Background: No meta-analysis has holistically analyzed and summarized the safety and therapeutic efficacy of the newer RNA interference (RNAi) therapies, olezarsen, plozasiran, and zodasiran, in managing conditions associated with hypertriglyceridemia (HTG).
Methods: Randomized controlled trials (RCTs) involving patients with HTG or mixed hyperlipidemia (MHL) receiving either olezarsen, plozasiran, or zodasiran in the intervention arm and a placebo in the control arm were searched through electronic databases. The primary outcome was the safety profile of the drugs studied; secondary outcomes included the percent change from baseline (CFB) in the lipid levels, including triglyceride (TG).
Results: Six RCTs with 334 participants were evaluated. Olezarsen, plozasiran, and zodasiran were well-tolerated with no higher risk of serious adverse events or injection-site reactions. After 24 weeks, plozasiran increased alanine aminotransferase and HbA1c more than placebo, although the difference was insignificant at 48 weeks. Plozasiran and zodasiran had little effect on hyperglycemia worsening. Olezarsen increased the likelihood of mild platelet count decreases without clinical harm. At their longest clinical trial follow-up, the highest doses of olezarsen, plozasiran, and zodasiran lowered TG by 55.2%, 50.57%, and 51.2% of baseline levels. All three drugs decreased non-HDL-C and remnant cholesterol. Olezarsen and plozasiran lowered ApoC-III and increased HDL-C, whereas zodasiran reduced HDL-C. Zodasiran decreased LDL-C, whereas olezarsen and plozasiran had no effects on LDL-C. Plozasiran and zodasiran lowered apolipoprotein B, but not olezarsen.
Conclusion: The newer RNA interference (RNAi) therapies appear safe and have excellent TG-lowering efficacy in patients with HTG and MHL.
Objective: This study evaluates the relationship between the Life's Essential 8 (LE8) scoring system and all-cause and cause-specific mortality among obese individuals using NHANES data.
Methods: Data from 9,143 obese participants (BMI ≥30 kg/m2) collected between 2005 and 2018 were analyzed. Participants were categorized based on their LE8 scores: low cardiovascular health (Low CVH, n=2264), moderate cardiovascular health (Moderate CVH, n=6541), and high cardiovascular health (High CVH, n=338). Associations between LE8 scores and mortality were assessed using Kaplan-Meier survival analysis and Cox proportional hazards models.
Results: Over a median follow-up of 7.3 years, there were 867 all-cause deaths (9.5%), including 246 cardiovascular disease (CVD) deaths (2.7%) and 621 non-CVD deaths (6.8%). In multivariable Cox regression analysis, compared to the Low CVH group, the Moderate CVH group had an adjusted hazard ratio (HR) for all-cause mortality of 0.63 (95% CI: 0.55-0.72), and the High CVH group had an HR of 0.25 (95% CI: 0.10-0.60). For CVD mortality, the HRs were 0.61 (95% CI: 0.47-0.78) for Moderate CVH and 0.19 (95% CI: 0.03-1.38) for High CVH. For non-CVD mortality, the HRs were 0.64 (95% CI: 0.54-0.75) for Moderate CVH and 0.27 (95% CI: 0.10-0.72) for High CVH. Each 10-point increase in LE8 score was associated with a 20% reduction in all-cause mortality (P<0.001), 21% reduction in CVD mortality (P<0.001), and 20% reduction in non-CVD mortality (P<0.001).
Conclusion: Higher LE8 scores are significantly associated with lower rates of all-cause, CVD, and non-CVD mortality among obese individuals. These findings support the LE8 scoring system as an effective predictor of health status and mortality risk.
The rapid evolution of ultrasound (US) technology has dramatically changed the medical field. Ideally suited for evaluation of anatomic disorders of the thyroid, coupled with its ease of use at the bedside, US has become an essential tool for Endocrinologists over the last 50 years. This noninvasive technology provides a sensitive and specific instrument for malignancy risk prediction of thyroid nodules, surveillance for recurrent thyroid cancer, and diagnosis of autoimmune thyroid disorders. While US has proven invaluable for such diagnostic purposes, its extensive use also has resulted in important negative consequences. This review will discuss the evolution of US equipment for the evaluation of thyroid disorders, its use in interventional procedures, and the unintended outcomes from the widespread adoption of this technology. Finally, this article will explore the potential future applications for US technology and its related advancements.
