Rosangela Rea

Aims/hypothesis: COMBINE 2 assessed the efficacy and safety of once-weekly IcoSema (a combination therapy of basal insulin icodec and semaglutide) vs once-weekly semaglutide (a glucagon-like peptide-1 analogue) 1.0 mg in individuals with type 2 diabetes inadequately managed with GLP-1 receptor agonist (GLP-1 RA) therapy, with or without additional oral glucose-lowering medications. Methods: This 52 week, randomised, multicentre, open-label, parallel group, Phase IIIa trial was conducted across 121 sites in 13 countries/regions. Adults with type 2 diabetes (HbA_1c 53.0–85.8 mmol/mol [7.0–10.0%]) receiving GLP-1 RA therapy with or without additional oral glucose-lowering medications were randomly assigned 1:1 to once-weekly IcoSema or once-weekly semaglutide 1.0 mg. The primary endpoint was change in HbA_1c from baseline to week 52; superiority of IcoSema to semaglutide 1.0 mg was assessed. Secondary endpoints included change in fasting plasma glucose and body weight (baseline to week 52), and combined clinically significant (level 2; n=342) or semaglutide 1.0 mg (n=341). Mean ± SD baseline characteristics were as follows: HbA_1c 64.0±8.2 mmol/mol (8.0±0.7%); diabetes duration 12.6±6.9 years; and BMI 31.1±4.7 kg/m². From baseline to week 52, mean change in HbA_1c was −14.7 mmol/mol (−1.35%-points) in the IcoSema group and −9.88 mmol/mol (−0.90%-points) in the semaglutide group; the estimated treatment difference (ETD) was –4.85 (95% CI −6.13, −3.57) mmol/mol (−0.44 [95% CI −0.56, −0.33]%-points), confirming superiority of IcoSema to semaglutide (pppp=0.66). The proportion of participants experiencing gastrointestinal adverse events was similar between treatment groups (IcoSema 31.4%; semaglutide 34.4%). Conclusions/interpretation: In people living with type 2 diabetes inadequately managed with GLP-1 RA therapy, with or without additional oral glucose-lowering medications, switching to once-weekly IcoSema in comparison with once-weekly semaglutide 1.0 mg demonstrated superiority in HbA_1c reduction, similar rates of clinically significant or severe hypoglycaemia, and similar frequency of gastrointestinal adverse events. However, weight change from baseline to week 52 was statistically significantly in favour of semaglutide 1.0 mg. Trial registration: ClinicalTrials.gov NCT05259033 Funding: This trial was funded by Novo Nordisk Graphical

Objectives To evaluate a postpartum telephone-based lifestyle intervention to prevent diabetes in high-risk women with recent gestational diabetes mellitus (GDM). Design Multicentre parallel randomised clinical trial. Setting Specialised antenatal clinics in the Brazilian National System. Methods Lifestyle Intervention for Diabetes Prevention After Pregnancy compared (1:1) postpartum telephone support for lifestyle changes with conventional care in women with recent GDM at substantial risk for diabetes. Randomisation started on 28 March 2015 and ended on 13 March 2020, with the onset of the COVID-19 pandemic. We used Cox regression to estimate HRs for diabetes and analysis of covariance adjusted for follow-up time to assess weight change. Outcomes The primary outcome was incident diabetes ascertained with blinded measurements of oral glucose tolerance tests. The secondary outcome was a change in measured weight. Results We enrolled 5323 women with GDM, 2735 (51%) being at high risk. After invitations, baseline assessment and exclusions, we assigned 466 women to intervention (231) or control (235) groups. Attendance was satisfactory (≥7/20 phone sessions) in 75%. Over an average follow-up of 29.7 (15.6) months, 142 (30.5%) women progressed to diabetes, 75 (32%) in the control and 67 (29%) in the intervention group. There was no reduction in the incidence of diabetes (HR=0.84; 0.60–1.19) and only a non-significant 0.97 kg less weight gain (p=0.09). Among the 305 women randomised more than 1 year before the COVID-19 pandemic, the intervention did not reduce the incidence of diabetes (HR=0.71; 0.48–1.04) despite a 2.09 kg (p=0.002) lesser weight gain. Conclusion The strategy to identify women with GDM at high risk proved valid, as women often gained weight and frequently developed diabetes. Over a 30-month follow-up, telephone support for lifestyle changes at postpartum did not reduce weight gain or diabetes incidence, although only 75% attended the minimum number of telephone sessions. The COVID-19 pandemic negatively impacted trial conduction. Trial registration number NCT02327286.

