The Emerging Role of Glucagon-Like Peptide-1 Receptor Agonists for the Treatment of Metabolic Dysfunction-Associated Steatohepatitis.

Metabolic dysfunction-associated steatotic liver disease (MASLD) affects 1 in 3-4 adult individuals and can progress to metabolic dysfunction-associated steatohepatitis (MASH) and cirrhosis. Insulin resistance plays a central role in MASLD/MASH pathophysiology with higher rates of MASLD (2 in 3) and MASH with fibrosis (1 in 5) in adults with obesity and diabetes. This review summarizes the role of glucagon-like peptide-1 receptor agonists in treating MASLD/MASH. Although not approved by the Food and Drug Administration for the treatment of MASLD, this class of medication is available to treat obesity and type 2 diabetes and has been shown to reverse steatohepatitis, reduce cardiovascular risk, and is safe to use across the spectrum of MASLD with or without fibrosis.

Curbing the Obesity Epidemic: Should GLP-1 Receptor Agonists Be the Standard of Care for Obesity?

PURPOSE OF REVIEW: This article summarizes the medical management of obesity with an emphasis on incretin-based therapeutics that target the neuro-hormonal basis of obesity. RECENT FINDINGS: Medications that mimic the effect of incretins, a group of peptide hormones released in response to nutrient intake that regulate appetite, result in potent and durable weight loss. Glucagon-like peptide 1 (GLP-1) agonists and glucose-dependent insulinotropic polypeptide (GIP) agonists such as semaglutide and tirzepatide are approved by the United States Food and Drug Administration (FDA) for the management of obesity. The SELECT trial demonstrated that semaglutide led to a reduction in major adverse cardiovascular events in patients without diabetes who were either overweight and had preexisting cardiovascular disease or obese. SUMMARY: The treatment of obesity is critical to prevent the progression of cardiovascular-kidney-metabolic syndrome. Incretin-based therapies offer remarkable weight loss and reduce major cardiovascular adverse events.

Single-leg exercise training augments in vivo skeletal muscle oxidative flux and vascular content and function in adults with type 2 diabetes.

KEY POINTS: People with type 2 diabetes (T2D) have impaired skeletal muscle oxidative flux due to limited oxygen delivery. In the current study, this impairment in oxidative flux in people with T2D was abrogated with a single-leg exercise training protocol. Additionally, single-leg exercise training increased skeletal muscle CD31 content, calf blood flow and state 4 mitochondrial respiration in all participants. ABSTRACT: Cardiorespiratory fitness is impaired in type 2 diabetes (T2D), conferring significant cardiovascular risk in this population; interventions are needed. Previously, we reported that a T2D-associated decrement in skeletal muscle oxidative flux is ameliorated with acute use of supplemental oxygen, suggesting that skeletal muscle oxygenation is rate-limiting to in vivo mitochondrial oxidative flux during exercise in T2D. We hypothesized that single-leg exercise training (SLET) would improve the T2D-specific impairment in in vivo mitochondrial oxidative flux during exercise. Adults with (n = 19) and without T2D (n = 22) with similar body mass indexes and levels of physical activity participated in two weeks of SLET. Following SLET, in vivo oxidative flux measured by 31 P-MRS increased in participants with T2D, but not people without T2D, measured by the increase in initial phosphocreatine synthesis (P = 0.0455 for the group × exercise interaction) and maximum rate of oxidative ATP synthesis (P = 0.0286 for the interaction). Additionally, oxidative phosphorylation increased in all participants with SLET (P = 0.0209). After SLET, there was no effect of supplemental oxygen on any of the in vivo oxidative flux measurements in either group (P > 0.02), consistent with resolution of the T2D-associated oxygen limitation previously observed at baseline in subjects with T2D. State 4 mitochondrial respiration also improved in muscle fibres ex vivo. Skeletal muscle vasculature content and calf blood flow increased in all participants with SLET (P < 0.0040); oxygen extraction in the calf increased only in T2D (P = 0.0461). SLET resolves the T2D-associated impairment of skeletal muscle in vivo mitochondrial oxidative flux potentially through improved effective blood flow/oxygen delivery.

Obesity Management in Cardiometabolic Disease: State of the Art.

