targeting a level from 7.0 to 7.9%). Of these patients, 38% were women, and 35% had had a previous cardiovascular event. The primary outcome was a composite of nonfatal myocardial infarction, nonfatal stroke, or death from cardiovascular causes. The finding of higher mortality in the intensive-therapy group led to a discontinuation of intensive therapy after a mean of 3.5 years of follow-up.ResultsAt 1 year, stable median glycated hemoglobin levels of 6.4% and 7.5% were achieved in the intensive-therapy group and the standard-therapy group, respectively. During follow-up, the primary outcome occurred in 352 patients in the intensive-therapy group, as compared with 371 in the standard-therapy group (hazard ratio, 0.90; 95% confidence interval [CI], 0.78 to 1.04; P=0.16). At the same time, 257 patients in the intensive-therapy group died, as compared with 203 patients in the standard-therapy group (hazard ratio, 1.22; 95% CI, 1.01 to 1.46; P=0.04). Hypoglycemia requiring assistance and weight gain of more than 10 kg were more frequent in the intensive-therapy group (P<0.001).ConclusionsAs compared with standard therapy, the use of intensive therapy to target normal glycated hemoglobin levels for 3.5 years increased mortality and did not significantly reduce major cardiovascular events. These findings identify a previously unrecognized harm of intensive glucose lowering in high-risk patients with type 2 diabetes. (ClinicalTrials.gov number, NCT00000620.)
| S-EPMC4551392 | biostudies-literature
Project description:BackgroundIntensive glucose lowering has previously been shown to increase mortality among persons with advanced type 2 diabetes and a high risk of cardiovascular disease. This report describes the 5-year outcomes of a mean of 3.7 years of intensive glucose lowering on mortality and key cardiovascular events.MethodsWe randomly assigned participants with type 2 diabetes and cardiovascular disease or additional cardiovascular risk factors to receive intensive therapy (targeting a glycated hemoglobin level below 6.0%) or standard therapy (targeting a level of 7 to 7.9%). After termination of the intensive therapy, due to higher mortality in the intensive-therapy group, the target glycated hemoglobin level was 7 to 7.9% for all participants, who were followed until the planned end of the trial.ResultsBefore the intensive therapy was terminated, the intensive-therapy group did not differ significantly from the standard-therapy group in the rate of the primary outcome (a composite of nonfatal myocardial infarction, nonfatal stroke, or death from cardiovascular causes) (P=0.13) but had more deaths from any cause (primarily cardiovascular) (hazard ratio, 1.21; 95% confidence interval [CI], 1.02 to 1.44) and fewer nonfatal myocardial infarctions (hazard ratio, 0.79; 95% CI, 0.66 to 0.95). These trends persisted during the entire follow-up period (hazard ratio for death, 1.19; 95% CI, 1.03 to 1.38; and hazard ratio for nonfatal myocardial infarction, 0.82; 95% CI, 0.70 to 0.96). After the intensive intervention was terminated, the median glycated hemoglobin level in the intensive-therapy group rose from 6.4% to 7.2%, and the use of glucose-lowering medications and rates of severe hypoglycemia and other adverse events were similar in the two groups.ConclusionsAs compared with standard therapy, the use of intensive therapy for 3.7 years to target a glycated hemoglobin level below 6% reduced 5-year nonfatal myocardial infarctions but increased 5-year mortality. Such a strategy cannot be recommended for high-risk patients with advanced type 2 diabetes. (Funded by the National Heart, Lung and Blood Institute; ClinicalTrials.gov number, NCT00000620.).
| S-EPMC4083508 | biostudies-literature