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

Jelena P. Seferovic, Brian Claggett, Sara B. Seidelmann, Ellen W. Seely, Milton Packer, Michael R. Zile, Jean L. Rouleau, Karl Swedberg, Martin Lefkowitz, Victor C. Shi, Akshay S. Desai, John J V McMurray, Scott D. Solomon

Research output: Contribution to journalArticle

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Abstract

Background: 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 HbA1c and time to first-time initiation of insulin or oral antihyperglycaemic drugs in patients with diabetes and HFrEF. Methods: 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. Findings: There were no significant differences in HbA1c concentrations between randomised groups at screening. During the first year of follow-up, HbA1c concentrations 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). HbA1c concentrations 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. Interpretation: Patients with diabetes and HFrEF enrolled in PARADIGM-HF who received sacubitril/valsartan had a greater long-term reduction in HbA1c than those receiving enalapril. These data suggest that sacubitril/valsartan might enhance glycaemic control in patients with diabetes and HFrEF. Funding: Novartis.

Original languageEnglish (US)
JournalThe Lancet Diabetes and Endocrinology
DOIs
StateAccepted/In press - 2017

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Enalapril
Heart Failure
Hypoglycemic Agents
Insulin
LCZ 696
Neprilysin
Angiotensin Receptors
Angiotensin-Converting Enzyme Inhibitors
Pharmaceutical Preparations
Type 2 Diabetes Mellitus
HDL Cholesterol
Insulin Resistance
Triglycerides
Therapeutics

ASJC Scopus subject areas

  • Internal Medicine
  • Endocrinology, Diabetes and Metabolism
  • Endocrinology

Cite this

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. / Seferovic, Jelena P.; Claggett, Brian; Seidelmann, Sara B.; Seely, Ellen W.; Packer, Milton; Zile, Michael R.; Rouleau, Jean L.; Swedberg, Karl; Lefkowitz, Martin; Shi, Victor C.; Desai, Akshay S.; McMurray, John J V; Solomon, Scott D.

In: The Lancet Diabetes and Endocrinology, 2017.

Research output: Contribution to journalArticle

Seferovic, JP, Claggett, B, Seidelmann, SB, Seely, EW, Packer, M, Zile, MR, Rouleau, JL, Swedberg, K, Lefkowitz, M, Shi, VC, Desai, AS, McMurray, JJV & Solomon, SD 2017, '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', The Lancet Diabetes and Endocrinology. https://doi.org/10.1016/S2213-8587(17)30087-6
Seferovic, Jelena P. ; Claggett, Brian ; Seidelmann, Sara B. ; Seely, Ellen W. ; Packer, Milton ; Zile, Michael R. ; Rouleau, Jean L. ; Swedberg, Karl ; Lefkowitz, Martin ; Shi, Victor C. ; Desai, Akshay S. ; McMurray, John J V ; Solomon, Scott D. / 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. In: The Lancet Diabetes and Endocrinology. 2017.
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abstract = "Background: 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 HbA1c and time to first-time initiation of insulin or oral antihyperglycaemic drugs in patients with diabetes and HFrEF. Methods: 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. Findings: There were no significant differences in HbA1c concentrations between randomised groups at screening. During the first year of follow-up, HbA1c concentrations 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). HbA1c concentrations 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. Interpretation: Patients with diabetes and HFrEF enrolled in PARADIGM-HF who received sacubitril/valsartan had a greater long-term reduction in HbA1c than those receiving enalapril. These data suggest that sacubitril/valsartan might enhance glycaemic control in patients with diabetes and HFrEF. Funding: Novartis.",
author = "Seferovic, {Jelena P.} and Brian Claggett and Seidelmann, {Sara B.} and Seely, {Ellen W.} and Milton Packer and Zile, {Michael R.} and Rouleau, {Jean L.} and Karl Swedberg and Martin Lefkowitz and Shi, {Victor C.} and Desai, {Akshay S.} and McMurray, {John J V} and Solomon, {Scott D.}",
year = "2017",
doi = "10.1016/S2213-8587(17)30087-6",
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TY - JOUR

T1 - Effect of sacubitril/valsartan versus enalapril on glycaemic control in patients with heart failure and diabetes

T2 - A post-hoc analysis from the PARADIGM-HF trial

AU - Seferovic, Jelena P.

AU - Claggett, Brian

AU - Seidelmann, Sara B.

AU - Seely, Ellen W.

AU - Packer, Milton

AU - Zile, Michael R.

AU - Rouleau, Jean L.

AU - Swedberg, Karl

AU - Lefkowitz, Martin

AU - Shi, Victor C.

AU - Desai, Akshay S.

AU - McMurray, John J V

AU - Solomon, Scott D.

PY - 2017

Y1 - 2017

N2 - Background: 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 HbA1c and time to first-time initiation of insulin or oral antihyperglycaemic drugs in patients with diabetes and HFrEF. Methods: 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. Findings: There were no significant differences in HbA1c concentrations between randomised groups at screening. During the first year of follow-up, HbA1c concentrations 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). HbA1c concentrations 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. Interpretation: Patients with diabetes and HFrEF enrolled in PARADIGM-HF who received sacubitril/valsartan had a greater long-term reduction in HbA1c than those receiving enalapril. These data suggest that sacubitril/valsartan might enhance glycaemic control in patients with diabetes and HFrEF. Funding: Novartis.

AB - Background: 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 HbA1c and time to first-time initiation of insulin or oral antihyperglycaemic drugs in patients with diabetes and HFrEF. Methods: 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. Findings: There were no significant differences in HbA1c concentrations between randomised groups at screening. During the first year of follow-up, HbA1c concentrations 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). HbA1c concentrations 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. Interpretation: Patients with diabetes and HFrEF enrolled in PARADIGM-HF who received sacubitril/valsartan had a greater long-term reduction in HbA1c than those receiving enalapril. These data suggest that sacubitril/valsartan might enhance glycaemic control in patients with diabetes and HFrEF. Funding: Novartis.

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