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.

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.

Updated guidance on the management of cancer treatment-induced bone loss (CTIBL) in pre- and postmenopausal women with early-stage breast cancer.

INTRODUCTION: Adjuvant endocrine therapy induces bone loss and increases fracture risk in women with hormone-receptor positive, early-stage breast cancer (EBC). We aimed to update a previous position statement on the management of aromatase inhibitors (AIs) induced bone loss and now included premenopausal women. METHODS: We conducted a systematic literature search of the medical databases from January 2017 to May 2020 and assessed 144 new studies. RESULTS: Extended use of AIs beyond 5 years leads to persistent bone loss in breast cancer extended adjuvant trials and meta-analyses. In addition to bone mineral density (BMD), vertebral fracture assessment (VFA) and trabecular bone score (TBS) were shown to independently predict fracture risk in real life prospective studies. FRAX® tool does not seem to be reliable for assessing fracture risk in CTIBL. In premenopausal women, there is strong evidence that intravenous zoledronate prevents bone loss but weak conflicting evidence on reducing disease recurrence from independent randomised controlled trials (RCTs). In postmenopausal women, the strongest evidence for fracture prevention is for denosumab based on a well-powered RCT while there is strong evidence for bisphosphonates (BPs) to prevent and reduce CTIBL but no convincing data on fractures. Adjuvant denosumab has failed to show anticancer benefits in a large, well-designed RCT. DISCUSSION AND CONCLUSIONS: Extended use of AIs and persistent bone loss from recent data reinforce the need to evaluate fracture risk in EBC women initiated on AIs. Fracture risk should be assessed with clinical risk factors and BMD along with VFA, but FRAX is not adapted to CTIBL. Anti-resorptive therapy should be considered in those with a BMD T-score < -2.0 SD or with ≥ 2 clinical risk factors including a BMD T-score < -1.0 SD. In premenopausal women, intravenous zoledronate is the only drug reported to prevent bone loss and may have additional anticancer benefits. In postmenopausal women, either denosumab or BPs can be prescribed for fracture prevention with pertinent attention to the rebound phenomenon after stopping denosumab. Adjuvant BPs, in contrast to denosumab, have shown high level evidence for reducing breast cancer recurrence in high-risk post-MP women which should be taken into account when choosing between these two.

Treatment with somatostatin analogues and PRRT in metastatic middle ear adenoma with neuroendocrine features.

SUMMARY: Middle ear adenomas with neuroendocrine features (ANEF) are rare, with an estimated 150 reported cases. They usually pursue an indolent clinical course. Four reported cases of middle ear ANEF with distant metastases were treated with surgery, external beam radiation therapy (EBRT) and chemotherapy. To date, no successful systemic treatment for malignant behaviour of this rare tumour has been reported. Long-acting somatostatin analogues (SSAs) and peptide receptor radionuclide therapy (PRRT) have been used in well-differentiated metastatic neuroendocrine tumours (NETs), but their use has never been described in cases of metastatic middle ear ANEF. We report two patients with grade 1 middle ear ANEF treated with surgery and EBRT. They had stable disease for several years, until clinical symptoms appeared and extensive metastases were detected on 68Ga-DOTA0-Tyr3-octreotate (DOTATATE) PET/CT. Treatment with long-acting SSA was started, with stable disease for 1 year. Afterwards, despite undergoing local treatments, both patients presented progressive disease. Due to high-uptake metastases at 68Ga-DOTATATE PET/CT, both cases underwent four cycles of PRRT with 177Lu-DOTATATE, which secured disease control and improvement of quality of life in both. Similar to other well-differentiated NETs, SSA and PRRT could constitute efficacious therapeutic options in metastatic middle ear ANEF. Its neuroendocrine differentiation, potential to metastasize and somatostatin receptor type 2 expression prompt consideration and management of this disease as a neuroendocrine neoplasm. LEARNING POINTS: Our cases oppose the 2017 WHO classification of middle ear adenoma with neuroendocrine features as a benign disease. This entity warrants long-term follow-up, as local recurrence or persistence of disease is reported in up to 18% of surgically treated patients. PET/CT scan with 68Ga-labelled somatostatin analogues (SSA) can be used for staging of metastatic middle ear adenoma with neuroendocrine features. Unlabelled SSA and peptide receptor radionuclide therapy (PRRT) with radiolabelled SSA can be the first systemic therapeutic options for patients with advanced middle ear adenoma with neuroendocrine features.

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.

Improved survival in patients with thyroid function test abnormalities secondary to immune-checkpoint inhibitors.

Immune-checkpoint inhibitors (ICI) are monoclonal antibodies which target molecules to enhance antitumor response. Several adverse events have been described and the major ICI-related endocrinopathies are thyroid dysfunction and hypophysitis. Its occurrence has been associated with improved outcomes, but it is still to be proven. We performed a retrospective study of patients treated with ICI between 2014 and 2019 at an oncologic center to characterize thyroid function test abnormalities (TFTA) and to evaluate clinical outcomes. We excluded patients without regular monitoring of thyroid function, with previous thyroid or pituitary disease, previous head/neck radiotherapy and who performed only one ICI cycle. We included 161 of 205 patients treated with pembrolizumab, nivolumab or ipilimumab for several neoplasms, with a median duration of 18.9 weeks (9.1-42.6) of ICI treatment and 49.4 weeks (26.5-75.8) of follow-up. New-onset TFTA was diagnosed in 18% of patients (n = 29), in median at 10.6 weeks (6.1-31.1) of ICI therapy. On the whole, 8.7% had primary hypothyroidism, 4.3% central hypothyroidism, 2.5% biphasic thyroiditis and 2.5% thyrotoxicosis. Patients who experienced primary or central thyroid dysfunction had a significantly improved overall response rate (58.6% vs 34.2%, p = 0.015) and overall survival (3.27 vs 1.76 years, p = 0.030), compared to the control group. The risk of mortality was two times higher for control group (adjusted HR = 2.43, 95% CI 1.13-5.23, p = 0.023). This study recognizes that primary and central thyroid dysfunction can be a predictive clinical biomarker of a better response to ICI across several neoplasms.

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.