Transporters, TBC1D4, and ARID5B Variants to Explain Glycated Hemoglobin Variability in Patients with Type 2 Diabetes

<b><i>Introduction:</i></b> Genetic variants could aid in predicting antidiabetic drug response by associating them with markers of glucose control, such as glycated hemoglobin (HbA1c). However, pharmacogenetic implementation for antidiabetics is still under development, as the list of actionable markers is being populated and validated. This study explores potential associations between genetic variants and plasma levels of HbA1c in 100 patients under treatment with metformin. <b><i>Methods:</i></b> HbA1c was measured in a clinical chemistry analyzer (Roche), genotyping was performed in an Illumina-GSA array and data were analyzed using PLINK. Association and prediction models were developed using R and a 10-fold cross-validation approach. <b><i>Results:</i></b> We identified genetic variants on <i>SLC47A1, SLC28A1, ABCG2, TBC1D4,</i> and <i>ARID5B</i> that can explain up to 55% of the interindividual variability of HbA1c plasma levels in diabetic patients under treatment. Variants on <i>SLC47A1</i>, <i>SLC28A1</i>, and <i>ABCG2</i> likely impact the pharmacokinetics (PK) of metformin, while the role of the two latter can be related to insulin resistance and regulation of adipogenesis. <b><i>Conclusions:</i></b> Our results confirm previous genetic associations and point to previously unassociated gene variants for metformin PK and glucose control.

Effectiveness of Nutrition and WASH/malaria educational community-based interventions in reducing anemia in children from Angola

We found no published data in Angola regarding the effect of combining nutrition-specific and nutrition-sensitive approaches in the reduction of anemia in preschool children. Thus, we implemented a cluster-randomized controlled trial to determine the effectiveness of two educational-plus-therapeutic interventions, in Nutrition and WASH/Malaria, in reducing anemia. We compared them to (1) a test-and-treat intervention and (2) with each other. A block randomization was performed to allocate 6 isolated hamlets to 3 study arms. A difference-in-difference technique, using Fit Generalized estimating models, was used to determine differences between the children successfully followed in all groups, between 2015 and 2016. We found no significant differences in anemia´s and hemoglobin variability between educational and the control group. However, the WASH/Malaria group had 22.8% higher prevalence of anemia when compared with the Nutrition group, having also higher prevalence of P. falciparum. Thus, our results suggest that adding a 12-month educational Nutrition or a WASH/Malaria component to a test-and-treat approach may have a limited effect in controlling anemia. Possibly, the intensity and duration of the educational interventions were not sufficient to observe the amount of behavior change needed to stop transmission and improve the general child feeding practices.

Glycated hemoglobin variability and microvascular complications in patients with type 1 diabetes mellitus

ObjectivesGlycated hemoglobin (HbA1c) has proven to be indicative in the development of microvascular complications. In this study, the contribution of HbA1c variability to microvascular complications was evaluated.MethodsTwenty-one cases with type 1 diabetes mellitus (T1DM) who developed microvascular complications and 39 cases without complications, that were similar in terms of gender, age of diagnosis, insulin treatment, insulin doses (U/kg), and mean HbA1c levels were included.ResultsMean age of T1DM diagnosis was 5.87 ± 3.93 years in the complication group and 4.63 ± 3.33 years in the control group. Nephropathy was detected in 17 cases, neuropathy in 8 cases, and retinopathy in 1 case. Nephropathy occurred at a mean age of 11.52 ± 4.12 years and neuropathy at 14.13 ± 5.68 years. The mean HbA1c during follow-up was similar in the group with complications and the control group (8.60 ± 0.63 vs. 8.84 ± 1.32). Adjusted HbA1c-standard deviation (SD) and HbA1c-variation coefficient (CV) values were 1.30 ± 0.65 and 14.36 ± 6.23 in the group with complications (p=0.014), and 0.91 ± 0.37 and 10.59 ± 4.01 in the control group (p=0.013). In the Receiver Operating Characteristic (ROC)-analysis for microvascular complications, the limit value HbA1c-CV was 11.99 (sensitivity: 61.9%, specificity: 71.9%). This value for HbA1c-SD was 0.9699 (sensitivity: 71.43%, specificity: 66.67%)ConclusionsThis study has shown that long-term fluctuations in HbA1c are associated with the development of microvascular complications in type 1 diabetes.

Glycated hemoglobin variability, mean HbA1c and heart failure in patients with type 2 diabetes

Background: Heart failure (HF) is a common presentation in patients with type 2 diabetes mellitus (T2DM). Previous studies revealed that HbA1c level is significantly associated with HF. However, little is known about the association between HbA1c variability and HF. We aimed to evaluate the association of HbA1c variability and mean HbA1c with HF in patients with T2DM. Methods: Using Diabetes Share Care Program data, patients with T2DM had mean HbA1c (HbA1c-Mean), HbA1c variability (tertiles of HbA1c-SD and HbA1c-adjSD) within 12-24 months during 2001-2008 were included. The cutoffs of HbA1c-Mean were set at <7%, 7-7.9%, and ≥8%. Hazard ratios (HRs) for HF during 2008-2018 were estimated using Cox proportional hazards models. Results: A total of 3824 patients were included, of whom 315 patients developed HF during the 11.72 years observation period. The associated risk of HF increased with tertiles of HbA1c variability and cutoffs of HbA1c-Mean. In mutually adjusted models, HbA1c-Mean showed a consistent dose-response association with HF, while the association of HbA1c variability with HF disappeared. Among patients with HbA1c-Mean < 7%, the associated risk of HF in patients with HbA1c variability in tertile 3 was comparable to patients with HbA1c-Mean ≥8%. Conclusions: Mean HbA1c was an independent predictor of HF and not explained by HbA1c variability. In addition to absolute HbA1c level, targeting on stability of HbA1c in patients with well glycemic control was also important for the development of HF in patients with T2DM.

