COMBINSI (COMBat to INSufficient Insulin therapy) - A Portuguese project in type 2 diabetes.

BACKGROUND: Inadequate glycemic control in type 2 diabetes (T2D) increases the risk of diabetes-related complications. Insulin initiation is often delayed for several years. This study aims to estimate the adequacy of insulin therapy prescription to people living with T2D in a primary care setting. MATERIAL AND METHODS: This was a cross-sectional study based on adults with T2D in a Portuguese local health unit between January 2019 and January 2020. Subjects under insulin therapy were compared with non-insulin-treated subjects with Hemoglobin A1c (HbA1c) ≥9% regarding clinical and demographic characteristics. The proportion of insulin-treated subjects in both of these groups was defined as insulin therapy index. RESULTS: Our study included 13,869 adults living with T2D, among whom 11.5% were treated with insulin therapy and 4.1% had HbA1c ≥ 9% and were not under insulin therapy. Insulin therapy index was 73.9%. When comparing with non-insulin-treated subjects with HbA1c ≥ 9%, insulin-treated subjects were significantly older (75.8 vs 66.2 years p < 0.001), had lower HbA1c (8.3 vs 10.3% p < 0.001), lower estimated glomerular filtration rate (66.4 vs 74.0 ml/min/1.73 m2p < 0.001), lower LDL-cholesterol (87.1 vs 105.8 mg/dl), and higher rates of atherosclerotic cardiovascular disease (32.7 vs 16.7% p < 0.001). CONCLUSION: Insulin therapy is underprescribed in T2D, with over 1-in-4 people living with T2D not being prescribed insulin despite deficient glycemic control. These findings highlight the need for insulin therapy when glycemic control is inadequate under other interventions.

Underprescription of SGLT2i and GLP-1 RA: CAREPRO-T2D (Cardiorenal Protection in Type 2 Diabetes) Cross-Sectional Study.

BACKGROUND: New glucose-lowering drugs have shown benefits regarding cardiovascular events, heart failure, and kidney-related outcomes in type 2 diabetes (T2D). This study aimed to estimate the adequacy of SGLT2 inhibitors (SGLT2i) and GLP-1 receptor agonists (GLP-1 RA) prescription to people living with T2D with established atherosclerotic cardiovascular disease (ASCVD) or heart failure (HF). MATERIAL AND METHODS: This was a cross-sectional study based on adults with T2D in a Portuguese local health unit between January 2019 and January 2020. Subjects with ASCVD were compared with subjects without ASCVD, and subjects with HF were compared with subjects without HF regarding clinical and demographic characteristics. RESULTS: Our study included 13,869 adults with T2D, among whom 5.9% were coded for HF and 20.4% were defined as having ASCVD. SGLT2i were prescribed to 36.0% of subjects with HF. SGLT2i and/or GLP-1 RA were prescribed to 36.1% of patients with ASCVD. When comparing with subjects without ASCVD, subjects with ASCVD were significantly older (70.8 vs. 66.5 years, p<0.001), had lower estimated glomerular filtration rate (68.2 vs. 74.6 mL/min/1.73 m2, p<0.001), and higher rates of prescription of SGLT2i and/or GLP-1 RA (36.1 vs. 31.4%, p<0.001). When comparing with subjects without HF, subjects with HF were significantly older (74.6 vs. 66.9 years, p<0.001), had lower estimated glomerular filtration rate (59.6 vs. 74.1, mL/min/1.73 m2, p<0.001), and higher rates of prescription of SGLT2i (36.0 vs. 30.3%, p<0.001). CONCLUSION: SGLT2i and GLP-1 RA are underprescribed in T2D, with almost two-thirds of patients not being prescribed these agents despite being strongly advised by current guidelines. These findings highlight the need for specific actions to improve T2D management at primary care level.

Portuguese versus Fenton Curve: Which one better explains maternal and neonatal outcomes in Portuguese women with gestational diabetes?

