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Purpose of Review Obesity, generally defined by body mass index (BMI), is an established risk factor for the development of cardiovascular disease (CVD), while cardiorespiratory fitness (CRF) decreases risk. In chronic CVD, an obesity survival paradox in which higher BMI is associated with improved prognosis has been reported. This paper will examine the effect of obesity on CVD risk, explore obesity as a risk factor in patients with established CVD, and investigate the relationship between CRF, obesity, and CVD. Recent Findings Through metabolic and hemodynamic changes, obesity increases the risk for CVD and contributes to the development of other cardiovascular risk factors such as diabetes, dyslipidemia, and hypertension. Obesity is associated with metabolic, hormonal, and inflammatory changes that leads to atherosclerosis increasing the risk for coronary artery disease, and myocardial remodeling increasing the risk for heart failure. However, it has also been observed that overweight/obese patients with established CVD have a better prognosis when compared to non-obese individuals termed the obesity paradox. CRF is a vital component of health associated with improved cardiovascular outcomes and furthermore has been shown to markedly attenuate or nullify the relationship between obesity and CVD risk/prognosis. Summary Increasing CRF mitigates CVD risk factors and improves overall prognosis in CVD regardless of obesity status.

Purpose of Review Body fat distribution plays a significant role in the cardiometabolic consequences of obesity. We review the impact of visceral and hepatic fat and highlight important interventions. Recent Findings Several epidemiologic studies have established a clear association between visceral fat and cardiovascular disease. The association between hepatic fat and cardiovascular disease is less clear with discordant results. Novel evidence demonstrates sodium glucose co-transporter-2 (SGLT2) inhibitors facilitate modest weight loss and reductions in ectopic fat depots in patient with type 2 diabetes. Glucagon-like peptide-1 (GLP-1) receptor agonists have been associated with decreased visceral/hepatic fat and reductions in MACE in populations with type 2 diabetes and with overweight/obesity. Summary Clear associations between visceral fat and cardiometabolic outcomes have been established, whereas the impact of hepatic fat remains less clear. Lifestyle modification and pharmacologic interventions remain the initial therapies, while surgical intervention is associated with improved long-term outcomes. Emerging therapies have demonstrated a profound impact on body fat distribution and cardiometabolic risk.

Purpose of ReviewSince the clinical benefit of proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors occurs in a setting of reducing low-density lipoprotein-cholesterol (LDL-C) to unprecedentedly low levels, it becomes of interest to investigate possible adverse effects pertaining to the risk of new-onset diabetes (NOD).Recent FindingsWhile safety results reported in either meta-analyses or cardiovascular outcome trials FOURIER (with evolocumab) and ODYSSEY (with alirocumab) did not rise the incidence of NOD, Mendelian randomization analyses were almost concordant in showing an increased risk of NOD. This evidence was in line with post-marketing safety reports highlighting that evolocumab and alirocumab were primarily related to mild hyperglycaemia rather than diabetes, with most of the hyperglycaemic events occurring during the first 6 months of treatment.SummaryConsidering the different nature of genetic studies and of randomized controlled trials, with careful monitoring of patients, particularly in the earlier phases of treatment, and the identification of those more susceptible to develop NOD, treatment with PCSK9 inhibitors should be of minimal concern.

