fumarates and Metabolic-Syndrome

There is evidence that patients with moderate to severe psoriasis have an increased risk of conditions such as cardiovascular disease, obesity, diabetes mellitus, and metabolic syndrome. The precise mechanisms underlying the observed increase in cardiovascular disease in psoriasis remain to be defined but inflammatory pathways mutual to both conditions are probably involved. Suppression of systemic inflammation in psoriasis could help reduce cardiovascular inflammation but robust evidence is still lacking evidence is lacking. This article summarizes the current literature on cardiovascular and metabolic comorbidities in psoriasis, identifies research gaps, and suggests management strategies to reduce cardiovascular risk in patients with moderate to severe psoriasis.

Topics: Acitretin; Adipokines; Alcoholism; Antibodies, Monoclonal, Humanized; Cardiovascular Diseases; Comorbidity; Cyclosporine; Dermatologic Agents; Diabetes Mellitus; Fumarates; Humans; Immunosuppressive Agents; Inflammation; Metabolic Syndrome; Methotrexate; Obesity; Psoriasis; Risk Factors; Smoking; Tumor Necrosis Factor-alpha; Ustekinumab

Topics: Adipocytes; Amides; Angiotensin-Converting Enzyme 2; Antihypertensive Agents; Biphenyl Compounds; Fumarates; Hypertension; Insulin Resistance; Irbesartan; Metabolic Syndrome; Peptidyl-Dipeptidase A; Prorenin Receptor; Receptors, Angiotensin; Receptors, Cell Surface; Renin-Angiotensin System; Tetrazoles; Vacuolar Proton-Translocating ATPases

Metabolic syndrome, a cluster of risk factors that increase the risk of cardiovascular morbidity and mortality, is common in patients with hypertension. Chronic renin-angiotensin-aldosterone system (RAAS) activation, shown by elevated plasma renin activity (PRA), is implicated in many of the features of metabolic syndrome. The direct renin inhibitor aliskiren may be of benefit in this patient group as aliskiren targets the RAAS at the rate-limiting step. In this double-blind study, 141 patients with hypertension (mean baseline BP 155/93 mm Hg) and metabolic syndrome (modified National Cholesterol Education Program ATP III criteria) were randomized to aliskiren 300 mg or irbesartan 300 mg once daily. Patients treated with aliskiren 300 mg had their mean sitting blood pressure (BP) lowered by 13.8/7.1 mm Hg after 12 weeks, significantly greater (P≤0.001) than the 5.8/2.8 mm Hg reduction observed in patients treated with irbesartan 300 mg. A significantly greater proportion of patients treated with aliskiren achieved BP control to <135/85 mm Hg (29.2 vs 16.7% with irbesartan; P=0.019). Aliskiren treatment led to a 60% decrease in PRA from baseline, whereas irbesartan increased PRA by 99% (both P<0.001). Aliskiren and irbesartan had similar effects on glucose and lipid profiles and on a panel of biomarkers of inflammation and cardiovascular risk. Both aliskiren and irbesartan were well tolerated. Collectively, these results suggest that aliskiren 300 mg may offer treatment benefits compared with irbesartan 300 mg for BP reduction in patients with hypertension and metabolic syndrome.

Topics: Adult; Aged; Amides; Antihypertensive Agents; Biphenyl Compounds; Blood Glucose; Cardiovascular Diseases; Double-Blind Method; Female; Fumarates; Humans; Hypertension; Inflammation; Irbesartan; Lipids; Male; Metabolic Syndrome; Middle Aged; Renin; Renin-Angiotensin System; Tetrazoles; Treatment Outcome

