Fracture risk and bone health in adrenal adenomas with mild autonomous cortisol secretion/subclinical Hypercortisolism: a systematic review, meta-analysis and meta-regression.

Adrenal adenomas/incidentalomas with mild autonomous cortisol secretion (MACS)/subclinical hypercortisolism (SH) are often associated with metabolic syndrome, glucocorticoid-induced osteoporosis and fractures. In this background, the present systematic review and meta-analysis aimed to collate the available evidence and provide a summary of effect of MACS/SH on bone health in terms of fractures, osteoporosis/osteopenia, microarchitecture, and bone turnover. PubMed/MEDLINE, Embase, and Web of Science databases were systematically searched for observational studies reporting prevalence of fractures, osteoporosis/osteopenia or data on bone microarchitecture/bone turnover markers (BTMs). Following literature search, 16 observational studies were included. Pooled prevalence of any fractures (vertebral and non-vertebral), vertebral fractures and osteoporosis/osteopenia in MACS/SH were 43% [95% confidence intervals (CI): 23%, 62%], 45% (95% CI: 22%, 68%) and 50% (95% CI: 33%, 66%), respectively. On meta-regression, age, sex, 24-hour urinary free cortisol and dehydroepiandrosterone-sulfate did not predict fracture risk. The likelihood of any fractures [odds ratio (OR) 1.61; 95% CI: 1.18, 2.20; p = 0.0026], vertebral fractures (OR 2.10; 95% CI: 1.28, 3.45; p = 0.0035) and osteoporosis/osteopenia (OR 1.46; 95% CI: 1.15, 1.85; p = 0.0018) was significantly higher in adrenal adenomas and MACS/SH than non-functional adrenal adenomas. Subjects with MACS/SH had significantly lower bone mineral density (BMD) at lumbar spine [mean difference (MD) -0.07 gm/cm2; 95% CI: -0.11, -0.03; p = 0.0004) and femoral neck (MD -0.05 gm/cm2; 95% CI: -0.08, -0.02; p = 0.0045) than their non-functional counterparts. Limited data showed no significant difference in BTMs. Publication bias was observed in the pooled prevalence of any fractures, vertebral fractures and pooled MD of femoral neck BMD. To conclude, people with adrenal adenomas/incidentalomas and MACS/SH are at 1.5 to 2-fold higher likelihood of fractures and osteoporosis/osteopenia compared to non-functional adrenal adenomas and should routinely be screened for bone disease. Nevertheless, considering the modest sample size of studies and evidence of publication bias, larger and high-quality studies are required (CRD42023471045).

Mild autonomous cortisol secretion (MACS), often also referred to as subclinical hypercortisolism (SH), is usually associated with an underlying adrenal incidentaloma (AI), an adrenal mass incidentally found during abdomen imaging. Although signs of overt cortisol excess are lacking, subjects with MACS/SH often have features of metabolic syndrome, osteoporosis and fractures. The present systematic review and meta-analysis showed that the pooled prevalence of any fractures (vertebral and non-vertebral), vertebral fractures and osteoporosis/osteopenia in MACS/SH were 43%, 45% and 50%, respectively. People with adrenal adenomas/incidentalomas and MACS/SH are at 1.5 to 2-fold higher likelihood of fractures and osteoporosis/osteopenia compared to non-functional adrenal adenomas. Besides, subjects with MACS/SH had significantly lower bone mineral density (BMD) at lumbar spine and femoral neck than their non-functional counterparts. It is thus imperative to assess bone health in all subjects with MACS/SH.

Normative data for insulin-like growth factor-1 (IGF-1) in healthy children and adolescents from India.

BACKGROUND: Serum IGF-1 is an important biochemical tool to diagnose and monitor GH-related disorders. However, ethnic-specific Indian data following consensus criteria for the establishment of normative data, are not available. Our objective was to generate chronological age (CA)-, bone age (BA)- and Tanner stage-specific normative data for IGF-1 in healthy Indian children and adolescents. METHODS: A cross-sectional epidemiological study was conducted in schools and the community, which enrolled apparently healthy children and adolescents with robust exclusion criteria. The outcome measure was serum IGF-1 assessed using an electro-chemiluminescence immunoassay (ECLIA). The 2.5th, 5th, 10th, 25th, 50th (median), 75th, 90th, 95th, and 97.5th centiles for IGF-1 were estimated using generalized additive models. RESULTS: We recruited 2226 apparently healthy participants and following exclusion, 1948 (1006 boys, 942 girls) were included in the final analysis. Girls had median IGF-1 peak at CA of 13 years (321.7 ng/mL), BA of 14 years (350.2 ng/mL) and Tanner stage IV (345 ng/mL), while boys had median IGF-1 peak at CA of 15 years (318.9 ng/mL) BA of 15 years (340.6 ng/mL) and Tanner stage III (304.8 ng/mL). Girls had earlier rise, peak and higher IGF-1 values. The reference interval (2.5th-97.5th percentile) was broader during peri-pubertal ages, indicating a higher physiological variability. CONCLUSION: This study provides ethnicity-specific normative data on serum IGF-1 and will improve the diagnostic utility of IGF-1 in the evaluation and management of growth disorders in Indian children and adolescents.

