Prandial Insulins: A Person-Centered Choice.

PURPOSE OF REVIEW: Postprandial hyperglycemia, or elevated blood glucose after meals, is associated with the development and progression of various diabetes-related complications. Prandial insulins are designed to replicate the natural insulin release after meals and are highly effective in managing post-meal glucose spikes. Currently, different types of prandial insulins are available such as human regular insulin, rapid-acting analogs, ultra-rapid-acting analogs, and inhaled insulins. Knowledge about diverse landscape of prandial insulin will optimize glycemic management. RECENT FINDINGS: Human regular insulin, identical to insulin produced by the human pancreas, has a slower onset and extended duration, potentially leading to post-meal hyperglycemia and later hypoglycemia. In contrast, rapid-acting analogs, such as lispro, aspart, and glulisine, are new insulin types with amino acid modifications that enhance their subcutaneous absorption, resulting in a faster onset and shorter action duration. Ultra-rapid analogs, like faster aspart and ultra-rapid lispro, offer even shorter onset of action, providing better meal-time flexibility. The Technosphere insulin offers an inhaled route for prandial insulin delivery. The prandial insulins can be incorporated into basal-bolus, basal plus, or prandial-only regimens or delivered through insulin pumps. Human regular insulin, aspart, lispro, and faster aspart are recommended for management of hyperglycemia during pregnancy. Ongoing research is focused on refining prandial insulin replacement and exploring newer delivery methods. The article provides a comprehensive overview of various prandial insulin options and their clinical applications in the management of diabetes.

Role of Teplizumab, a Humanized Anti-CD3 Monoclonal Antibody, in Managing Newly Diagnosed Type 1 Diabetes: An Updated Systematic Review and Meta-Analysis.

OBJECTIVE: Teplizumab has emerged as a potential disease-modifying drug in type 1 diabetes (T1D). This meta-analysis sought to summarize the therapeutic effect of teplizumab in newly diagnosed patients with T1D. METHODS: Randomized controlled trials involving patients with T1D receiving teplizumab in the intervention arm and placebo (or no active intervention) in the control arm were searched throughout the electronic databases. The primary outcome was the change in area under the curve of C-peptide levels from baseline. RESULTS: Seven reports from 6 studies involving 834 subjects met the inclusion criteria. Compared to teplizumab, greater reductions in area under the curve of C-peptide from the baseline values were observed in the control group after 6 months (mean difference [MD] 0.07 nmol/L [0.01, 0.13], P = .02), after 12 months (MD 0.07 nmol/L [0.04, 0.11], P = .0001), after 18 months (MD 0.10 nmol/L [0.06, 0.14], P < .00001), and after 24 months (MD 0.07 nmol/L [0.01, 0.14], P = .03) of interventions. Moreover, fewer patients treated with teplizumab had a decreased C-peptide response after 6 months (odds ratio [OR] 0.21), after 12 months (OR 0.17), after 18 months (OR 0.30), and after 24 months (OR 0.12) of treatment. The preservation of endogenous insulin production was supported by reduced use of exogenous insulin with maintenance of comparable glycemic control for up to 18 months post-treatment. Teplizumab imparted higher risks of grade 3 or higher adverse events, adverse events leading to study medication discontinuation, nausea, rash, and lymphopenia. CONCLUSION: The results of the meta-analysis support teplizumab as a promising disease-modifying therapy for newly diagnosed T1D.

Fostering Excellence in Endocrinology Research: The Inaugural Edition of the Yuvaratna Awards of the Endocrine Society of India.

The Endocrine Society of India (ESI) has introduced a new award, the Yuvaratna Awards, for recognizing the best research conducted by recently graduated endocrinologists across the country. This research should be carried out independently and not as part of or as a continuation of work initiated during residency. Two distinct categories were established: one for individuals working in academic institutions and another for those employed in private hospitals. This distinction acknowledges the unique benefits and challenges faced in both settings. This initiative serves as an excellent means to foster and promote research enthusiasm among young endocrinologists. This article elaborates on our firsthand experience as participants in the inaugural session of this award and delves into how it influenced our motivation for further research.

Glucagon-Like Peptide-1 Receptor Agonists in Post-bariatric Surgery Patients: A Systematic Review and Meta-analysis.

