Washington – Patients with heart failure with reduced ejection fraction and comorbid diabetes whose heart failure was treated with sacubitril/valsartan experienced significantly enhanced glycemic control in addition to reduced morbidity and mortality due to heart failure in the landmark PARADIGM-HF trial, Jelena P. Seferovic, MD, reported at the annual meeting of the American College of Cardiology.
PARADIGM-HF was a randomized, double-blind clinical trial of oral sacubitril/valsartan, an angiotensin receptor–neprilysin inhibitor, or ARNI, at 97 mg/103 mg twice daily versus enalapril at 10 mg twice daily in 8,442 patients with heart failure with reduced ejection fraction (HFrEF). The primary results, which demonstrated significant reductions in heart failure morbidity and mortality in the sacubitril/valsartan group, have been published (N Engl J Med. 2014 Sep 11;371[11]:993-1004). The findings led to Food and Drug Administration approval of the drug, marketed as Entresto, for HFrEF, as well as a top level Class I recommendation for the drug’s use in the 2016 ACC/AHA heart failure management guidelines.
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Dr. Jelena P. Seferovic
Dr. Seferovic presented a new post hoc secondary analysis of PARADIGM-HF focused on the 3,778 participants with HFrEF and diabetes. During the first year of study follow-up, hemoglobin A1c decreased by 0.26% from a baseline of 7.44% in the ARNI group, significantly greater than the 0.16% reduction in enalapril-treated controls. This benefit persisted during years 2 and 3.
Moreover, this effect was accompanied by a 29% reduction in new use of insulin in the ARNI group, 7% of whom began insulin therapy during follow-up compared with 10% of controls. Similarly, a 23% reduction in new use of oral antihyperglycemic drugs was seen in the ARNI group, reported Dr. Seferovic of Brigham and Women’s Hospital, Boston.
“Our post hoc study findings should be considered hypothesis-generating, but they suggest that sacubitril/valsartan, which has already been proven to reduce morbidity and mortality in heart failure, might provide additional metabolic benefits in patients with diabetes. Also, our findings suggest that diabetic patients who are treated with sacubitril/valsartan for their heart failure may require dose adjustment of their antihyperglycemic therapy,” she said.
Dr. Seferovic added that this need for dose adjustment is not just a theoretical concern. It actually occurred during the PARADIGM-HF trial.
The impetus for the post hoc analysis was driven in part by animal studies demonstrating that neprilysin inhibition improves insulin sensitivity. Although the mechanism of metabolic benefit for sacubitril/valsartan is not fully understood, it’s known that neprilysin is expressed in adipocytes, cardiac myocytes, smooth muscle cells, and endothelial cells. Neprilysin increases postprandial lipid oxidation, promotes adiponectin release, and boosts the oxidative capacity of muscle. Moreover, neprilysin is responsible for breakdown of natriuretic peptides as well as glucagon-like peptide 1.
“We hypothesize that the beneficial antihyperglycemic effect of sacubitril/valsartan revealed in this analysis is most probably due to the neprilysin inhibition and modulation of its circulating substrates,” said Dr. Seferovic.
One audience member asked Dr. Seferovic if she deemed the 0.14% greater absolute reduction in HbA1c achieved with the ARNI over the course of 3 years to be clinically meaningful. She responded with an emphatic yes.
“We believe any decrease in HbA1c is clinically important,” she declared.
Comorbid diabetes is present in up to 40% of patients with heart failure and has been shown to be a strong independent risk factor for heart failure progression.
Simultaneously with her presentation of the new PARADIGM-HF analysis at ACC 17, the study results were published online in The Lancet Diabetes & Endocrinology.
In an accompanying editorial, Gregory Giamouzis, MD, and Javed Butler, MD, cited a handful of reasons why the new findings are important and exciting. For example, polypharmacy has been linked to poor treatment adherence in heart failure, so a drug that can simultaneously improve diabetes and heart failure is attractive. Also, beta blockers and diuretics – cornerstones of heart failure therapy – have been implicated in worsening hyperglycemia.
“Thus, any heart failure therapy that is protective against incident diabetes or worsening glycemic control is a welcome addition,” according to Dr. Giamouzis of the University of Thessaly, Greece, and Dr. Butler of Stony Brook (N.Y.) University.
They added that important unresolved questions include whether sacubitril/valsartan will provide meaningful metabolic benefits in patients with heart failure and comorbid metabolic syndrome, as well as the effects of the ARNI in diabetic patients with heart failure with preserved ejection fraction. The latter issue is the focus of the ongoing major multicenter PARAGON-HF trial.
The PARADIGM-HF trial was sponsored by Novartis. Dr. Seferovic reported having no financial conflicts.