We aimed to identify HLA-DRB1, -DQA1, and -DQB1 alleles/haplotypes associated with European, African, or Native American genomic ancestry (GA) in admixed Brazilian patients with type 1 diabetes (T1D). This exploratory nationwide study enrolled 1599 participants. GA percentage was inferred using a panel of 46 ancestry informative marker-insertion/deletion. Receiver operating characteristic curve analysis (ROC) was applied to identify HLA class II alleles related to European, African, or Native American GA, and showed significant (p < 0.05) accuracy for identifying HLA risk alleles related to European GA: for DRB1*03:01, the area under the curve was (AUC) 0.533; for DRB1*04:01 AUC = 0.558, for DRB1*04:02 AUC = 0.545. A better accuracy for identifying African GA was observed for the risk allele DRB1*09:01AUC = 0.679 and for the protective alleles DRB1*03:02 AUC = 0.649, DRB1*11:02 AUC = 0.636, and DRB1*15:03 AUC = 0.690. Higher percentage of European GA was observed in patients with risk haplotypes (p < 0.05). African GA percentage was higher in patients with protective haplotypes (p < 0.05). Risk alleles and haplotypes were related to European GA and protective alleles/haplotypes to African GA. Future studies with other ancestry markers are warranted to fill the gap in knowledge regarding the genetic origin of T1D in highly admixed populations such as that found in Brazil.

We aimed to investigate the relationship between HLA alleles in patients with type 1 diabetes from an admixed population and the reported race/skin color of their relatives. This cross-sectional, multicenter study was conducted in public clinics in nine Brazilian cities and included 662 patients with type 1 diabetes and their relatives. Demographic data for patients and information on the race/skin color and birthplace of their relatives were obtained. Typing of the HLA-DRB1, -DQA1, and -DQB1 genes was performed. Most studied patients reported having a White relative (95.17%), and the most frequently observed allele among them was DRB1*03:01. Increased odds of presenting this allele were found only in those patients who reported having all White relatives. Considering that most of the patients reported having a White relative and that the most frequent observed allele was DRB1*03:01 (probably a European-derived allele), regardless of the race/skin color of their relatives, we conclude that the type 1 diabetes genotype comes probably from European, Caucasian ethnicity. However, future studies with other ancestry markers are needed to fill the knowledge gap regarding the genetic origin of the type 1 diabetes genotype in admixed populations such as the Brazilian.

Aim: To assess what drives change in health‐related quality of life (HRQoL) in type 2 diabetes in the SUSTAIN 6 trial and identify potential mediators of the treatment effect of semaglutide on HRQoL scores. Materials and Methods: The Short Form (SF)‐36v2® questionnaire [comprising physical component summary (PCS) and mental component summary (MCS)] was used to assess changes in HRQoL from baseline to week 104, by treatment, in a prespecified analysis. This post‐hoc analysis assessed change in PCS and MCS using the following factors as parameter/covariate, using descriptive statistics and linear regressions: major adverse cardiac events, hypoglycaemia, gastrointestinal adverse events, at least one episode of nausea, vomiting or diarrhoea, and change in glycated haemoglobin (HbA1c), body weight, blood pressure, heart rate and estimated glomerular filtration rate. Results: Mean change in overall PCS score was +1.0 with semaglutide versus +0.4 with placebo, and +0.5 versus −0.2 for MCS. The treatment effect of semaglutide versus placebo (unadjusted estimate) was 0.7 [(95% confidence interval 0.1, 1.2); P = 0.018] on PCS and this was reduced when adjusted for change in HbA1c [0.4 (−0.2, 1.0), P = .167] and body weight [0.3 (−0.3, 0.9), P = .314]. The unadjusted treatment effect on MCS [0.7 (−0.0, 1.5), P = .054] was only reduced when adjusted for change in HbA1c [0.3 (−0.4, 1.1), P = .397]. When adjusting for all other parameters separately, the estimated effect of semaglutide on PCS and MCS qualitatively did not change. Conclusions: Semaglutide improved HRQoL versus placebo; greater improvements with semaglutide versus placebo were possibly mediated, in part, by change in HbA1c and body weight. Clinicaltrials.gov : NCT01720446 (SUSTAIN 6).