Purpose of ReviewDespite significant progress in plasma lipid lowering strategies, recent clinical trials highlight the existence of residual cardiovascular risk. Angiopoietin-like protein 3 (ANGPTL3) and apolipoprotein C-III (Apo C-III) have been identified as novel lipid-lowering targets.Recent FindingsApo C-III and ANGPTL3 have emerged as novel regulators of triglyceride (TG) and low-density lipoprotein-cholesterol (LDL-C) levels. ANGPTL3 is an inhibitor of lipoprotein lipase (LPL), reducing lipolysis of Apo B-containing lipoproteins. Loss-of-function ANGPLT3 mutations are associated with reduced plasma cholesterol and TG, while novel ANGPLT3 inhibition strategies, including monoclonal antibodies (evinacumab), ANGPLT3 antisense oligonucleotides (IONIS-ANGPTL3-LRx), and small interfering RNA (siRNA) silencing techniques (ARO-ANG3), result in increased lipolysis and significant reductions of LDL-C and TG levels in phase I and II clinical trials. Similarly, Apo C-III inhibits LPL while promoting the hepatic secretion of TG-rich lipoproteins and preventing their clearance. Loss-of-function APOC3 mutations have been associated with reduced TG levels. Targeting of Apo C-III with volanesorsen, an APOC3 siRNA, results in significant reduction in plasma TG levels but possibly also increased risk for thrombocytopenia, as recently demonstrated in phase I, II, and III clinical trials. ARO-APOC3 is a novel siRNA-based agent targeting Apo C-III which is currently under investigation with regard to its lipid-lowering efficiency.SummaryANGPTL3 and Apo C-III targeting agents have demonstrated striking lipid-lowering effects in recent clinical trials; however, more thorough safety and efficacy data are required. Here, we evaluate the role of ANGPLT3 and Apo C-III in lipid metabolism, present the latest clinical advances targeting those molecules, and outline the remaining scientific challenges on residual lipid-associated cardiovascular risk.

Purpose of Review In this narrative review, we discuss the current evidence related to the role of dietary interventions to prevent and treat type 2 diabetes mellitus (T2DM) and cardiovascular disease (CVD). We also propose alternative therapeutic strategies other than weight loss in this population, namely, improvements in cardiorespiratory fitness and its determinants. Recent Findings While weight loss has been consistently associated with the prevention of T2DM and improvements in glycemic control in those with established diseases, its role in preventing and treating CVD is less clear. In fact, in this setting, improvements in diet quality have provided greater benefits, suggesting that this might represent an alternative, or an even more effective strategy than energy-restriction. Summary Improvements in diet quality, with and without caloric restriction have been shown to improve CVD risk and to prevent the development of T2DM in individuals at risk; however, with regard to glycemic control in patients with T2DM, any dietary intervention resulting in significant weight loss may produce clinically meaningful benefits. Finally, dietary interventions with and without energy restriction that can improve cardiorespiratory fitness, even in absence of weight loss in patients with obesity, should be encouraged.

Purpose of Review Specific measures of body fat distribution may have particular value in the development and treatment of cardiometabolic conditions, such as cardiovascular disease (CVD) and diabetes mellitus (DM). Here, we review the pathophysiology, epidemiology, and recent advances in the identification and management of body fat distribution as it relates to DM and CVD risk. Recent Findings Accumulation of visceral and ectopic fat is a major contributor to CVD and DM risk above and beyond the body mass index (BMI), yet implementation of fat distribution assessment into clinical practice remains a challenge. Newer imaging-based methods offer improved sensitivity and specificity for measuring specific fat depots. Lifestyle, pharmacological, and surgical interventions allow a multidisciplinary approach to reduce visceral and ectopic fat. Summary A focus on implementation of body fat distribution measurements into clinical practice should be a priority over the next 5 to 10 years, and clinical assessment of fat distribution can be considered to refine risk evaluation and to develop improved and effective preventive and therapeutic strategies for high-risk obesity.

Purpose of Review Narrative review of the author’s main contributions to the field of cardiovascular health spanning four decades, with a focus on findings related to 1- the pathophysiology of obesity, insulin resistance, type 2 diabetes and cardiovascular disease, and 2- the management/prevention of these conditions. Particular attention is given to the importance of regular physical activity. Recent Findings Because behaviors and their physiological consequences are still not measured in clinical practice, it is proposed to systematically assess and target “lifestyle vital signs” (waist circumference, cardiorespiratory fitness, food-based diet quality and level of leisure-time physical activity) in primary care. However, cardiometabolic health of the population will not be substantially improved until our living and economic conditions are permissive to the adoption of healthy behaviors. Summary Closing the gap between primary care and public health should be a priority to address the socioeconomic determinants of cardiometabolic health.

