Is the Current Cut Point for Glycated Haemoglobin (HbA1c) Correct for Diagnosing Diabetes Mellitus in Premenopausal Women? Evidence to Inform Discussion.

INTRODUCTION: Women are on average diagnosed with diabetes mellitus at later age than men but have higher mortality. As the diagnosis of diabetes mellitus is primarily based on HbA1c, the use of a non-specific reference range and cut point for diabetes mellitus that does not account for gender differences in diabetes could potentially lead to underdiagnosis of diabetes mellitus in women and missed opportunities for intervention. We investigated whether a contributing factor to the later diagnosis in women may be a difference in distribution of HbA1c in premenopausal women versus men of the same age by comparing HbA1c values in men and women across multiple sites in the UK. METHODS: We analysed the HbA1c levels of 146,907 individuals who underwent single testing only and had HbA1c ≤ 50 mmol/mol between 2012 and 2019 in one laboratory (cohort 1). This was replicated in six laboratories with 938,678 individuals tested between 2019 and 2021 (cohort 2). RESULTS: In cohort 1, women < 50 years old had an HbA1c distribution markedly lower than that in men by a mean of 1.6 mmol/mol (p < 0.0001), while the difference in the distribution of HbA1c for individuals aged ≥ 50 years was less pronounced (mean difference 0.9 mmol/mol, p < 0.0001). For individuals under the age of 50, HbA1c in women lagged by up to 10 years compared to men. Similar findings were found in cohort 2. We estimated an additional 17% (n = 34,953) of undiagnosed women aged < 50 years in England and Wales could be reclassified to have diabetes mellitus, which may contribute to up to 64% of the difference in mortality rates between men/women with diabetes mellitus aged 16-50 years. CONCLUSION: The HbA1c cut point for diagnosis of diabetes mellitus may need to be re-evaluated in women under the age of 50 years. Early identification of diabetes mellitus in women has the potential to improve women's health outcomes in the longer term.

The Utility of Salivary Cortisone in the Overnight Dexamethasone Suppression Test in Adrenal Incidentalomas.

CONTEXT: Guidelines recommend the assessment of cortisol secretion in patients with adrenal incidentalomas (AI) using the overnight dexamethasone suppression test (ONDST). This requires attendance at a health care facility and venepuncture. Alternatively, the ONDST can be done by measuring salivary cortisol and cortisone, which can be collected at home. OBJECTIVE: We aimed to assess the utility of these measurements in patients with AI. METHODS: A retrospective analysis of data from 173 patients with AI who underwent an ONDST and salivary cortisol/cortisone diurnal studies. Serum and salivary cortisol and salivary cortisone were collected at 09:00, late night, and at 09:00 the following morning after dexamethasone. Dexamethasone levels were measured in the postdexamethasone samples. Serum and salivary samples were analyzed with liquid chromatography-tandem mass spectrometry. RESULTS: We identified a strong correlation between salivary cortisone and serum cortisol after 1 mg of dexamethasone (r = 0.95). Stepwise multivariate regression showed that postdexamethasone salivary cortisone, baseline serum cortisol, salivary cortisone suppression (predexamethasone/postdexamethasone ratio), and sex were the only significant or near-significant independent variables. Performance of predictive indices using these 4 parameters (sensitivity = 88.5%, specificity = 91.2%; kappa 0.80) and postdexamethasone salivary cortisone alone (sensitivity = 85.3%, specificity = 91.7%; kappa 0.77) were comparable when used to predict an ONDST serum cortisol of ≤50 nmol/L. No correlation was observed with any of the other measured parameters. CONCLUSION: In AI patients, after dexamethasone, salivary cortisone correlates very strongly with serum cortisol in the ONDST and could therefore be used as an alternative sampling method which does not require venepuncture or attendance at hospital.

Variability in Test Interval Is Linked to Glycated Haemoglobin (HbA1c) Trajectory over Time.

