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Efficacy and safety of meal-time administration of short-acting exenatide for glycaemic control in type 1 diabetes (MAG1C): a randomised, double-blind, placebo-controlled trial.
Johansen, NJ, Dejgaard, TF, Lund, A, Schlüntz, C, Frandsen, CS, Forman, JL, Wewer Albrechtsen, NJ, Holst, JJ, Pedersen-Bjergaard, U, Madsbad, S, et al
The lancet. Diabetes & endocrinology. 2020;(4):313-324
Abstract
BACKGROUND In type 2 diabetes, long-acting GLP-1 receptor agonists lower fasting plasma glucose and improve glycaemic control via their insulinotropic and glucagonostatic effects. In type 1 diabetes, their efficacy as an add-on treatment to insulin therapy is modest. Short-acting GLP-1 receptor agonists also lower postprandial glucose excursions in type 2 diabetes by decelerating gastric emptying rate. We aimed to test the efficacy of a short-acting GLP-1 receptor agonist in type 1 diabetes. METHODS In the single-centre, parallel-group, randomised, double-blind, placebo-controlled MAG1C trial, patients with type 1 diabetes on multiple daily injection therapy aged 18 years and older with HbA1c 59-88 mmol/mol (7·5-10·0%) and a BMI of more than 22·0 kg/m2 were randomly assigned (1:1) through a computer-generated randomisation list to preprandial subcutaneous injection of 10 μg exenatide (Byetta) or placebo three times daily for 26 weeks as an add-on treatment to usual insulin therapy. Clinically assessed insulin titration was done by study staff. Participants and investigators were masked to treatment allocation. The primary endpoint was between-group difference in HbA1c after 26 weeks. Data were analysed with a baseline-adjusted linear mixed model in the intention-to-treat population. This study is registered with ClinicalTrials.gov, NCT03017352, and is completed. FINDINGS Between Jan 4, 2017, and Jan 16, 2019, 108 participants were randomly assigned, 54 to exenatide and 54 to placebo; 23 participants discontinued treatment (17 in the exenatide group and six in the placebo group). From a baseline-adjusted mean of 66·4 mmol/mol (95% CI 64·9-67·8 [8·2%, 8·1-8·4]), HbA1c changed by -3·2 mmol/mol (-5·0 to -1·4 [-0·3%, -0·5 to -0·1]) with exenatide and -2·1 mmol/mol (-3·7 to -0·6 [-0·2%, -0·3 to -0·1]) with placebo after 26 weeks (estimated treatment difference of -1·1 mmol/mol (-3·4 to 1·2 [-0·1%, -0·3 to 0·1]; p=0·36). Exenatide increased the number of self-reported gastrointestinal adverse events (primarily nausea [48 events among 37 patients with exenatide, nine with placebo among 9 patients]). Two serious adverse events occurred in the exenatide group, and six occurred in the placebo group (none were considered to be related to the study drug). INTERPRETATION Short-acting exenatide does not seem to have a future as a standard add-on treatment to insulin therapy in type 1 diabetes. FUNDING AstraZeneca.
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Role of Composite Glycemic Indices: A Comparison of the Comprehensive Glucose Pentagon Across Diabetes Types and HbA1c Levels.
