A Randomized Controlled Trial of the Effects of Pioglitazone Treatment on Sympathetic Nervous System Activity and Cardiovascular Function in Obese Subjects With Metabolic Syndrome

• Published in: The journal of clinical endocrinology and metabolism Vol. 99; no. 9; pp. E1701 - E1707
• Main Authors: Straznicky, Nora E., Grima, Mariee T., Sari, Carolina I., Eikelis, Nina, Lambert, Gavin W., Nestel, Paul J., Karapanagiotidis, Sofie, Wong, Chiew, Richards, Katrina, Marusic, Petra, Dixon, John B., Schlaich, Markus P., Lambert, Elisabeth A.
• Format: Journal Article
• Language: English
• Published: United States Oxford University Press 01.09.2014
• Subjects: Baroreceptors; Blood pressure; Blood Pressure - drug effects; Body mass index; Body measurements; Cardiovascular diseases; Clinical trials; Diastole - drug effects; Doppler effect; Double-Blind Method; Echocardiography; Echocardiography, Doppler; Endothelium, Vascular - drug effects; Female; Glucose; Glucose tolerance; Glucose Tolerance Test; Heart; Humans; Hyperinsulinemia; Hyperinsulinism - drug therapy; Hyperinsulinism - physiopathology; Hypertension - drug therapy; Hypertension - physiopathology; Hypoglycemic Agents - administration & dosage; Insulin resistance; Male; Metabolic syndrome; Metabolic Syndrome - drug therapy; Metabolic Syndrome - physiopathology; Methoxyhydroxyphenylglycol - analogs & derivatives; Methoxyhydroxyphenylglycol - blood; Methoxyhydroxyphenylglycol - pharmacokinetics; Middle Aged; Models, Biological; Nervous system; Norepinephrine; Norepinephrine - blood; Norepinephrine - pharmacokinetics; Obesity - drug therapy; Obesity - physiopathology; Pioglitazone; Placebos; Reflexes; Sensitivity analysis; Sympathetic nerves; Sympathetic nervous system; Sympathetic Nervous System - drug effects; Thiazolidinediones - administration & dosage; Tritium
• ISSN: 0021-972X; 1945-7197; 1945-7197
• DOI: 10.1210/jc.2014-1976

Context:Insulin resistance and sympathetic nervous system overactivity are closely associated and contribute to cardiovascular risk.Objective:The objective of the study was to test the hypotheses that pharmacological improvement in insulin sensitivity would (1) attenuate sympathetic neural drive and (2) enhance neuronal norepinephrine uptake.Participants and Methods:A randomized, double-blind trial was conducted in 42 obese, unmedicated individuals with metabolic syndrome (mean age 56 ± 1 y, body mass index 34 ± 0.6 kg/m2) who received 12 weeks of pioglitazone (PIO; 15 mg for 6 wk, then 30 mg daily) or matched placebo. Clinical measurements included whole-body norepinephrine kinetics [spillover rate, plasma clearance, and the steady state ratio of tritiated 3,4-dihydroxyphenylglycol to tritiated norepinephrine ([3H]-DHPG to [3H]-NE) as an index of neuronal uptake-1], muscle sympathetic nerve activity, spontaneous baroreflex sensitivity, euglycemic hyperinsulinemic clamp, oral glucose tolerance test, ambulatory blood pressure, and Doppler echocardiography.Results:PIO treatment increased glucose uptake by 35% and was accompanied by significant reductions in diastolic blood pressure and improved left ventricular diastolic and endothelial function. Resting muscle sympathetic nerve activity burst frequency decreased by −6 ± 3 burst/min compared with baseline (P = .03), but the magnitude of change was not different from placebo (P = .89). Norepinephrine spillover and clearance rates and baroreflex sensitivity were unchanged. Post hoc subgroup analyses revealed an 83% increase in [3H]-DHPG to [3H]-NE ratio in hyperinsulinemic (P = .04) but not normoinsulinemic subjects (time × group interaction, P = .045). Change in [3H]-DHPG to [3H]-NE ratio correlated with improvements in diastolic blood pressure (r = −0.67, P = .002), the ratio of early (E) to late (A) peak transmitral diastolic inflow velocity (r = 0.62, P = .008), E wave deceleration time (r = −0.48, P = .05), and Δinsulin area under the curve0–120 during the oral glucose tolerance test (r = −0.42, P = .08).Conclusions:Compared with placebo, PIO does not affect resting sympathetic drive or norepinephrine disposition in obese subjects with metabolic syndrome. Treatment induced changes in the [3H]-DHPG to [3H]-NE ratio related to reduction in hyperinsulinemia and improvements in diastolic function.