Impact of short-term application of continuous glucose monitoring system(CGMS) on long-term glycemic profile in adolescents and adults with type 1 diabetes mellitus: An open-label randomized control cross over study.

AIMS: The use of Continuous Glucose Monitoring System (CGMS) improves glycemic parameters in Type 1 Diabetes Mellitus (T1D), but the cost is prohibitive. Here, we investigated the effect of short-term application of real-time and intermittently-scanned CGMS (rt and is-CGMS) in T1D individuals on change in HbA1c at the end of 3 months. METHODS: T1D individuals were randomized into three groups in a ratio of 1:1:2 - Group A (rt-CGMS for 2 weeks initially, followed by is-CGMS for 2 weeks at 3 months), Group B (is-CGMS for 2 weeks initially followed by rt-CGMS for 2 weeks at 3 months) and Group C (only self-monitoring of blood glucose), respectively. HbA1c at baseline, 3, and 6 months were compared. RESULTS: Out of a total 68 T1D patients, HbA1c decreased significantly in groups A and B at 6 months compared to the baseline, but not in group C. HbA1c was significantly lower in Group A compared to Group C at 3 and 6 months. Fructosamine levels significantly decreased in Group B before and after cross-over. Glycemic variability indices improved significantly after cross-over from is-CGMS to rt-CGMS. CONCLUSION: Intermittent application of CGMS for 2 weeks improves short- and long-term blood glucose control in T1D.

GLP-1 receptor agonists, SGLT2 inhibitors and noncardiovascular mortality in type 2 diabetes: Insights from a meta-analysis.

OBJECTIVE: Type-2 diabetes (T2D) poses a higher risk of noncardiovascular mortality in addition to the burden of cardiovascular mortality. The well-established cardiovascular benefits of glucagon-like peptide-1 receptor agonists (GLP-1 RAs) and sodium-glucose cotransporter-2 inhibitors (SGLT2i) could solely explain their apparent effects on all-cause mortality in T2D. The present meta-analysis aims to pool their effects on noncardiovascular mortality in T2D and summarize the recent evidence on plausible pathways mediating these effects. METHODS: PubMed, Embase, Web of Science, and clinical trial registries were searched for randomized controlled trials (RCTs) with ≥1-year duration in adults with T2D reporting both cardiovascular and all-cause mortality in treatment versus placebo arms (PROSPERO: CRD42022337559). Noncardiovascular mortality was calculated by subtracting cardiovascular mortality events from all-cause mortality and risk ratios (RRs) were calculated. Random-effects meta-analysis was done. GRADE framework was used to assess evidence quality. RESULTS: We identified 17 eligible RCTs pooling data retrieved from 109,892 patients. Randomization to GLP-1 RA treatment versus placebo was associated with reduced noncardiovascular mortality (RR = 0.90; 95%CI: 0.81-0.99; I2 = 0 %; p < 0.05), consistent with their effects on cardiovascular mortality (RR = 0.88; 95%CI: 0.81-0.95; I2 = 0 %; p < 0.01) in T2D. Compared to placebo, SGLT2i significantly reduced noncardiovascular mortality (RR = 0.90; 95%CI: 0.82-0.99; I2 = 0 %; p < 0.05) along with cardiovascular mortality (RR = 0.84; 95%CI: 0.77-0.92; I2 = 28 %; p < 0.001). Subgroup analysis showed no significant effects of heart failure or renal function on treatment benefits of SGLT2i on noncardiovascular mortality (p value > 0.2 for subgroup differences). CONCLUSION: The impact of GLP-1RAs and SGLT2i on mortality in people with T2D extends beyond their cardiovascular benefits.

Sarcopenia is common in ulcerative colitis and correlates with disease activity.