The effect of glycated hemoglobin variability on the development of microvascular complications in patients with type 1 diabetes

Introduction. The results of a 25-year observational program to assess the effect of glycated hemoglobin variability on the development of microvascular complications in patients with type 1 diabetes mellitus are presented.Objective: This study aimed to evaluate the effect of glycated hemoglobin (HbA1c) variability on the development of microvascular complications in patients with type 1 diabetes mellitus (DM1) and disease duration of 25 years.Materials and methods: A retrospective analysis of the database of patients with DM1 was performed from the moment of the disease manifestation until the time of the last visit. Determination of HbA1c level is carried out using parameters certified in accordance with the National Standard for Glycohemoglobin Standardization (NGSP) or the International Federation of Clinical Chemists (IFCC). HbA1c variability was determinated by average current HbA1c, average of longitudinal HbA1c (from the manifestation to the last visit – 2019), median and maximum of difference in changes of HbA1c (median and max∆HbA1c). Statistical analysis was performed by IBM SPSS Statistics ver.22. A statistically significant difference is the value p < 0.05.Results. A total of 88 patients were enrolled in this study, they were divided in 3 groups depending on the registered microvascular complications (MVC): without MVC (n = 38), isolated MVC (retinopathy or nephropathy) (n = 25) and multiple MVC (retinopathy and nephropathy) (n = 25). Clinical characteristics [median (25; 75 percentile)]: age of manifestation of DM1 is 9 years (5; 12), age of patients at the time of the last visit is 33 years (29; 35), duration of DM1 is 24 years (20; 27), body mass index 24 kg/m2 (21; 25). Medication: basal-bolus insulin therapy (n = 82) or pump insulin therapy (n = 6). The average level of longitudinal HbA1c for the three groups was: 8% (7.6; 8.9), 8.5% (7.9; 8.9), 8.6% (7.8; 10), p = 0.2. Average of current (at the time of the last visit) HbA1c – 8.2% (7.2; 9.0), 8.1% (7.5; 9.0), 8.4% (7.3; 9.7), p = 0.4. Statistically significant differences were determined in the group without complications and in the group with multiple complications between the levels of maxΔ HbA1c 2.3% (1.8; 2.8) vs 4.7% (3.2; 5.6), p < 0.0001 and median Δ HbA1c 0.7% (0.6; 0.9) vs 1.4% (1; 1.7), р < 0.0001. There were no statistically significant relationships between the maximum and medianΔ HbA1c in the groups without complications and in the group with isolated complications.Conclusions: Longitudinal HbA1c and current HbA1c are not associated with the development of microvascular complications. The potential role in the development of microvascular complications was determined for the maximum and median Δ HbA1c.

Timing of Transfusion, not Hemoglobin Variability, Is Associated with 3-Month Outcomes in Acute Ischemic Stroke

Objectives: This study aimed to investigate whether transfusions and hemoglobin variability affects the outcome of stroke after an acute ischemic stroke (AIS). Methods: We studied consecutive patients with AIS admitted in three tertiary hospitals who received red blood cell (RBC) transfusion (RBCT) during admission. Hemoglobin variability was assessed by minimum, maximum, range, median absolute deviation, and mean absolute change in hemoglobin level. Timing of RBCT was grouped into two categories: admission to 48 h (early) or more than 48 h (late) after hospitalization. Late RBCT was entered into multivariable logistic regression model. Poor outcome at three months was defined as a modified Rankin Scale score ≥3. Results: Of 2698 patients, 132 patients (4.9%) received a median of 400 mL (interquartile range: 400–840 mL) of packed RBCs. One-hundred-and-two patients (77.3%) had poor outcomes. The most common cause of RBCT was gastrointestinal bleeding (27.3%). The type of anemia was not associated with the timing of RBCT. Late RBCT was associated with poor outcome (odd ratio (OR), 3.55; 95% confidence interval (CI), 1.43–8.79; p-value = 0.006) in the univariable model. After adjusting for age, sex, Charlson comorbidity index, and stroke severity, late RBCT was a significant predictor (OR, 3.37; 95% CI, 1.14–9.99; p-value = 0.028) of poor outcome at three months. In the area under the receiver operating characteristics curve comparison, addition of hemoglobin variability indices did not improve the performance of the multivariable logistic model. Conclusion: Late RBCT, rather than hemoglobin variability indices, is a predictor for poor outcome in patients with AIS.