BACKGROUND: A significant number of patients face the issue of weight gain (WG) or inadequate weight loss (IWL) post-bariatric surgery for obesity. Several studies have been published evaluating the role of glucagon-like peptide-1 receptor agonists (GLP1RA) for weight loss post-bariatric surgery. However, no systematic review and meta-analysis (SRM) till date has evaluated the efficacy, safety and tolerability of GLP1RA in this clinical scenario. Hence, this SRM aimed to address this knowledge gap. METHODS: Databases were searched for randomized controlled trials (RCTs), case-control, cohort and observational studies involving use of GLP1RA in the intervention arm post-bariatric surgery. Primary outcome was weight loss post at least 3 months of therapy. Secondary outcomes were evaluation of body composition parameters, total adverse events (TAEs) and severe adverse events (SAEs). RESULTS: From initially screened 1759 articles, 8 studies (557 individuals) were analysed. Compared to placebo, patients receiving liraglutide had significantly greater weight loss after 6-month therapy [MD - 6.0 kg (95% CI, - 8.66 to - 3.33); P < 0.001; I2 = 79%]. Compared to liraglutide, semaglutide had significantly greater percent reduction in body weight after 6-month [MD - 2.57% (95% CI, - 3.91 to - 1.23); P < 0.001; I2 = 0%] and 12-month [MD - 4.15% (95% CI, - 6.96 to - 1.34); P = 0.004] therapy. In study by Murvelashvili et al. (2023), after 12-month therapy, semaglutide had significantly higher rates of achieving > 15% [OR 2.15 (95% CI, 1.07-4.33); P = 0.03; n = 207] and > 10% [OR 2.10 (95% CI, 1.19-3.71); P = 0.01; n = 207] weight loss. A significant decrease in fat mass [MD - 4.78 kg (95% CI, - 7.11 to - 2.45); P < 0.001], lean mass [MD - 3.01 kg (95% CI, - 4.80 to - 1.22); P = 0.001] and whole-body bone mineral density [MD - 0.02 kg/m2 (95% CI, - 0.04 to - 0.00); P = 0.03] was noted with liraglutide. CONCLUSION: Current data is encouraging regarding use of GLP1RAs for managing WG or IWL post-bariatric surgery. Deterioration of bone health and muscle mass remains a concern needing further evaluation. TRIAL REGISTRATION: The predefined protocol has been registered in PROSPERO having registration number of CRD42023473991.

Impact of early initiation of ezetimibe in patients with acute coronary syndrome: A systematic review and meta-analysis.

OBJECTIVE: Scant data is available on the efficacy and safety of adding ezetimibe to high-intensity statin therapy for early and rapid reduction of low-density lipoprotein cholesterol (LDL-C) within 4-12 weeks of an acute-event in acute coronary syndrome (ACS). We undertook this meta-analysis to address this knowledge-gap. METHODS: Electronic databases were searched for RCTs involving patients with ACS receiving ezetimibe in intervention arm, and placebo/active comparator in control arm. Primary outcome was to evaluate changes in LDL-C levels post-ACS. Secondary outcomes were to evaluate alterations in other lipid parameters and adverse events. RESULTS: From initially screened 4561 articles, data from 11 studies (20,291 patients) were analyzed. Compared to controls, patients receiving ezetimibe had significantly lower LDL-C at 7-days [MD -19.55 mg/dl(95 %CI:-36.46 to -2.63);P = 0.02;I2 = 91 %], 1-month [MD-24.67 mg/dl (95 %CI:-34.59 to -14.76);P < 0.001;I2 = 81 %], 3-months [MD -18.01 mg/dl(95 %CI:-24.11 to -11.90);P < 0.001;I2 = 92 %] and 10-12 months [MD -16.90 mg/dl (95 % CI: -17.67 to -16.12); P < 0.001; I2 = 0 %] of treatment. Compared to controls, patients receiving ezetimibe had significantly lower total cholesterol at 7-days [MD-21.05 mg/dl(95 %CI:-26.73 to -15.37);P < 0.001;I2 = 0 %], 1-month [MD-25.56 mg/dl(95 %CI:-38.29 to -12.83);P < 0.001;I2 = 85 %], 3-months [MD-22.54 mg/dl(95 %CI:-36.90 to -8.19);P = 0.002;I2 = 22 %] and 12-months [MD-19.68 mg/dl(95 %CI:-20.78 to -18.59);P < 0.001;I2 = 0 %] of treatment. Death from any cause, ACS and non-fatal stroke [OR0.89(95 %CI:0.83-0.96);P = 0.002;I2 = 0 %], non-fatal myocardial infarction [OR0.86(95 %CI:0.79-0.94);P = 0.001;I2 = 0 %] and ischemic stroke [OR0.80(95 %CI:0.68-0.94);P = 0.009;I2 = 0 %] was significantly reduced in patients receiving ezetimibe. CONCLUSION: Addition of ezetimibe to high-intensity statin therapy at the time of ACS event is associated with significantly better cholesterol reduction at day-7,1-month, 3- months and 1-year of follow-up, which translates into a significantly lower recurrent cardiovascular events post an index event of ACS. CONCISE SUMMARY OF FINDINGS: Addition of ezetimibe to high-intensity statin therapy at the time of acute coronary syndrome (ACS) index event is associated with significantly better low density lipoprotein cholesterol and total cholesterol reduction at day-7, 1-month, 3-months and 1-year of follow-up, which translates into a significantly lower recurrent cardiovascular events (death from any cause, major ACS, non-fatal stroke, non-fatal myocardial infarction, and ischemic stroke) post an index event of ACS.

