Cardiometabolic Effects Research Articles

The effects of regular exercise on cognitive and cardiometabolic health in testicular cancer survivors subjected to platinum-based chemotherapy.

Platinum-based chemotherapy provides curative treatment to more than 95% of patients with testicular germ cell tumor but it has negative cardiometabolic and neurological effects. Regular exercise can alleviate late chemotherapy-related toxicities. We examined the impact of a 6-month supervised aerobic-strength training on cognitive and cardiometabolic health and residual level of platinum in cancer survivors. Twenty-eight middle-aged (42.1±7.6 years) testicular germ cell tumor survivors subjected to platinum-based chemotherapy (1-8 cycles, 0-24 years ago) were recruited into exercise (n=20) and control (n=8) groups. Effects of 6-month exercise training on the whole-body and muscle metabolism, cognitive functions, cardiopulmonary fitness, residual plasma platinum, and plasma adiponectin were examined. Exercise intervention improved cardiopulmonary fitness and cognitive functions, reduced residual plasma platinum, visceral adiposity and muscle lipids, improved glucose (glycosylated hemoglobin) and lipid (high-density lipoprotein cholesterol) metabolism, and enhanced dynamics of muscle post-exercise phosphocreatine recovery. Exercise-related decline in plasma platinum was paralleled by decline of muscle glycerophosphocholines and by the enhanced metabolic flexibility during low-intensity exercise, and predicted training-induced increase in cognitive functions. The 6-month exercise intervention resulted in improved cognitive and cardiometabolic health in testicular germ cell tumor survivors, which was paralleled by reduced plasma platinum, providing evidence that structured supervised exercise brings multiple health benefits to testicular germ cell tumor survivors.

Cardiometabolic effect of switching from an efavirenz-based therapy to a dolutegravir-based therapy on clinical and virological outcomes among people living with HIV at the Yaoundé Central Hospital

Cardiometabolic effect of switching from an efavirenz-based therapy to a dolutegravir-based therapy on clinical and virological outcomes among people living with HIV at the Yaoundé Central Hospital

Violence victimisation and young adult cardiometabolic health: the role of timing and social identity

Background Adolescent violence victimisation is associated with a spectrum of adult social and behavioural health outcomes, including adverse mental health symptoms. However, underlying social stress mechanisms linking adolescent victimisation to adult cardiometabolic health remains poorly understood. Aim The current study aims to reveal how adolescent and adult interpersonal violence exposures each get “under the skin” to affect adult metabolic syndrome, including direct victimisation and, additionally, witnessing violence. Subjects and methods We use a nationally representative longitudinal cohort, the National Longitudinal Study of Adolescent to Adult Health, and leverage a quasi-experimental approach, propensity score matching regression analysis (n = 14,267). Results We find that adolescent violence exposure carries an enduring effect on young adult metabolic syndrome risk factor incidence and high-risk status, which is independent of young adult violence. Violence effects do not vary by sex or racial identity. Conclusion In sum, adolescent exposure to direct interpersonal violence significantly affects young adult cardiometabolic health in ways suggesting adolescence is a sensitive period for the onset of harmful cardiometabolic effects in early adulthood. Findings warrant future study of underlying pathways and how these effects shape social inequities in cardiometabolic health among U.S. adults broadly.

Angiotensin-(1-7) and Central Control of Cardiometabolic Outcomes: Implications for Obesity Hypertension.

Hypertension is a leading independent risk factor for the development of cardiovascular disease, the leading cause of death globally. Importantly, the prevalence of hypertension is positively correlated with obesity, with obesity-related hypertension being difficult to treat due to a lack of current guidelines in this population as well as limited efficacy and adverse off-target effects of currently available antihypertensive therapeutics. This highlights the need to better understand the mechanisms linking hypertension with obesity to develop optimal therapeutic approaches. In this regard, the renin-angiotensin system, which is dysregulated in both hypertension and obesity, is a prime therapeutic target. While research and therapies have typically focused on the deleterious angiotensin II axis of the renin-angiotensin system, emerging evidence shows that targeting the protective angiotensin-(1-7) axis also improves cardiovascular and metabolic functions in animal models of obesity hypertension. While the precise mechanisms involved remain under investigation, in addition to peripheral actions, evidence exists to support a role for the central nervous system in the beneficial cardiometabolic effects of angiotensin-(1-7). This review will highlight emerging translational studies exploring the cardiovascular and metabolic regulatory actions of angiotensin-(1-7), with an emphasis on its central actions in brain regions including the brainstem and hypothalamus. An improved understanding of the central mechanisms engaged by angiotensin-(1-7) to regulate cardiovascular and metabolic functions may provide insight into the potential of targeting this hormone as a novel therapeutic approach for obesity-related hypertension.

