Changes in Blood Lipids Following Initiation of Gender Affirming Hormone Therapy: A Systematic Review and Meta-Analysis.

Aim: The aim of this study was to conduct a systematic review and meta-analysis of changes in low density lipoprotein cholesterol (LDL-C), high density lipoprotein cholesterol (HDL-C), total cholesterol, and triglycerides following initiation of feminizing or masculinizing gender affirming hormone therapy (GAHT). Methods: A search of Ovid MEDLINE, Embase, Web of Science, SCOPUS, and CINAHL databases identified potentially relevant articles published from 1990 through 2024. Both observational and randomized trials of adults receiving feminizing or masculinizing GAHT with baseline and follow-up measures were included. Articles were reviewed for eligibility using Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) 2020 guidelines. The risk of bias in each study was quantified using the NHLBI Study Quality Assessment Tool for Before-After (Pre-Post) Studies with No Control Group. Random effects models were used to compute the before-and-after meta-differences in mean values for each parameter along with the I2 statistic to assess heterogeneity of results. Results: Thirty-five studies met the criteria for inclusion in the meta-analysis. Masculinizing GAHT was associated with significant changes in serum lipids from baseline up through the 60-month timepoint with meta-difference of means (95% CI) estimates of 26.2mg/dL (23.3,29.0) for LDL-C, 26.1mg/dL (22.8,29.4) for total cholesterol, 30.7mg/dL (6.9,54.6) for triglycerides and -9.4mg/dL (-12.1, -6.7) for HDL-C. Studies evaluating the effects of feminizing GAHT on balance demonstrated no notable changes in HDL-C or triglycerides while the results for LDL-C and total cholesterol were inconsistent. Heterogeneity of results ranged from minimal (I2 = 0%) to substantial (I2 = 90%). Conclusions: While the results for transfeminine individuals on GAHT appear somewhat reassuring, transmasculine patients receiving testosterone may benefit from closer monitoring of lipid profiles.

Race and ethnicity and pharmacy dispensing of SGLT2 inhibitors and GLP-1 receptor agonists in type 2 diabetes.

Background: Sodium-Glucose Cotransporter 2 Inhibitors (SGLT2i) and Glucagon-Like Peptide-1 Receptor Agonists (GLP-1 RA) improve cardiorenal outcomes in patients with type 2 diabetes. Equitable use of SGLT2i and GLP-1 RA has the potential to reduce racial and ethnic health disparities. We evaluated trends in pharmacy dispensing of SGLT2i and GLP-1 RA by race and ethnicity. Methods: Retrospective cohort study of patients (≥18 years) with type 2 diabetes using 2014-2022 electronic health record data from six US care delivery systems. Entry was at earliest pharmacy dispensing of any type 2 diabetes medication. We used multivariable logistic regression to evaluate the association between pharmacy dispensing of SGLT2i and GLP1-RA and race and ethnicity. Findings: Our cohort included 687,165 patients (median 6 years of dispensing data; median 60 years; 0.3% American Indian/Alaska Native (AI/AN), 16.6% Asian, 10.5% Black, 1.4% Hawaiian or Pacific Islander (HPI), 31.1% Hispanic, 3.8% Other, and 36.3% White). SGLT2i was lower for AI/AN (OR 0.80, 95% confidence interval 0.68-0.94), Black (0.89, 0.86-0.92) and Hispanic (0.87, 0.85-0.89) compared to White patients. GLP-1 RA was lower for AI/AN (0.78, 0.63-0.97), Asian (0.50, 0.48-0.53), Black (0.86, 0.83-0.90), HPI (0.52, 0.46-0.57), Hispanic (0.69, 0.66-0.71), and Other (0.78, 0.73-0.83) compared to White patients. Interpretation: Dispensing of SGLT2is, and GLP-1 RAs was lower in minority group patients. There is a need to evaluate approaches to increase use of these cardiorenal protective drugs in patients from racial and ethnic minority groups with type 2 diabetes to reduce adverse cardiorenal outcomes and improve health equity. Funding: Patient-Centered Outcomes Research Institute and National Institutes of Health.

One episode of low intensity aerobic exercise prior to systemic AAV9 administration augments transgene delivery to the heart and skeletal muscle.