Orforglipron, a novel non-peptide oral daily glucagon-like peptide-1 receptor agonist as an anti-obesity medicine: A systematic review and meta-analysis.

Background: Orforglipron is a novel once-daily oral non-peptide glucagon-like peptide-1 receptor agonist with several recently published randomized controlled trials (RCTs) evaluating its role in diabetes and obesity. No meta-analysis has analyzed the efficacy and safety of orforglipron; this meta-analysis aimed to address this knowledge gap. Methods: A systematic search was conducted in electronic databases to identify RCTs that included individuals with obesity who were administered orforglipron and compared to either a placebo or an active comparator. The primary outcome of interest was the percent change in body weight. Results: From 12 initially screened articles, data from three RCTs involving 774 people were analyzed with a follow-up duration of up to 36 weeks. Compared to placebo, patients receiving orforglipron 12 mg/day (mean difference (MD), MD -5.48%, 95% CI [-7.64, -3.33], p < 0.01), 24 mg/day (MD -8.51%, 95% confidence interval (CI) [-9.88, -7.14], p < 0.01), 36 mg/day (MD -8.84%, 95% CI [-11.68, -6.00], p < 0.01) and 45 mg/day (MD -8.24%, 95% CI [-12.84, -3.63], p < 0.01) had a significantly greater percent reduction in body weight. The percentage of patients being able to achieve >15% weight loss from baseline was significantly higher with orforglipron 24 mg/day [Odds ratio (OR) 21.90 (95% CI [4.06, 118.15], p = 0.0003), 36 mg/day (OR 17.43, 95% CI [3.18, 95.66], p = 0.001) and 45 mg/day (OR 23.17, 95% CI [4.37, 123.03], p = 0.0002). Total but not severe adverse events were significantly higher with all the doses of orforglipron compared to placebo, with the hazard ratios being higher with higher doses. Gastrointestinal side-effects were predominant side effects, being dose-dependent, with nausea, vomiting, constipation, and gastroesophageal reflux being the predominant ones. Conclusion: Orforglipron at 24-45 mg/day doses is an effective weight loss medication. The efficacy versus side effect profile suggests that 24-36 mg/day is the most optimal dose for orforglipron as an anti-obesity medicine.

Safety and tolerability of sodium glucose cotransporter-2 inhibitors in children and young adults: A systematic review and meta-analysis.

Purpose: Sodium glucose co-transporter-2 inhibitors (SGLT2i) have been evaluated in children with type-2 diabetes (T2DM), Type-1 diabetes (T1DM) and several other non-diabetic conditions. Potential tolerability issues have been preventing us from routinely using SGLT2i in children with diabetes. No meta-analysis till date has evaluated the safety and tolerability of SGLT2i in children. This systematic review and meta-analysis aimed to address this knowledge-gap. Methods: Databases were searched for randomized controlled trials (RCTs), case-control and cohort studies involving children receiving SGLT2i in intervention-arm. Primary outcome was occurrence of treatment-emergent adverse events (TAEs). Secondary outcomes were evaluation of glycaemic efficacy and occurrence of severe adverse-events (SAEs), hypoglycaemia, ketosis, genital or urinary infections and any other adverse-events. Results: From initially screened 27 articles, data from 4 RCT (258 children) was analyzed. In children with T2DM, occurrence of TAEs [OR 1.77(95%CI:0.93-3.36);P=0.08;I2=0%], SAEs [OR 0.45(95%CI:0.08-2.54);P=0.37;I2=0%], ketoacidosis [OR 0.33(95%CI:0.01-8.37);P=0.50], urinary tract infections [OR 2.34(95%CI:0.44-12.50);P=0.32;I2=0%] and severe hypoglycaemia [OR 4.47(95%CI:0.21-96.40);P=0.34] were comparable among SGLTi group and placebo. Compared to placebo, T2DM children receiving SGLTi had significantly lower HbA1C at 24-26 weeks [MD -0.79%(95%CI:-1.33--0.26);P=0.004;I2=0%]. In T1DM children, ß-hydroxybutyrate levels were significantly higher in SGLTi group compared to placebo [MD 0.11mmol/L(95%CI:0.05-0.17);P=0.0005;I2=53%]. In T1DM, there was not a single report of SAE, ketoacidosis, severe hypoglycaemia among both groups, with time in range considerably greater in SGLT2i group (68%±6% vs. 50%±13%;P<0.001). Conclusion: This study provides us with reassuring data on safety of use of SGLT2i in children and young adults.