Plant-based meat alternatives and cardiometabolic health: a systematic review and meta-analysis.

Plant-based meat alternatives (PBMAs) are emerging in global markets. However, the effects of substituting meat for PBMAs on cardiometabolic health are uncertain. This study aimed to determine the effects of replacing meat consumption by PBMAs on cardiometabolic parameters in adults. Five databases were systematically explored from inception to July 2024, searching for RCTs assessing the effects of replacing meat consumption by PBMAs on cardiometabolic parameters in adults without cardiovascular diseases. Meta-analyses were conducted when ≥4 studies addressed the same outcome (i.e. blood lipids, blood pressure, fasting glucose, and body weight). Pooled raw mean differences (MDs) with their 95% CIs were estimated using a random-effects method. Sensitivity analyses were conducted to assess the robustness of our estimates. Eight publications from 7 RCTs comprising 369 adults (60% females; mean age range: 24-61 y) were included. The substitution of PBMAs for meat was associated with significant reductions in LDL-cholesterol: -0.25 mmol/L (95% CI: -0.42, -0.08 mmol/L; I2 = 65.8%; n = 7), total cholesterol (TC): -0.29 mmol/L (95% CI: -0.52, -0.06 mmol/L; I2 = 64.8.%; n = 6), and body weight: -0.72 kg (95% CI: -1.02, -0.42 kg; I2 = 0%; n = 5). No significant changes were shown in HDL-cholesterol, triglycerides, blood pressure, or fasting glucose concentrations. Sensitivity analyses considering mycoprotein-based alternatives showed a significant reduction in LDL-cholesterol (MD: -0.37 mmol/L; 95% CI: -0.61, -0.13 mmol/L; I2 = 52.5%; n = 4), and TC (MD: -0.39 mmol/L; 95% CI: -0.56, -0.21 mmol/L; I2 = 0%; n = 4). Our findings suggest substituting PBMAs for meat for ≤8 wk lowered TC (6%), LDL-cholesterol (12%), and body weight (1%) in adults without cardiovascular diseases. PBMAs may facilitate the transition to a plant-based diet, but long-term studies are needed to evaluate their cardiometabolic effects. This trial was registered at PROSPERO as CRD42024556191.

Abstract 4113164: Central Arterial Stiffness in Young Adults with Perinatal HIV Exposure

Intro: Young adults with perinatally acquired HIV (YPHIV) have higher morbidity and mortality than uninfected persons. Antiretroviral therapy (ART) has extended life expectancy making adult CV disease a concern. Perinatal exposure to HIV increases inflammation which is associated with increased arterial stiffness which predicts CV disease. Aims: We compared arterial stiffness between YPHIV and young adults perinatally HIV exposed but uninfected (YPHEU), and evaluated the association of type and duration of ART regimens, HIV disease severity, and cardiac structure and function with arterial stiffness. Methods: In a substudy of the Pediatric HIV/AIDS Cohort Study, 150 participants (95 YPHIV, 55 YPHEU, mean 23.4 yrs, 60% female, 72% Black, 24% Hispanic) had echocardiography and pulse wave velocity (PWV) measured. We compared PWV between YPHIV and YPHEU, adjusting for covariates. Among YPHIV, we fit linear regression models to evaluate the association of current (within 1 year of PWV) and historical measures of HIV disease severity with PWV. We computed correlations between PWV and measures of left ventricular (LV) structure and function, overall and by HIV status. Results: Mean PWV and hemodynamic parameters did not differ between YPHIV and YPHEU (YPHIV 5.63 vs YPHEU 5.39 m/s; p=0.5). HIV control was good (82% with viral load <400 copies/ml), 91% used combination ART: integrase strand inhibitors (INSTIs; median duration 4.6 years), protease inhibitors (PIs 15.1 years), or non-nucleoside reverse transcriptase inhibitors (NNRTIs 5.2 years). Most participants had normal PWV compared to healthy controls but all values above 11.8 m/sec ( Figure , level associated with CV events in adults) were only in YPHIV. Only weak correlations were observed between PWV and echocardiographic measures (<0.20) in both YPHEU and YPHIV. Among YPHIV, HIV severity measures were not associated with PWV using either current or historical measures. Mean PWV was 1.68 (-0.36, 3.72) m/s higher among YPHIV with current PI use than those on INSTIs, and 1.58 (-0.94, 4.11) m/s higher than those on NNRTIs, although these differences were not significant. Conclusions: PWV was within normal ranges in most YPHIV and YPHEU although 5% YPHIV had elevated PWV. PWV may be higher with PI use due to cardiometabolic side effects. Successful HIV treatment and control of traditional CV risk factors may prevent premature vascular aging and subsequent cardiac compromise in YPHIV.