INTRODUCTION: The promising potential of adeno-associated virus (AAV) gene delivery strategies to treat genetic disorders continues to grow with an additional three AAV-based therapies recently approved by the Food and Drug Administration and dozens of others currently under evaluation in clinical trials. With these developments, it has become increasingly apparent that the high doses currently needed for efficacy carry risks of toxicity and entail enormous manufacturing costs, especially for clinical grade products. Strategies to increase the therapeutic efficacy of AAV-mediated gene delivery and reduce the minimal effective dose would have a substantial impact on this field. We hypothesized that an exercise-induced redistribution of tissue perfusion in the body to favor specific target organs via acute aerobic exercise prior to systemic intravenous (IV) AAV administration could increase efficacy. BACKGROUND: Aerobic exercise triggers an array of downstream physiological effects including increased perfusion of heart and skeletal muscle, which we expected could enhance AAV transduction. Prior preclinical studies have shown promising results for a gene therapy approach to treat Barth syndrome (BTHS), a rare monogenic cardioskeletal myopathy, and clinical studies have shown the benefit of low intensity exercise in these patients, making this a suitable disease in which to test the ability of aerobic exercise to enhance AAV transduction. METHODS: Wild-type (WT) and BTHS mice were either systemically administered AAV9 or completed one episode of low intensity treadmill exercise immediately prior to systemic administration of AAV9. RESULTS: We demonstrate that a single episode of acute low intensity aerobic exercise immediately prior to IV AAV9 administration improves marker transgene delivery in WT mice as compared to mice injected without the exercise pre-treatment. In BTHS mice, prior exercise improved transgene delivery and additionally increased improvement in mitochondrial gene transcription levels and mitochondrial function in the heart and gastrocnemius muscles as compared to mice treated without exercise. CONCLUSIONS: Our findings suggest that one episode of acute low intensity aerobic exercise improves AAV9 transduction of heart and skeletal muscle. This low-risk, cost effective intervention could be implemented in clinical trials of individuals with inherited cardioskeletal disease as a potential means of improving patient safety for human gene therapy.

Cardiovascular disease risk among transgender women living with HIV in the United States.

BACKGROUND: Transgender women (TW) are disproportionately affected by both HIV and cardiovascular disease (CVD). OBJECTIVES: We aim to quantify prevalence of elevated predicted CVD risk for TW compared to cisgender women (CW) and cisgender men (CM) in HIV care and describe the impact of multiple operationalizations of CVD risk score calculations for TW. DESIGN: We conducted a cross-sectional analysis of patients engaged in HIV care between October 2014 and February 2018. SETTING: The Centers for AIDS Research Network of Integrated Clinical Systems, a collaboration of 8 HIV clinical sites in the United States contributed data for this analysis. PATIENTS: 221 TW, 2983 CW, and 13467 CM. MEASUREMENTS: The measure of interest is prevalence of elevated 10-year cardiovascular disease risk based on ACC/AHA Pooled Cohort Risk Assessment equations (PCE) and the Framingham Risk Score (FRS), calculated for TW by: birth-assigned sex (male); history of exogenous sex hormone use (female/male); and current gender (female). RESULTS: Using birth-assigned sex, the adjusted prevalence ratio (aPR) was 2.52 (95% CI: 1.08,5.86) and 2.58 (95% CI: 1.71,3.89) comparing TW to CW, by PCE and FRS, respectively. It was 1.25 (95% CI: 0.54,2.87) and 1.25 (95% CI: 0.84,1.86) comparing TW to CM, by PCE and FRS, respectively. If TW were classified according to current gender versus birth-assigned sex, their predicted CVD risk scores were lower. LIMITATIONS: PCE and FRS have not been validated in TW with HIV. Few adjudicated CVD events in the data set precluded analyses based on clinical outcomes. CONCLUSIONS: After adjustment for demographics and history of HIV care, prevalence of elevated CVD risk in TW was similar to CM and equal to or higher than in CW, depending operationalization of the sex variable. Future studies with CVD outcomes are needed to help clinicians accurately estimate CVD risk among TW with HIV.

AAV-Mediated TAZ Gene Replacement Restores Mitochondrial and Cardioskeletal Function in Barth Syndrome.

Barth syndrome (BTHS) is a rare mitochondrial disease that affects heart and skeletal muscle and has no curative treatment. It is caused by recessive mutations in the X-linked gene TAZ, which encodes tafazzin. To develop a clinically relevant gene therapy to restore tafazzin function and treat BTHS, three different adeno-associated virus serotype 9 vectors were tested and compared to identify the optimal promoter-cytomegalovirus (CMV), desmin (Des), or a native tafazzin promoter (Taz)-for TAZ expression following intravenous administration of 1 × 1013 vector genomes/kilogram to a mouse model of BTHS as either neonates (1-2 days of age) or adults (3 months of age). At 5 months of age, evaluations of biodistribution and TAZ expression levels, mouse activity assessments, fatigue in response to exercise, muscle strength, cardiac function, mitochondrial structure, oxygen consumption, and electron transport chain complex activity assays were performed to measure the extent of improvement in treated mice. Each promoter was scored for significant improvement over untreated control mice and significant improvement compared with the other two promoters for every measurement and within each age of administration. All three of the promoters resulted in significant improvements in a majority of the assessments compared with untreated BTHS controls. When scored for overall effectiveness as a gene therapy, the Des promoter was found to provide improvement in the most assessments, followed by the CMV promoter, and finally Taz regardless of injection age. This study provides substantial support for translation of an adeno-associated virus serotype 9-mediated TAZ gene replacement strategy using a Des promoter for human BTHS patients in the clinic.