The aim of this study was to compare the effect of aliskiren and losartan on fibrinolysis and insulin sensitivity (IS) in hypertensive patients with metabolic syndrome. After 2-week placebo period, 76 outpatients with mild to moderate hypertension and metabolic syndrome were randomized to aliskiren 300 mg od or losartan 100 mg od for 12 weeks. Clinic blood pressure (BP), plasma PAI-1 antigen, and tPA activity were evaluated after 2, 4, 8, and 12 weeks of treatment. At the end of each treatment period patients performed an euglycemic hyperinsulinemic clamp and IS was assessed by glucose infusion rate (GIR). Both aliskiren and losartan induced a significant and similar SBP/DBP reduction (-15.6/10.7 mmHg and -15.5/10.5 mmHg, p<0.001 vs. baseline, respectively). Both drugs decreased PAI-1 antigen and activity after 2 weeks of treatment; subsequently, only the decreasing effect of aliskiren was sustained throughout the 12 weeks [-7.5 ng/ml (-31%) p<0.05 vs. baseline], while with losartan PAI-1 increased at week 12 [+3.6 ng/ml (+15%), p<0.05 vs. baseline and p<0.01 vs. aliskiren)]. The tPA activity showed no significant change with aliskiren and a decrease with losartan [-0.04 IU/ml (-8%), p<0.05 vs. baseline and p<0.01 vs. aliskiren]. Aliskiren significantly increased GIR [+1.4 mg/min/kg (+28%), p<0.01 vs. baseline] while losartan did not change it [+0.2 mg/min/kg (+4%), NS vs. baseline, p<0.05 vs. aliskiren)]. These results indicated that in this type of patients, despite similar BP reduction, aliskiren improved the fibrinolytic balance as well as IS, while losartan worsened the fibrinolytic balance and did not affect IS. The clinical relevance of these different effects remains to be clarified.

Topics: Adolescent; Adult; Aged; Amides; Antihypertensive Agents; Blood Pressure; Female; Fibrinolysis; Fumarates; Humans; Hypertension; Insulin; Losartan; Male; Metabolic Syndrome; Middle Aged; Young Adult

Renin-angiotensin system in visceral fat plays a crucial role in the pathogenesis of metabolic syndrome in fructose-fed rats. However, the effects of renin inhibition on visceral adiposity in metabolic syndrome are not fully investigated. We investigated the effects of renin inhibition on visceral adiposity in fructose-fed rats. Male Wistar-Kyoto rats were divided into 4 groups for 8-week experiments: Group Con (standard chow diet), Group Fru (high-fructose diet; 60% fructose), Group FruA (high-fructose diet and concurrent aliskiren treatment; 100 mg/kg body weight [BW] per day), and Group FruB (high-fructose diet and subsequent, i.e. 4 weeks after initiating high-fructose feeding, aliskiren treatment; 100 mg/kg BW per day). The high-fructose diet induced metabolic syndrome, increased visceral fat weights and adipocyte sizes, and augmented angiotensin II (Ang II), NADPH oxidase (NOX) isoforms expressions, oxidative stress, and dysregulated production of adipocytokines from visceral adipose tissues. Concurrent and subsequent aliskiren administration ameliorated metabolic syndrome, dysregulated adipocytokines, and visceral adiposity in high fructose-fed hypertensive rats, and was associated with reducing Ang II levels, NOX isoforms expressions and oxidative stress in visceral fat tissues. Therefore, this study demonstrates renin inhibition could improve metabolic syndrome, and reduce Ang II levels and oxidative stress in visceral fat tissue in fructose-fed rats, and suggests that visceral adipose Ang II plays a crucial role in the pathogenesis of metabolic syndrome in fructose-fed rats.

Topics: Adipocytes; Adipokines; Amides; Angiotensin II; Animals; Blood Glucose; Blood Pressure; Cell Size; Cholesterol; Feeding Behavior; Fructose; Fumarates; Insulin; Intra-Abdominal Fat; Male; Metabolic Syndrome; Oxidative Stress; Rats, Inbred WKY; Renin; Superoxide Dismutase; Systole; Thiobarbituric Acid Reactive Substances; Triglycerides

Fructose is a commonly used sweetener associated with diets that increase the prevalence of metabolic syndrome (MS). Inhibition of the renin-angiotensin system (RAS) has been consistently demonstrated to reduce MS. However, there has been no direct comparison among different pharmacological modes of inhibiting the RAS concerning their effects on MS. This study investigated the effect of aliskiren, a direct renin inhibitor, versus telmisartan, an angiotensin II-receptor blocker, in the treatment of fructose-induced MS in rats. MS was induced by high fructose (FRC) diet feeding for 12 weeks. Oral administrations of telmisartan (TEL, 5 mg/kg), aliskiren (ALS, 30 mg/kg) or vehicle were started in the last 4 weeks. Results showed that administration of either TEL or ALS with FRC diet equally ameliorated the metabolic parameters (glucose level, oral glucose tolerance test, insulin resistance and serum lipids profile), systolic blood pressure and oxidative stress markers (malondialdehyde, nitric oxide, reduced glutathione levels and catalase activity). Additionally, the effects of TEL and ALS were associated with a decrease in body composition index and attenuation of liver index, serum liver enzyme activities and hepatic expressions of inflammatory and fibrotic markers (tumor necrosis factor-α, nuclear factor kappa-B and transforming growth factor-β) with a significant increase in hepatic glucose transporter-2 and peroxisome proliferator-activated receptors-alpha and gamma expressions. The results suggested that, at indicated dosage, ALS has ameliorative effect equal to that of TEL against FRC-induced metabolic and hepatic disorders; implying that drugs which inhibit the RAS, by different mode of inhibition, profoundly affect fructose-induced MS in rats.