Abstract 4116298: Once Weekly Utreglutide (GL0034), a Glucagon-like Peptide-1 Receptor Agonist, at 4 × 450 µg Doses Reduces Blood Pressure, Lipids, and Body Weight in Post-menopausal Females: A Phase I Study

Background: Utreglutide (GL0034), a novel, once weekly glucagon-like peptide-1 receptor agonist (GLP-1RA), previously demonstrated significant reductions in body weight (BW) after a single dose ascending study in individuals with obesity . BW reductions after pharmacological treatment of obesity with GLP-1RA is associated with blood pressure (BP) lowering effects. Aim: This phase I study assessed the safety, tolerability, and cardio-metabolic effects of utreglutide after multiple ascending doses in post-menopausal female volunteers with overweight and obesity. Methods: In this randomized, double-blind, placebo-controlled study 12 post-menopausal female volunteers with overweight/obesity, aged 18 to 65 years old with a body mass index (BMI) ≥26 kg/m 2 were randomized (9:3) to subcutaneous utreglutide fixed doses (4 × 450 µg); or placebo once weekly for four weeks. Safety, tolerability, and key cardio-metabolic parameters were assessed. Biomarker measurements included oral glucose tolerance test (OGTT) insulin and glucose area under the curve (AUC), systolic- and diastolic BP, lipid profile (triglycerides (TG), total cholesterol (TC), low density lipoprotein (LDL), and non-high-density lipoprotein (non-HDL), creatinine, potassium, BW and leptin. Results: Utreglutide was generally well tolerated and related adverse effects were mainly gastrointestinal with dose-dependent nausea, vomiting and decreased appetite. Reductions in OGTT AUCs of insulin ( p <0.05) and glucose ( p <0.01) were noted on Day 23 after four weeks treatment with Utreglutide. This was accompanied by a decrease ( p <0.001) in mean systolic and diastolic BP on Day 23 from baseline (BL). On Day 23, significant reductions in TC ( p <0.01), LDL ( p <0.05) and non-HDL ( p <0.05) were observed. BW reduction versus BL ( p <0.001) was 2.0 kg and 1.8 kg respectively on Day 29 and End of Study (EoS). Leptin levels significantly reduced from BL on Day 23 ( p< 0.01) and EoS ( p <0.001). No significant changes were observed for TG, creatinine and potassium (Table). Conclusions: Once weekly utreglutide dosing for four weeks at a dose of 450 µg in post-menopausal females with overweight and obesity, demonstrated clinically relevant reductions of systolic and diastolic BP. This was associated with improved performance of OGTT AUC of insulin and glucose, lipids, BW and leptin with an overall good tolerability and with potential to demonstrate cardio-metabolic benefits.

Abstract 4134990: Body Fat Quantitation Predicts Progressive Cardiac Dysfunction with Age: Sex-Dependent Variations And Clinical Outcomes

Background: Among older adults whose body mass index (BMI) readings may be spuriously reduced due to loss of skeletal muscle, BMI alone may lack specificity for body fat quantitation. In addition, sex-based hormones differentially influence body fat composition between the sexes with aging. To evaluate the cardiometabolic effect of body fat on older adults, we hypothesize that sex would exert differential effects on baseline and progression of cardiac dysfunction in older adults. Methods: Community older adults without cardiovascular disease (CVD) underwent prospective transthoracic echocardiography with simultaneous body fat quantitation (body fat mass (BFM), percentage body fat (PBF), and waist-hip ratio (WHR) by bioimpedance, at baseline and five-year intervals. Mitral early diastolic inflow velocity to early diastolic annular tissue velocity (E/e') and early to late diastolic inflow velocity (E/A) ratios were recorded. Multivariable regression models were adjusted for significant clinical variables. Adverse clinical outcomes were defined as mortality or hospitalization during follow-up. Results: Baseline and interval annotation of 409 older adults (mean age 61±12.7 years, 52% females) demonstrated deteriorations in E/A ratios of -0.1 ± 0.3 and E/e' ratios of 1.8 ± 2.8, over a mean duration of 4.9 ± 0.4 years. Baseline BFM (β -0.01, p<0.001; β 0.023, p=0.352) and PBF (β -0.008, p=0.002; β -0.007, p=0.759) predicted interval changes in E/A but not E/e' respectively independent of covariates (Table 1). In sex-specific analyses, higher baseline PBF was associated with deteriorations in E/A (β 0.010, p=0.028) among women and E/e' among men (β -0.069, p=0.020). Increases in PBF over time were particularly associated with reductions in E/A among women (β -0.005, p=0.047) independent of higher baseline PBF, in addition to significant interactions between sex and PBF in predicting changes in E/A. (Figure 1). Higher baseline WHR predicted adverse clinical outcomes [w1] among women (HR 1.09, 95%CI 1.03-1.16, p=0.005). Conclusion: Baseline and longitudinal increases in fat quantity defined a trajectory of deteriorations in cardiac function among older adults, and prognosticated poorer future outcomes, particularly among women with central adiposity as represented by WHR. Refining CVD risk based upon quantitative sex-specific fat targets for older adults may be a strategy in the future.