PURPOSE OF REVIEW: To summarize research from the last 5 years on the effects of weight loss treatments, including lifestyle changes, anti-obesity medications, and bariatric procedures on cardiovascular disease (CVD) risk factors and CVD outcomes in adults. RECENT FINDINGS: This narrative review includes and summarizes the contemporary evidence of the effects of these different weight loss approaches individually. A literature search was performed using the key words obesity, weight loss, CVD, cardiometabolic, and risk factors and included key clinical trials from the past 5 years. Obesity management through weight loss is associated with improvements in CVD risk factors, such as improved blood pressure, lipid profiles, and glycemic control, with greater weight loss leading to greater improvements in CVD risk factors. Bariatric surgery is associated with greater weight loss than the other procedures and treatments for obesity, and for this, and possibly for other reasons, it is associated with greater reductions in CVD outcomes and mortality. Obesity is an independent risk factor and modulator of other CVD risk factors, and thus, treatment of obesity should be an integral part of management strategies to reduce CVD risk. Future trials and real-world studies of longer duration are needed to inform providers and patients on how to individualize the approach to modifying risks of cardiometabolic disorders through obesity management.

Effect of Treating Vitamin D Deficiency in Uncontrolled Type 2 Diabetes: A Randomized, Placebo-Controlled Study.

BACKGROUND: Literature increasingly supports the inverse relationship of vitamin D (VitD) level and type 2 diabetes (T2DM). Proposed protective mechanisms of VitD include its anti-inflammatory effects, increased insulin secretion via pancreatic ß-cell stimulation, and downregulation of parathyroid hormone levels. Interventional studies show mixed results of VitD therapy in prediabetic patients with VitD deficiency or diabetic patients with normal VitD levels. STUDY QUESTION: Does high-dose VitD replacement improve glycemic control and microalbuminuria (MAU) in uncontrolled T2DM and concurrent VitD deficiency? STUDY DESIGN: This placebo-controlled, double-blinded study randomized 30 subjects aged 30-65 years with an elevated HbA1c level of 7.5%-10% and a low total 25-hydroxyvitamin-D value of <20 ng/mL to either placebo (n = 16) or ergocalciferol 50,000 IU (n = 14) once weekly for 8 weeks then once monthly for 4 months. MEASURES AND OUTCOMES: Primary outcome was difference in HbA1c from baseline to month 6 between the VitD-intervention group and the placebo-controlled group. Secondary end points were differences in total 25-hydroxyvitamin-D and MAU. Paired t tests and linear mixed-effects models were used for statistical analysis. RESULTS: No significant differences were seen in HbA1c or MAU between baseline versus postintervention visits within the placebo group (HbA1c: 8.4% ± 0.2 vs. 8.1% ± 0.3, P = 0.088; MAU: 94.1 mg/g ± 43.9 vs. 45.9 mg/g ± 20.2, P = 0.152) and the intervention group (HbA1c: 8.8% ± 0.3 vs. 8.7% ± 0.4, P = 0.692; MAU: 167.8 mg/g ± 70.1 vs. 108.5 mg/g ± 39.9, P = 0.356). The difference between placebo-slope and intervention-slope was nonsignificant for MAU (ß = -0.1 mg/g ± 0.4, P = 0.835) but was significant for total 25-hydroxyvitamin-D (ß = 11.7 ng/mL ± 2.5, P ≤ 0.001). Greater HbA1c reduction occurred unexpectedly in the placebo group ((Equation is included in full-text article.)= -0.4% ± 0.2) than in the intervention group ((Equation is included in full-text article.)= -0.2% ± 0.4), although the difference in slopes was not significant (ß = 0.2% ± 0.4, P = 0.640). CONCLUSIONS: Our proof-of-concept study found no benefit of high-dose VitD therapy in glycemic control and MAU in uncontrolled T2DM and VitD deficiency. Post hoc analyses raise concerns for high-dose VitD therapy to delay glycemic improvement. Large-scale interventional trials are much needed in this patient population to substantiate our findings and elucidate VitD's mechanisms on glucose metabolism.

Social Vulnerability and Cardiovascular-Related Mortality Among Older Adults in the United States.