BACKGROUND/AIMS: Association of sarcopenia with disease severity in ulcerative colitis (UC) is not clearly defined. We planned to estimate the prevalence of sarcopenia in patients with UC as per the revised definition and its relation with the disease severity. METHODS: A cross-sectional assessment of sarcopenia in patients with UC was performed. Disease activity was graded according to complete Mayo score. Hand grip strength was assessed with Jamar hand dynamometer, muscle mass using a dual energy X-ray absorptiometry scan, and physical performance with 4-m walk test. Sarcopenia was defined as a reduction of both muscle mass and strength. Severe sarcopenia was defined as reduced gait speed in presence of sarcopenia. RESULTS: Of 114 patients (62 males, mean age: 36.49±12.41 years), 32 (28%) were in remission, 46 (40.4%) had mild-moderate activity, and 36 (31.6%) had severe UC. Forty-three patients (37.7%) had probable sarcopenia, 25 (21.9%) had sarcopenia, and 14 (12.2%) had severe sarcopenia. Prevalence of sarcopenia was higher in active disease (2 in remission, 6 in active, and 17 in severe, P<0.001). Of 14 with severe sarcopenia, 13 had severe UC while 1 had moderate UC. On multivariate analysis, lower body mass index and higher Mayo score were associated with sarcopenia. Of 37 patients with acute severe colitis, 16 had sarcopenia. Requirement of second-line therapy was similar between patients with and without sarcopenia. On follow-up (median: 18 months), there was a non-significant higher rate of major adverse events in those with sarcopenia (47.4% vs. 33.8%, P=0.273). CONCLUSIONS: Sarcopenia and severe sarcopenia in UC correlate with the disease activity.

Risk of Gallstone Disease in Primary Hyperparathyroidism: A Systematic Review and Meta-analysis.

OBJECTIVE: Apart from renal stones, primary hyperparathyroidism (PHPT) has been linked to the occurrence of gallstone disease (GSD). Nevertheless, the association is not consistent across all studies. The present systematic review and meta-analysis aims to collate the hitherto available evidence and provide a pooled estimate of the association between GSD and PHPT. METHODS: PubMed/MEDLINE, Embase, and Web of Science databases were systematically searched from inception till May 10, 2023 for observational studies reporting the prevalence of GSD (in terms of absolute numbers) in patients with PHPT. The pooled prevalence of GSD and odds ratio with 95% CI of the occurrence of GSD in patients with PHPT as compared to age- and sex-matched controls were calculated. Subgroup analysis was performed based on patient ethnicity (Indian/Caucasian). Statistical analysis was carried out using R version 4.2.2. Random-effects model with Hartung-Knapp adjustment was used for analyses. RESULTS: A total of 7 observational studies were included, pooling data from 15 949 patients with PHPT. The pooled prevalence of GSD in patients with PHPT was 16% (95% CI: 7%, 25%, I2 = 99%), being 13% (95% CI: 0%, 66%, I2 = 76%) in Indians, and 17% (95% CI: 4%, 31%, I2 = 99%) in Caucasians. Data consolidated from 3 studies showed that the pooled odds ratio of occurrence of GSD in patients with PHPT compared to controls was 1.77 (95% CI: 1.60, 1.97, P < .001, I2 = 0%). CONCLUSIONS: GSD is more prevalent in patients with PHPT than in the general population. Thus, PHPT may be considered an additional risk factor for GSD.

Phosphate: An underrated component of primary hyperparathyroidism.

Primary hyperparathyroidism (PHPT) is a systemic disease that affects all the systems of the body, specifically the bones and the kidneys. Its main action is on calcium homeostasis. It tries to preserve the body's calcium level at the cost of phosphate. The criteria for surgery in asymptomatic PHPT patients revolve around raised serum calcium levels, renal dysfunction or nephrolithiasis, and bone health. It does not take into account the serum phosphate levels. Depending on the serum level, Hypophosphatemia is divided into mild, moderate, and severe categories. In PHPT, several studies have suggested that asymptomatic PHPT patients with moderate hypophosphatemia may warrant surgical intervention. Treatment of hypophosphatemia in PHPT is based upon the degree of hypophosphatemia, and treatment is given according to that oral or intravenous route; after surgical and medical treatment of PHPT, phosphate levels gradually normalized. But even after these considerations, phosphate levels in PHPT are not given much importance.

Do vitamin D levels or supplementation play A role in COVID-19 outcomes?-a narrative review.