Trabecular bone score in adults with type 1 diabetes: a meta-analysis.

Type 1 diabetes mellitus (T1DM) is associated with a disproportionately high fracture rate despite a minimal decrease in bone mineral density. Though trabecular bone score (TBS), an indirect measure of bone architecture, is lower in adults with T1DM, the modest difference is unlikely to account for the large excess risk and calls for further exploration. INTRODUCTION: Fracture rates in type 1 diabetes mellitus (T1DM) are disproportionately high compared to the modestly low bone mineral density (BMD). Distortion of bone microarchitecture compromises bone quality in T1DM and is indirectly measured by trabecular bone score (TBS). TBS could potentially be used as a screening tool for skeletal assessment; however, there are inconsistencies in the studies evaluating TBS in T1DM. We performed this meta-analysis to address this knowledge gap. METHODS: An electronic literature search was conducted using PubMed, Scopus, and Web of Science resources (all-year time span) to identify studies relating to TBS in T1DM. Cross-sectional and retrospective studies in adults with T1DM were included. TBS and BMD data were extracted for pooled analysis. Fracture risk could not be analyzed as there were insufficient studies reporting it. RESULT: Data from six studies were included (T1DM: n = 378 and controls: n = 286). Pooled analysis showed a significantly lower TBS [standardized mean difference (SMD) = - 0.37, 95% CI - 0.52 to - 0.21; p < 0.00001] in T1DM compared to controls. There was no difference in the lumbar spine BMD (6 studies, SMD - 0.06, 95% CI - 0.22 to 0.09; p = 0.43) and total hip BMD (6 studies, SMD - 0.17, 95% CI - 0.35 to 0.01; p = 0.06) in the case and control groups. CONCLUSIONS: Adults with T1DM have a lower TBS but similar total hip and lumbar spine BMD compared to controls. The risk attributable to the significant but limited difference in TBS falls short of explaining the large excess propensity to fragility fracture in adults with T1DM. Further studies on clarification of the mechanism and whether TBS is suited to screen for fracture risk in adults with T1DM are necessary.

Growth hormone therapy is associated with improved uterine dimensions in girls with Turner syndrome prior to oestrogen replacement.

BACKGROUND: Adult women with Turner syndrome (TS) have high rates of miscarriage, presumably due to the abnormal size and shape of the uterus. There is a paucity of data regarding the determinants of uterine volume (UtVol) in young girls with TS before the initiation of oestrogen replacement therapy (ERT). METHODS: We performed a cross-sectional study on premenarchal girls with TS, aged 5-15 years, pubertal stage B1-B3, not having received ERT (n = 73) and 50 age-matched healthy controls. Anthropometric parameters and a history of growth hormone (GH) therapy (≥1 year) were noted. Uterine length (UtL), UtVol, and mean-ovarian-volume (MOV) standard-deviation scores (SDS) were determined from transabdominal ultrasonography data. RESULTS: Girls with TS had lower median UtVol-SDS (-1.07 vs. 0.86; p < .001), UtL-SDS (-3.72 vs. -0.41; p < .001) and MOV-SDS (-5.53 vs. 1.96; p < .001) compared to age-matched controls. Among TS girls, recipients of GH (n = 38) had higher UtVol-SDS (-0.63 vs. -1.39; p = .0001), UtL-SDS (-1.73 vs. -6.49; p < .0001) but similar MOV-SDS compared to nonrecipients (n = 35). Those with normal uterine volume for age (NUVA, n = 29) had earlier initiation (7.8 vs. 9.3 years; p = .03) and a longer duration of GH (3.71 vs. 2.14 years; p = .002) than those with low UtVol for age (n = 44). UtVol-SDS correlated with duration of GH (ρ = 0.411, p = .01) and negatively with age at GH initiation (ρ = -0.479, p = .003). In a model adjusted for pubertal status, karyotype and height-SDS, GH use could independently predict having NUVA (odds ratio: 5.09, confidence interval: 1.63-15.94, p = .005). CONCLUSION: GH therapy has a stimulatory effect on uterine dimensions in pre-and peripubertal girls with TS. Earlier initiation and longer duration of GH is important in TS girls before ERT.

