Heart Failure Medications Evaluated for Effects on Comorbid Diabetes

New analysis of data from a study on patients with heart failure with reduced ejection fraction (HFrEF) determined that those who also had type 2 diabetes (T2D) experienced greater glycemic control with sacubitril/valsartan (Entresto, Novartis) than with enalapril (Norvasc, Pfizer).

In addition to finding a greater reduction in the hemoglobin A1c (HbA1c) marker of hyperglycemic events in the patients with T2D receiving the sacubitril/valsartan combination, the post-hoc analysis revealed that fewer patients also required initiation of insulin over the median 27-month follow-up.

“To our knowledge, this is the first study investigating the effect of sacubitril/valsartan on glycemic control,” Scott Solomon, MD, of the Cardiovascular Division of Brigham and Women’s Hospital, Harvard Medical School, Boston, MA (pictured), said. “Our results showed that in patients with diabetes and heart failure with reduced ejection fraction, treatment with sacubitril/valsartan resulted in improved glycemic control compared with enalapril.”

The trial, PARADIGM-HF (Prospective Comparison of ARNI with ACEI to Determine Impact on Global Mortality and morbidity in Heart Failure), compared the angiotensin receptor-neprilysin inhibitor (ARNI) sacubitril/valsartan combination with the angiotensin-converting enzyme inhibitor (ACEI) enalapril in 3778 patients with HF who were identified to also have diabetes, with 98% of those having T2D. More than half (57%) were taking an oral antihyperglycemic agent at baseline. The mean age was 64 years and most of the patients were men.

Glycemic control was ascertained from HbA1c measurements at baseline and yearly through the 3-year study. In addition to HbA1c, changes in triglycerides, high-density lipoprotein cholesterol, and body mass index were assessed in a mixed effects longitudinal analysis model. There were no significant differences in HbA1c concentrations at baseline between the patients randomized to receive ARNI or those randomized to the ACEI group.

Solomon and colleagues reported that the sacubitril/valsartan group demonstrated a 0.26% reduction in HbA1c during the first year of follow-up, compared to a 0.13% decrease in the enalapril group. They noted that the HbA1c concentrations in the sacubitril/valsartan group were persistently lower over the 3-year follow-up period than in the enalapril group. New use of insulin occurred in 29% fewer patients receiving sacubitiril/valsartan (n = 114, 7%) than in those on enalapril (n = 153, 10%).

The investigators suggest that the favorable findings with sacubitril/valsartan could reflect the effect of the neprilysin inhibitor on insulin sensitivity, which has been previously investigated. Possible mechanisms include promoting lipid mobilization from adipose tissue, increasing postprandial lipid oxidation, promoting adiponectin release, and enhancing muscular oxidative capacity.

“These post-hoc findings should be considered hypothesis-generating and should help inform clinicians who will be using sacubitirl/valsartan in patients with heart failure,” Solomon and colleagues wrote, “especially because doses of insulin or other antihyperglycemic drugs might need to be adjusted if HbA1c concentrations decrease.”

The analysis of data on diabetic patients from the PARADIGM-HF trial was published in the May issue of The Lancet Diabetes & Endocrinology.

Related Coverage:

Heart Failure, Diabetes, and Medication: An Interesting Triad

Researchers Still Looking for Effective Treatment for Heart Failure with Preserved Ejection Fraction

Novel Strategies in Type 2 Diabetes and CVD