BACKGROUND AND AIMS: Growth charts are commonly used to identify foetal growth alterations, playing an important role as extreme growth centiles correlate with worse foetal and neonatal outcomes. This study aim was to compare birthweight classification (small for gestational age (SGA), adequate for gestational age and large for gestational age (LGA)) from women with gestational diabetes mellitus (GDM) by applying the population-based growth chart (Fenton Curve) and the standard chart customised for our country (Portuguese Curve). Moreover, we compared obstetric and neonatal outcomes according to birthweight classification between these curves. METHODS: A multicentre observational study with prospectively collected data from 19,470 pregnant women diagnosed with GDM (30 Portuguese institutions) was conducted. RESULTS: The proportion of SGA neonates was higher with Fenton Chart than with Portuguese standard chart (12.7% vs 10.9%) and the prevalence of LGA was higher using the Portuguese Chart (4.1%vs 10.9%). Statistically significant differences in the classifications given by the two curves and for maternal/neonatal outcomes were found. The Area Under the Curve and Akaike Information Criterion pointed out to a better correlation between weight classification of the Portuguese Curves and the majority of expected maternal and neonatal outcomes: gestational hypertension, preeclampsia, hydramnios, vaginal dystocic labour, hyperbilirubinemia, respiratory distress syndrome, trauma from delivery, admission in neonatal intensive care unit, prematurity and neonatal morbidity. CONCLUSION: Our study highlights the importance of having a standard birthweight curve specifically designed for each population. Neonates' weight classification carries prognostic implication and misclassification could lead to potential mistreatment or overtreatment.

HbA1c as a predictor of postpartum diabetes mellitus after gestational diabetes mellitus.

AIMS: Women diagnosed with Gestational Diabetes Mellitus (GDM) should be evaluated postpartum with an Oral Glucose Tolerance Test (OGTT). Nevertheless, women frequently fail to it. We intend to evaluate the performance of third trimester HbA1c in the prediction of postpartum diabetes mellitus (PDM). METHODS: We conducted a retrospective study of 10245 women with GDM based on the National Registry of GDM. A receiver-operating characteristic (ROC) curve was plotted to evaluate the diagnostic performance of third trimester HbA1c in PDM prediction. RESULTS: The mean third trimester HbA1c level was 5.81% (SD 0.69%) in women who developed PDM, 5.40% (SD 0.52%) in women with pre-diabetes and 5.21% (SD 0.43%) in women with normal glucose tolerance in postpartum OGTT, with statistically significant differences (p < 0.0001). As to the ROC curve ability to predict PDM was fair, with an optimal cut-off point of HbA1c of 5.4%. Women presenting HbA1c values ≥ 5.4% were 6.1 times more likely to develop PDM. CONCLUSIONS: A third trimester HbA1c level ≥5.4% is associated with a significant higher risk of PDM (p < 0.0001). It could be used as a reliable tool for screening women with GDM and detect who will benefit the most from a close follow-up after pregnancy.

Monogenic diabetes caused by GCK gene mutation is misdiagnosed as gestational diabetes - A multicenter study in Portugal.

AIMS: Monogenic diabetes is an underdiagnosed type of diabetes mellitus, which can be harmful in pregnancy. We aim to estimate the prevalence of diabetes caused by the mutation of the glucokinase gene (GCK-MODY) in pregnant women diagnosed with gestational diabetes mellitus (GDM) and to characterize pregnant women with this suspicion. METHODS: A multicenter observational study with data prospectively collected from pregnancies with GDM was conducted. Two groups of pregnant women were considered: those with GCK-MODY criteria and those without those criteria. RESULTS: Of 18421 women with GDM, 3.6% (n = 730) had the GCK-MODY clinical criteria. A prevalence of 1.5% of GCK-MODY is estimated in women with GDM in Portugal, which is higher than in Northern European countries. Suspected GCK-MODY women had statistically higher odds of having neonates below the 25th percentile (OR = 1.23, 95%CI = 1.04-1.46, p = 0.016) and having prediabetes and diabetes in postpartum reclassification (OR = 2.11, 95%CI = 1.55-2.82, p < 0.001 and OR = 5.96, 95%CI = 3.38-10.06, p < 0.001, respectively). CONCLUSIONS: Higher odds of neonates below the 25th percentile was probably due to excessive insulin treatment in cases where both the mother and the fetus have the mutation. It is essential to consider the diagnosis of GCK-MODY in all women with GDM criteria for better management of diabetes in pregnancy.

Benefit of insufficient gestational weight gain in obese women with gestational diabetes mellitus: A multicenter study in Portugal.

