Cardiovascular outcome trials in obesity: A review.

Obesity is a global epidemic associated with over 200 health complications and a significant risk of developing cardiovascular disease (CVD), partly by increasing classical risk factors such as lipid and glucose levels and blood pressure. Weight loss through lifestyle interventions, pharmacotherapy and/or bariatric surgery improves CV risk factors. Cardiovascular outcome trials (CVOTs) of anti-obesity medications aim to evaluate the CV safety and benefits of pharmacotherapy. Many CVOTs in obesity have either failed to demonstrate a CV benefit or have been terminated prematurely because of safety issues, prompting regulatory agencies to define new requirements (based on those for CVOTs in type 2 diabetes [T2D]). CVOTs of glucagon-like peptide-1 receptor agonists (GLP-1RAs) in T2D have demonstrated that some GLP-1RAs reduce CV risk and may help inform future CVOTs in obesity, given the approval of liraglutide 3.0 mg for obesity. In this review, the evidence for the link between obesity and CVD is considered in the context of studies showing that weight loss improves markers of CV risk and risk of adverse CV events. The review also examines the CVOTs in obesity that have been conducted to date and those under way, such as the SELECT trial with subcutaneous semaglutide of 2.4 mg

The 1α,25(OH)2D3 Analogs ZK159222 and ZK191784 Show Anti-Inflammatory Properties in Macrophage-Induced Preadipocytes via Modulating the NF-κB and MAPK Signaling.

Purpose:Key research findings suggest that attenuating metaflammation in adipose tissue might be a strategic step to prevent the metabolic syndrome and its associated disease outcomes. The anti-inflammatory effects of 1α,25(OH)2D3 have been confirmed in our previous studies, but adverse effects induced at high concentrations restrict its potential clinical translation. Two synthetic 1α,25(OH)2D3 analogs ZK159222 and ZK191784 have manifested promising tissue-specific immunomodulatory actions, but limited data are available on adipose tissue. Hence, in this study, we investigated whether ZK159222 and ZK191784 act on preadipocytes or macrophages to attenuate metaflammatory responses via modulating inflammatory and metabolic signaling in macrophage-induced preadipocytes. Methods:Preadipocyte-specific effects of ZK159222 and ZK191784 on macrophage-induced preadipocytes were tested by pre-incubating and incubating preadipocytes with the analogs and MacCM. Separately, macrophage-specific effects of both analogs on macrophage-induced preadipocytes were tested by incubating preadipocytes with analog-MacCM or MacCM. The effects of 1α,25(OH)2D3 were also examined and set as the positive control. Metaflammatory responses were determined as the concentrations and gene expression of major pro-inflammatory cytokines including IL-1β, IL-6, IL-8, MCP-1 and RANTES, measured using ELISA and qPCR. Inflammatory and metabolic signaling including NF-κB and MAPK were probed using Western blotting. Results:ZK159222 and ZK191784 act on preadipocytes and macrophages to decrease the secretion and gene expression of the major pro-inflammatory cytokines in macrophage-induced preadipocytes. The anti-inflammatory effects were at least as potent as 1α,25(OH)2D3, and no preadipocyte apoptosis was induced at high concentrations. In addition, mostly at high concentrations, both analogs moderately decreased the phosphorylation of relA, p44/42 and p38 MAPK in macrophage-induced preadipocytes. Conclusion:ZK159222 and ZK191784 act on macrophages and preadipocytes to attenuate metaflammatory responses in macrophage-induced preadipocytes, by decreasing phosphorylation of relA/NF-κB, p44/42 and p38 MAPK

1,25(OH)(2)D-3 attenuates IL-6 and IL-1-mediated inflammatory responses in macrophage conditioned medium-stimulated human white preadipocytes by modulating p44/42 MAPK and NF-B signaling pathways