Adiponectin may play a crucial role in the metabolic effects of GLP-1RAs treatment in patients with Type 2 Diabetes Mellitus: a preliminary longitudinal study.

Type 2 diabetes mellitus (T2DM) stands as the most prevalent metabolic disorder globally. T2DM entails numerous cardiovascular complications, which contribute significantly to morbidity, mortality, and increased public spending worldwide. The real challenge for new diabetes drugs lies not only in reducing blood glucose levels and glycated hemoglobin but also in preventing cardiovascular risk. Emerging receptor agonists for glucagon-like peptide-1 (GLP-1RAs) have demonstrated a pivotal role in diabetes management and mitigating cardiovascular risk. We conducted a 12-month longitudinal investigation evaluating the cardio-metabolic effects of GLP-1RAs on a cohort of 65 Caucasian patients diagnosed with T2DM who were scheduled for treatment with GLP-1RAs. Fifty-four T2DM patients successfully completed the 12-month study period, with 30 receiving dulaglutide and 24 receiving semaglutide. In our study population, GLP-1RAs resulted in several positive changes beyond the observed weight loss: a shift in fat distribution, indicated by a reduction in the percentage of visceral fat (1.21 vs. 1.17, p < 0.05); a significant decrease in LDL cholesterol levels (p < 0.05) and triglycerides (p < 0.01); and a significant increase in serum adiponectin levels (p < 0.05), potentially indicating a reduction in insulin resistance and inflammation. Additionally, we observed a significant decrease in microalbuminuria and media-intimal thickness at the carotid vessel level (p < 0.05). In patients with T2DM 1-year therapy with GLP-1RAs has a positive effect on the main determinants of cardiovascular risk including body weight, visceral fat, dyslipidemia, and atherosclerosis. Moreover, the increase in adiponectin may play a pivotal role in controlling the inflammatory state and the mechanisms of vascular damage.

Cardiometabolic outcomes in patients with overweight and obesity undergoing weight loss trials : a network meta-analysis

Abstract Objective Cardiometabolic outcomes are intrinsically linked with obesity. According to a study by Jayedi A et al. a 5kg weight gain could increase CVD mortality and MI risk by 11% and 18% respectively, with most overweight and obese patient also suffering from cardiometabolic derangements. This network meta-analysis evaluates cardiometabolic effects bought about by glucagon-like peptide 1 receptor agonists (GLP-1 RA) and other weight loss drugs in an overweight and obese population. Methods Cochrane CENTRAL, Embase and Medline were searched for randomised clinical trials (RCTs) on GLP-1 RA and United States Food and Drug administration weight loss drugs. A network meta-analysis was performed, using risk ratios(RR) to compare the efficacy of the interventions against one another. Network diagrams and surface under the cumulative ranking curve analysis were generated for the following cardiometabolic outcomes ( LDL, HDL, TC, TG, HbA1c, FPG, SBP and DBP). Results Among the cardiometabolic outcomes analysed, the GLP-1RA’s consistently ranked on top, with tirzepatide followed by semaglutide and then liraglutide. In terms of glycaemic control, tirzepatide 15, 10 and 5mg ranked first in a dose dependent manner(SUCRA = 0.8480, 0.8410, 0.6725) followed by semaglutide1.7mg(SUCRA= 0.6232). Tirzepatide 15mg did not achieve statistical significance compared to semaglutide 1.0mg (MD: -0.77, 95%CI: -2.04 to 0.50) or liraglutide1.8mg (MD: -0.64, 95%CI: -1.68 to 0.41). In reducing blood pressure, tirzepatide exhibiting a dose dependent reduction with Tirzepatide 15mg, (SUCRA =0.9457),10mg(SUCRA=0.9069)and 5mg(SUCRA=0.8419) followed by semaglutide 1.7mg (SUCRA =0.7415) then liraglutide 1.8mg(SUCRA = 0.5521).Tirzepatide 15mg demonstrated statistical significance compared to semaglutide 1.0mg (MD: -3.53, 95%CI: -6.78 to -0.27) and liraglutide 3.0mg (MD: -3.47, 95%CI: -5.59 to -1.36). The GLP-1RA’s also exhibited superiority in lipid reduction for TC and TG, with tirzepatide reducing TC (SUCRA = 0.7867) and TG(SUCRA = 0.9843) followed by semaglutide 1.7 mg (SUCRA = 0.7796) for TC and tirzepatide 10 mg (SUCRA = 0.9018) for TG. Orlistat 120mg(SUCRA =0.8789) and 60mg(SUCRA= 0.8458) were superior in reducing LDL, with tirzepatide 15mg(SUCRA =0.7806) and then semaglutide 2.4mg(SUCRA=0.7260) coming in behind. Naltrexone 32mg/Bupropion 360mg(SUCRA = 0.8757) ranked first followed by tirzepatide(SUCRA=0.8593) in increasing HDL, however the increase was not statistically significant (MD: 0.00, 95%CI: -0.04 to 0.05). Conclusion GLP-1 RAs’ superiority in addressing cardiometabolic parameters that are often deranged in patients with overweight and obesity highlights the need for weight lost medication transitioning from one that decreases and suppresses appetite or prevent the absorption of lipids to one that targets the altered metabolic mileu of patients with overweight and obesity, highlighting the multipronged approach needed to treat this metabolic disease.