Objective: The risk of venous thromboembolism (VTE) with feminizing gender-affirming hormone therapy (GAHT) is an area of concern. This analysis aimed to assess whether GAHT and other potential risk factors are associated with VTE in transfeminine and gender diverse (TGD) individuals.
Methods: We conducted a chart review of 2,126 TGD adults receiving care within a large urban health system. The primary outcomes were the prevalence of VTE and odds ratios for the association of VTE with insurer, use of estrogen, and select comorbidities.
Results: A history of VTE was documented in 0.8% of the cohort. Those with a history of VTE were older (p<.001), more often self-identified as Hispanic or Black compared to white or Asian (p<.05) and were more likely to have Medicaid or Medicare (p<.01) when compared to those without a history of VTE. The prevalence of hyperlipidemia (p<.001), diabetes mellitus (p<.05), and hypercoagulable conditions (p<.001) were all greater in the +VTE group. Hyperlipidemia (p<.001), diabetes mellitus (p<.05), and insurer (p<.05) were associated with increased odds of VTE in univariate analyses. None of the exposure variables analyzed were associated with VTE when controlling for age, race, and the number of comorbidities.
Conclusions: The prevalence of VTE in our cohort was lower than previously observed. VTE was not associated with any one risk factor, including estrogen use, when controlling for age, race, and the number of comorbidities. Those of advanced age and those with multiple cardiometabolic comorbidities may benefit from increased surveillance and mitigation of modifiable risk factors.
To investigate the risk of developing diabetes and ketoacidosis in clinical patients with immune checkpoint inhibitors (ICIs).
We looked in the FDA Adverse Event Reporting System for reports of ICIs-associated diabetes mellitus (DM) and ketoacidosis between January 2004 and March 2022. We explored the signals using fourfold table-based proportional imbalance algorithms. Patient characteristics, country distribution, and outcomes of adverse reactions were described. Kruskal-Wallis test was used to compare the time of onset and prognosis of adverse reactions.
A total of 2110 reports of ICIs-related DM were included in the study. The largest number of reports was from Japan (752, 35.64%), followed by the United States and France (624, 29.57%; 183, 8.67%). Seven drugs detected signals of DM and ketoacidosis according to 4 proportional imbalance algorithms: nivolumab, pembrolizumab, cemiplimab, dostarlimab, atezolizumab, avelumab, and durvalumab. Diabetes and ketoacidosis generally occurred early in the course of ICIs treatment, the median time to event onset was 144.5 (interquartile range 27-199) days. ICIs-related diabetes and ketoacidosis events resulted in 934 major medical events (44.3%), 524 hospitalizations (24.8%), 60 life-threatening events (2.8%), 42 deaths (2.0%), and 39 disability events (1.8%).
The study reveals the risk and characteristics of diabetes and ketoacidosis associated with ICIs, which may provide evidence for postmarketing evaluation. Careful consideration should be given to the possibility of an increased risk of diabetes and ketoacidosis after using ICIs, and careful monitoring for diabetes and ketoacidosis is recommended.
Data are scant on the impact of metformin use in gestational diabetes mellitus/diabetes in pregnancy on long-term outcomes in children and mothers beyond 5 years of childbirth. This systematic review and meta-analysis aimed to evaluate the long-term impact of metformin use in pregnancy on children and their mothers.
Electronic databases were searched for studies evaluating metformin compared with insulin for managing gestational diabetes mellitus/diabetes in pregnancy. The primary outcome was the change in body mass index (BMI) in children at the ages of 5 to 11 years. The secondary outcomes were alterations in other anthropometric measures, obesity, and changes in the levels of lipids and adipocytokines in children and mothers.
