azilsartan and Insulin-Resistance

Topics: Albuminuria; Angiotensin II; Angiotensin II Type 1 Receptor Blockers; Animals; Antihypertensive Agents; Benzimidazoles; Blood Pressure; Diabetes Mellitus, Type 2; Disease Models, Animal; Humans; Hypertension; Insulin Resistance; Obesity; Oxadiazoles

Based on non-clinical data, it is expected that azilsartan, an angiotensin II receptor blocker, will help improve insulin resistance in addition to its hypotensive action. The present study is aimed to explore the effect of azilsartan compared to telmisartan on insulin sensitivity in hypertensive patients in the clinical setting.. This multicenter, randomized, open-label, parallel-group exploratory study was conducted in Japan. We randomized adult patients (≥20 years old) with grade I or II essential hypertension and coexisting type 2 diabetes (1:1) to receive either oral azilsartan (20 mg/day;17 patients) or telmisartan (40 mg/day;16 patients) for 12 weeks. The primary endpoint was the change in the homeostasis model assessment ratio of insulin resistance (HOMA-R) from the baseline at the end of the treatment period. We also evaluated its safety and efficacy on other diabetes-related variables and blood pressure.. The mean changes in HOMA-R at the end of treatment were 0.22 (95% CI, -1.09-1.52) in the azilsartan group and -0.23 (95% CI, -0.72-0.27) in the telmisartan group. We found no clinically remarkable changes between the groups in diabetes-related variables such as fasting blood glucose, fasting insulin, HbA1c (NGSP), HOMA-β, or 1,5-anhydroglucitol. Reductions in clinic systolic and diastolic blood pressure were observed at week 4 and the reduced levels were maintained throughout the treatment period in both groups. No serious treatment-emergent adverse events (TEAEs) were observed. Only one drug-related TEAE (mild decrease in blood pressure) was reported in one patient in the azilsartan group.. Neither azilsartan nor telmisartan had any clinically remarkable effects on insulin resistance parameters when administered for 12 weeks to patients with grade I or II essential hypertension and coexisting type 2 diabetes mellitus. Azilsartan (20 mg/day) and telmisartan (40 mg/day) exerted comparable antihypertensive effects.. ClinicalTrials.gov NCT02079805.

Topics: Adult; Aged; Aged, 80 and over; Benzimidazoles; Blood Pressure; Diabetes Mellitus, Type 2; Female; Humans; Hypertension; Insulin Resistance; Male; Middle Aged; Oxadiazoles; Telmisartan

An association between the loss of skeletal muscle mass and obesity in the geriatric population has been identified as a disease known as sarcopenic obesity. Therefore, therapeutic/preventive interventions are needed to ameliorate sarcopenia. The present study investigates the effect of azilsartan (AZL) on skeletal muscle loss in High-Fat Diet (HFD)-induced sarcopenic obese (SO) rats. Four- and fourteen-months male Sprague Dawley rats were used and randomized in control and azilsartan treatment. 14 months animals were fed with HFD for four months and labeled as HFD-fed SO rats. Young & old rats received 0.5% carboxymethyl cellulose as a vehicle/AZL (8 mg/kg, per oral) treatment for six weeks. Grip strength and body composition analysis were performed after the last dose of AZL. Serum and gastrocnemius (GN)muscles were collected after animal sacrifice. AZL treatment significantly increased lean muscle mass, grip strength, myofibrillar protein, and antioxidant (superoxide dismutase & nitric oxide) levels in SO rats. AZL also restored the muscle biomarkers (creatine kinase, myostatin & testosterone), and insulin levels. AZL improves cellular, and ultracellular muscle structure and prevents type I to type II myofiber transitions in SO rats. Further, immunohistochemistry results showed increased expressions of pAkt and reduced expression of MuRF-1 and TNF-α exhibiting that AZL intervention could decrease protein degradation in SO rats. In conclusion, present results showed that AZL significantly increased lean mass, and restored muscle biomarkers, and muscle architecture. Taken together, the aforementioned findings suggest that azilsartan could be a possible therapeutic approach to reduce muscle wasting in sarcopenic obesity.

