Novel role for adiponectin-enhancing drugs for asthma in the obese

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DESCRIPTION (provided by applicant): Asthma is a chronic lung disease that affects 8.2% of all American adults, particularly obese individuals. Current treatment for asthma primarily involves inhaled corticosteroids but these drugs are less effective among obese individuals. There is therefore an unmet need to discover more efficacious asthma medications targeting obese individuals. Recent research has shown that low serum concentrations of adiponectin, a unique anti-inflammatory product of adipose tissue, predict both incident asthma and worse clinical severity of asthma in some populations. In addition, low adiponectin is similarly associated with depression and ischemic cardiovascular disease. Potent adiponectin-enhancing drugs include the antidiabetic drug class of thiazolidinediones (TZD) and antihypertensive drug class of angiotensin receptor blockers (ARB). Our overarching hypothesis is that use of adiponectin-enhancing drugs among obese adults can help prevent or treat asthma as well as depression and ischemic cardiovascular disease. Specific Aim 1: To determine the effect of adiponectin-enhancing drugs on incident asthma, depression or ischemic cardiovascular disease among obese subjects with concomitant diabetes and/or hypertension. Based upon our preliminary data, our working primary hypothesis is that TZD and/or ARB use is associated with a lower risk for developing incident asthma than use of other antidiabetic and/or antihypertensive drugs and this association is stronger among women than men. Our secondary hypotheses are that similar beneficial effects are seen with respect to incident depression and incident ischemic cardiovascular disease in this population. The proposed study examines a longitudinal cohort of veteran Americans over two decades, using the Veterans Administration (VA) National Data System. We will conduct parallel analyses for each disease in which we first exclude prevalent disease at 'baseline' visit and analyze incident disease at subsequent visits. Specific Aim 2: To determine the effect of adiponectin-enhancing drugs on risk for disease complications among subjects with that disease (i.e. asthma, depression or ischemic cardiovascular disease) plus obesity plus concomitant diabetes and/or hypertension. Based upon our preliminary data, our working primary hypothesis is that TZD and/or ARB use in our population subgroup with asthma is associated with a lower risk for asthma exacerbations than use of other antidiabetic and/or antihypertensive drugs and this association is stronger among women than men. Our secondary hypotheses are that similar beneficial effects are seen with respect to emergency room visits or hospitalizations from depression or ischemic cardiovascular disease. For Specific Aim 2, we will include only those with prevalent disease in each statistical model and analyze risk for complications related to that disease. Survival analysis will be used to study the events in Aims 1 and 2. If our research shows that adiponectin-enhancing drugs favorably affect the natural history of diseases related to hypoadiponectinemia, it will help develop novel strategies for preventing and treating asthma as well as depression and ischemic cardiovascular disease in the obese.