Children at the age of 9 years born to mothers who were treated with metformin during pregnancy had similar BMI (mean difference [MD], 1.09 kg/m2 [95% confidence interval {CI}, −0.44 to 2.62]; P = .16; I2 = 16%), waist circumference-to-height ratio (MD, 0.13 [95% CI, −0.05 to 0.30]; P = .16; I2 = 94%), dual-energy X-ray absorptiometry (DXA) total fat mass (MD, 0.68 kg [95% CI, −2.39 to 3.79]; P = .66; I2 = 70%), DXA total fat percent (MD, 0.04% [95% CI, −3.44 to 3.51]; P = .98; I2 = 56%), DXA total fat-free mass (MD, 0.81 kg [95% CI, −0.96 to 2.58]; P = .37; I2 = 55%), magnetic resonance imaging visceral adipose tissue volume (MD, 80.97 cm3 [95% CI, −136.47 to 298.41]; P = .47; I2 = 78%), and magnetic resonance spectroscopy liver fat percentage (MD, 0.27% [95% CI, −1.26 to 1.79]; P = .73; I2 = 0%) to those born to mothers who were treated with insulin. Serum adiponectin, leptin, alanine aminotransferase, and ferritin were comparable among groups. In children between the ages of 9 and 11 years, the occurrence of obesity, diabetes, or challenges in motor and social development were comparable between the 2 groups. After 9 years of childbirth, BMI and the risk of developing diabetes were similar between the 2 groups of women.
Metformin use in pregnancy did not show any adverse effects compared with insulin on long-term outcomes in children and their mothers.
Feminizing gender-affirming hormone therapy is the mainstay of treatment for many transgender and gender diverse people. Injectable estradiol preparations are recommended by the World Professional Association for Transgender Health Standards of Care 8 and the Endocrine Society guidelines. Many patients prefer this route of administration, but few studies have rigorously assessed optimal dosing or route.
We performed a scoping review of the available data on estradiol levels achieved with various dosages of estradiol injections in transgender and gender diverse adults on feminizing gender-affirming hormone therapy. We also report on testosterone suppression, route (ie, subcutaneous vs intramuscular), and type of injectable estradiol ester as well as timing of blood draw relative to the most recent dose, where available.
The data we reviewed suggest that the current guidelines, which recommend starting doses 2 to 10 mg weekly or 5 to 30 mg every 2 weeks of estradiol cypionate or valerate, are too high and likely lead to patients having supraphysiologic levels across much of their injection cycle.
The optimal starting dose for injectable estradiol remains unclear and whether it should differ for cypionate and valerate. Based on the data available, we suggest that clinicians start injectable estradiol cypionate or valerate via subcutaneous or intramuscular injections at a dose ≤5 mg weekly and then titrate accordingly to keep levels within guideline-recommended range. Future studies should assess timing of injections and subsequent levels more precisely across the injection cycle and between esters.
To describe adherence to daily somatropin treatment and impact on height velocity within 1 year of treatment start among patients with pediatric growth hormone deficiency in a real-world US population.
This retrospective cohort study included pediatric patients aged ≥3 years to <16 years with pediatric growth hormone deficiency prescribed somatropin by a pediatric endocrinologist at a US-based center of excellence between January 1, 2015 and December 31, 2020. Patient data were collected using hospital electronic health records linked to a specialty pharmacy patient prescription records. Adherence, evaluated over 12 months, was measured using the proportion of days covered metric and patients were categorized as adherent if their proportion of days covered ≥80%. Height velocity was annualized to compare across adherent and nonadherent patients.
One hundred eighty-one patients were identified and included in this study, of which 70.2% were male,73.5% were white, and mean age (standard deviation [SD]) at index was 12.1 (2.8). In the height velocity analysis, 174 patients were included and the mean (SD) annualized change in height was 10.2 (5.7) cm/y in the adherent group (n = 108) and 9.8 (7.6) in the nonadherent group (n = 66). The difference in height velocity between the groups was not statistically significant.
Minor improvements in average height velocity were observed in the patient group who were adherent to somatropin therapy, although not statistically significant. Lack of observed significance may be due to small sample sizes, short observation period, a likely heterogenous population in terms of growth hormone prescribing, data bias due to single-center origin, or potential patient misclassification.
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