Anti-Inflammatory Effects of Pioglitazone and/or Simvastatin in High Cardiovascular Risk Patients With Elevated High Sensitivity C-Reactive Protein

Hanefeld, Markolf; Pfützner, Andreas; Baurecht, Werner; Lübben, G.; Karagiannis, E.; Stier, Ulf; Forst, Thomas

doi:10.1016/j.jacc.2006.08.054

Cited by 155 publications

(129 citation statements)

References 48 publications

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“…Lung function as quantified by FEV 1 (liters) was lowest in the overweight/obese subjects with asthma (P ¼ 0.022 compared with lean asthma; P ¼ 0.034 compared with obese normal). No subjects took statins or thiazolidinediones, which could have a potential antiinflammatory effect (23)(24)(25). Twenty-two subjects were included in the ex vivo experiments and the characteristics of this cohort are included in Table 2.…”

Section: Subject Characteristicsmentioning

confidence: 99%

Alveolar Macrophages from Overweight/Obese Subjects with Asthma Demonstrate a Proinflammatory Phenotype

Lugogo¹,

Hollingsworth

Howell³

et al. 2012

Am J Respir Crit Care Med

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Rationale: Obesity is associated with increased prevalence and severity of asthma. Adipose tissue macrophages can contribute to the systemic proinflammatory state associated with obesity. However, it remains unknown whether alveolar macrophages have a unique phenotype in overweight/obese patients with asthma. Objectives: We hypothesized that leptin levels would be increased in the bronchoalveolar lavage fluid from overweight/obese subjects and, furthermore, that leptin would alter the response of alveolar macrophages to bacterial LPS. Methods: Forty-two subjects with asthma and 46 healthy control subjects underwent research bronchoscopy. Bronchoalveolar lavage fluid from 66 was analyzed for the level of cellular inflammation, cytokines, and soluble leptin. Cultured primary macrophages from 22 subjects were exposed to LPS, leptin, or leptin plus LPS. Cytokines were measured in the supernatants. Measurements and Main Results: Leptin levels were increased in overweight/obese subjects, regardless of asthma status (P ¼ 0.013), but were significantly higher in overweight/obese subjects with asthma. Observed levels of tumor necrosis factor-a were highest in overweight/obese subjects with asthma. Ex vivo studies of primary alveolar macrophages indicated that the response to LPS was most robust in alveolar macrophages from overweight/obese subjects with asthma and that preexposure to high-dose leptin enhanced the proinflammatory response. Leptin alone was sufficient to induce production of proinflammatory cytokines from macrophages derived from overweight/obese subjects with asthma. Conclusions: Ex vivo studies indicate that alveolar macrophages derived from overweight/obese subjects with asthma are uniquely sensitive to leptin. This macrophage phenotype, in the context of higher levels of soluble leptin, may contribute to the pathogenesis of airway disease associated with obesity.Keywords: tumor necrosis factor-a; leptin; innate immunity; lipopolysaccharide; environmental lung disease There is an increased risk of developing asthma in individuals who are overweight and obese (subsequently referred to as overweight/obese) (1-5). The risk of asthma increases steadily with increasing body mass index (BMI) and is higher in women (1, 6). Furthermore, BMI negatively impacts asthma quality of life scores, asthma control scores, severity of exacerbations, and asthma-related hospitalizations (6-9). Together, these studies suggest a role of obesity in the pathogenesis of asthma. However, the mechanisms by which obesity may contribute to airway disease remain poorly understood.Evidence suggests that adipose tissue is metabolically active, participating not only in energy homeostasis but also in inflammation (12). Adipose tissue secretes biologically active cytokines, including tumor necrosis factor (TNF)-a and IL-6, as well as adipokines, including leptin, adiponectin, plasminogen activator inhibitor (PAI)-1, and resistin (10, 11). Obesity is associated with systemic inflammation, which is characterized by elevated serum levels of...

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Section: Subject Characteristicsmentioning

confidence: 99%

Alveolar Macrophages from Overweight/Obese Subjects with Asthma Demonstrate a Proinflammatory Phenotype

Lugogo¹,

Hollingsworth

Howell³

et al. 2012

Am J Respir Crit Care Med

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“…Moreover, CRP directly facilitates the development of cardiovascular disease by decreasing nitric oxide synthesis and inducing adhesion molecule expression in human endothelial cells [17,18]. Recently, CRP was reported to be independently associated with short-term mortality risk in type 2 diabetes mellitus patients [19]; and several studies have shown that pioglitazone reduces plasma CRP levels [3][4][5][6][7][8][9][10][11][12][13]. Moreover, 16 weeks of pioglitazone treatment decreased CRP levels by 42% in type 2 diabetes mellitus patients [12]; and pioglitazone further reduced CRP in patients with hypertension and diabetes who were receiving angiotensin II receptor blockers [5].…”