Topics: Amides; Animals; Antihypertensive Agents; Benzimidazoles; Benzoates; Blood Glucose; Fructose; Fumarates; Insulin Resistance; Male; Metabolic Syndrome; Rats; Rats, Wistar; Telmisartan; Treatment Outcome

Inflammation and oxidative stress have been implicated in the pathogenesis of metabolic disturbances. Esters of fumaric acid, mainly dimethyl fumarate, exhibit immunomodulatory, anti-inflammatory, and anti-oxidative effects. In the current study, we tested the hypothesis that fumaric acid ester (FAE) treatment of an animal model of inflammation and metabolic syndrome, the spontaneously hypertensive rat transgenically expressing human C-reactive protein (SHR-CRP), will ameliorate inflammation, oxidative stress, and metabolic disturbances. We studied the effects of FAE treatment by administering Fumaderm, 10 mg/kg body weight for 4 weeks, to male SHR-CRP. Untreated male SHR-CRP rats were used as controls. All rats were fed a high sucrose diet. Compared to untreated controls, rats treated with FAE showed significantly lower levels of endogenous CRP but not transgenic human CRP, and amelioration of inflammation (reduced levels of serum IL6 and TNFα) and oxidative stress (reduced levels of lipoperoxidation products in liver, heart, kidney, and plasma). FAE treatment was also associated with lower visceral fat weight and less ectopic fat accumulation in liver and muscle, greater levels of lipolysis, and greater incorporation of glucose into adipose tissue lipids. Analysis of gene expression profiles in the liver with Affymetrix arrays revealed that FAE treatment was associated with differential expression of genes in pathways that involve the regulation of inflammation and oxidative stress. These findings suggest potentially important anti-inflammatory, anti-oxidative, and metabolic effects of FAE in a model of inflammation and metabolic disturbances induced by human CRP.

Topics: Animals; Anti-Inflammatory Agents; Antioxidants; C-Reactive Protein; Fumarates; Hemodynamics; Humans; Inflammation; Male; Metabolic Syndrome; Oxidative Stress; Rats; Rats, Inbred SHR; Transcriptome

To test the hypothesis that aliskiren improves the metabolic phenotype in a genetic mouse model of the metabolic syndrome (the caveolin-1 (cav-1) knock out (KO) mouse).. Eleven-week-old cav-1 KO and genetically matched wild-type (WT) mice were randomized to three treatment groups: placebo (n=8/group), amlodipine (6 mg/kg/day, n=18/ group), and aliskiren (50 mg/kg/day, n=18/ group). After three weeks of treatment, all treatment groups were assessed for several measures of insulin resistance (fasting insulin and glucose, HOMA-IR, and the response to an intraperitoneal glucose tolerance test (ipGTT)) as well as for triglyceride levels and the blood pressure response to treatment.. Treatment with aliskiren did not affect the ipGTT response but significantly lowered the HOMA-IR and insulin levels in cav-1 KO mice. However, treatment with amlodipine significantly degraded the ipGTT response, as well as the HOMA-IR and insulin levels in the cav-1 KO mice. Aliskiren also significantly lowered triglyceride levels in the cav-1 KO but not in the WT mice. Moreover, aliskiren treatment had a significantly greater effect on blood pressure readings in the cav-1 KO vs. WT mice, and was marginally more effective than amlodipine.. Our results support the hypothesis that aliskiren reduces insulin resistance as indicated by improved HOMA-IR in cav-1 KO mice whereas amlodipine treatment resulted in changes consistent with increased insulin resistance. In addition, aliskiren was substantially more effective in lowering blood pressure in the cav-1 KO mouse model than in WT mice and marginally more effective than amlodipine.

Topics: Amides; Animals; Antihypertensive Agents; Blood Glucose; Blood Pressure; Caveolin 1; Disease Models, Animal; Fumarates; Glucose Tolerance Test; Insulin; Insulin Resistance; Male; Metabolic Syndrome; Mice; Mice, Knockout; Random Allocation; Renin; Triglycerides