J Am Heart Assoc. 2021 May 16:e022069. doi: 10.1161/JAHA.121.022069. Online ahead of print.
Background Dyslipidemia is common in heart failure with preserved ejection fraction (HFpEF). Sacubitril/valsartan improves insulin sensitivity and augments natriuretic peptide (NP) signaling, providing mechanisms by which sacubitril/valsartan may affect serum lipids. However, empiric data on these effects are lacking. Methods and Results We analyzed 4,744 participants from PARAGON-HF with available screening lipids. During follow-up visits, we analyzed the treatment effect on lipid levels and assessed for interaction by baseline lipid levels. At the 16-week visit, we adjusted these treatment effects for the change in several biomarkers (including hemoglobin A1c and urinary cyclic guanosine monophosphate (cGMP)/creatinine [a biomarker of NP activation]). The average age was 73±8 years, 52% were women, 43% had diabetes mellitus, and 64% were on statin therapy. Compared with valsartan, sacubitril/valsartan reduced triglycerides -5.0% (-6.6%, -3.5%), increased high-density lipoprotein cholesterol (HDL-c) +2.6% (+1.7%, +3.4%), and increased low-density lipoprotein cholesterol (LDL-c) +1.7% (+0.4%, +3.0%). Sacubitril/valsartan reduced triglycerides most among those with elevated baseline levels (triglycerides≥200 mg/dL) (p-interaction<0.001), and at 16-weeks by -13.0% (-18.1%, -7.6%), or -29.9 (-44.3, -15.5) mg/dL, in this group. Adjusting for the change in urinary cGMP/creatinine significantly attenuated treatment effects on triglycerides and HDL-c, but not LDL-c, while adjusting for other biomarkers did not significantly alter the treatment effects. Conclusions Sacubitril/valsartan significantly reduces triglycerides compared with valsartan, an effect that was substantially stronger in those with elevated baseline triglycerides. Modest increases in HDL-c and LDL-c cholesterol were also observed with therapy. The underlying mechanism(s) of changes in HDL-c and triglycerides are related to sacubitril/valsartan's effects on NP activity.