Section: Discussionmentioning

confidence: 99%

“…reduction of proinflammatory markers including C-reactive protein (CRP) [3][4][5][6][7][8][9][10][11][12][13]. C-reactive protein is an acute-phase reactant that is known as a proinflammatory marker and a predictor of cardiovascular events [14][15][16].…”

mentioning

confidence: 99%

Fat redistribution preferentially reflects the anti-inflammatory benefits of pioglitazone treatment

Moon

Kim

et al. 2011

Metabolism

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“…The inconsistent results may reflect the relatively small number of patients on pioglitazone; however, previous studies suggest beneficial effects. [21][22][23][24][25][26] Its use in patients with ESRD and diabetes will be the subject of future DOPPS analyses once additional data become available.…”

Section: Discussionmentioning

confidence: 99%

Rosiglitazone Is Associated with Mortality in Chronic Hemodialysis Patients

Ramirez

Albert

Blayney

et al. 2009

Journal of the American Society of Nephrology

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Recent studies have associated rosiglitazone, a thiazolidinedione drug, with adverse cardiovascular outcomes in the general population with diabetes. Using data from the Dialysis Outcomes and Practice Patterns Study in the United States, we examined cardiovascular hospitalization and mortality associated with prescription of rosiglitazone, compared with other oral hypoglycemic agents, among 2393 long-term hemodialysis patients who were followed for a median of 1.1 yr. We assessed mortality risk using Cox models in patient-level and dialysis facility-level analyses that used the facility proportion of patients on rosiglitazone as the predictor (instrumental variable approach) and adjusted the models for demographics, comorbid conditions, laboratory values, and achieved dialysis dosage. Compared with patients prescribed other oral hypoglycemic agents, patients prescribed rosiglitazone had significantly higher all-cause (hazard ratio [HR] 1.38; 95% confidence interval [CI] 1.05 to 1.82) and cardiovascular (HR 1.59; 95% CI 1.14 to 2.22) mortality, and their adjusted HR for hospitalization with myocardial infarction was 3.5-fold higher (P ϭ 0.02). We did not observe similar associations in a secondary analysis evaluating pioglitazone. By the instrumental variable approach, facilities with more than the median adjusted percentage (6.2%) of patients who had diabetes and were prescribed rosiglitazone had significantly higher all-cause mortality (HR 1.36; 95% CI 1.15 to 1.62) and cardiovascular mortality (HR 1.42; 95% CI 1.07 to 1.88) than facilities with less than the median expected percentage prescribed rosiglitazone. Our practice-based findings suggest significant associations of rosiglitazone use with higher cardiovascular and all-cause mortality among hemodialysis patients with diabetes. 20: 109420: -110120: , 200920: . doi: 10.1681 Thiazolidinedione (TZD) use is increasing in patients with diabetes. For example, its reported use rose from 7.2% in 1998 to 16.2% in 2001 in a population of Medicare patients who were hospitalized for diabetes 1 ; however, concern exists that the TZD rosiglitazone may increase the risk for adverse outcomes. A meta-analysis of 42 randomized, controlled trials comparing rosiglitazone with other oral hypoglycemic agents (OHAs), insulin, or placebo in the general population suggested a significantly higher risk for myocardial infarction (MI) and a borderline increased risk for death from cardiovascular causes. 2 Another meta-analysis of four randomized, controlled clinical trials demonstrated a 42% significantly increased risk for MI and a twofold significantly increased risk for congestive heart failure (CHF). 3 Whether rosiglitazone results in adverse clinical outcomes remains uncertain, given the limitations of meta-analysis design 2 and literature demonstrating rosiglitazone's favorable influence on glycemic control. 4,5 J Am Soc Nephrol

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Anti-Inflammatory Effects of Pioglitazone and/or Simvastatin in High Cardiovascular Risk Patients With Elevated High Sensitivity C-Reactive Protein

Abstract: Pioglitazone, probably by reducing insulin resistance, has additive anti-inflammatory effects to simvastatin in non-diabetic subjects with CVD and high hs-CRP.

Cited by 155 publications

References 48 publications

Alveolar Macrophages from Overweight/Obese Subjects with Asthma Demonstrate a Proinflammatory Phenotype

Alveolar Macrophages from Overweight/Obese Subjects with Asthma Demonstrate a Proinflammatory Phenotype

Fat redistribution preferentially reflects the anti-inflammatory benefits of pioglitazone treatment

Rosiglitazone Is Associated with Mortality in Chronic Hemodialysis Patients

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