Hyperprolactinemia Due to Prolactinoma has an Adverse Impact on Bone Health with Predominant Impact on Trabecular Bone: A Systematic Review and Meta-Analysis.

BACKGROUND: No meta-analysis has holistically analysed and summarized the effect of prolactin excess due to prolactinomas on bone mineral metabolism. We undertook this meta-analysis to address this knowledge-gap. METHODS: Electronic databases were searched for studies having patients with hyperprolactinemia due to prolactinoma and the other being a matched control group. The primary outcome was to evaluate the differences in BMD Z-scores at different sites. The secondary outcomes of this study were to evaluate the alterations in bone mineral density, bone mineral content and the occurrence of fragility fractures. RESULTS: Data from 4 studies involving 437 individuals was analysed to find out the impact of prolactinoma on bone mineral metabolism. Individuals with prolactinoma had significantly lower Z scores at the lumbar spine [MD -1.08 (95 % CI: -1.57 - -0.59); P < 0.0001; I2 = 54 % (moderate heterogeneity)] but not at the femur neck [MD -1.31 (95 % CI: -3.07 - 0.45); P = 0.15; I2 = 98 % (high heterogeneity)] as compared to controls. Trabecular thickness of the radius [MD -0.01 (95 % CI: -0.02 - -0.00); P = 0.0006], tibia [MD -0.01 (95 % CI: -0.02 - -0.00); P=0.03] and cortical thickness of the radius [MD -0.01 (95 % CI: -0.19 - -0.00); P = 0.04] was significantly lower in patients with prolactinoma as compared to controls. The occurrence of fractures was significantly higher in patients with prolactinoma as compared to controls [OR 3.21 (95 % CI: 1.64 - 6.26); P = 0.0006] Conclusion: Bone mass is adversely affected in patients with hyperprolactinemia due to prolactinoma with predominant effects on the trabecular bone.

Parathyroid Carcinoma Presenting as Recurrent Primary Hyperparathyroidism and Neck Mass: A Case Report.

Parathyroid carcinoma is a rare endocrine neoplasm that accounts for <1% of cases of primary hyperparathyroidism. The management of parathyroid carcinoma is a challenge due to the high rate of local recurrence of the tumour. We report the case of a middle-aged north Indian woman who presented with recurrent primary hyperparathyroidism due to parathyroid carcinoma. She presented with a recurrent palpable hard neck mass and underwent radical dissection of the neck six times. At the time of writing this report, she was referred for external beam radiotherapy to the neck. Parathyroid carcinoma is a rare malignancy with an indolent but tenacious course. Complete resection at the time of initial surgery determines the prognosis of the neoplasm. Chemotherapy and radiotherapy are usually ineffective. Hypercalcaemia needs to be aggressively managed. A multidisciplinary team is required to effectively manage parathyroid carcinoma.

Etiological Profile, Targeted Levothyroxine Dosing and Impact of Partial Newborn Screening in Congenital Hypothyroidism-A Single Centre Experience.

Background: Congenital hypothyroidism (CH) is the most common cause of preventable intellectual disability. Newborn screening (NBS) for CH has been in vogue in many parts of the world since 1970, but despite its well-known benefits, many developing countries including India have not been able to establish universal NBS for CH till date. Objective: The aim of this study was to review the clinical aspects of congenital hypothyroidism in a tertiary care university referral teaching hospital, focusing on aetiology of CH, predictors of permanence, optimal targeted dose strategies based on aetiology and the effect of newborn screening on the time to diagnosis. Material and Methods: The electronic medical records of 233 children with CH referred to our centre between January 2009 and December 2019 were analysed. A partial NBS was established in the state in 2012. Results: Dyshormonogenesis (57.5%) was the most common aetiology of CH. The incidence of transient CH in children with a gland in situ (GIS) was 35%. Levothyroxine (LT-4) dose of >2.75 µg/kg/day (sensitivity 76.5, specificity 72), >2.15 µg/kg/day (sensitivity 82.4, specificity 61.9) and >1.85 µg/kg/day (sensitivity 76.5, specificity 61.9) at years 1, 2 and 3, respectively, were predictors of permanent CH. An initial LT-4 dose ≥8 µg/kg was sufficient and very seldom led to undertreatment in children with dyshormonogenesis. On the contrary, even doses ≥13 mcg/kg/day led to frequent undertreatment in children with thyroid dysgenesis. After the introduction of newborn screening, the median age at diagnosis came down from 45 days (IQR 14-180 days) to ten days (IQR 3-12 days). Conclusion: Targeted dosing based on aetiology of CH may be more appropriate to optimise outcomes. The time to diagnosis of CH reduced significantly after the adoption of even a partial NBS program highlighting the urgent need for implementation of the same in resource poor settings.