BACKGROUND AND OBJECTIVE: Hypovitaminosis D has been proposed as a risk factor for increased susceptibility to severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection and severe outcomes in coronavirus disease 2019 (COVID-19). Likewise, vitamin D supplementation has been proposed as an effective means for preventing and improving clinical outcomes in COVID-19. Nevertheless, available data are markedly inconsistent and contradictory. Considering the heterogeneity in the available clinical evidence, we planned to undertake a narrative review and provide a precise summary of the role of vitamin D in COVID-19. METHODS: PubMed/MEDLINE database was searched from inception till September 30, 2023 using appropriate MeSH terms. The initial search revealed 900 results. Thereafter, titles and abstracts were scanned and commentaries, letters, and editorials were excluded. Relevant observational studies and clinical trials/randomized controlled trials (RCTs) were full-text assessed and pertinent data were extracted for this narrative review. KEY CONTENT AND FINDINGS: Data from observational and ecological studies suggest that hypovitaminosis D is associated with a higher risk of acquiring COVID-19. Similarly, evidence support a negative association between 25-hydroxyvitamin D levels and COVID-19 severity, nevertheless, causality remains to be established. With regard to vitamin D supplementation and COVID-19-related health outcomes, data from observational studies and RCTs are contradictory. Even in moderate-to-severe/severe COVID-19, vitamin D supplementation has not been shown to be beneficial. Besides, data suggest that vitamin D levels might alter COVID-19 vaccine efficacy and be associated with long COVID. CONCLUSIONS: Vitamin D deficiency is linked to an increased risk of acquiring SARS-CoV-2 infection and poor COVID-19 prognosis, however, available evidence with regard to improved clinical outcomes with vitamin D supplementation is inconsistent.

Diabetes and Osteoporosis.

Bone fragility is an emerging complication of diabetes. People with diabetes are at a significantly higher risk of fractures compared to the general population. Bone fragility occurs in diabetes as a result of complex and poorly understood mechanisms occurring at the cellular level contributed by vascular, inflammatory and mechanical derangements. Bone mineral density (BMD) as assessed by DEXA is low in type 1 diabetes. Type 2 diabetes has a high risk of fracture despite a normal to raised BMD. DEXA thus underestimates the fracture risk in diabetes. Data are scare regarding the efficacy of the available therapies in this low bone turnover state.

Efficacy of zoledronate, denosumab or teriparatide in postmenopausal women with type 2 diabetes mellitus at high risk of fragility fractures: protocol of an open, blinded endpoint randomized controlled pilot trial.

Background: People with type 2 diabetes (T2D) are at high risk of fragility fractures; however, there are no randomized controlled trials evaluating the efficacy of anti-osteoporosis drugs as a primary pre-specified endpoint in T2D. Objectives: To compare the efficacy of anti-osteoporotic drugs in postmenopausal women with T2D. Design: Prospective, randomized, open, blinded endpoint clinical pilot trial. Methods: Postmenopausal women (⩾50 years) with T2D (duration ⩾5 years), HbA1c 7-10%, eGFR ⩾45 mL/min/1.73 m2 and prior vertebral (clinical/morphometric), hip, radius, humeral fragility fracture or bone mineral density (BMD) T-score (adjusted for diabetes) at lumbar spine/femoral neck ⩽-2.5 and high FRAX score will be eligible for inclusion. Subjects with secondary causes of osteoporosis, prior exposure to bone-active therapies or history of use of glucocorticoids/pioglitazone/thiazides/canagliflozin will be excluded. Finally, eligible subjects will undergo estimation of serum calcium, phosphate, alkaline phosphatase, parathyroid hormone, 25-hydroxyvitamin D and bone turnover markers (BTMs) (total procollagen type I N-propeptide, ß-CTX) along with trabecular bone score (TBS) and high-resolution peripheral quantitative computed tomography (HR-pQCT) of non-dominant hand and leg. After a 2-week run in phase, they will be randomized in a 1:1:1:1 ratio to receive yearly zoledronate, or biannually denosumab or daily teriparatide (in addition to standard of care, i.e., calcium 1000 mg/day and cholecalciferol 1000 IU/day) or only standard of care (control). The primary endpoints will be change in areal BMD and frequency of incident fractures at 18 months. The secondary endpoints will be change in HR-pQCT parameters, TBS and BTMs at 18 months. Adverse events will be recorded for all randomized participants. Ethics: The study has been approved by the Institute Ethics Committee. Written informed consent will be obtained from each participant. Discussion: The trial is expected to provide information regarding optimal anti-osteoporotic therapy in people with T2D and bone fragility. Registration: Prospectively registered in Clinical Trial Registry of India (CTRI/2022/02/039978).

