Effect of sacubitril/valsartan versus enalapril on glycaemic control in patients with heart failure and diabetes: a post-hoc analysis from the PARADIGM-HF trial.
Diabetes is an independent risk factor for heart failure progression. Sacubitril/valsartan, a combination angiotensin receptor-neprilysin inhibitor, improves morbidity and mortality in patients with heart failure with reduced ejection fraction (HFrEF), compared with the angiotensin-converting enzyme inhibitor enalapril, and improves peripheral insulin sensitivity in obese hypertensive patients. We aimed to investigate the effect of sacubitril/valsartan versus enalapril on HbA1cand time to first-time initiation of insulin or oral antihyperglycaemic drugs in patients with diabetes and HFrEF.



In a post-hoc analysis of the PARADIGM-HF trial, we included 3778 patients with known diabetes or an HbA1c≥6·5% at screening out of 8399 patients with HFrEF who were randomly assigned to treatment with sacubitril/valsartan or enalapril. Of these patients, most (98%) had type 2 diabetes. We assessed changes in HbA1c, triglycerides, HDL cholesterol and BMI in a mixed effects longitudinal analysis model. Time to initiation of oral antihyperglycaemic drugs or insulin in subjects previously not treated with these agents were compared between treatment groups.



There were no significant differences in HbA1cconcentrations between randomised groups at screening. During the first year of follow-up, HbA1cconcentrations decreased by 0·16% (SD 1·40) in the enalapril group and 0·26% (SD 1·25) in the sacubitril/valsartan group (between-group reduction 0·13%, 95% CI 0·05-0·22, p=0·0023). HbA1cconcentrations were persistently lower in the sacubitril/valsartan group than in the enalapril group over the 3-year follow-up (between-group reduction 0·14%, 95% CI 0·06-0·23, p=0·0055). New use of insulin was 29% lower in patients receiving sacubitril/valsartan (114 [7%] patients) compared with patients receiving enalapril (153 [10%]; hazard ratio 0·71, 95% CI 0·56-0·90, p=0·0052). Similarly, fewer patients were started on oral antihyperglycaemic therapy (0·77, 0·58-1·02, p=0·073) in the sacubitril/valsartan group.



Patients with diabetes and HFrEF enrolled in PARADIGM-HF who received sacubitril/valsartan had a greater long-term reduction in HbA1cthan those receiving enalapril. These data suggest that sacubitril/valsartan might enhance glycaemic control in patients with diabetes and HFrEF.



Novartis.
Cardiovascular Division, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
Jelena P
JP
Seferovic
Cardiovascular Division, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
Brian
B
Claggett
Cardiovascular Division, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
Sara B
SB
Seidelmann
Endocrinology, Diabetes, and Hypertension Division, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
Ellen W
EW
Seely
Baylor University Medical Center, Dallas, TX, USA.
Milton
M
Packer
The Medical University of South Carolina and RHJ Department of Veterans Administration Medical Center, Charleston, SC, USA.
Michael R
MR
Zile
Université de Montréal, Institut de Cardiologie, Montréal, QC, Canada.
Jean L
JL
Rouleau
Department of Molecular and Clinical Medicine, Sahlgrenska University Hospital, Göteborg, Sweden.
Karl
K
Swedberg
Novartis Pharmaceutical Corporation, East Hanover, NJ, USA.
Martin
M
Lefkowitz
Novartis Pharmaceutical Corporation, East Hanover, NJ, USA.
Victor C
VC
Shi
Cardiovascular Division, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
Akshay S
AS
Desai
BHF Cardiovascular Research Centre, University of Glasgow, Glasgow, UK.
John J V
JJV
McMurray
Cardiovascular Division, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA. Electronic address: ssolomon@bwh.harvard.edu.
Scott D
SD
Solomon
D000368:Aged; D000613:Aminobutyrates / Q000494:pharmacology / Q000627:therapeutic use*; D047228:Angiotensin II Type 1 Receptor Blockers / Q000494:pharmacology / Q000627:therapeutic use*; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D001713:Biphenyl Compounds; D001786:Blood Glucose / Q000187:drug effects*; D003924:Diabetes Mellitus, Type 2 / Q000150:complications; D004338:Drug Combinations; D004656:Enalapril / Q000494:pharmacology / Q000627:therapeutic use*; D005260:Female; D006333:Heart Failure / Q000150:complications / Q000188:drug therapy*; D006801:Humans; D008297:Male; D008875:Middle Aged; D013777:Tetrazoles / Q000494:pharmacology / Q000627:therapeutic use*; D000068756:Valsartan / Q000494:pharmacology / Q000627:therapeutic use*
D000613:Aminobutyrates; D047228:Angiotensin II Type 1 Receptor Blockers; D000806:Angiotensin-Converting Enzyme Inhibitors; D001713:Biphenyl Compounds; D001786:Blood Glucose; D004338:Drug Combinations; D013777:Tetrazoles; D004656:Enalapril; D000068756:Valsartan; C549068:sacubitril and valsartan sodium hydrate drug combination