Unequal effects of adolescent health behaviors on adult cardiometabolic conditions: a cohort study

Abstract Background Health behaviors in adolescence could have a life-long effect on cardiometabolic health and differ by parental socioeconomic conditions. Adopting a life course perspective and a causal inference framework, we aimed to quantify the differential effect of adolescent unhealthy behaviors on adult cardiometabolic conditions by parental financial situation. Methods Using the National Longitudinal Study of Adolescent to Adult Health in the United States (n = 3,772), we estimated conditional causal effect by parental financial situation through inverse probability-weighted marginal structural models. Exposures were adolescent health behaviors (dietary habits, cigarette smoking, alcohol consumption and physical activity) and the effect modifier was parental financial situation (difficulty paying bills vs. no difficulty), both measured at ages 12-19 (1994-1995). Outcomes were cardiometabolic conditions (hypertension, stroke, cardiac failure, diabetes, chronic kidney disease), measured at ages 33 - 43 (2016-2018) using biomarkers and self-reports. Results There were 1,206 participants with cardiometabolic conditions after 20 years of follow-up. Alcohol consumption among adolescents with parental financial difficulty led to 325 more cardiometabolic cases (95% confidence interval: 2 - 647) compared to alcohol consumption by their peers without financial difficulty. This differential effect is driven more by cardiovascular conditions (hypertension, stroke, or cardiac failure) than by metabolic conditions (diabetes or chronic kidney disease). There were no differential effects of dietary habits, cigarette smoking and physical inactivity on the occurrence of adult cardiometabolic conditions. Conclusions Public health initiatives targeting alcohol consumption during adolescence could mitigate socioeconomic inequalities in adult cardiometabolic conditions. Key messages • Socioeconomically disadvantaged adolescents are more susceptible to the long-term detrimental health effects of alcohol consumption. • These susceptible groups may need targeted interventions to mitigate the cardiometabolic effect of alcohol consumption.

Narrative review of lifestyle interventions in breast cancer survivors: current evidence and future directions.

In 8 females, 1 will be diagnosed with breast cancer in their lifetime. Although medical advances have increased the likelihood of survival, up to 90% of females will gain weight during and after treatment increasing the risk of breast cancer recurrence and obesity-related comorbidities in survivorship. Behavioral lifestyle interventions focused on diet with or without physical activity can provide breast cancer survivors nonpharmacological options to decrease weight gain and cardiometabolic risk. A PubMed search was conducted to identify all behavioral lifestyle interventions focused on diet or diet combined with physical activity longer than 4 weeks of duration in breast cancer survivors that included body weight as an outcome. This review aims to summarize the effects on body weight, body composition, and cardiometabolic risk markers. The review shows there is high heterogeneity in type and duration of the intervention to affect weight and cardiometabolic risk in survivorship. Calorie restriction with and without physical activity appears to promote weight loss among breast cancer survivors. However, the effects on cardiometabolic factors are less clear. Future studies should be powered for body weight and cardiometabolic effects. Researchers should also consider interventions that (1) are less complex, (2) recruit a more racially and ethnically diverse sample, (3) integrate resistance training, (4) implement the intervention in closer proximity to diagnosis, (5) target weight management in this population before it occurs, and (6) analyze body composition in addition to body weight measurements.