PURPOSE: The association of social vulnerability and cardiovascular disease-related mortality in older adults has not been well characterized. METHODS: The Centers for Disease Control and Prevention database was evaluated to examine the relationship between county-level Social Vulnerability Index (SVI) and age-adjusted cardiovascular disease-related mortality rates (AAMRs) in adults aged 65 and above in the United States between 2016 and 2020. RESULTS: A total of 3139 counties in the United States were analyzed. Cardiovascular disease-related AAMRs increased in a stepwise manner from first (least vulnerable) to fourth SVI quartiles; (AAMR of 2423, 95% CI [confidence interval] 2417-2428; 2433, 95% CI 2429-2437; 2516, 95% CI 2513-2520; 2660, 95% CI 2657-2664). Similar trends among AAMRs were noted based on sex, all race and ethnicity categories, and among urban and rural regions. Higher AAMR ratios between the highest and lowest SVI quartiles, implying greater relative associations of SVI on mortality rates, were seen among Hispanic individuals (1.52, 95% CI 1.49-1.55), Non-Hispanic-Asian and Pacific Islander individuals (1.32, 95% CI 1.29-1.52), Non-Hispanic- American Indian or Alaskan Native individuals (1.43, 95% CI 1.37-1.50), and rural counties (1.21, 95% CI 1.20-1.21). CONCLUSION: Social vulnerability as measures by the SVI was associated with cardiovascular disease-related mortality in older adults, with the association being particularly prominent in ethnic minority patients and rural counties.

Bempedoic Acid in Secondary Prevention.

•Bempedoic acid has been shown to reduce major adverse cardiovascular outcomes in patients unable to take statins due to statin-associated side effects.•Analysis of CLEAR Outcomes trial data reveals possible differences in baseline characteristics between the primary and secondary prevention subgroups.•Further research is needed to optimize use of bempedoic acid and clarify its impact on cardiovascular outcomes in diverse patient populations.

Racial and ethnic disparities in cardiovascular disease - analysis across major US national databases.

BACKGROUND: There are several studies that have analyzed disparities in cardiovascular disease (CVD) health using a variety of different administrative databases; however, a unified analysis of major databases does not exist. In this analysis of multiple publicly available datasets, we sought to examine racial and ethnic disparities in different aspects of CVD, CVD-related risk factors, CVD-related morbidity and mortality, and CVD trainee representation in the US. METHODS: We used National Health and Nutrition Examination Survey, National Ambulatory Medical Care Survey, National Inpatient Sample, Centers for Disease Control and Prevention Wide-Ranging OnLine Data for Epidemiologic Research, United Network for Organ Sharing, and American Commission for Graduate Medical Education data to evaluate CVD-related disparities among Non-Hispanic (NH) White, NH Black and Hispanic populations. RESULTS: The prevalence of most CVDs and associated risk factors was higher in NH Black adults compared to NH White adults, except for dyslipidemia and ischemic heart disease (IHD). Statins were underutilized in IHD in NH Black and Hispanic patients. Hospitalizations for HF and stroke were higher among Black patients compared to White patients. All-cause, CVD, heart failure, acute myocardial infarction, IHD, diabetes mellitus, hypertension and cerebrovascular disease related mortality was highest in NH Black or African American individuals. The number of NH Black and Hispanic trainees in adult general CVD fellowship programs was disproportionately lower than NH White trainees. CONCLUSION: Racial disparities are pervasive across the spectrum of CVDs with NH Black adults at a significant disadvantage compared to NH White adults for most CVDs.

Rosiglitazone improves insulin resistance but does not improve exercise capacity in individuals with impaired glucose tolerance: A randomized clinical study.

Dysmetabolic states, such as type 2 diabetes (T2D), characterized by insulin resistance (IR), are associated with fatty liver, increased cardiovascular disease (CVD) risk, and decreased functional exercise capacity (FEC). Rosiglitazone (RO) improves exercise capacity and IR in T2D. However, the effects of RO on FEC and other markers of CVD risk in prediabetes are unknown. We hypothesized that insulin sensitization with RO would improve exercise capacity and markers of CVD risk in participants with impaired glucose tolerance (IGT). Exercise performance (peak oxygen consumption and oxygen uptake kinetics), IR (homeostasis model assessment of IR and quantitative insulin sensitivity check index), and surrogate cardiovascular endpoints (coronary artery calcium (CAC) volume and density and C-reactive protein (CRP)) were measured in participants with IGT after 12 and 18 months of RO or placebo (PL). RO did not significantly improve exercise capacity. Glycemic measures and IR were significantly lower in people on RO compared to PL at 18 months. CAC volume progression was not different between PL and RO groups. RO did not improve exercise capacity during an 18-month intervention despite improved IR and glycemia in people with IGT. Future studies should explore why effects on FEC with RO occur in T2D but not IGT. Understanding these questions may help in targeting therapeutic approaches in T2D and IGT.

Muscle mitochondrial function is impaired in adults with type 1 diabetes.