In 2014–2015, the largest international survey of insulin injection technique in patients with diabetes taking insulin was conducted in 42 countries, totaling 13,289 participants. In Brazil, patients from five public health centers were included. This study aims to evaluate insulin injection technique in Brazilian patients and compare results with Latin America (LatAm) and World data. The insulin Injection Technique Questionnaire (ITQ) survey consisted of an initial patient section (questions applied by an experienced nurse), followed by observation of injection technique and examination of the injection sites by the health care professional. In Brazil, 255 patients were evaluated: 25% had type 1 diabetes mellitus (T1DM) and 75% had T2DM. In this study, 79% of patients injected less than 4 times a day, and 17.3% used insulin pens, compared to 28% in LatAm and 86% worldwide. Syringes were used by 78% of patients in Brazil, compared to 65% in LatAm and 10% globally. Differences in needle length were substantial—nearly 64% in Brazil inject with 8 mm length needle compared to 48% in LatAm and 27% worldwide. Additionally, 48% of patients in Brazil skip doses, 80% reuse pen needles and 57% reuse syringes with 27% having lipohypertrophy by exam. Brazilian patients use syringes more and pens less, inject with larger needles and have more lipohypertrophy when compared to Latin America and World data. Their re-use of needles and syringes is also high. This study showed that in Brazil, teaching of proper injection technique has to be more widespread, and more intensive during diabetes educational sessions, and the type of delivered supplies must be updated to smaller, shorter needles preferred by patients, in order to facilitate adherence to treatment. From the ITQ, we conclude that there are many aspects of insulin injection technique that may be improved in Brazil.

In type 1 diabetes mellitus (T1DM) management, enhancing health-related quality of life (HRQoL) is as important as good metabolic control and prevention of secondary complications. This study aims to evaluate possible regional differences in HRQoL, demographic features and clinical characteristics of patients with T1DM in Brazil, a country of continental proportions, as well as investigate which variables could influence the HRQoL of these individuals and contribute to these regional disparities. This was a retrospective, cross-sectional, multicenter study performed by the Brazilian Type 1 Diabetes Study Group (BrazDiab1SG), by analyzing EuroQol scores from 3005 participants with T1DM, in 28 public clinics, among all geographical regions of Brazil. Data on demography, economic status, chronic complications, glycemic control and lipid profile were also collected. We have found that the North-Northeast region presents a higher index in the assessment of the overall health status (EQ-VAS) compared to the Southeast (74.6 ± 30 and 70.4 ± 19, respectively; p < 0.05). In addition, North-Northeast presented a lower frequency of self-reported anxiety-depression compared to all regions of the country (North-Northeast: 1.53 ± 0.6; Southeast: 1.65 ± 0.7; South: 1.72 ± 0.7; Midwest: 1.67 ± 0.7; p < 0.05). These findings could not be entirely explained by the HbA1c levels or the other variables examined. Our study points to the existence of additional factors not yet evaluated that could be determinant in the HRQoL of people with T1DM and contribute to these regional disparities.

To evaluate the determinants of intensive insulin regimens (ITs) in patients with type 1 diabetes (T1D). This multicenter study was conducted between December 2008 and December 2010 in 28 public clinics in 20 Brazilian cities. Data were obtained from 3,591 patients (56.0% female, 57.1% Caucasian). Insulin regimens were classified as follows: group 1, conventional therapy (CT) (intermediate human insulin, one to two injections daily); group 2 (three or more insulin injections of intermediate plus regular human insulin); group 3 (three or more insulin injections of intermediate human insulin plus short-acting insulin analogues); group 4, basal-bolus (one or two insulin injections of long-acting plus short-acting insulin analogues or regular insulin); and group 5, basal-bolus with continuous subcutaneous insulin infusion (CSII). Groups 2 to 5 were considered IT groups. We obtained complete data from 2,961 patients. Combined intermediate plus regular human insulin was the most used therapeutic regimen. CSII was used by 37 (1.2%) patients and IT by 2,669 (90.2%) patients. More patients on IT performed self-monitoring of blood glucose and were treated at the tertiary care level compared to CT patients (p < 0.001). The majority of patients from all groups had HbA1c levels above the target. Overweight or obesity was not associated with insulin regimen. Logistic regression analysis showed that economic status, age, ethnicity, and level of care were associated with IT (p < 0.001). Given the prevalence of intensive treatment for T1D in Brazil, more effective therapeutic strategies are needed for long term-health benefits.