Rama Chandran, S, A Vigersky, R, Thomas, A, Lim, LL, Ratnasingam, J, Tan, A, S L Gardner, D
Diabetes technology & therapeutics. 2020;(2):103-111
Abstract
Background: Complex changes of glycemia that occur in diabetes are not fully captured by any single measure. The Comprehensive Glucose Pentagon (CGP) measures multiple aspects of glycemia to generate the prognostic glycemic risk (PGR), which constitutes the relative risk of hypoglycemia combined with long-term complications. We compare the components of CGP and PGR across type 1 and type 2 diabetes. Methods: Participants: n = 60 type 1 and n = 100 type 2 who underwent continuous glucose monitoring (CGM). Mean glucose, coefficient of variation (%CV), intensity of hypoglycemia (INThypo), intensity of hyperglycemia (INThyper), time out-of-range (TOR <3.9 and >10 mmol/L), and PGR were calculated. PGR (median, interquartile ranges [IQR]) for diabetes types, and HbA1c classes were compared. Results: While HbA1c was lower in type 1 (type 1 vs. type 2: 8.0 ± 1.6 vs. 8.6 ± 1.7, P = 0.02), CGM-derived mean glucoses were similar across both groups (P > 0.05). TOR, %CV, INThypo, and INThyper were all higher in type 1 [type 1 vs. type 2: 665 (500, 863) vs. 535 (284, 823) min/day; 39% (33, 46) vs. 29% (24, 34); 905 (205, 2951) vs. 18 (0, 349) mg/dL × min2; 42,906 (23,482, 82,120) vs. 30,166 (10,276, 57,183) mg/dL × min2, respectively, all P < 0.05]. Across each HbA1c class, the PGR remained consistently and significantly higher in type 1. While mean glucose remained the same across HbA1c classes, %CV, TOR, INThyper, and INThypo were significantly higher for type 1. Even within the same HbA1c class, the variation (IQR) of each parameter in type 1 was wider. The PGR increased across diabetes groups; type 2 on orals versus type 2 on insulin versus type 1 (PGR: 1.6 vs. 2.2 vs. 2.9, respectively, P < 0.05). Conclusion: Composite indices such as the CGP capture significant differences in glycemia independent of HbA1c and mean glucose. The use of such indices must be explored in both the clinical and research settings.
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Hemoglobin A1c Levels Modify Associations between Dietary Acid Load and Breast Cancer Recurrence.
Wu, T, Hsu, FC, Wang, S, Luong, D, Pierce, JP
Nutrients. 2020;(2)
Abstract
BACKGROUND Metabolic acidosis promotes cancer metastasis. No prospective studies have examined the association between dietary acid load and breast cancer recurrence among breast cancer survivors, who are susceptible to metabolic acidosis. Hyperglycemia promotes cancer progression and acid formation; however, researchers have not examined whether hyperglycemia can modify the association between dietary acid load and breast cancer recurrence. METHODS We studied 3081 early-stage breast cancer survivors enrolled in the Women's Healthy Eating and Living study who provided dietary information through 24-h recalls at baseline and during follow-up and had measurements of hemoglobin A1c (HbA1c) at baseline. We assessed dietary acid load using two common dietary acid load scores, potential renal acid load (PRAL) score and net endogenous acid production (NEAP) score. RESULTS After an average of 7.3 years of follow-up, dietary acid load was positively associated with recurrence when baseline HbA1c levels were ≥ 5.6% (median level) and ≥5.7% (pre-diabetic cut-point). In the stratum with HbA1c ≥ 5.6%, comparing the highest to the lowest quartile of dietary acid load, the multivariable-adjusted hazard ratio was 2.15 (95% confidence interval [CI] 1.34-3.48) for PRAL and was 2.31 (95% CI 1.42-3.74) for NEAP. No associations were observed in the stratum with HbA1c levels were <5.6%. P-values for interactions were 0.01 for PRAL and 0.05 for NEAP. CONCLUSIONS Our study demonstrated for the first time that even at or above normal to high HbA1c levels, dietary acid load was associated with increased risk of breast cancer recurrence among breast cancer survivors. IMPACTS Our study provides strong evidence for developing specific dietary acid load guidelines based on HbA1c levels.
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Glycemic Monitoring and Management in Advanced Chronic Kidney Disease.
Galindo, RJ, Beck, RW, Scioscia, MF, Umpierrez, GE, Tuttle, KR
Endocrine reviews. 2020;(5):756-74
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Abstract
Glucose and insulin metabolism in patients with diabetes are profoundly altered by advanced chronic kidney disease (CKD). Risk of hypoglycemia is increased by failure of kidney gluconeogenesis, impaired insulin clearance by the kidney, defective insulin degradation due to uremia, increased erythrocyte glucose uptake during hemodialysis, impaired counterregulatory hormone responses (cortisol, growth hormone), nutritional deprivation, and variability of exposure to oral antihyperglycemic agents and exogenous insulin. Patients with end-stage kidney disease frequently experience wide glycemic excursions, with common occurrences of both hypoglycemia and hyperglycemia. Assessment of glycemia by glycated hemoglobin (HbA1c) is hampered by a variety of CKD-associated conditions that can bias the measure either to the low or high range. Alternative glycemic biomarkers, such as glycated albumin or fructosamine, are not fully validated. Therefore, HbA1c remains the preferred glycemic biomarker despite its limitations. Based on observational data for associations with mortality and risks of hypoglycemia with intensive glycemic control regimens in advanced CKD, an HbA1c range of 7% to 8% appears to be the most favorable. Emerging data on the use of continuous glucose monitoring in this population suggest promise for more precise monitoring and treatment adjustments to permit fine-tuning of glycemic management in patients with diabetes and advanced CKD.