AIMS: Type 1 diabetes has been associated with mitochondrial dysfunction. However, the mechanism of this dysfunction in adults remains unclear. METHODS: A secondary analysis was conducted using data from several clinical trials measuring in-vivo and ex-vivo mitochondrial function in adults with type 1 diabetes (n = 34, age 38.8 ± 14.6 years) and similarly aged controls (n = 59, age 44.6 ± 13.9 years). In-vivo mitochondrial function was assessed before, during, and after isometric exercise with 31phosphorous magnetic resonance spectroscopy. High resolution respirometry of vastus lateralis muscle tissue was used to assess ex-vivo measures. RESULTS: In-vivo data showed higher rates of anaerobic glycolysis (p = 0.013), and a lower maximal mitochondrial oxidative capacity (p = 0.012) and mitochondrial efficiency (p = 0.024) in adults with type 1 diabetes. After adjustment for age and percent body fat maximal mitochondrial capacity (p = 0.014) continued to be lower and anaerobic glycolysis higher (p = 0.040) in adults with type 1 diabetes. Ex-vivo data did not demonstrate significant differences between the two groups. CONCLUSIONS: The in-vivo analysis demonstrates that adults with type 1 diabetes have mitochondrial dysfunction. This builds on previous research showing in-vivo mitochondrial dysfunction in youths with type 1 diabetes and suggests that defects in substrate or oxygen delivery may play a role in in-vivo dysfunction.

N-acetylaspartate from fat cells regulates postprandial body temperature.

N-acetylaspartate (NAA), the brain's second most abundant metabolite, provides essential substrates for myelination through its hydrolysis. However, activities and physiological roles of NAA in other tissues remain unknown. Here, we show aspartoacylase (ASPA) expression in white adipose tissue (WAT) governs systemic NAA levels for postprandial body temperature regulation. Proteomics and mass spectrometry revealed NAA accumulation in WAT of Aspa knockout mice stimulated the pentose phosphate pathway and pyrimidine production. Stable isotope tracing confirmed higher incorporation of glucose-derived carbon into pyrimidine metabolites in Aspa knockout cells. Additionally, serum NAA positively correlates with the pyrimidine intermediate orotidine and this relationship predicted lower body mass index in humans. Using whole-body and tissue-specific knockout mouse models, we demonstrate that fat cells provided plasma NAA and suppressed postprandial body temperature elevation. Furthermore, exogenous NAA supplementation reduced body temperature. Our study unveils WAT-derived NAA as an endocrine regulator of postprandial body temperature and physiological homeostasis.

Obesity dominates early effects on cardiac structure and arterial stiffness in people with type 2 diabetes.

OBJECTIVE: Type 2 diabetes (T2D) and obesity are global epidemics leading to excess cardiovascular disease (CVD). This study investigates standard and novel cardiac MRI parameters to detect subclinical cardiac and central vascular dysfunction in inactive people with and without T2D. METHODS: Physically inactive age and BMI-similar premenopausal women and men with ( n  = 22) and without [ n  = 34, controls with overweight/obesity (CWO)] uncomplicated T2D were compared to an age-similar and sex-similar reference control cohort ( n  = 20). Left ventricular (LV) structure, function, and aortic stiffness were assessed by MRI. Global arterial pulse wave velocity (PWV) was assessed using carotid-to-femoral applanation tonometry. Regional PWV was measured via 2D phase-contrast MRI and 4D flow MRI. RESULTS: Global arterial PWV did not differ between CWO and T2D. 2D PC-MRI PWV in the ascending aorta was higher in people with T2D compared with CWOs ( P  < 0.01). 4D flow PWV in the thoracic aorta was higher in CWO ( P  < 0.01), and T2D ( P  < 0.001) compared with RC. End-diastolic volume, end-systolic volume, stroke volume, and cardiac output were lower in CWO and T2D groups compared with reference control. CONCLUSION: Subclinical changes in arterial stiffening and cardiac remodeling in inactive CWO and T2D compared with reference control support obesity and/or physical inactivity as determinants of incipient CVD complications in uncomplicated T2D. Future studies should determine the mechanistic causes of the CVD complications in greater detail in order to create therapeutic targets. CLINICAL TRIAL REGISTRATION: Cardiovascular Mechanisms of Exercise Intolerance in Diabetes and the Role of Sex (NCT03419195).

Correlates of Glucagon-Like Peptide-1 Receptor Agonist Use Among Patients With Atherosclerotic Cardiovascular Disease and Type 2 Diabetes Mellitus (from the Department of Veterans Affairs).

