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PDE5 Inhibition for Obesity-Related Cardiometabolic Dysfunction

Award Number: R01HL128983
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 06/01/2016
PERIOD OF PERFORMANCE END DATE: 05/31/2021

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PDE5 Inhibition for Obesity-Related Cardiometabolic Dysfunction - DESCRIPTION (provided by applicant): The metabolic and cardiovascular sequelae of obesity constitute a major financial and public health burden. Increased cardiovascular risk in obesity is directly related to metabolic dysregulation, key features of which include abnormalities in energy homeostasis and insulin resistance. The effectiveness of weight loss efforts to reduce cardiometabolic risk in obesity is limited due to high weight gain recidivism. Therefore, interventions that directly target metabolic fitness in obesity represent an important area of investigation. Evidence in experimental models and our preliminary data in humans suggest that the cyclic guanylate monophosphate pathway (cGMP) is a critical mediator of insulin resistance and energy homeostasis. Increased cGMP signaling raises resting energy expenditure and provides resistance to obesity and diabetes. Cyclic GMP also stimulates mitochondrial biogenesis and oxidative capacity in skeletal muscle. Phosphodiesterase type 5 (PDE5) inhibitors such as tadalafil prevent the degradation of cGMP. These medications are well-tolerated and improve glucose metabolism, but have not been comprehensively tested as a target for obesity-related cardiometabolic dysfunction in humans. We propose a randomized, placebo-controlled study to examine the cardiometabolic effects of PDE5 inhibition in obese prediabetic individuals. Participants will receive tadalafil 20 mg per day or placebo for 12 weeks. Aim 1 will examine the effect of chronic PDE5 inhibition on resting and exercise energy expenditure using a metabolic chamber. In Aim 2, we will test the effect of PDE5 inhibition on insulin sensitivity and secretion. We will also assess body composition, quality of life, and sexual function. A Secondary Aim will examine the effect of PDE5 inhibition on cGMP sensitivity and circulating mediators of diabetes risk. The proposed study will be the first large comprehensive evaluation of PDE5 inhibition in a population at high risk of cardiovascular disease. Our endpoints were selected to provide highly relevant clinical outcomes and mechanistic insight into the cardiometabolic effects of cGMP action. Therapy that improves metabolic fitness independent of weight loss would represent an important advance in the effort to reduce cardiovascular risk in obesity.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2021 ( Subtotal = -$372 )
2021	2019	VANDERBILT UNIVERSITY, THE	2301 VANDERBILT PL	NASHVILLE	TN	37235	DAVIDSON	USA	Cardiovascular Diseases Research	000	4	8/25/2021	NON-COMPETING CONTINUATION	-$372
														Subtotal = -$372

Issue Date FY: 2019 ( Subtotal = $728,870 )
2019	2019	VANDERBILT UNIVERSITY, THE	2301 VANDERBILT PL	NASHVILLE	TN	37235	DAVIDSON	USA	Cardiovascular Diseases Research	000	4	5/2/2019	NON-COMPETING CONTINUATION	$728,870
														Subtotal = $728,870

Issue Date FY: 2018 ( Subtotal = $728,848 )
2018	2018	VANDERBILT UNIVERSITY, THE	2301 VANDERBILT PL	NASHVILLE	TN	37235	DAVIDSON	USA	Cardiovascular Diseases Research	000	3	5/25/2018	NON-COMPETING CONTINUATION	$728,848
														Subtotal = $728,848

Issue Date FY: 2017 ( Subtotal = $693,135 )
2017	2017	VANDERBILT UNIVERSITY, THE	211 KIRKLAND HALL	NASHVILLE	TN	37240	DAVIDSON	USA	Cardiovascular Diseases Research	000	2	6/20/2017	NON-COMPETING CONTINUATION	$693,135
														Subtotal = $693,135

Issue Date FY: 2016 ( Subtotal = $777,818 )
2016	2016	VANDERBILT UNIVERSITY MEDICAL CENTER	1161 21ST AVE S STE D3300 MCN	NASHVILLE	TN	37232	DAVIDSON	USA	Cardiovascular Diseases Research	000	1	5/31/2016	NEW	$777,818
														Subtotal = $777,818

Grand Total All Awards = $2,928,299

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PDE5 Inhibition for Obesity-Related Cardiometabolic Dysfunction

Award Number: R01HL128983

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 06/01/2016

PERIOD OF PERFORMANCE END DATE: 05/31/2021

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