BACKGROUND: Both obesity and gestational diabetes mellitus (GDM) are independent risk factors for adverse maternal and fetal outcomes. The Institute of Medicine (IOM) recommends different targets for an adequate gestational weight gain (GWG), depending on the prepregnancy body mass index, but they have been questioned. We aim to compare obese pregnant women with GDM according to GWG stratification (insufficient, adequate and excessive) with regard to maternal and neonatal outcomes and to clarify whether insufficient GWG can be associated with better outcomes. METHODS: A multicenter observational study with prospectively collected data of obese singleton pregnant women with GDM was conducted. GWG was expressed according to the 2009 IOM's recommendations. RESULTS: Of 4563 obese women with GDM, 34.5%, 30.4% and 35.2% registered insufficient, adequate and excessive GWG, respectively. Multiple logistic regression analysis revealed that women with insufficient GWG had lower odds of gestational hypertension, preeclampsia, caesarean section, large for gestational age (LGA) neonates and prediabetes in postpartum. Despite the higher incidence of small for gestational age (SGA) neonates, they were not associated with adverse outcomes. Women with excessive GWG had higher odds of caesarean section, macrosomic and LGA neonates. CONCLUSIONS: Insufficient GWG in obese women with GDM was beneficial due to better maternal and neonatal outcomes. In clinical practice, we should be strict with regard to weight gain in obese pregnant women with GDM and encourage a reduced GWG, provided an adequate fetal growth is guaranteed.

Portuguese-Brazilian evidence-based guideline on the management of hyperglycemia in type 2 diabetes mellitus.

BACKGROUND: In current management of type 2 diabetes (T2DM), cardiovascular and renal prevention have become important targets to be achieved. In this context, a joint panel of four endocrinology societies from Brazil and Portugal was established to develop an evidence-based guideline for treatment of hyperglycemia in T2DM. METHODS: MEDLINE (via PubMed) was searched for randomized clinical trials, meta-analyses, and observational studies related to diabetes treatment. When there was insufficient high-quality evidence, expert opinion was sought. Updated positions on treatment of T2DM patients with heart failure (HF), atherosclerotic CV disease (ASCVD), chronic kidney disease (CKD), and patients with no vascular complications were developed. The degree of recommendation and the level of evidence were determined using predefined criteria. RESULTS AND CONCLUSIONS: In non-pregnant adults, the recommended HbA1c target is below 7%. Higher levels are recommended in frail older adults and patients at higher risk of hypoglycemia. Lifestyle modification is recommended at all phases of treatment. Metformin is the first choice when HbA1c is 6.5-7.5%. When HbA1c is 7.5-9.0%, dual therapy with metformin plus an SGLT2i and/or GLP-1RA (first-line antidiabetic agents, AD1) is recommended due to cardiovascular and renal benefits. If an AD1 is unaffordable, other antidiabetic drugs (AD) may be used. Triple or quadruple therapy should be considered when HbA1c remains above target. In patients with clinical or subclinical atherosclerosis, the combination of one AD1 plus metformin is the recommended first-line therapy to reduce cardiovascular events and improve blood glucose control. In stable heart failure with low ejection fraction (< 40%) and glomerular filtration rate (eGFR) > 30 mL/min/1.73 m2, metformin plus an SGLT-2i is recommended to reduce cardiovascular mortality and heart failure hospitalizations and improve blood glucose control. In patients with diabetes-associated chronic kidney disease (CKD) (eGFR 30-60 mL/min/1.73 m2 or eGFR 30-90 mL/min/1.73 m2 with albuminuria > 30 mg/g), the combination of metformin and an SGLT2i is recommended to attenuate loss of renal function, reduce albuminuria and improve blood glucose control. In patients with severe renal failure, insulin-based therapy is recommended to improve blood glucose control. Alternatively, GLP-1RA, DPP4i, gliclazide MR and pioglitazone may be considered to reduce albuminuria. In conclusion, the current evidence supports individualizing anti-hyperglycemic treatment for T2DM.

Controversial Screening for Thyroid Dysfunction in Preconception and Pregnancy: An Evidence-Based Review.

Objective: To evaluate the recommendations on the most adequate screening method (universal or selective) for thyroid dysfunction. Although thyroid dysfunction is a common disorder in fertile women and untreated cases may have negative maternal, fetal and neonatal outcomes, its screening in preconception and early pregnancy is controversial. Materials and methods: An evidence-based review was conducted to identify publications since 2017 of American Thyroid Association (ATA) guidelines, according to the following Population, Intervention, Comparison, Outcomes and Study (PICOS): women in preconception or pregnancy without thyroid disease who underwent universal or selective screening for thyroid dysfunction. Study selection obeyed the PRISMA criteria. Results: We included 15 of 325 publications. The 2017 ATA guidelines recommend selective screening in both preconception and pregnancy. The only two reviews on preconception recommended universal screening. For pregnancy, nine articles suggested universal screening, while a prospective study advocated selective screening. The main benefits advocated for universal screening were easy and low-cost tests; absence of missed diagnosis; safe and inexpensive treatment and its potential in preventing negative outcomes. Iodine deficiency is a decisive indication, but it was not evaluated in all clinical studies. Screening harms and knowledge gaps were the main arguments against universal screening. There are very few cost-effectiveness studies. Conclusion: We recommend universal screening for thyroid dysfunction in early pregnancy, which is a distinct point of view from 2017 ATA guidelines (weak recommendation, low-quality evidence). It is not possible to make a formal recommendation for preconception (insufficient evidence). We strongly suggest an individualized analysis by each country.