Cardiometabolic effects of sacubitril/valsartan in a rat model of heart failure with preserved ejection fraction

The promising results obtained in the PARADIGM-HF trial prompted the approval of sacubitril/valsartan (SAC/VAL) as a first-in-class treatment for heart failure with reduced ejection fraction (HFrEF) patients. The effect of SAC/VAL treatment was also studied in patients with heart failure with preserved ejection fraction (HFpEF) and, although improvements in New York Heart Association (NYHA) class, HF hospitalizations, and cardiovascular deaths were observed, these results were not so promising. However, the demand for HFpEF therapies led to the approval of SAC/VAL as an alternative treatment, although further studies are needed. We aimed to elucidate the effects of a 9-week SAC/VAL treatment in cardiac function and metabolism using a preclinical model of HFpEF, the Zucker Fatty and Spontaneously Hypertensive (ZSF1) rats. We found that SAC/VAL significantly improved diastolic function parameters and modulated respiratory quotient during exercise. Ex-vivo studies showed that SAC/VAL treatment significantly decreased heart, liver, spleen, and visceral fat weights; cardiac hypertrophy and percentage of fibrosis; lipid infiltration in liver and circulating levels of cholesterol and sodium. Moreover, SAC/VAL reduced glycerophospholipids, cholesterol, and cholesteryl esters while increasing triglyceride levels in cardiac tissue. In conclusion, SAC/VAL treatment improved diastolic and hepatic function, respiratory metabolism, reduced hypercholesterolemia and cardiac fibrosis and hypertrophy, and was able to modulate cardiac metabolic profile. Our findings might provide further insight into the therapeutic benefits of SAC/VAL treatment in obese patients with HFpEF.

7792 Efficacy of Retatrutide for Weight Reduction and Its Cardiometabolic Effects Among Adults: A Systematic Review and Meta-Analysis

Abstract Disclosure: D.C. Lopez: None. J.T. Pajimna: None. M.D. Milan: None. G.V. Jasul: None. G. Orpilla: None. I. Zapanta: None. B. Serquiña: None. G. Dychiao: None. Background: Obesity remains to be a global health challenge and it is associated with several complications such as diabetes, cardiovascular disease, fatty liver disease, and reduced life expectancy. Although lifestyle modifications are the mainstay for weight management, long term maintenance of weight loss can be a challenge for many affected adults. There have been proven safe and effective pharmacologic interventions but these remain limited to date. One of the novel anti-obesity drugs, retatrutide, is a single peptide with agonist activity at the GLP-1, glucose-dependent insulinotropic polypeptide (GIP), and glucagon receptors. The aim of this systematic review and meta-analysis is to evaluate the effectiveness of this triple-hormone receptor agonist, Retatrutide, in weight reduction and assess its cardiometabolic effects in adults. Methodology: An extensive electronic database search was done to identify studies published from inception until December 2023. All randomized controlled trials (RCT) that evaluated the use of retatrutide for adult patients were included. The Cochrane Risk of Bias 2.0 tool was used to assess the risk of bias of each study. Meta-analysis was conducted to determine weight reduction and glycemic control using random effects model which was reported at 95% confidence interval. Statistical heterogeneity was assessed using I2 statistics and random effects analysis and sensitivity analysis were done to control for the heterogeneity. Results: A total of 3 eligible RCTs were included in the study, all of which had risk of bias ranging from low to unclear. Of these articles, in 2 RCTs involving 353 participants with type 2 diabetes mellitus, retatrutide showed significant weight reduction by 11.89kg as compared to placebo (MD -11.89; 95% CI -13.53 to -10.25) and decreased glycosylated hemoglobin (HbA1C) by 1.64% as compared to placebo (MD: -1.64%, 95% CI [-2.38, -0.89]). Using direct comparison, retatrutide 12mg reduced body weight by 11.83kg as compared to dulaglutide 1.5mg with significant difference (MD -11.83; 95% CI -18.50 to -5.16), and retatrutide showed slight decrease in HbA1C by 0.61% as compared to dulaglutide (MD -0.66; 95% CI -0.66 to -0.56). In another 1 RCT involving 338 non-diabetic adult patients with obesity, retatrutide decreased least-squares mean percentage in body weight by 24.2% and 83% of participants who received retatrutide achieved weight reduction of 15% or more at 48 weeks. Conclusion: The use of retatrutide may result in substantial reductions in mean body weight and HbA1C as compared to controls in adult patients, with low to moderate certainty of evidence. In addition, retatrutide showed marked decrease in body weight but with modest glucose lowering effect when compared to a single GLP1 agonist drug. Presentation: 6/3/2024