PURsuit of Endocrinology (PURE): A National Survey among First-Year Endocrinology Residents Across India.

Background: Endocrinology has been a popular choice of super-specialisation in India in recent years. The PURsuit of Endocrinology (PURE) survey aims to determine the factors that facilitated the selection of endocrinology as the area of super-specialisation among first-year residents across India. Methods: We conducted an electronic questionnaire-based survey among first-year residents across India. The questionnaire evaluated the respondents' demographics, feeder speciality, challenges during preparation, factors influencing endocrinology as a career preference, unappealing aspects of the subject and future career plans. Results: A total of 81 (43 males and 38 females) responses were recorded. The mean age was 31.3 ± 3.3 years, with 63% married. Internal medicine was the feeder speciality in 92.5% of cases. Work-life balance was the critical consideration for pursuing endocrinology in 91.4%, followed by professional satisfaction (64.2%) and the scope of having a solo practice (43.2%). Interestingly, there was less emphasis on monetary satisfaction (12.3%). Almost half of the respondents intended to practice in a government academic institution (46.9%) or in an independent set-up (45.7%). Conclusions: The PURE survey suggests that work-life balance and professional satisfaction are the key driving factors behind the choice of endocrinology. An increasing interest among the residents to join as faculty in academic institutions, apart from having self-owned private clinics, is a welcome finding.

Cardiac Autonomic Neuropathy in Prediabetes: A Case-Control Study.

Introduction: Early detection and diagnosis of diabetic autonomic neuropathy, especially cardiac autonomic neuropathy (CAN), have gained attention recently because of their elevated cardiovascular mortality risk. Although the connection between type 2 diabetes mellitus and autonomic neuropathy is well established, evidence is emerging that the association might predate the stage of prediabetes. Objective: The present study was undertaken to compare the prevalence of CAN in prediabetes versus that in normoglycemic controls. Materials and Methods: The study population was selected by purposive sampling from individuals attending a tertiary care hospital from January 2018 to June 2019. Fifty individuals with prediabetes diagnosed by the American Diabetes Association's glycated haemoglobin criteria and 50 age- and gender-matched healthy controls were recruited. CAN was assessed by standard cardiovascular reflex tests, as described by Ewing and Clarke. Changes in R-R with deep breathing, Valsalva manoeuver, and changes in blood pressure (BP) in response to standing and sustained handgrip were evaluated. Three-time domains [standard deviation of normal-to-normal intervals (SDNN), root mean square of successive RR intervals (rMSSD) and percentage of successive normal to normal R-R (NN) intervals that differ by more than 50 ms (pNN50)] and four frequency domain indices [very low-frequency band (VLF), low-frequency band (LF), high-frequency band (HF), LF/HF ratio) of heart rate variability (HRV)] were examined. Results: The mean heart rate was 71.37 ± 7.94 and 65.59 ± 8.73 beats/min in patients with prediabetes and controls, respectively (P < 0.05). All three-time-domain indices of HRV were significantly lower in persons with prediabetes compared to controls. The peak frequency of LF, peak power of LF, normalised unit of LF, and LF/HF ratio was significantly lower in subjects with prediabetes than in controls. There was no difference in the traditional cardiovascular autonomic reflex testing. Conclusion: Our study demonstrates the presence of subclinical autonomic dysfunction in persons with prediabetes. Early detection of CAN in prediabetes can have future implications for cardiovascular risk reduction.

Optimal use of once weekly icodec insulin in type-2 diabetes: An updated meta-analysis of phase-2 and phase-3 randomized controlled trials.

