Risk Related to Pre–Diabetes Mellitus and Diabetes Mellitus in Heart Failure With Reduced Ejection Fraction: Insights From Prospective Comparison of ARNI With ACEI to Determine Impact on Global Mortality and Morbidity in Heart Failure Trial
Open accessAbstract
BACKGROUND: The prevalence of pre-diabetes mellitus and its consequences in patients with heart failure and reduced ejection fraction are not known. We investigated these in the Prospective Comparison of ARNI With ACEI to Determine Impact on Global Mortality and Morbidity in Heart Failure (PARADIGM-HF) trial. METHODS AND RESULTS: We examined clinical outcomes in 8399 patients with heart failure and reduced ejection fraction according to history of diabetes mellitus and glycemic status (baseline hemoglobin A1c [HbA1c]: < 6.0% [< 42 mmol/mol], 6.0%-6.4% [42-47 mmol/mol; pre-diabetes mellitus], and ≥ 6.5% [≥ 48 mmol/mol; diabetes mellitus]), in Cox regression models adjusted for known predictors of poor outcome. Patients with a history of diabetes mellitus (n = 2907 [35%]) had a higher risk of the primary composite outcome of heart failure hospitalization or cardiovascular mortality compared with those without a history of diabetes mellitus: adjusted hazard ratio, 1.38; 95% confidence interval, 1.25 to 1.52; P < 0.001. HbA1c measurement showed that an additional 1106 (13% of total) patients had undiagnosed diabetes mellitus and 2103 (25%) had pre-diabetes mellitus. The hazard ratio for patients with undiagnosed diabetes mellitus (HbA1c, > 6.5%) and known diabetes mellitus compared with those with HbA1c < 6.0% was 1.39 (1.17-1.64); P < 0.001 and 1.64 (1.43-1.87); P < 0.001, respectively. Patients with pre-diabetes mellitus were also at higher risk (hazard ratio, 1.27 [1.10-1.47]; P < 0.001) compared with those with HbA1c < 6.0%. The benefit of LCZ696 (sacubitril/valsartan) compared with enalapril was consistent across the range of HbA1c in the trial. CONCLUSIONS: In patients with heart failure and reduced ejection fraction, dysglycemia is common and pre-diabetes mellitus is associated with a higher risk of adverse cardiovascular outcomes (compared with patients with no diabetes mellitus and HbA1c < 6.0%). LCZ696 was beneficial compared with enalapril, irrespective of glycemic status. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT01035255.
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T2DM is often unrecognized in HF patients, and vice versa.
“T2DM is often unrecognized in HF patients, and vice versa, which emphasizes the importance of an active search for both”
From Type 2 diabetes mellitus and heart failure: A position statement from the Heart Failure Association of the European Society of Cardiology (2018) · cites this paper as [69]
Patients with T2DM and HFrEF have shorter 6-minute walk distances and decreased peak oxygen uptake compared to non-diabetics.
“Patients with T2DM and HFrEF also have shorter 6-minute walk distances and decreased peak oxygen uptake in comparison to non-diabetics.55,69,72”
From Type 2 diabetes mellitus and heart failure: A position statement from the Heart Failure Association of the European Society of Cardiology (2018) · cites this paper as [69]
Patients with T2DM and both HFrEF and HFpEF have worse NYHA functional class and more HF-related symptoms and signs than patients without T2DM, despite having similar ejection fraction.
“Patients with T2DM and both HFrEF 1,34,69,70 and HFpEF 1 have worse NYHA functional class and more HF-related symptoms and signs than patients without T2DM, despite having similar ejection fraction.69,70”
From Type 2 diabetes mellitus and heart failure: A position statement from the Heart Failure Association of the European Society of Cardiology (2018) · cites this paper as [69]
Most trials demonstrated worse quality of life in patients with T2DM and concurrent HF (both HFrEF and HFpEF) compared to patients without T2DM.
“Most trials also demonstrated worse quality of life in patients with T2DM and concurrent HF (both HFrEF and HFpEF), as compared to patients without T2DM.40,69”
From Type 2 diabetes mellitus and heart failure: A position statement from the Heart Failure Association of the European Society of Cardiology (2018) · cites this paper as [69]
The PARADIGM-HF study reported that patients with T2DM and HFrEF were more likely to die of cardiovascular as well as all-cause mortality compared with patients without T2DM.