AGEs accumulation with vascular complications, glycemic control and metabolic syndrome: A narrative review.

BACKGROUND: Multiple pathogenetic mechanisms are involved in the genesis of various microvascular and macrovascular complications of diabetes mellitus. Of all these, advanced glycation end products (AGEs) have been strongly implicated. OBJECTIVES: The present narrative review aims to summarize the available literature on the genesis of AGEs and their potential role in the causation of both micro- and macrovascular complications of diabetes mellitus. RESULTS: Uncontrolled hyperglycemia triggers the formation of AGEs through non-enzymatic glycation reactions between reducing sugars and proteins, lipids, or nucleic acids. AGEs accumulate in bloodstream and bodily tissues under chronic hyperglycemia. AGEs create irreversible cross-linkages of various intra- and extracellular molecules and activate the receptor for advanced glycation end products (RAGE), which stimulates downstream signaling pathways that generate reactive oxygen species (ROS) and contribute to oxidative stress. Additionally, intracellular glycation of mitochondrial respiratory chain proteins by AGEs contributes to the further generation of ROS, which, in turn, sets a vicious cycle that further promotes the production of endogenous AGEs. Through these pathways, AGEs play a principal role in the pathogenesis of various diabetic complications, including diabetic retinopathy, nephropathy, neuropathy, bone disease, atherosclerosis and non-alcoholic fatty liver disease. Multiple clinical studies and meta-analyses have revealed a positive association between tissue or circulating levels of AGEs and development of various diabetic complications. Besides, exogenous AGEs, primarily those derived from diets, promote insulin resistance, obesity, and metabolic syndrome. CONCLUSIONS: AGEs, triggered by chronic hyperglycemia, play a pivotal role in the pathogenesis of various complications of diabetes mellitus.

Mineralocorticoid receptor antagonists with sodium-glucose co-transporter-2 inhibitors in heart failure: a meta-analysis.

BACKGROUND AND AIMS: To investigate the cardiovascular effects of sodium-glucose co-transporter-2 inhibitors (SGLT2i) with concomitant mineralocorticoid receptor antagonist (MRA) use in heart failure (HF) regardless of ejection fraction (EF) and explore the risk of MRA-associated adverse events in individuals randomized to SGLT2i vs. placebo. METHODS: PubMed/MEDLINE, Web of Science, Embase, and clinical trial registries were searched for randomized controlled trials/post-hoc analyses evaluating SGLT2i in HF with or without MRA use (PROSPERO: CRD42023397129). The main outcomes were composite of first hospitalization or urgent visit for HF/cardiovascular death (HHF/CVD), HHF, and CVD. Others were all-cause mortality, composite renal and safety outcomes. Hazard ratios (HR)/risk ratios were extracted. Fixed-effects meta-analyses and subgroup analyses were performed. RESULTS: Five eligible studies were included, pooling data from 21 947 people with HF (type 2 diabetes mellitus, n = 10 805). Compared to placebo, randomization to SGLT2i showed a similar reduction in HHF/CVD and HHF in people who were or were not using MRAs [HHF/CVD: hazard ratio (HR) 0.75; 95% confidence interval (CI) 0.68-0.81 vs. HR 0.79; 95% CI 0.72-0.86; P-interaction = .43; HHF: HR 0.74; 95% CI 0.67-0.83 vs. HR 0.71; 95% CI 0.63-0.80; P-interaction = .53], with a suggestion of greater relative reduction in CVD in chronic HF people randomized to SGLT2i and using MRAs irrespective of EF (HR 0.81; 95% CI 0.72-0.91 vs. HR 0.98; 95% CI 0.86-1.13; P-interaction = .034). SGLT2i reduced all-cause mortality (P-interaction = .27) and adverse renal endpoints regardless of MRA use (P-interaction = .73) despite a higher risk of volume depletion with concomitant MRAs (P-interaction = .082). SGLT2i attenuated the risk of mild hyperkalaemia (P-interaction < .001) and severe hyperkalaemia (P-interaction = .051) associated with MRA use. CONCLUSIONS: MRAs did not influence SGLT2i effects on the composite of HHF/CVD, HHF or all-cause mortality; however, findings hinted at a more pronounced relative reduction in CVD in chronic HF patients regardless of EF who were randomized to SGLT2i and receiving an MRA compared to those randomized to SGLT2i and not receiving MRAs. SGLT2i attenuated the risk of MRA-associated treatment-emergent hyperkalaemia. These findings warrant further validation in well-designed randomized controlled trials.