BACKGROUND: Previously published meta-analysis have analysed data from 3 small phase-2 randomized controlled trials (RCTs). Since then, 5 big phase-3 RCTs have been published on use of icodec in type-2 diabetes (T2D). This updated systematic review aimed to establish the best practices and safety of icodec in T2D. METHODS: Databases were searched for RCTs involving T2D patients receiving icodec. Primary outcome was change in HbA1c. Secondary outcomes were alterations in glycaemic parameters and adverse events. RESULTS: Data from 8 studies (4317 patients) was analysed. Compared to other basal insulins, icodec had comparable HbA1c lowering at 16-weeks [MD-0.19 %(95%CI: 0.58-0.20); P = 0.35; I2 = 92 %], better HbA1c lowering at 26-weeks [MD-0.19 %(95%CI: 0.35-0.013); P = 0.02; I2 = 94 %] and 52-weeks [MD -0.28 %(95%CI: 0.45-0.12); P = 0.0008; I2 = 100 %]. Percentage of participants achieving HbA1c<7 % with icodec was higher at 16-weeks [OR2.37(95%CI:1.05-5.35); P = 0.04], comparable at 26-weeks [OR1.38(95%CI:0.91-2.11); P = 0.13; I2 = 80 %], and higher at 52-weeks [OR1.55(95%CI:1.30-1.85); P < 0.00001; I2 = 0 %]. Percentage of participants achieving HbA1c<7 % without level 2/3 hypoglycaemia was higher with icodec at 26-weeks [OR1.37(95%CI:1.10-1.71); P = 0.004; I2 = 28 %] and 52-weeks [OR1.48(95%CI:1.24-1.77); P < 0.001; I2 = 0 %]. At 26-weeks, injection-site reactions was higher with icodec [OR1.95(95%CI:1.06-3.56); P = 0.03; I2 = 0 %]. At 26-weeks level-1 hypoglycemia [OR1.40(95%CI:1.02-1.94); P = 0.04; I2 = 58 %], but not level-2/3 hypoglycaemia was higher with icodec. Subset analysis revealed increased occurrence of level-1 [OR 4.19 (95 % CI: 3.20-5.50); P < 0.00001] and level-2 [OR 3.97 (95 % CI: 3.04-5.18); P < 0.00001] hypoglycaemia in participants who received one-time additional 50 % icodec loading dose as compared to those who did not. At 26-weeks, weight-gain was significantly higher with icodec [MD0.61 kg(95%CI:0.38-0.84); P < 0.00001; I2 = 98 %]. CONCLUSION: Icodec insulin is well tolerated with glycaemic efficacy similar to all other available basal insulins.

Metformin in COVID-19: Is There a Role Beyond Glycemic Control?

Context: The coronavirus disease 2019 (COVID-19) pandemic is still a cause of worldwide health concern. Diabetes and its associated comorbidities are risk factors for mortality and morbidity in COVID-19. Selecting the right antidiabetic drug to achieve optimal glycemic control might mitigate some of the negative impacts of diabetes. Metformin continues to be the most widely administered antidiabetic agent. There is evidence of its beneficial outcome in COVID-19 independent of its glucose-lowering effect. Evidence Acquisition: A thorough literature search was conducted in PubMed, Google Scholar, Scopus, and Web of Science to identify studies investigating metformin in COVID-19. Results: Several overlapping mechanisms have been proposed to explain its antiviral properties. It could bring about conformational changes in the angiotensin-converting enzyme-2 receptor and decrease viral entry. The effects on the mammalian target of the rapamycin pathway and cellular pH have been proposed to reduce viral protein synthesis and replication. The immunomodulatory effects of metformin might counter the detrimental effects of hyperinflammation associated with COVID-19. Conclusions: These findings call for broader metformin usage to manage hyperglycemia in COVID-19.

Simultaneous pancreas-kidney transplantation for end-stage renal failure in type 1 diabetes mellitus: Current perspectives.

Type 1 diabetes mellitus (T1DM) is one of the important causes of chronic kidney disease (CKD) and end-stage renal failure (ESRF). Even with the best available treatment options, management of T1DM poses significant challenges for cli nicians across the world, especially when associated with CKD and ESRF. Substantial increases in morbidity and mortality along with marked rise in treatment costs and marked reduction of quality of life are the usual consequences of onset of CKD and progression to ESRF in patients with T1DM. Simultaneous pancreas-kidney transplant (SPK) is an attractive and promising treatment option for patients with advanced CKD/ESRF and T1DM for potential cure of these diseases and possibly several complications. However, limited availability of the organs for transplantation, the need for long-term immunosuppression to prevent rejection, peri- and post-operative complications of SPK, lack of resources and the expertise for the procedure in many centers, and the cost implications related to the surgery and postoperative care of these patients are major issues faced by clinicians across the globe. This clinical update review compiles the latest evidence and current recommendations of SPK for patients with T1DM and advanced CKD/ESRF to enable clinicians to care for these diseases.