Hypoparathyroidism as the single major component for decades of autoimmune polyglandular syndrome type 1.

SUMMARY: Autoimmune polyglandular syndrome type 1 (APS-1) is a very rare autoimmune entity, accounting for about 400 cases reported worldwide. It is characterized by the presence of at least two of three cardinal components: chronic mucocutaneous candidiasis (CMC), hypoparathyroidism and Addison's disease. It typically manifests in childhood with CMC and years later with hypoparathyroidism. A 50-year-old man was referred to the Endocrinology outpatient clinic due to irregular follow-up of primary hypoparathyroidism diagnosed at age 7. Previous analysis reported frequent fluctuations of calcium and phosphate levels and persistent hypercalciuria. He presented several comorbidities, including bilateral cataracts, other ocular disorders, transient alopecia and chronic gastritis. Due to weight loss, fatigue, gastrointestinal complaints and the findings at objective examination, Addison's disease and CMC were investigated and confirmed. Antifungal therapy and hormonal replacement were started with evident clinical improvement. Regarding hypoparathyroidism, calcium-phosphate product decreased and other extraskeletal calcifications were diagnosed, such as nephrolithiasis and in basal ganglia. Further evaluation by genetic analysis revealed homozygosity for a frameshift mutation considered to be a pathogenic variant. It was reported only in two Asian siblings in compound heterozygosity. This case highlights the broad phenotypic spectrum of APS-1 and the significative intra-familial phenotype variability. A complete clinical history taking and high index of suspicion allowed the diagnosis of this rare entity. This case clarifies the need for regular long-term follow-up. In the specific case of hypoparathyroidism and Addison's disease in combination, the management of APS-1 can be complex. LEARNING POINTS: Autoimmune polyglandular syndrome type 1 (APS-1) is a deeply heterogeneous genetic entity with a broad spectrum of clinical manifestations and a significant intra-family phenotypic variability. Early diagnosis of APS-1 is challenging but clinically relevant, as endocrine and non-endocrine manifestations may occur during its natural history. APS-1 should be considered in cases of acquired hypoparathyroidism, and even more so with manifestations with early onset, family history and consanguinity. APS-1 diagnosis needs a high index of suspicion. Key information such as all the comorbidities and family aspects would never be valued in the absence of a complete clinical history taking. Especially in hypoparathyroidism and Addison's disease in combination, the management of APS-1 can be complex and is not a matter of simply approaching individually each condition. Regular long-term monitoring of APS-1 is essential. Intercalary contact by phone calls benefits the control of the disease and the management of complications.

El carcinoma diferenciado incidental de tiroides es menos prevalente en la enfermedad de Graves que en el bocio multinodular / Incidental differentiated thyroid carcinoma is less prevalent in Graves’ disease than in multinodular goiter

Objetivos Entre los factores moduladores de prevalencia de carcinoma diferenciado de tiroides (CDT) destacan la concentración plasmática de TSH, la nodularidad tiroidea y la asociación con la autoinmunidad. La TSH estimula la proliferación de células foliculares normales y neoplásicas. Los anticuerpos contra el receptor de TSH (TSI), por su acción TSH-like, deberían estimular el crecimiento del CDT. El objetivo fue comparar la prevalencia de CDT incidental en pacientes tiroidectomizados por enfermedad benigna. Pacientes y métodos Se estudió la anatomía patológica de 372 pacientes con diagnósticos prequirúrgicos de bocio multinodular normofuncionante (BMN) o hipertiroidismo. La gammagrafía, y/o presencia de TSI diferenció entre bocio multinodular hiperfuncionante (BMH) y enfermedad de Graves (EG). Se comparó la prevalencia de CDT en cada categoría (χ). Resultados Se encontraron 221 sujetos con BMN, 125 con EG y 26 con BMH. Se hallaron 58 CDT con la siguiente distribución: BMN, 49 (22,2%); EG, 8 (6,4%) y BMH, 1 (3,8%). La diferencia de prevalencia de CDT entre los grupos fue estadísticamente significativa (p<0,001). Ajustando por edad, el BMN tiene mayor prevalencia de CDT respecto a EG, con OR de 4,17 (p<0,001). El tamaño (mm) tumoral (media±DE) fue: 6,92±11,26; 1,97±1,85 y 9,0 en BMN, EG y BMH respectivamente (p=0,017). Conclusiones La prevalencia de CDT incidental es menor en EG que en BMN, siendo el resultado independiente de la edad. Este hallazgo puede indicar una predisposición hacia el desarrollo de CDT en pacientes con enfermedad nodular tiroidea y/o que la reacción autoinmunitaria puede resultar un factor protector contra el desarrollo de enfermedad neoplásica (AU)