12326 Is Non-functional Adrenal Incidentaloma (AI) Benign Or A Long-haul Culprit?

Abstract Disclosure: J. Mehta: None. F. Rauf: None. C. Salafia: None. S. Salam: None. R.K. Trousdale: None. I. Sachmechi: None. Introduction: Patients with non-functional AI have adrenal tumors that are incidentally discovered during abdominal imaging performed for clinical indications unrelated to adrenal glands and their AM serum cortisol post overnight 1 mg dexamethasone suppression test (DST) are ≤1.8µg/dL. There has been emerging evidence that non-functional AI may pose cardiometabolic risks. Hypothesis: Patients considered to have non-functional AI have increased cardiometabolic risks as compared to patients without AI. Methodology: A cohort study via retrospective chart review utilizing electronic medical records across NYC Health and Hospitals sites. The data collection was from 1/1/2000 to 7/31/2022 and 2965 records were reviewed. Primary composite outcome assessed was the presence of at least one out of hypertension, peripheral vascular disease, coronary artery disease, transient ischemic attack or cerebral vascular accident. Target had patients considered to have non-functional AI and ≥5-year follow-up, and the three target cohorts categorized based on AM serum cortisol post 1mg overnight DST were: Target Cohort 1: 0 to 1µg/dL (lower limit inclusive and upper limit exclusive), Target Cohort 2: 1 to 1.5µg/dL, and Target Cohort 3:1.5 to 1.8µg/dL. Control had patients from general adult population with absence of adrenal incidentaloma, absence of pregnancy during the time points of chart review and presence of ≥5-year follow-up. Two by two comparisons were made between target (N=76) versus control (N=100) at baseline and ≥5-year follow-up. The target cohorts were also compared individually against control at baseline and ≥5-year follow-up. Results: Mean age for target and control at follow-up were 64.4 (±12.1) and 56.2 (±14.2) years respectively (association between age and target versus control status of p=0.001). 54% of target had primary outcome at baseline, compared to 36% of control (p=0.017). When target cohorts were compared individually against control at baseline, 70% of Target Cohort 2 had primary outcome compared to 36% of control (p=0.0003). At follow-up, 68% of Target Cohort 2 had primary outcome compared to 47% of control (p=0.028). Discussion and Conclusion: Patients considered to have non-functional AI show correlations between target status and age, and target status and primary outcome. This study’s results clearly show that patients considered to have non-functional AI are not free of their cortisol’s adverse cardiometabolic effects. Non-functional AI, along with Cushing’s and subclinical Cushing’s syndromes, may present a continuum of cortisol secretion that poses cardiometabolic risks. Current clinical guidelines may require re-evaluation such that patients considered to have non-functional AI are monitored regularly for an early diagnosis, prevention and management of cardiometabolic outcomes. Presentation: 6/3/2024

Efficacy of retatrutide for weight reduction and its cardiometabolic effects among adults: A systematic review and meta-analysis

Efficacy of retatrutide for weight reduction and its cardiometabolic effects among adults: A systematic review and meta-analysis

Total adiponectin in indigenous Melanesians on Kitava.

Experimental and small human studies have indicated that high total adiponectin levels have beneficial cardiometabolic effects. In contrast, however, high total adiponectin levels are also associated with higher all-cause and cardiovascular mortality in thoroughly adjusted epidemiological studies. To gain further insight into these seemingly contradictory results, we report results on total adiponectin from the indigenous Melanesian population of Kitava, Trobriand Islands, Papua New Guinea, where an apparent absence of cardiometabolic disease has been previously reported. Fasting levels of serum total adiponectin were measured cross-sectionally in ≥40-year-old Kitavans (n = 102) and Swedish controls matched for age and sex (n = 108). Multivariable linear regression was used for the analysis of associations with total adiponectin when controlled for group, sex, smoking, hypertension and/or type 2 diabetes, age, and body mass index. Total adiponectin was lower for Kitavans compared to Swedish controls (Median [Mdn] 4.6 μg/mL, range 1.0-206 μg/mL and Mdn 9.7 μg/mL, range 3.1-104 μg/mL, respectively, r = .64, p < .001). Lower total adiponectin was associated with Kitavan group, male sex (only in Swedish controls), smoking (only in Kitavans and Swedish controls combined), younger age (not in Swedish controls), higher BMI, lower total, low-density lipoprotein, high-density lipoprotein (HDL) (only in Kitavans and Swedish controls combined), and non-HDL cholesterol, and higher anti-PC IgG (only in Kitavans and Swedish controls combined). Total adiponectin in Kitavans was significantly lower than in Swedish controls.

GLP-1 Receptor Agonists and SGLT2 Inhibitors in Type 2 Diabetes: Pleiotropic Cardiometabolic Effects and Add-on Value of a Combined Therapy.

