Does Sacubitril/Valsartan Prevent Myocardial Remodeling in Heart Failure Patients with Type 2 Diabetes?

Heart Failure and DM2 – Current Knowledge and Recommendations

The fundamental mechanism of heart failure development in patients with DM2 is myocardial remodeling. It arises due to dysregulation of glucose and lipid metabolism, which induces oxidative stress, activates inflammatory processes, and disrupts the regulation of cardiomyocyte hyperplasia and hypertrophy. These processes result in left ventricular dilation, decreased contractility, and consequently reduced ejection fraction. 

Current recommendations for the treatment of heart failure with reduced ejection fraction (HFrEF) favor the use of drugs from the ARNI group (angiotensin II AT₁ receptor and neprilysin inhibitors). The PARADIGM-HF and PROVE-HF studies demonstrated the positive impact of sacubitril/valsartan on reverse cardiac chamber remodeling in the general population of patients with HFrEF. A post hoc analysis of the PROVE-HF study aimed to assess whether similar benefits are seen in patients with type 2 diabetes.

Post Hoc Analysis of the PROVE-HF Study

Methodology and Course

The observed population consisted of a total of 794 patients over 18 years of age with EF ≤ 40%, of whom 361 (45.5%) had type 2 diabetes (DM2). Patients with DM2 were considered those on antidiabetic treatment or with a glycated hemoglobin (HbA_1c) level > 6.5%. During the study, participants were administered sacubitril/valsartan at a target dose of 97/103 mg twice daily. Left ventricular remodeling parameters were monitored echocardiographically at the start of the study and at 6 and 12 months after screening. Another examined parameter was the NT-proBNP level (on days 14, 30, 45, 60, 90, 180, 270, and 360). The 23-item KCCQ-23 Questionnaire (Kansas City Cardiomyopathy Questionnaire) was used to assess and quantify symptoms, independence, physical limitations, and quality of life.

Results and Discussion

Initial NT-proBNP concentrations were slightly higher in individuals with DM2 than without DM2 (854 vs. 706 pg/ml), but decreased to 513 and 441 pg/ml, respectively, after starting sacubitril/valsartan therapy. Longitudinal reduction in NT-proBNP levels was similar in patients with and without DM2 (-5.6 vs. -7.1%, indicating a significant decrease in both groups; p for intergroup difference = 0.64). The increase in ejection fraction was also similar in patients with DM2 (from 28.3% at the start to 37% after 12 months) and without DM2 (from 28.1% to 38%). Longitudinal analysis showed an insignificant difference in the increase in KCCQ-23 scores over 12 months in patients with DM2 (increase from 71 to 83 points) and without DM2 (increase from 76 to 88 points; p for intergroup difference = 0.07).

The benefits of ARNI in patients with DM2 and HFrEF can be explained by three mechanisms:

1. Sacubitril/valsartan inhibits neprilysin, whose function is to degrade vasoactive peptides such as bradykinin, angiotensin I and II, and glucagon-like peptide 1 (GLP-1). This increases the concentration of these vasoactive peptides, affecting tissue insulin sensitivity. The result is better glycemic control, mobilization of lipids from adipose tissue, and release of adiponectin. These factors play a role in the pathological myocardial remodeling associated with diabetic cardiomyopathy.
2. ARNI contribute to preventing cardiomyocyte hypertrophy by increasing cyclic guanosine monophosphate. This improves diastolic function and left ventricular filling.
3. Reduction of angiotensin II and aldosterone levels induced by sacubitril/valsartan inhibits the formation of NO, which is responsible for inflammation and subsequent tissue fibrosis. 

Conclusion

The results of the PARADIGM-HF and PROVE-HF studies confirmed the positive effect of ARNI on reverse myocardial remodeling in patients with HFrEF. This post hoc analysis demonstrated that sacubitril/valsartan provides the same benefits in patients with and without DM2.

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Source: Khan M. S., Felker G. M., Piña I. L. et al. Reverse cardiac remodeling following initiation of sacubitril/valsartan in patients with heart failure with and without diabetes. JACC Heart Fail 2021 Feb; 9 (2): 137−145, doi: 10.1016/j.jchf.2020.09.014.