The Effects of Neprilysin Inhibition on Cardiometabolic Health in Black Individuals

PROJECT SUMMARY
Black individuals have a higher prevalence of insulin resistance and are more likely to have
cardiometabolic diseases, which is associated with an increased risk of mortality. The reasons for the
increased insulin resistance in Blacks are incompletely understood. The natriuretic peptide hormonal
system contributes to the regulation of glucose utilization and energy homeostasis, and is one of the major
determinants of cardiometabolic health. We have shown that Black individuals have 30-40% lower
natriuretic peptide levels compared with Whites, and this is evident at a young age. Black individuals also
have an impaired glucagon-like peptide-1 (GLP-1) response to meals. Both these metabolic regulators are
cleared by the neprilysin enzyme. We have shown that Blacks have a higher expression of neprilysin, and
the neprilysin mediated clearance pathway in Blacks may be a biological contributor to their higher
cardiometabolic disease risk. Sacubitril/valsartan is a Food & Drugs Administration approved inhibitor of
neprilysin that augments natriuretic peptide and GLP-1 levels. Increasing NP and GLP-1 concentrations in
Black individuals who have relatively low levels or impaired activity of these hormonal regulators of
metabolism may be an attractive strategy to improve their cardiometabolic health. We hypothesize that
neprilysin inhibition using sacubitril/valsartan will improve cardiometabolic health as measured by insulin
sensitivity and energy expenditure in Black adults. We propose to conduct a patient-oriented physiological
trial in Black individuals with insulin resistance to test the hypotheses that sacubitril/valsartan will (1)
improve insulin sensitivity, (2) increase resting and exercise energy expenditure, (3) improve GLP-1
response to meal as compared with neprilysin neutral medication (valsartan). In our aim 1 of the study, we
will enroll 200 self-identified Black individuals with insulin resistance and randomize them in a 1:1, double-
blind manner to sacubitril/valsartan (neprilysin inhibitor) or valsartan alone (neprilysin neutral) for 12 weeks.
We will compare the difference in the change in insulin sensitivity, as measured by the intravenous glucose
tolerance test, between those receiving sacubitril/valsartan and those receiving valsartan only for 12 weeks.
In the second aim of the study, we will compare the difference in change in resting energy expenditure after
12 weeks of the study drug between the two treatment arms. We will also assess the difference in the
change in exercise energy expenditure after 12 weeks. In our aim 3, we will assess the difference in the
change in the GLP-1 response to standardized mixed meals after 12-weeks of treatment with study
medications. This study targets a potentially important and innovative approach to understand and improve
the regulation of cardiometabolic indices among Black individuals through multiple mechanisms. The
findings from this study will provide a therapeutic pathway that may help in controlling the high
cardiometabolic disease burden in Black individuals.

Grant Number: 5R01HL163852-04
NIH Institute/Center: NIH
Principal Investigator: Pankaj Arora