Abstract Background Metabolic syndrome is characterized by macrophage infiltration and inflammatory responses—metaflammation in adipose tissue. IL-6 and IL-1β could mediate the inflammatory responses in macrophage stimulated-preadipocytes by modulating MAPK and NF-κB pathways. To test this hypothesis we used antibodies to block IL-6 and IL-1β action in macrophage conditioned medium (MacCM)-stimulated human white preadipocytes. Moreover, as interventions that prevent this could potentially be used to treat or prevent metabolic syndrome, and 1α,25(OH)2D3 has previously been reported to exert an anti-inflammatory action on macrophage-stimulated adipocytes, in this study we also investigated whether 1α,25(OH)2D3 could attenuate inflammatory responses in MacCM-stimulated preadipocytes, and explored the potential anti-inflammatory mechanisms. Methods Human white preadipocytes were cultured with 25% MacCM for 24 h to elicit inflammatory responses. This was confirmed by measuring the concentrations and mRNA levels of major pro-inflammatory factors [IL-1β, IL-6, IL-8, monocyte chemoattractant protein (MCP)-1 and regulated on activation, normal T cell expressed and secreted (RANTES)] by ELISA and qPCR, respectively. IL-6 and IL-1β actions were blocked using IL-6 antibody (300 ng/ml) and IL-1β antibody (15 μg/ml), respectively. Potential anti-inflammatory effects of 1α,25(OH)2D3 were investigated by pre-treatment and treatment of 1α,25(OH)2D3 (0.01 to 10 nM) for 48 h in MacCM-stimulated preadipocytes. In parallel, western blotting was used to determine inflammatory signaling molecules including relA of the NF-κB pathway and p44/42 MAPK modified during these processes. Results MacCM enhanced the secretion and gene expression of IL-1β, IL-6, IL-8, MCP-1 and RANTES by increasing the phosphorylation levels of relA and p44/42 MAPK in preadipocytes, whereas blocking IL-6 and IL-1β action inhibited the inflammatory responses by decreasing p44/42 MAPK and relA phosphorylation, respectively. Furthermore, 10 nM of 1α,25(OH)2D3 generally inhibited the IL-6 and IL-1β-mediated inflammatory responses, and reduced both p44/42 MAPK and relA phosphorylation in MacCM-stimulated preadipocytes. Conclusions 1α,25(OH)2D3 attenuates IL-6 and IL-1β-mediated inflammatory responses, probably by inhibiting p44/42 MAPK and relA phosphorylation in MacCM-stimulated human white preadipocytes

Adipocytes in obesity: A perfect reservoir for SARS-CoV-2?

Research evidence suggests that adipocytes in obesity might facilitate SARS-CoV-2 replication, for it was only found in adipose tissue of individuals with overweight or obesity but not lean individuals who died from COVID-19. As lipid metabolism is key to adipocyte function, and viruses are capable of exploiting and manipulating lipid metabolism of host cells for their own benefit of infection, we hypothesize that adipocytes could not only impair host immune defense against viral infection, but also facilitate SARS-CoV-2 entry, replication and assembly as a reservoir to boost the viral infection in obesity. The latter of which could mainly be mediated by SARS-CoV-2 hijacking the abnormal lipid metabolism in the adipocytes. If these were to be confirmed, an approach to combat COVID-19 in people with obesity by taking advantage of the abnormal lipid metabolism in adipocytes might be considered, as well as modifying lipid metabolism of other host cells as a potential adjunctive treatment for COVID-19

Obesity pharmacotherapy in older adults: a narrative review of evidence.

The prevalence of obesity in older adults (people aged >60 years) is increasing in line with the demographic shift in global populations. Despite knowledge of obesity-related complications in younger adults (increased risk of type 2 diabetes, liver and cardiovascular disease and malignancy), these considerations may be outweighed, in older adults, by concerns regarding weight-loss induced reduction in skeletal muscle and bone mass, and the awareness of the 'obesity paradox'. Obesity in the elderly contributes to various obesity-related complications from cardiometabolic disease and cancer, to functional decline, worsening cognition, and quality of life, that will have already suffered an age-related decline. Lifestyle interventions remain the cornerstone of obesity management in older adults, with emphasis on resistance training for muscle strength and bone mineral density preservation. However, in older adults with obesity refractory to lifestyle strategies, pharmacotherapy, using anti-obesity medicines (AOMs), can be a useful adjunct. Recent evidence suggests that intentional weight loss in older adults with overweight and obesity is effective and safe, hence a diminishing reluctance to use AOMs in this more vulnerable population. Despite nine AOMs being currently approved for the treatment of obesity, limited clinical trial evidence in older adults predominantly focuses on incretin therapy with glucagon-like peptide-1 receptor agonists (liraglutide, semaglutide, and tirzepatide). AOMs enhance weight loss and reduce cardiometabolic events, while maintaining muscle mass. Future randomised controlled trials should specifically evaluate the effectiveness of novel AOMs for long-term weight management in older adults with obesity, carefully considering the impact on body composition and functional ability, as well as health economics