Topics: Aged; Animals; Diet, High-Fat; Humans; Insulin Resistance; Male; Muscle, Skeletal; Obesity; Proto-Oncogene Proteins c-akt; Rats; Rats, Sprague-Dawley; Sarcopenia

Hypertension often coexists with insulin resistance. However, most metabolic effects of the antihypertensive agents have been investigated in nomotensive animals, in which different conclusions may arise. We investigated the metabolic effects of the new angiotensin II type 1 receptor blocker azilsartan using the obese Koletsky rats superimposed on the background of the spontaneously hypertensive rats.. Male Koletsky rats were treated with azilsartan (2 mg/kg/day) over 3 weeks. Blood pressure was measured by tail-cuff. Blood biochemical and hormonal parameters were determined by enzymatic or ELISA methods. Gene expression was assessed by RT-PCR.. In Koletsky rats, azilsartan treatment lowered blood pressure, basal plasma insulin concentration and the homeostasis model assessment of insulin resistance index, and inhibited over-increase of plasma glucose and insulin concentrations during oral glucose tolerance test. These effects were accompanied by decreases in both food intake and body weight (BW) increase. Although two treatments showed the same effect on BW gain, insulin sensitivity was higher after azilsartan treatment than pair-feeding. Azilsartan neither affected plasma concentrations of triglyceride and free fatty acids, nor increased adipose mRNA levels of peroxisome proliferator-activated receptor (PPAR)γ and its target genes such as adiponectin, aP2. In addition, azilsartan downregulated 11β-hydroxysteroid dehydrogenase type 1 expression.. These results show the insulin-sensitizing effect of azilsartan in obese Koletsky rats. This effect is independent of decreases in food intake and BW increase or of the activation of adipose PPARγ. Our findings indicate the possible usefulness of azilsartan in the treatment of metabolic syndrome.

Topics: Animals; Antihypertensive Agents; Benzimidazoles; Blood Glucose; Blood Pressure; Enzyme-Linked Immunosorbent Assay; Hypertension; Insulin; Insulin Resistance; Male; Obesity; Oxadiazoles; Polymerase Chain Reaction; PPAR gamma; Rats; Rats, Inbred SHR

The effects of a new AT(1) receptor blocker (ARB), TAK-536, on insulin resistance were explored using type 2 diabetic KK-A(y) mice and compared with those of candesartan cilexetil (candesartan).. Male KK-A(y) mice were treated with TAK-536 or candesartan at doses of 0.0005%, 0.001%, and 0.005% in laboratory chow for 2 weeks. Results of an oral glucose tolerance test (OGTT) and tissue glucose uptake were examined. Expression of markers for insulin resistance and adipocyte differentiation was measured by quantitative reverse transcriptase-polymerase chain reaction.. Both TAK-536 and candesartan suppressed the increase in plasma glucose level in the OGTT without significant change in insulin concentration and improved insulin sensitivity. Both ARBs also increased tissue glucose uptake, especially in skeletal muscle and adipose tissue. These effects of TAK-536 on glucose intolerance were stronger than those of candesartan. In skeletal muscle, TAK-536 but not candesartan decreased the expression of TNF-alpha at doses of 0.001%. In adipose tissue, TAK-536 and candesartan reduced TNF-alpha expression but increased the expression of adiponectin, PPARgamma, C/EBalpha, and aP2. The effects of TAK-536 on these parameters were also greater than those of candesartan. Adipose tissue weight and cell size were decreased by TAK-536 at 0.005%.. These results indicate the greater beneficial effects of TAK-536 in improving glucose intolerance, insulin sensitivity, and induction of adipocyte differentiation, and suggest that TAK-536 is advantageous as a new ARB for treatment of metabolic syndrome.

Topics: Adipocytes; Adipose Tissue; Angiotensin II Type 1 Receptor Blockers; Animals; Benzimidazoles; Biphenyl Compounds; Blood Pressure; Body Weight; Cell Differentiation; Cell Size; Eating; Glucose; Glucose Intolerance; Insulin Resistance; Male; Mice; Muscle, Skeletal; Oxadiazoles; Tetrazoles; Tumor Necrosis Factor-alpha