Novel homozygous leptin receptor mutation in an infant with monogenic obesity.

Monogenic obesity can be caused by a mutation in one of the single genes involved in hunger and satiety. The most common mutations affect melanocortin 4 (MC4) followed by the leptin gene and its receptor. Leptin receptor (LEPR) gene mutation is an extremely rare endocrine disease characterized by early-onset obesity, hyperphagia in addition to pituitary hormone deficiency, and metabolic abnormalities. We report the case of a 12-month-old male infant born of a non-consanguineous marriage. He presented to us with rapid weight gain from 2 months of age along with hyperphagia. Biochemistry revealed a deranged lipid profile, elevated transaminases, and markedly raised serum leptin levels. On genetic analysis, a novel mutation was detected, which was a homozygous variation In exon 12 of the LEPR gene (chr1:g.65608901G>A) that resulted in the synonymous amino acid change of lysine at codon 584 proximal to donor splice site (p.Lys584). The in silico prediction of the variant was 'damaging' by MutationTaster2. The mutation was classified as a 'variant of uncertain significance' due to a lack of published literature and had to be correlated carefully with the clinical symptoms. It was recommended to do Sanger sequencing of the parents and other family members. However, due to financial constraints, the family could not afford the same. At the time of writing, funds were being arranged for procuring setmelanotide, which is a novel and effective therapy for monogenic obesity due to LepR mutation.

Impact of early initiation of proprotein convertase subtilisin/kexin type 9 inhibitors in patients with acute coronary syndrome: A systematic review meta-analysis.

OBJECTIVE: Scant data is available on the efficacy and safety of proprotein convertase subtilisin/kexin type-9 inhibitors (PCSK9i) for early and rapid reduction of low-density lipoprotein cholesterol (LDL-C) within 4-8 weeks of an acute event in patients with acute coronary syndrome (ACS). We undertook this meta-analysis to address this knowledge-gap. METHODS: Electronic databases were searched for RCTs involving patients with ACS receiving PCSK9i in intervention arm, and placebo/active comparator in control arm. Primary outcome was to evaluate changes in 1-month LDL-C post ACS. Secondary outcomes were to evaluate alterations in other lipid parameters and adverse events. RESULTS: From initially screened 194 articles, data from 3 studies was analyzed. After 4-weeks therapy, patients receiving PCSK9i had lower LDL-C [MD -0.95 mmol/L (95%CI:-1.51 to -0.40); P = 0.0007; I2 = 96%, total cholesterol (TC) [MD-1.05 mmol/L (95%CI:-1.83 to -0.27); P = 0.009; I2 = 94%] and triglycerides (TG) [MD-0.27 mmol/L (95%CI:-0.44 to -0.10); P = 0.002; I2 = 0%] compared to controls. After 4-8 weeks therapy, patients receiving PCSK9i has lower apolipoprotein B [MD-27.74% (95%CI:-42.59 to -12.89); P = 0.0003; I2 = 89%] as compared to controls. High density lipoprotein cholesterol (HDL-C) [MD 0.05 mmol/L (95%CI:-0.00-0.11); P = 0.05; I2 = 0%], lipoprotein(a) [MD-20.63 mmol/L (95%CI:-41.86- 0.59); P = 0.06; I2 = 54%] and apolipoprotein A1 [MD 0.02 g/L (95%CI:-0.02-0.07); P = 0.32; I2 = 0%] were comparable between groups. Hospital readmission for ACS was significantly lower in group receiving PCSK9i compared to controls [OR0.25 (95%CI:0.07-0.85); P = 0.03; I2 = 0%]. Occurrence of cardiac death [OR3.75 (95%CI:0.41-34.22); P = 0.24; I2 = 0%], serious adverse events [OR0.71 (95% CI:0.13-3.83); P = 0.69; I2 = 70%] and total adverse events [OR1.01 (95%CI: 0.19-5.30); P = 0.99; I2 = 92%] was comparable between groups. CONCLUSION: PCSK9i are highly effective in early reduction of LDL-C along with reduction of early hospital readmissions post-ACS.