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.

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.

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.

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).

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.

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.

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.

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.

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.

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.

Very Unusual Sellar/Suprasellar Region Masses: A Review.

The cause of sellar region masses in large retrospective series is overwhelmingly pituitary adenomas (84.6%), followed by craniopharyngiomas (3.2%), cystic nonneoplastic lesions (2.8%), inflammatory lesions (1.1%), meningiomas (0.94%), metastases (0.6%), and chordomas (0.5%) (1). While other rare lesions were also identified (collectively 6.0%), single unusual entities in the above-cited series numbered <1-2 examples each out of the 4122 cases, underscoring their rarity. We searched our joint files for rare, often singular, sellar/suprasellar masses that we had encountered over the past several decades in our own specialty, tertiary care specialty pituitary center practices. Cases for this review were subjectively selected for their challenging clinical and/or histological features as well as teaching value based on the senior authors' (MBSL, BKD) collective experience with over 7000 examples. We excluded entities deemed to be already well-appreciated by neuropathologists such as mixed adenoma-gangliocytoma, posterior pituitary tumors, metastases, and hypophysitis. We identified examples that, in our judgment, were sufficiently unusual enough to warrant further reporting. Herein, we present 3 diffuse large cell B cell pituitary lymphomas confined to the sellar region with first presentation at that site, 2 sarcomas primary to sella in nonirradiated patients, and 1 case each of granulomatosis with polyangiitis and neurosarcoidosis with first presentations as a sellar/suprasellar mass. Other cases included 1 of chronic lymphocytic leukemia within a gonadotroph adenoma and 1 of ectopic nerve fascicles embedded within a somatotroph adenoma, neither of which impacted patient care. Our objective was to share these examples and review the relevant literature.