Objective Risk factors for differentiated thyroid carcinoma (DTC) are poorly understood, but serum TSH levels, thyroid nodularity, and presence of autoimmunity are well-recognized factors that modulate DTC prevalence. TSH stimulates proliferation of both normal and neoplastic follicular cells. Consequently, thyroid-stimulating immunoglobulins (TSI), because of its TSH-like action, should induce DTC progression in patients with Graves’ disease (GD). The study objective was to compare the prevalence of incidental DTC in patients undergoing thyroidectomy for benign thyroid disease. Methods The pathology reports of 372 patients with preoperative diagnosis of euthyroid multinodular goiter (EMG) or hyperthyroidism were reviewed. Scintigraphy results and serum TSI levels were used to diagnosed either GD or hyperactive MG (HMG) to hyperthyroid subjects. Prevalence of DTC in each category was calculated using a Chi-square test. Results EMG, GD, and HMG were diagnosed in 221, 125, and 26 patients. There were 58 DTCs, distributed as follows [n (%)]: EMG, 49 (22.2%); GD, 8 (6.4%), and HMG, 1 (3.8%). Difference in prevalence of incidental DTC between the groups was statistically significant (p<0.001). After adjustment for age, patients with EMG had a greater DTC prevalence than GD patients, with an OR of 4.17 (p<0.001). Tumor size (mm, mean±SD) was 6.92±11.26, 1.97±1.85, and 9.0 for EMG, GD and HMG respectively (p=0.017). Conclusions Incidental DTC was less prevalent in GD as compared to EMG irrespective of age. This finding may suggest a predisposition to develop DTC in patients with thyroid nodular disease and/or a potential effect of autoimmunity to protect against development of neoplastic disease (AU)

[Incidental differentiated thyroid carcinoma is less prevalent in Graves' disease than in multinodular goiter]. / El carcinoma diferenciado incidental de tiroides es menos prevalente en la enfermedad de Graves que en el bocio multinodular.

OBJECTIVE: Risk factors for differentiated thyroid carcinoma (DTC) are poorly understood, but serum TSH levels, thyroid nodularity, and presence of autoimmunity are well-recognized factors that modulate DTC prevalence. TSH stimulates proliferation of both normal and neoplastic follicular cells. Consequently, thyroid-stimulating immunoglobulins (TSI), because of its TSH-like action, should induce DTC progression in patients with Graves' disease (GD). The study objective was to compare the prevalence of incidental DTC in patients undergoing thyroidectomy for benign thyroid disease. METHODS: The pathology reports of 372 patients with preoperative diagnosis of euthyroid multinodular goiter (EMG) or hyperthyroidism were reviewed. Scintigraphy results and serum TSI levels were used to diagnosed either GD or hyperactive MG (HMG) to hyperthyroid subjects. Prevalence of DTC in each category was calculated using a Chi-square test. RESULTS: EMG, GD, and HMG were diagnosed in 221, 125, and 26 patients. There were 58 DTCs, distributed as follows [n (%)]: EMG, 49 (22.2%); GD, 8 (6.4%), and HMG, 1 (3.8%). Difference in prevalence of incidental DTC between the groups was statistically significant (p<0.001). After adjustment for age, patients with EMG had a greater DTC prevalence than GD patients, with an OR of 4.17 (p<0.001). Tumor size (mm, mean ± SD) was 6.92 ± 11.26, 1.97 ± 1.85, and 9.0 for EMG, GD and HMG respectively (p=0.017). CONCLUSIONS: Incidental DTC was less prevalent in GD as compared to EMG irrespective of age. This finding may suggest a predisposition to develop DTC in patients with thyroid nodular disease and/or a potential effect of autoimmunity to protect against development of neoplastic disease.