Serum uric acid lowering and effects of sodium-glucose cotransporter-2 inhibitors on gout: A meta-analysis and meta-regression of randomized controlled trials.

AIMS: To pool the effects of sodium-glucose cotransporter-2 (SGLT2) inhibitors on gout and to investigate the association of these effects with baseline serum uric acid (SUA), SUA lowering, and underlying conditions, such as type 2 diabetes mellitus (T2DM)/heart failure (HF). METHODS: PubMed, Embase, Web of Science, Cochrane Library and clinical trial registry websites were searched for randomized controlled trials (RCTs) or post hoc analyses (≥1-year duration; PROSPERO:CRD42023418525). The primary outcome was a composite of gouty arthritis/gout flares and commencement of anti-gout drugs (SUA-lowering drugs/colchicine). Hazard ratios (HRs) with 95% confidence interval (CI) were pooled using a generic inverse-variance method with a random-effects model. Mixed-effects model univariate meta-regression analysis was performed. RESULTS: Five RCTs involving 29 776 patients (T2DM, n = 23 780) and 1052 gout-related events were identified. Compared to placebo, SGLT2 inhibitor use was significantly associated with reduced risk of composite gout outcomes (HR 0.55, 95% CI 0.45-0.67; I2 = 61%, P < 0.001). Treatment benefits did not differ between trials being conducted exclusively in baseline HF versus those conducted in patients with T2DM (P-interaction = 0.37), but were greater with dapagliflozin 10 mg and canagliflozin 100/300 mg (P < 0.01 for subgroup differences). Sensitivity analysis excluding trials that evaluated the effects of empagliflozin 10/25 mg (HR 0.68, 95% CI 0.57-0.81; I2 = 0%) accentuated the benefits of SGLT2 inhibitors with no between-trial heterogeneity (HR 0.46, 95% CI 0.39-0.55; I2 = 0%). Univariate meta-regression found no impact of baseline SUA, SUA lowering on follow-up, diuretic use, or other variables on their anti-gout effects. CONCLUSION: We found that SGLT2 inhibitors significantly reduced the risk of gout in individuals with T2DM/HF. Lack of an association with SUA-lowering effects suggests that metabolic and anti-inflammatory effects of SGLT2 inhibitors may predominantly mediate their anti-gout benefits.

Autonomous growth hormone secretion due to McCune Albright syndrome in paediatric age group: an ominous triad.

PURPOSE: The current study aimed to report cases of McCune Albright syndrome (MAS) with growth hormone (GH) hyper secretion along with a systematic review of literature to elucidate challenges and intricacies in its diagnosis and management. METHODS: It was a single centre study carried out in individuals with MAS and autonomous GH secretion (AGHS). In addition, a systematic search of literature across three databases (PubMed, Scopus and EMBASE) was performed from inception until May 31, 2021 to identify cases of MAS with AGHS in the pediatric age group (<18 years). RESULTS: Three cases from authors centre and 42 cases identified from systematic literature review were analysed. Precocious puberty was the most common presenting endocrinopathy seen in 56.8% (25/44) cases, followed by hyperthyroidism (10/45), hypophosphatemia (4/45), and hypercortisolism (2/45). Cranio-facial fibrous dysplasia (CFFD) was seen in all while polyostotic fibrous dysplasia and Café au lait macule was seen in 40/45 (88.9%) and 35/45 (77.8%), respectively. Pituitary adenoma (58.3% microadenoma) was localized in 53.3% (24/45) cases on pituitary imaging. Biochemical and clinical remission of AGHS was achieved in 61.5% (24/45) cases with medical therapy. CONCLUSION: Diagnosing AGHS in MAS is challenging because of concomitant presence of CFFD, non-GH endocrinopathies associated height spurt and elevated serum IGF-1. GH-GTT should be performed in presence of elevated growth velocity and serum IGF-1 (>1 X ULN) despite adequate control of non-GH endocrinopathies. Medical management can lead to disease control in substantial number of cases and often entails use of multiple agents.

SGLT2 inhibitors and cardiovascular outcomes in heart failure with mildly reduced and preserved ejection fraction: A systematic review and meta-analysis.