This study used data from the Veterans Affairs administrative and clinical dataset to evaluate determinants of glucagon-like peptide-1 receptor agonist (GLP-1 RA) use among patients with concomitant atherosclerotic cardiovascular disease and diabetes mellitus and an antecedent primary care provider visit. The prevalence of GLP-1 RA use was 8.0%. In multivariable-adjusted models, White race, hypertension, obesity, higher hemoglobin A1c, ischemic heart disease, chronic kidney disease, a higher number of primary care provider visits, and previous cardiology or endocrinology visits were directly associated with GLP-1 RA use. Older age, having a physician primary care provider, and receiving care at a teaching facility were inversely associated with GLP-1 RA use. Our data can help inform targeted interventions to promote equitable access to GLP-1 RA and incentivize the adoption of these disease-modifying agents in high-risk patient populations.

Sex Differences in Physical Activity Among Individuals With Type 2 Diabetes Across the Life Span: A Systematic Review and Meta-analysis.

BACKGROUND: Physical activity (PA) is a cornerstone of type 2 diabetes mellitus (T2DM) treatment. Sex differences in PA behavior or barriers/facilitators to PA among individuals with T2DM are unclear. PURPOSE: To summarize the evidence related to sex differences in participation in PA and barriers/facilitators to PA among individuals with T2DM across the life span. DATA SOURCES: Systematic searches (CRD42021254246) were conducted with Ovid MEDLINE, Embase, Web of Science, Cumulative Index to Nursing and Allied Health Literature (CINAHL), Allied and Complementary Medicine Database (AMED), APA PsychInfo, and SPORTDiscus. STUDY SELECTION: We included studies with assessment of PA, sedentary behaviors (SB), or barriers/facilitators to PA among individuals with T2DM by sex or gender. DATA EXTRACTION: Participant characteristics, meeting PA guidelines, participation in PA and SB, and barriers/facilitators to PA were extracted by two independent reviewers. DATA SYNTHESIS: A total of 53 articles (65,344 participants) were included in the systematic review and 21 articles in the meta-analysis. Sex differences were not observed in meeting of PA guidelines among adolescents (odds ratio 0.70 [95% CI 0.31, 1.59]), but males were more likely than females to meet PA guidelines among adults (1.65 [1.36, 2.01]) and older adults (1.63 [1.27, 2.09]). Males performed more moderate-to-vigorous PA (MVPA) than females across all age-groups. Common barriers to PA were lack of time (men) and lack of social support and motivation (women). LIMITATIONS: Limitations include heterogeneity of measures used to assess PA and lack of stratification of data by sex. CONCLUSIONS: Sex differences in meeting PA guidelines were not observed among adolescents but were apparent among adults and older adults with T2DM. Females consistently engaged in less MVPA than males across the life span.

Evolving Concepts of Type 2 Diabetes Management.

With the concept of patient-centered care in mind, this article outlines the current diabetes medications available for glucose lowering and the characteristics of each of these medications that need to be considered in shared decision-making for durable and effective therapy. Important patient characteristics such as weight, risk for hypoglycemia, cost, social determinants of health, and medical literacy need to be considered. The evidence-base informing the use of antihyperglycemic agents has changed dramatically due to 2008 FDA guidance for cardiovascular safety and cardiorenal protection with antihyperglycemic agents. New evidence supports an approach to diabetes management that addresses pre-existing cardiorenal disease.

Mechanistic Causes of Reduced Cardiorespiratory Fitness in Type 2 Diabetes.

Type 2 diabetes (T2D) has been rising in prevalence in the United States and worldwide over the past few decades and contributes to significant morbidity and premature mortality, primarily due to cardiovascular disease (CVD). Cardiorespiratory fitness (CRF) is a modifiable cardiovascular (CV) risk factor in the general population and in people with T2D. Young people and adults with T2D have reduced CRF when compared with their peers without T2D who are similarly active and of similar body mass index. Furthermore, the impairment in CRF conferred by T2D is greater in women than in men. Various factors may contribute to this abnormality in people with T2D, including insulin resistance and mitochondrial, vascular, and cardiac dysfunction. As proof of concept that understanding the mediators of impaired CRF in T2D can inform intervention, we previously demonstrated that an insulin sensitizer improved CRF in adults with T2D. This review focuses on how contributing factors influence CRF and why they may be compromised in T2D. Functional exercise capacity is a measure of interrelated systems biology; as such, the contribution of derangement in each of these factors to T2D-mediated impairment in CRF is complex and varied. Therefore, successful approaches to improve CRF in T2D should be multifaceted and individually designed. The current status of this research and future directions are outlined.