“The PARADIGM-HF study also reported that patients with T2DM and HFrEF were more likely to die of CV as well as all-cause mortality compared with patients without T2DM.69”
From Type 2 diabetes mellitus and heart failure: A position statement from the Heart Failure Association of the European Society of Cardiology (2018) · cites this paper as [69]
The effect of sacubitril/valsartan compared with enalapril for the primary endpoint was similar in patients with and without T2DM (HR 0.83 and 0.77; respectively, interaction P=0.40).
“AT 2 D M subgroup analysis has shown that the effect of sacubitril/valsartan compared with enalapril for the primary endpoint was similar in patients with and without T2DM (HR 0.83 and 0.77; respectively, interaction P=0.40).69”
From Type 2 diabetes mellitus and heart failure: A position statement from the Heart Failure Association of the European Society of Cardiology (2018) · cites this paper as [69]
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Self-citation
- Authors
- Kristensen, S. L., Preiss, D., Jhund, P. S., Squire, I., Cardoso, J. S., Merkely, B., Martinez, F., Starling, R. C., Desai, A. S., Lefkowitz, M. P., Rizkala, A. R., Rouleau, J. L., Shi, V. C., Solomon, S. D., Swedberg, K., Zile, M. R., McMurray, J. J. V., & Packer, M.
- Affiliations
- University of Leicester (GB)
- From the British Heart Foundation, Cardiovascular Research Centre, University of Glasgow, Glasgow, United Kingdom (S.L.K., D.P., P.J., J.J.V.M.); Department of Cardiology, Gentofte University Hospital, Copenhagen, Denmark (S.L.K.); Department of Cardiovascular Sciences, University of Leicester, Leicester, UK (I.S.); NIHR Cardiovascular Biomedical Research Unit, Glenfield Hospital, Leicester, UK (I.S.); Department of Cardiology, Porto Medical School, Porto, Portugal (J.S.C.); Heart and Vascular...
- Corresponding author
- McMurray, John J.V.
- ORCID
- Venue
- Circulation Heart Failure
- Published
- 2016-01
- Volume
- 9
- Issue
- 1
- ISSN
- 1941-3289 (ISSN-L)
- 1941-3297
- PMC
- PMC4718182
- OpenAlex
- W2579945710
- Cited by
- 359
- References
- 29
- Citations by year
- 2026: 2 · 2025: 9 · 2024: 40 · 2023: 23 · 2022: 43 · 2021: 51 · 2020: 51 · 2019: 49 · 2018: 39 · 2017: 35 · 2016: 17
- FWCI
- 38.43
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- cc-by-nc-nd
- Locations
- Circulation Heart Failure (publishedVersion, cc-by-nc-nd)
- PubMed Central (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- SZTE Publicatio Repozitórium (University of Szeged) (acceptedVersion, other-oa)
- ENLIGHTEN (Jurnal Bimbingan dan Konseling Islam) (acceptedVersion)
- Keele Research Repository (Keele University) (submittedVersion, cc-by)
- Open Repository and Bibliography (University of Luxembourg) (submittedVersion, other-oa)
- Research Bank (Australian Catholic University) (submittedVersion, cc-by-nc)
- HAL (submittedVersion)
- IRIS Research product catalog (Sapienza University of Rome) (submittedVersion)
- Funders
- National Heart, Lung, and Blood Institute (R01HL123478)
- Topics
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Heart Failure Treatment and Management
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiovascular Function and Risk Factors
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes Treatment and Management
- Keywords
- diabetes mellitus, heart failure with reduced ejection fraction, glycemic status, HbA1c, undiagnosed diabetes, heart failure hospitalization, cardiovascular mortality, sacubitril/valsartan, enalapril, PARADIGM-HF, angiotensin receptor-neprilysin inhibitors, ACE inhibitors, dysglycemia
- MeSH terms
- Valsartan, Aged, Aminobutyrates, Angiotensin-Converting Enzyme Inhibitors, Biphenyl Compounds, Blood Glucose, Diabetes Mellitus, Drug Combinations, Enalapril, Female, Heart Failure, Glycated Hemoglobin, Humans, Male, Middle Aged, Prediabetic State, Prospective Studies, Risk Factors, Stroke Volume, Tetrazoles, Time Factors, Biomarkers, Comorbidity, Prevalence, Proportional Hazards Models, Single-Blind Method, Ventricular Function, Left, Treatment Outcome, Risk Assessment, Disease-Free Survival, Kaplan-Meier Estimate, Angiotensin Receptor Antagonists
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