Aims: We previously showed that the glycated haemoglobin (HbA1c) testing frequency links to diabetes control. Here, we examine the effect of variability in test interval, adjusted for the frequency, on change in HbA1c (ΔHbA1c). Materials & Methods. HbA1c results were collected on 83,872 people with HbA1c results at baseline and 5 years (±3 months) later and ≥6 tests during this period. We calculated the standard deviation (SD) of test interval for each individual and examined the link between deciles of SD of the test interval and ΔHbA1c level, stratified by baseline HbA1c. Results: In general, less variability in testing frequency (more consistent monitoring) was associated with better diabetes control. This was most evident with moderately raised baseline HbA1c levels (7.0-9.0% (54-75 mmol/mol)). For example, in those with a starting HbA1c of 7.0-7.5% (54-58 mmol/mol), the lowest SD decile was associated with little change in HbA1c over 5 years, while for those with the highest decile, HbA1c rose by 0.4-0.6% (4-6 mmol/mol; p < 0.0001). Multivariate analysis showed that the association was independent of the age/sex/hospital site. Subanalysis suggested that the effect was most pronounced in those aged <65 years with baseline HbA1c of 7.0-7.5% (54-58 mmol/mol). We observed a 6.7-fold variation in the proportion of people in the top-three SD deciles across general practices. Conclusions: These findings indicate that the consistency of testing interval, not the just number of tests/year, is important in maintaining diabetes control, especially in those with moderately raised HbA1c levels. Systems to improve regularity of HbA1c testing are therefore needed, especially given the impact of COVID-19 on diabetes monitoring.

Adrenal Incidentaloma: Prevalence and Referral Patterns From Routine Practice in a Large UK University Teaching Hospital.

CONTEXT: Adrenal incidentalomas (AIs) are increasingly being identified during unrelated imaging. Unlike AI clinical management, data on referral patterns in routine practice are lacking. OBJECTIVE: This work aimed to identify factors associated with AI referral. METHODS: We linked data from imaging reports and outpatient bookings from a large UK teaching hospital. We examined (i) AI prevalence and (ii) pattern of referral to endocrinology, stratified by age, imaging modality, scan anatomical site, requesting clinical specialty, and temporal trends. Using key radiology phrases to identify scans reporting potential AI, we identified 4097 individuals from 479 945 scan reports (2015-2019). Main outcome measures included prevalence of AI and referral rates. RESULTS: Overall, AI lesions were identified in 1.2% of scans. They were more prevalent in abdomen computed tomography and magnetic resonance imaging scans (3.0% and 0.6%, respectively). Scans performed increased 7.7% year-on-year from 2015 to 2019, with a more pronounced increase in the number with AI lesions (14.7% per year).Only 394 of 4097 patients (9.6%) had a documented endocrinology referral code within 90 days, with medical (11.8%) more likely to refer than surgical (7.2%) specialties (P < .001). Despite prevalence increasing with age, older patients were less likely to be referred (P < .001). CONCLUSION: While overall AI prevalence appeared low, scan numbers are large and rising; the number with identified AI are increasing still further. The poor AI referral rates, even in centers such as ours where dedicated AI multidisciplinary team meetings and digital management systems are used, highlights the need for new streamlined, clinically effective systems and processes to appropriately manage the AI workload.

Efficacy and Cardiovascular Safety of SGLT2 Inhibitors.

Patients with diabetes continued to exhibit a high risk for cardiovascular and renal events despite achieving satisfactory glycemic, blood pressure and lipid targets. Studies evaluating new diabetes medications focused on cardiovascular events, largely overlooking heart failure (HF). The latter has recently been recognised as a major cause of morbidity and mortality in patients with diabetes mellitus. There had been an unmet need for drugs with cardiovascular (including HF) and renal protection, with an expectation that an ideal diabetic drug should improve these endpoints. Moreover, an ideal drug should have weight reducing benefits. Recently published outcome trials have shown that sodium-glucose cotransporter 2 (SGLT2) inhibitors and glucagon-like peptide 1 receptor agonists (GLP-1RAs) can reduce cardiovascular and renal events, together with statistically significant weight reduction. As a result, many recently published international guidelines have recommended SGLT2 inhibitors and GLP-1RAs in patients with diabetes and pre-existing cardiovascular disease (CVD). In this review, we will critically analyse the efficacy and cardiovascular (CV) safety of SGLT2 inhibitors, based on the available literature to help position them in the clinical decision process.

Adrenal lesions found incidentally: how to improve clinical and cost-effectiveness.