Glucagon-like peptide-1 receptor agonists (GLP-1RAs) and sodium-glucose cotransporter 2 inhibitors (SGLT2is) have proven efficacy and safety in randomized clinical trials and observational real-life studies. Besides improving glucose control, reducing body weight, and lowering arterial blood pressure (surrogate endpoints), the breakthroughs were the demonstration of a significant reduction in cardiovascular and renal events in patients with type 2 diabetes at high risk. GLP-1RAs reduce events linked to atherogenic cardiovascular disease (especially ischemic stroke) and also renal outcomes (FLOW trial with semaglutide), with a limited effect on heart failure. The most striking protective effects of SGLT2is were a marked reduction in hospitalization for heart failure and a remarkable reduced progression of chronic kidney disease. These benefits have been attributed to numerous pleiotropic effects beyond glucose-lowering action. Underlying mechanisms contributing to cardiovascular and renal protection are at least partially different between GLP-1RAs (mainly anti-atherogenic and vascular effects) and SGLT2is (mainly systemic and intrarenal hemodynamic changes). Thus, patients at high risk may benefit from complementary actions when being treated with a GLP-1RA/SGLT2i combination. Such combination has proven its efficacy on surrogate endpoints. Furthermore, posthoc subgroup analyses of cardiovascular outcome trials have suggested a greater cardiorenal protection in patients treated with a combination versus either monotherapy. The benefits of a combined therapy have been confirmed in a few retrospective cohort studies. A dedicated prospective trial comparing a combined therapy versus either monotherapy is ongoing (PRECIDENTD); however, several challenges still remain, especially the higher cost of a combined therapy and the worldwide underuse of either GLP-1RAs or SGLT2is in clinical practice, even in patients at high cardiorenal risk.

Higher fiber higher carbohydrate diets better than lower carbohydrate lower fiber diets for diabetes management: Rapid review with meta-analyses.

Some dietary recommendations continue to recommend carbohydrate restriction as a cornerstone of dietary advice for people with diabetes. We compared the cardiometabolic effects of diets higher in both fiber and carbohydrate with lower carbohydrate lower fiber diets in type 1 or type 2 diabetes. MEDLINE, Embase, and the Cochrane Database of Systematic Reviews up to June 24, 2024, with additional hand searching. Randomized controlled trials in which both dietary fiber and carbohydrate amount had been modified were identified from source evidence syntheses on carbohydrate amount in people with diabetes. Two reviewers independently. Ten eligible trials including 499 participants with diabetes (98% with T2) were identified from the potentially eligible 828 trials included in existing evidence syntheses. Pooled findings indicate that higher fiber higher carbohydrate diets reduced HbA1c (mean difference [MD] -0.50% [95% confidence interval -0.99 to -0.02]), fasting insulin (MD -0.99 μIU/mL [-1.83 to -0.15]), total cholesterol (MD -0.16 mmol/L [-0.27 to -0.05]) and low-density lipoprotein cholesterol (MD -0.16 mmol/L (-0.31 to -0.01) when compared with lower carbohydrate lower fiber diets. Trials with larger differences in fiber and carbohydrate intakes between interventions reported greater reductions. Certainty of evidence for these outcomes was moderate or high, with most outcomes downgraded due to heterogeneity unexplained by any single variable. Our predefined scope excluded trials with co-interventions such as energy restriction, which may have provided addition information. Findings indicate the greater importance of promoting dietary fiber intakes, and the relative unimportance of carbohydrate amount in recommendations for people with diabetes.

Clinical and Cardiometabolic Effects of Reducing Sedentary Behavior in Postmenopausal Women with Rheumatoid Arthritis.

We investigated the effects of a 4-month intervention targeting sedentary behavior on sedentary time and physical activity level, clinical parameters, cardiometabolic risk factors, inflammatory markers, and health-related quality of life in postmenopausal women with rheumatoid arthritis. This was a 4-month, parallel-group, randomized controlled trial ( ClinicalTrials.gov identifier: NCT03186924). One hundred and three postmenopausal rheumatoid arthritis patients were randomized (1:1) to either a newly developed intervention targeting sedentary behavior (Take a STAND for Health [TS4H]) or standard of care (SOC). Sedentary behavior (primary outcome) and physical activity levels, clinical parameters, anthropometric parameters and body composition, blood samples and oral glucose tolerance test, blood pressure, muscle function, and health-related quality of life were assessed at baseline (Pre) and after 4 months (Post). Between- and within-group differences were tested using linear mixed models following the intention-to-treat principle. Total sedentary time, time in prolonged sitting bouts, standing, and stepping did not change in either group (all P ≥ 0.337). No significant between- and within-group differences were detected for any of the clinical parameters, markers of cardiometabolic health and inflammation, and health-related quality of life variables (all P ≥ 0.136). Among responders in TS4H group (those who reduced sedentary time by ≥30 min·d -1 ), Pre to Post IL-10 concentrations tended to reduce (group-time: P = 0.086; estimated mean difference [EMD]: -12.0 pg·mL -1 [-23.5 to -0.6], P = 0.037) and general health (group-time: P = 0.047; EMD: 10.9 A.U. [-1.1 to 22.9], P = 0.086) and overall physical health tended to improve (group-time: P = 0.067; EMD: 7.9 A.U. [-0.9 to 16.6], P = 0.089). TS4H did not change sedentary behavior, physical activity levels, clinical, cardiometabolic, inflammatory, or health-related quality of life outcomes. However, TS4H tended to reduce IL-10 levels and improve health-related quality of life in responders.