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Risk Factor Control and Cardiovascular Event Risk in People With Type 2 Diabetes in Primary and Secondary Prevention Settings.
Wright, AK, Suarez-Ortegon, MF, Read, SH, Kontopantelis, E, Buchan, I, Emsley, R, Sattar, N, Ashcroft, DM, Wild, SH, Rutter, MK
Circulation. 2020;(20):1925-1936
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Abstract
BACKGROUND To examine the association between the degree of risk factor control and cardiovascular disease (CVD) risk in type 2 diabetes and to assess if the presence of cardio-renal disease modifies these relationships. METHODS A retrospective cohort study using data from English practices from CPRD GOLD (Clinical Practice Research Datalink) and the SCI-Diabetes dataset (Scottish Care Information-Diabetes), with linkage to hospital and mortality data. We identified 101 749 with type 2 diabetes (T2D) in CPRD matched with 378 938 controls without diabetes and 330 892 with type 2 diabetes in SCI-Diabetes between 2006 and 2015. The main exposure was number of optimized risk factors: nonsmoker, total cholesterol ≤4 mmol/L, triglycerides ≤1.7 mmol/L, glycated haemoglobin (HbA1c) ≤53 mmol/mol (≤7.0%), systolic blood pressure <140mm Hg, or <130 mm Hg if high risk. Cox models were used to assess cardiovascular risk associated with levels of risk factor control. RESULTS In CPRD, the mean baseline age in T2D was 63 years and 28% had cardio-renal disease (SCI-Diabetes: 62 years; 35% cardio-renal disease). Over 3 years follow-up (SCI-Diabetes: 6 years), CVD events occurred among 27 900 (27%) CPRD-T2D, 101 362 (31%) SCI-Diabetes-T2D, and 75 520 (19%) CPRD-controls. In CPRD, compared with controls, T2D participants with optimal risk factor control (all risk factors controlled) had a higher risk of CVD events (adjusted hazard ratio, 1.21; 95% confidence interval, 1.12-1.29). In T2D participants from CPRD and SCI-Diabetes, pooled hazard ratios for CVD associated with 5 risk factors being elevated versus optimal risk factor control were 1.09 (95% confidence interval, 1.01-1.17) in people with cardio-renal disease but 1.96 (95% confidence interval, 1.82-2.12) in people without cardio-renal disease. People without cardio-renal disease were younger and more likely to have likely to have suboptimal risk factor control but had fewer prescriptions for risk factor modifying medications than those with cardio-renal disease. CONCLUSIONS Optimally managed people with T2D have a 21% higher CVD risk when compared with controls. People with T2D without cardio-renal disease would be predicted to benefit greatly from CVD risk factor intervention.
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Identification of MODY among patients screened for gestational diabetes: a clinician's guide.
Urbanová, J, Brunerová, L, Nunes, M, Brož, J
Archives of gynecology and obstetrics. 2020;(2):305-314
Abstract
PURPOSE Screening of gestational diabetes/GDM (although different in different countries) represents a standard procedure allowing to identify women with pregnancy-associated diabetes. Some of the women with GDM (up to 5%) may, however, suffer from previously undiagnosed MODY (Maturity-Onset Diabetes of the Young). Currently, no international or local guidelines focused on the identification of MODY among GDM exist. Thus, the aim of this manuscript is to propose a clear guide for clinicians on how to detect MODY among pregnant women with gestational diabetes. METHODS Based on the available literature about diagnosis (in general population) of MODY and management of MODY (both, in general population and in pregnant women), we propose a clear clinical guide on how to diagnose and manage MODY in pregnancy. RESULTS The manuscript suggests a feasible clinical approach how to recognize MODY among patients with GDM and how to manage pregnancy of women with three most common MODY subtypes. CONCLUSION A correct classification of diabetes is, nonetheless, essential, particularly in case of MODY, as the management of pregnant women with MODY is different and the correct diagnosis of MODY enables individualized treatment with regard to optimal pregnancy outcomes.