Differential vascular dysfunction in response to diets of differing macronutrient composition: a phenomenonological study

<p>Abstract</p> <p>Background</p> <p>Vascular dysfunction can develop from consumption of an energy-rich diet, even prior to the onset of obesity. However, the roles played by different dietary components remain uncertain. While attempting to develop models of obesity in a separate study, we observed that two high-energy diets of differing macronutrient compositions affected vascular function differently in overweight rats.</p> <p>Methods</p> <p>Male Wistar rats (<it>n </it>= 6/group) were fed diets providing varying percentages of energy from fat and carbohydrate (CHO). For 10 weeks, they were fed either chow, as control diet (10% of energy from fat; 63% from CHO), chow supplemented with chocolate biscuit (30% fat; 56% CHO) or a high-fat diet (45% fat; 35% CHO). Blood concentrations of biochemical markers of obesity were measured, and epididymal fat pads weighed as a measure of adiposity. Mesenteric arteries were dissected and their contractile and relaxant properties analysed myographically. Data were tested by analysis of variance (ANOVA).</p> <p>Results</p> <p>Weight gain and plasma concentrations of glucose, insulin and leptin were similar in all groups. However, biscuit-fed animals showed increased food intake (+27%; <it>p </it>< 0.01) and elevated concentrations of TGs and NEFAs (+41% and +17%; both <it>p </it>< 0.05). High-fat-fed animals showed an increase only in NEFAs (+38%; <it>p </it>< 0.01). Arterial vasoconstriction in response to NA and KCl increased only in biscuit-fed rats (both <it>p </it>< 0.01), while vasorelaxation in response to CCh and SNP, but not histamine, was attenuated in both groups (both <it>p </it>< 0.01). Furthermore, whereas the effect of the high-fat diet was most pronounced in endothelium-dependent vasorelaxation, the biscuit diet had the greater effect on endothelium-independent vasorelaxation.</p> <p>Conclusion</p> <p>Vascular dysfunction resulting from consumption of a high-fat or combined relatively high-fat/high-CHO diet occurs through different physiological processes, which may be attributable to their differing macronutrient compositions. Combining potentially atherogenic macronutrients induces more extensive vascular impairment than that of high-fat alone, and may be attributable to the more marked dyslipidaemia observed with such a diet. Thus, these findings help clarify the role of dietary components in vascular impairment, which has implications for clinical approaches to preventing cardiovascular disease.</p

The expanding role of SGLT2 inhibitors beyond glucose-lowering to cardiorenal protection

The kidney plays a major physiological role in glucose homeostasis but also contributes to the pathophysiology of type 2 diabetes (T2D), mediated by renal sodium glucose cotransporters (SGLTs). This recognition led to development of SGLT2 inhibitors that inhibit proximal renal tubular renal glucose and sodium reabsorption. The glucoretic and natriuretic effect of SGLT2 inhibitors is associated with reductions in HbA1c levels, body weight, systolic blood pressure and triglycerides. Major vascular complications of T2D include cardiovascular disease and chronic kidney disease (CKD). Results from several cardiovascular outcome trials (CVOTs) with these drugs have highlighted benefits in reducing major adverse cardiovascular events by 11%, reducing the risk of cardiovascular death or hospitalisation for heart failure (HF) by 23% and reducing risk of progression of renal disease by 45%. Their cardiorenal benefits are apparent across a range of eGFRs (within CKD1-3 groups) and the presence or absence of ischaemic heart disease, HF or T2D. In patients with HF with reduced ejection fraction (HFrEF), similar risk reductions in cardiovascular death and HF events are also seen; results from studies in patients with HF with preserved ejection fraction (HFpEF) are awaited. Cardiorenal benefits have been recently reported in patients with CKD, regardless of the presence or absence of T2D. Indications for use of SGLT2 inhibitors has extended beyond glucose-lowering to a central role in cardiorenal protection. This review will first explore the mechanisms by which glycaemic control, weight loss and cardiovascular risk factors are modulated therapeutically with SGLT2 inhibitors. Subsequently we outline putative mechanisms underpinning the cardiorenal benefits seen, including in HF and CKD, in the context of completed and ongoing clinical studies. Treatment strategies with SGLT2 inhibitors in individuals with CKD or HF, with and/or without T2D are increasingly appealing. Combination therapy with complementary therapeutic agents is also explored