AIM: To provide a pooled effect of sodium-glucose cotransporter-2 inhibitors (SGLT2i) on cardiovascular outcomes in patients with heart failure with preserved ejection fraction (HFpEF: ≥50%) or/and mildly reduced EF (HFmrEF: 41-49%) regardless of baseline diabetes. METHODS: We systemically searched PubMed/MEDLINE, Embase, Web of Science databases and clinical trial registries using appropriate keywords till August 28, 2022, to identify randomized controlled trials (RCTs) or post-hoc analysis of RCTs, reporting cardiovascular death (CVD) and/or urgent visits/hospitalization for heart failure(HHF) in patients with HFmrEF/HFpEF receiving SGLTi vs. placebo. Hazard ratios (HR) with 95% confidence intervals (CI) for outcomes were pooled together using generic inverse variance method with fixed-effects model. RESULTS: We identified six RCTs, pooling data retrieved from 15,769 patients with HFmrEF/HFpEF. Pooled analysis showed that compared to placebo, SGLT2i use was significantly associated with improved CVD/HHF outcomes in HFmrEF/HFpEF (pooled HR 0.80, 95% CI: 0.74, 0.86, p < 0.001, I2 = 0%). When separately analyzed, benefits of SGLT2i remained significant across HFpEF (N = 8891, HR 0.79, 95% CI: 0.71, 0.87, p < 0.001, I2 = 0%) and HFmrEF (N = 4555, HR 0.77, 95% CI: 0.67, 0.89, p < 0.001, I2 = 40%). Consistent benefits were observed also in HFmrEF/HFpEF subgroup without baseline diabetes (N = 6507, HR 0.80, 95% CI: 0.70, 0.91, p < 0.001, I2 = 0%). Sensitivity analysis including the DELIVER and EMPEROR-Preserved trials found a trend towards significant beneficial effects on CV deaths with no heterogeneity (HR 0.90, 95% CI: 0.79, 1.02, p = 0.08, I2 = 0%). CONCLUSIONS: This meta-analysis established the place of SGLT2i as a foundational therapy among patients with HF with preserved and mildly reduced EF regardless of diabetes.

Characterization of primary hyperparathyroidism based on target organ involvement: An analysis from the Indian PHPT registry.

BACKGROUND: It has been a matter of debate for long time about the existence of two distinct phenotypes of primary hyperparathyroidism (PHPT) predisposed to either renal or skeletal manifestation. OBJECTIVE: To differentiate characteristics of symptomatic PHPT patients based on the presence of skeletal or renal involvement. DESIGN: Retrospective analysis of data from the Indian PHPT registry. PATIENTS: PHPT patients were divided into four discrete groups: asymptomatic, presenting with renal manifestations alone, skeletal manifestations alone, and both skeletal and renal manifestations. MEASUREMENTS: Clinical, biochemical, and tumour weight and histopathological characteristics of these groups were compared. RESULTS: Of the 229 eligible patients, 45 were asymptomatic, 62 had renal manifestations, 55 had skeletal manifestations, and 67 had both skeletal and renal manifestations. Patients with both skeletal and renal manifestations had higher serum calcium levels than those with isolated skeletal involvement [12.5 (11.1-13.7) mg/dL, 11.2 (10.6-12.3) mg/dL, respectively; p < .05]. Serum alkaline phosphatase (AP), plasma parathyroid hormone (PTH) levels, and parathyroid tumour weight were significantly higher in patients with isolated skeletal, and both skeletal and renal manifestations, compared to the other two groups. A preoperative PTH and AP level of 300 pg/mL and 152 U/L, predicted the risk of developing skeletal involvement with sensitivity and specificity of 71%, 70%, and 69%, 67%, respectively. CONCLUSIONS: We observed distinct skeletal and renal phenotypic subgroups among PHPT patients with characteristic biochemical and hormonal patterns with higher parathyroid disease burden in patients with skeletal complications compared to those with isolated renal manifestation.

GLP-1 Receptor Agonists and Risk of Adverse Cerebrovascular Outcomes in Type 2 Diabetes: A Systematic Review and Meta-Analysis of Randomized Controlled Trials.