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Fibrinogen is associated with glucose metabolism and cardiovascular outcomes in patients with coronary artery disease.
Liu, SL, Wu, NQ, Shi, HW, Dong, Q, Dong, QT, Gao, Y, Guo, YL, Li, JJ
Cardiovascular diabetology. 2020;(1):36
Abstract
BACKGROUND The present cohort study aims to examine the relationship between fibrinogen (Fib) levels and glucose metabolism [fasting blood glucose (FBG) and hemoglobin A1c (HbA1c)] and investigate the impact of high Fib on cardiovascular outcomes in patients with stable CAD and pre-diabetes mellitus (pre-DM) or diabetes mellitus (DM). METHODS This study included 5237 patients from March 2011 to December 2015. Patients were distributed into three groups according to Fib levels (low Fib, median Fib, high Fib) and further categorized by glucose metabolism status [normal glucose regulation (NGR), Pre-DM, DM]. All patients were followed up for the occurrences of major adverse cardiovascular events (MACEs), including cardiovascular mortality, nonfatal MI, stroke, and unplanned coronary revascularization. RESULTS Linear regression analyses showed that FBG and HbA1c levels were positively associated with Fib in overall CAD participants, either with or without DM (all P < 0.001). During an average of 18,820 patient-years of follow-up, 476 MACEs occurred. High Fib was independently associated with MACEs after adjusting for confounding factors [Hazard Ratio (HR): 1.57, 95% confidence interval (CI) 1.26-1.97, P < 0.001]. Furthermore, DM but not pre-DM was a significant predictor of MACEs (P < 0.001 and P > 0.05, respectively). When patients were stratified by both glucose metabolism status and Fib levels, high Fib was associated with a higher risk of MACEs in pre-DM (HR 1.66, 95% CI 1.02-2.71, P < 0.05). Medium and high Fib levels were associated with an even higher risk of MACEs in DM (HR 1.86, 95% CI 1.14-3.05 and HR 2.28, 95% CI 1.42-3.66, all P < 0.05). After adding the combination of Fib and glucose status to the Cox model, the C-statistic was increased by 0.015 (0.001-0.026). CONCLUSIONS The present study suggested that Fib levels were associated with FBG and HbA1c in stable CAD patients. Moreover, elevated Fib was independently associated with MACEs in CAD patients, especially among those with pre-DM and DM, suggesting that Fib may provide incremental value in the cardiovascular risk stratification of pre-DM and DM patients.
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Associations between area socioeconomic status, individual mental health, physical activity, diet and change in cardiometabolic risk amongst a cohort of Australian adults: A longitudinal path analysis.
Carroll, SJ, Dale, MJ, Niyonsenga, T, Taylor, AW, Daniel, M
PloS one. 2020;(5):e0233793
Abstract
Presumed pathways from environments to cardiometabolic risk largely implicate health behaviour although mental health may play a role. Few studies assess relationships between these factors. This study estimated associations between area socioeconomic status (SES), mental health, diet, physical activity, and 10-year change in glycosylated haemoglobin (HbA1c), comparing two proposed path structures: 1) mental health and behaviour functioning as parallel mediators between area SES and HbA1c; and 2) a sequential structure where mental health influences behaviour and consequently HbA1c. Three waves (10 years) of population-based biomedical cohort data were spatially linked to census data based on participant residential address. Area SES was expressed at baseline using an established index (SEIFA-IEO). Individual behavioural and mental health information (Wave 2) included diet (fruit and vegetable servings per day), physical activity (meets/does not meet recommendations), and the mental health component score of the 36-item Short Form Health Survey. HbA1c was measured at each wave. Latent variable growth models with a structural equation modelling approach estimated associations within both parallel and sequential path structures. Models were adjusted for age, sex, employment status, marital status, education, and smoking. The sequential path model best fit the data. HbA1c worsened over time. Greater area SES was statistically significantly associated with greater fruit intake, meeting physical activity recommendations, and had a protective effect against increasing HbA1c directly and indirectly through physical activity behaviour. Positive mental health was statistically significantly associated with greater fruit and vegetable intakes and was indirectly protective against increasing HbA1c through physical activity. Greater SES was protective against increasing HbA1c. This relationship was partially mediated by physical activity but not diet. A protective effect of mental health was exerted through physical activity. Public health interventions should ensure individuals residing in low SES areas, and those with poorer mental health are supported in meeting physical activity recommendations.