INTRODUCTION: Adrenal incidentalomas are lesions that are incidentally identified while scanning for other conditions. While most are benign and hormonally non-functional, around 20% are malignant and/or hormonally active, requiring prompt intervention. Malignant lesions can be aggressive and life-threatening, while hormonally active tumours cause various endocrine disorders, with significant morbidity and mortality. Despite this, management of patients with adrenal incidentalomas is variable, with no robust evidence base. This project aimed to establish more effective and timely management of these patients. METHODS: We developed a web-based, electronic Adrenal Incidentaloma Management System (eAIMS), which incorporated the evidence-based and National Health Service-aligned 2016 European guidelines. The system captures key clinical, biochemical and radiological information necessary for adrenal incidentaloma patient management and generates a pre-populated outcome letter, saving clinical and administrative time while ensuring timely management plans with enhanced safety. Furthermore, we developed a prioritisation strategy, with members of the multidisciplinary team, which prioritised high-risk individuals for detailed discussion and management. Patient focus groups informed process-mapping and multidisciplinary team process re-design and patient information leaflet development. The project was partnered by University Hospital of South Manchester to maximise generalisability. RESULTS: Implementation of eAIMS, along with improvements in the prioritisation strategy, resulted in a 49% reduction in staff hands-on time, as well as a 78% reduction in the time from adrenal incidentaloma identification to multidisciplinary team decision. A health economic analysis identified a 28% reduction in costs. CONCLUSIONS: The system's in-built data validation and the automatic generation of the multidisciplinary team outcome letter improved patient safety through a reduction in transcription errors. We are currently developing the next stage of the programme to proactively identify all new adrenal incidentaloma cases.

The frequency of testing for glycated haemoglobin, HbA1c, is linked to the probability of achieving target levels in patients with suboptimally controlled diabetes mellitus.

Background We previously showed, in patients with diabetes, that >50% of monitoring tests for glycated haemoglobin (HbA1c) are outside recommended intervals and that this is linked to diabetes control. Here, we examined the effect of tests/year on achievement of commonly utilised HbA1c targets and on HbA1c changes over time. Methods Data on 20,690 adults with diabetes with a baseline HbA1c of >53 mmol/mol (7%) were extracted from Clinical Biochemistry Laboratory records at three UK hospitals. We examined the effect of HbA1c tests/year on (i) the probability of achieving targets of ≤53 mmol/mol (7%) and ≤48 mmol/mol (6.5%) in a year using multi-state modelling and (ii) the changes in mean HbA1c using a linear mixed-effects model. Results The probabilities of achieving ≤53 mmol/mol (7%) and ≤48 mmol/mol (6.5%) targets within 1 year were 0.20 (95% confidence interval: 0.19-0.21) and 0.10 (0.09-0.10), respectively. Compared with four tests/year, having one test or more than four tests/year were associated with lower likelihoods of achieving either target; two to three tests/year gave similar likelihoods to four tests/year. Mean HbA1c levels were higher in patients who had one test/year compared to those with four tests/year (mean difference: 2.64 mmol/mol [0.24%], p<0.001). Conclusions We showed that ≥80% of patients with suboptimal control are not achieving commonly recommended HbA1c targets within 1 year, highlighting the major challenge facing healthcare services. We also demonstrated that, although appropriate monitoring frequency is important, testing every 6 months is as effective as quarterly testing, supporting international recommendations. We suggest that the importance HbA1c monitoring frequency is being insufficiently recognised in diabetes management.

Pheochromocytomas and Hypertension.

PURPOSE OF REVIEW: Pheochromocytomas and paragangliomas (PPGLs) are uncommon catecholamine-producing neuroendocrine neoplasms that usually present with secondary hypertension. This review is to update the current knowledge about these neoplasms, the pathophysiology, genetic aspects and diagnostic and therapeutic algorithms based on scientific literature mostly within the past 3 years. RECENT FINDINGS: Eighty to eighty-five percent of PPGLs arise from the adrenal medulla (pheochromocytomas; PCCs) and the remainder from the autonomic neural ganglia (paragangliomas; PGLs). Catecholamine excess causes chronic or paroxysmal hypertension associated with sweating, headaches and palpitations, the presenting features of PPGLs, and increases the cardiovascular morbidity and mortality. Genetic testing should be considered in all cases as mutations are reported in 35-40% of cases; 10-15% of PCCs and 20-50% of PGLs can be malignant. Measurements of plasma-free metanephrines or 24-h urine-fractionated metanephrines help biochemical diagnosis with high sensitivity and specificity. Initial anatomical localization after biochemical confirmation is usually with computed tomography (CT) or magnetic resonance imaging (MRI). 123Iodine metaiodobenzylguanidine (123I-MIBG) scintigraphy, positron emission tomography (PET) or single-photon emission computed tomography (SPECT) is often performed for functional imaging and prognostication prior to curative or palliative surgery. Clinical and biochemical follow-up is recommended at least annually after complete tumour excision. Children, pregnant women and older people have higher morbidity and mortality risk. De-bulking surgery, chemotherapy, radiotherapy, radionuclide agents and ablation procedures are useful in the palliation of incurable disease. PPGLs are unique neuroendocrine tumours that form an important cause for endocrine hypertension. The diagnostic and therapeutic algorithms are updated in this comprehensive article.