Purpose of ReviewTo discuss evidence supporting the use of glucagon-like peptide 1 receptor agonists (GLP-1RA) to treat obesity and their role as a cardioprotective drug. Obesity is not just a hypertrophy of the adipose tissue because it may become dysfunctional and inflamed resulting in increased insulin resistance. Being overweight is associated with increased incidence of cardiovascular events and weight loss achieved through lifestyle changes lowers risk factors, but has no clear effect on cardiovascular outcomes. In contrast, treating obesity with GLP-1RA decreases cardiovascular risk and the possible mechanisms of cardioprotection achieved by this class of drugs are discussed. GLP-1RA were initially developed to treat type 2 diabetes patients, in whom the effects upon glycemia and, moreover, weight loss, especially with long-acting GLP-1RA, were evident. However, cardiovascular safety trials in type 2 diabetes patients, the majority presenting cardiovascular disease and excess weight, showed that GLP-1 receptor agonists were indeed capable of decreasing cardiovascular risk.Recent FindingsType 2 diabetes treatment with GLP-1RA liraglutide and semaglutide paved way to a ground-breaking therapy specific for obesity, as shown with the SCALE 3 mg/day liraglutide program and the STEP 2.4 mg/week semaglutide program. A novel molecule with superior performance is tirzepatide, a GLP-1 and GIP (Gastric Inhibitory Peptide) receptor agonist and recent results from the SURPASS and SURMOUNT programs are briefly described. Liraglutide was approved without a CVOT (Cardiovascular Outcome Trial) because authorities accepted the results from the LEADER study, designed for superiority. The SELECT study with semaglutide will report results only in 2023 and tirzepatide is being tested in patients with diabetes in the SURPASS-CVOT.SummaryClinical studies highlight that GLP-1RA to treat obesity, alongside their concomitant cardioprotective effects, have become a hallmark in clinical science.

The global surge in cardiometabolic diseases, including type 2 diabetes, obesity, and cardiovascular diseases, has reached pandemic levels, demanding bold and innovative solutions. Dual glucagon (Gcg) and glucagon-like peptide-1 (GLP-1) receptor agonists represent a groundbreaking advancement in the treatment of this complex and interconnected spectrum of disorders. By harnessing the synergistic power of GLP-1 and Gcg receptor activation, these agents go beyond glucose lowering and weight loss, unlocking new frontiers in energy expenditure, fat oxidation, and liver fat reduction—key targets in conditions such as metabolic dysfunction-associated steatotic liver disease (MASLD). Emerging clinical evidence on agents such as survodutide and cotadutide has revealed striking improvements in glycated hemoglobin (HbA1c) levels and body weight, consistently outperforming traditional GLP-1 receptor agonists. More importantly, early evidence suggests meaningful benefits in cardiovascular and renal outcomes, positioning these therapies as comprehensive, disease-modifying tools for patients with multiple high-risk comorbidities. This review highlights the transformative potential of dual GLP-1/Gcg receptor agonists, providing a thorough examination of their mechanisms of action, clinical efficacy, and safety profiles across the cardio–metabolic continuum. As the limitations of existing therapies become increasingly evident, these next-generation agents are poised to redefine the standard of care across the cardiometabolic continuum, ushering in a new era of precision medicine for metabolic disease.

Purpose of Review To provide a narrative overview of trends and disparities in the cardiometabolic profiles of U.S. adults by synthesizing findings from nationally representative studies conducted between 1999 and 2020. Recent Findings During the study period, the cardiometabolic profiles of U.S. adults displayed a complex mix of trends. While there were notable improvements in specific risk factors, such as reductions in total cholesterol, triglycerides, and low-density lipoprotein cholesterol levels, other aspects of cardiometabolic health worsened. The mean body mass index and hemoglobin A1c levels increased, accompanied by significant rises in the prevalence of obesity, type 2 diabetes, and metabolic syndrome. Despite some progress in blood pressure and lipid profiles, the overall cardiometabolic health of the population declined, with only a small percentage of adults maintaining optimal health by 2018. Furthermore, significant disparities persisted across racial and socioeconomic groups, with non-Hispanic Black participants and those with lower education and income facing higher cardiometabolic risks compared to their counterparts. Summary Despite improvements in certain aspects of cardiometabolic profiles among U.S. adults, significant challenges remain, particularly with the rising rates of obesity, type 2 diabetes, and metabolic syndrome. Persistent disparities in cardiometabolic health across sociodemographic groups emphasize the need for comprehensive public health strategies that address medical care, lifestyle factors, and social determinants of health. Future efforts should prioritize reducing these disparities and enhancing health equity to mitigate the overall burden of cardiometabolic disease.