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Effect of a Moderate Carbohydrate-Restricted Diet on DPP-4 Inhibitor Action among Individuals with Type 2 Diabetes Mellitus: A 6-Month Intervention Study.
Kobayashi, M, Miura, T, Miura, K, Hiroyama, N, Akashi, K
Journal of nutritional science and vitaminology. 2020;(2):114-118
Abstract
To decrease body weight and insulin resistance, a calorie-restricted diet-with minimal caloric intake required for daily activities-is the primary treatment strategy for patients with type 2 diabetes (T2D) in Japan. However, many patients cannot continue with this diet for long, because calorie restriction is difficult and nutritional balance is hard to understand. Carbohydrate-restricted diets are easier for patients than conventional calorie-restricted diet. In this study we aimed to elucidate the effects of a moderate carbohydrate-restricted diet on glucose metabolism and renal function in patients with T2D on dipeptidyl peptidase-4 (DPP-4) inhibitors. Nineteen outpatients with T2D continued on a moderate carbohydrate-restricted diet (targeting 50% of calories) for 6 mo. Meanwhile, 10 other outpatients with T2D on DPP-4 inhibitors had the conventional calorie-restricted diet using the food exchange table. No change in prescription drugs occurred for both groups during the study period. After the intervention, the carbohydrate content in dietary intake was lowered significantly from 56.8±8.3 to 46.8±10.1%, while the lipid concentration, primarily n-6 polyunsaturated fatty acids, was significantly increased. There was no significant change in protein intake. Hemoglobin A1c (HbA1c) fell from 7.22±0.74% to 6.95±0.72% (mean±SD). Furthermore, salt intake decreased significantly from 6.8±2.5 g prior to the intervention, to 5.7±1.9 g after the intervention. The estimated glomerular filtration rates (eGFR) decreased slightly, while serum creatinine levels did not change. These findings suggest that a moderate carbohydrate-restricted diet (50%) is effective in patients with T2D, without affecting kidney function.
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Influence of Metabolic Parameters and Treatment Method on OCT Angiography Results in Children with Type 1 Diabetes.
Wysocka-Mincewicz, M, Baszyńska-Wilk, M, Gołębiewska, J, Olechowski, A, Byczyńska, A, Hautz, W, Szalecki, M
Journal of diabetes research. 2020;:4742952
Abstract
AIM: To evaluate the influence of metabolic parameters and the treatment method in children with type 1 diabetes (T1D) on the optical coherence tomography angiography (OCTA) results as early markers of diabetic retinopathy (DR). Material and Methods. This prospective study enrolled 175 consecutive children with T1D. OCTA was performed using AngioVue (Avanti, Optovue). Whole superficial capillary vessel density (wsVD), fovea superficial vessel density (fsVD), parafovea superficial vessel density (psVD), whole deep vessel density (wdVD), fovea deep vessel density (fdVD), parafovea deep vessel density (pdVD), foveal thickness (FT), parafoveal thickness (PFT), and foveal avascular zone (FAZ) in superficial plexus were evaluated and analyzed in relation to individual characteristics, i.e., sex, weight, height, body mass index (BMI), and metabolic factors: current and mean value of glycated hemoglobin A1c (HbA1c). Furthermore, the analysis concerned the diabetes duration, age at the T1D onset, and type of treatment-multiple daily insulin injections (MDI) or continuous subcutaneous insulin infusion (CSII). RESULTS In the study group, we did not identify any patient with DR in fundus ophthalmoscopy. Age at the onset of diabetes correlated negatively with FAZ (r = -0.17, p < 0.05). The higher level of HbA1c corresponded to a decrease of wsVD (r = -0.13, p < 0.05). We found significantly lower fsVD (32.25 ± .1 vs. 33.98 ± .1, p < 0.01), wdVD (57.87 ± .1 vs. 58.64 ± .9, p < 0.01), and pdVD (60.60 ± .2 vs. 61.49 ± .1, p < 0.01) and larger FAZ area (0.25 ± .1 vs. 0.23 ± .1, p < 0.05) in the CSII vs. MDI group. CONCLUSION The metabolic parameters, age of the onset of diabetes, and treatment method affected the OCTA results in children with T1D. Further studies and observation of these young patients are needed to determine if these findings are important for early detection of DR or predictive of future DR severity.