CONTEXT: The effect of glucagon-like peptide-1 receptor agonists (GLP-1RAs) on ischemic/hemorrhagic stroke and transient ischemic attacks (TIA) in type 2 diabetes mellitus (T2DM) remains undetermined. OBJECTIVE: To pool effects of GLP-1RAs on adverse cerebrovascular outcomes and investigate impact of baseline variables on these effects. METHODS: PubMed, Embase, Web of Science, Cochrane Library, and clinical trial registry websites were searched for randomized controlled trials (RCTs) ≥24 weeks duration in adults with T2DM (PROSPERO: CRD42022331547). Adjudicated cerebrovascular events in GLP-1RA treatment vs control arms were pooled together to calculate risk ratios (RR) using fixed-effects model. Subgroup analysis was performed based on individual drugs, treatment duration, and baseline patient characteristics. Quality of evidence was assessed using GRADE framework. RESULTS: We identified 28 RCTs involving 74 148 patients (57% male; median [range], age 58 [52-67] years, BMI 32 [25.4-37.2] kg/m2, T2DM duration 9 [3.5-15.4] years, treatment duration 52 [24-259] weeks). GLP-1RA use in T2DM was associated with significantly decreased risk of adverse cerebrovascular outcomes vs placebo/active comparator (RR, 0.83; 95% CI, 0.76-0.91; I2 = 0%). Pooling data from cardiovascular outcome trials (n = 8), GLP-1RA treatment vs placebo was associated with reduced risk of nonfatal stroke (RR, 0.85; 95% CI, 0.76-0.94; I2 = 0%) but not fatal stroke (RR, 0.80; 95% CI, 0.61-1.05; I2 = 0%). GLP-1RA use was associated with reduced risk of ischemic stroke (RCTs = 12; RR, 0.73; 95% CI, 0.60-0.89; I2 = 0%), composite of ischemic stroke/TIA (RCTs = 16; RR, 0.76; 95% CI, 0.65-0.90; I2 = 0%), but not hemorrhagic stroke (RCTs = 3; RR, 0.92; 95% CI, 0.51-1.64; I2 = 0%). Treatment benefits differed according to baseline eGFR and diabetes duration (P interaction < .1). Benefits were statistically significant for dulaglutide, subcutaneous/oral semaglutide (P < .05). Sensitivity analysis, excluding shorter-acting lixisenatide, eliminated the heterogeneity between individual GLP-1RA effects. CONCLUSION: GLP-1RAs, particularly longer-acting formulations, reduced ischemic cerebrovascular events in T2DM. Observed benefits were significantly higher in patients with shorter T2DM duration and higher eGFR.

Large parathyroid adenomas: Potential mechanisms to reconcile adenoma size and disease phenotype.

Parathyroid adenomas weighing more than 3.5 g are reported variously as "atypical", "large" or "giant" parathyroid adenomas. All such adenomas are rare variants accounting for no more than 1.5% of all parathyroid adenomas. Large parathyroid adenomas are often associated with more severe form of the disease, including osteitis fibrosa cystica (OFC) and share many biochemical, histological, and molecular features of both benign and malignant parathyroid neoplasms, and are considered a distinct clinical entity. However, the pathogenesis of oversized parathyroid adenomas and the often-associated skeletal phenotype remains unclear. We present 5 cases of primary hyperparathyroidism (PHPT) with OFC, an uncommon manifestation of contemporary PHPT, associated with larger parathyroid adenomas, seen in the Bone and Mineral Disorders Clinic of the Henry Ford Health in the last 30 years to illustrate the critical role of vitamin D nutrition in the pathogenesis of both the OFC and adenoma size. The estimated prevalence of OFC was very low 0.2%, 5 of the >3000 surgically confirmed cases of PHPT seen during this time. The mean ± SD values were: age: 36.8 ± 22.1 years (4 of the 5 <36years), serum calcium 11.6 ± 1.1 mg/dl, alkaline phosphatase 799 ± 487 IU/L, PTH 1440 ± 477 pg/ml, 25-hydroxyvitamin D 13.0 ± 8.9 ng/ml, 1,25-dihyroxyvitamin D 26.5 ± 13.7 pg/ml, urine calcium 562 ± 274 mg/day, and parathyroid adenoma weight 4.53 ± 2.2 g. Parathyroidectomy led to the resolution of both the biochemical indices and OFC in each patient without recurrence over >10 years of follow-up. Because OFC is a very rare in the West, but very common areas of endemic vitamin D deficiency, we also examined the relationship between vitamin D nutrition, as assessed by serum 25-hydroxyvitamin D level, and parathyroid adenoma weight as well as prevalence of OFC in two large secularly diverse cohorts of patients with PHPT (Detroit, USA and Chandigarh, India). Based on this relationship and the relative prevalence of OFC in these two large cohorts, we propose that vitamin D nutrition (and perhaps calcium nutrition) best explains both the adenoma size and prevalence of OFC.