Risk related to pre-diabetes mellitus and diabetes mellitus in heart failure with reduced ejection fraction

Risk related to pre-diabetes mellitus and diabetes mellitus in heart failure with reduced ejection fraction


Sylvia Okoma, Mercer University College of Pharmacy


According to the American Journal of Cardiology, the association between diabetes and heart failure may be because of the shared pathophysiological processes of “neurohomonal activation, endothelial dysfunction and oxidative stress.” However, it is stated that from observation the relationship of the causative properties of the disease states do not appear similar.  It has been suggested that there has been a greater causative association of diabetes to heart failure rather than between heart failure and pre-existing diabetes that leads to less favorable outcomes. [1,2]


Studies are focusing on demonstrating the relationship between the pre-existing risks of diabetes and heart failure.  These efforts could likely assist in optimizing strategies to manage diabetes mellitus in patients with chronic heart failure. [3]


Title: Risk related to pre-diabetes mellitus and diabetes mellitus in heart failure with reduced ejection fraction [3]  
Design Single and double blind study, randomized control trial, retrospective analysis; N = 8,399  
Objective To investigate the prevalence of diabetes mellitus and pre-diabetes mellitus in patients with heart failure and a reduced ejection fraction (HF-REF)  
Study Groups Previous diagnosis of diabetes mellitus (n = 2,907), no previous diagnosis of diabetes mellitus and HbA1c: < 6.0 (n = 2,158); 6.0-6.4 (n = 2,103); > 6.4 (n = 1106)  
Methods Patients received enalapril 10 mg twice daily for 2 weeks (single blind) and then sacubitril/valsartan (LCZ696) for an additional 4 to 6 weeks, initially at 100 mg twice daily and then 200 mg twice daily.     The patients who tolerated the drugs at the target doses were randomly assigned in a 1:1 ratio to double-blind treatment with either enalapril 10 mg twice daily or LCZ696 200 mg twice daily.  
Duration Prespecified boundary for overwhelming benefit for both cardiovascular mortality and primary outcome had been reached, up to 27 months  
Primary Outcome Measure The composite of death from cardiovascular causes or a first hospitalization for heart failure (initially stated to be 1,229 patients who experienced cardiovascular deaths and 2,410 patients who experienced their first hospitalization for heart failure or cardiovascular death)  
Baseline Characteristics No previous diagnosis of diabetes mellitus Previous diabetes mellitus  
< 6.0
HbA1c, 6.0-6.4 HbA1c,
> 6.4
Any HbA1c p value  
Patients, n 2,158 2,103 1,106 2,907    
LCZ696 treatment, n 1087 1,040 549 1,451 0.9426  
HbA1c, median 5.6 6.1 6.6 7.2 < 0.0001  
HF duration (years), n         < 0.0001  
0-1 707 629 379 765    
> 1-5 841 834 414 1,106    
> 5 610 640 313 1,036    
NYHA class, n         <0.0001  
  I 109 102 56 115    
  II 1,614 1,474 750 1,996    
  III 420 502 294 770    
  IV 10 22 4 24    
Results The rates of the primary composite outcome and all cause death were the lowest in the normal HbA1c group (0.62 (0.48 – 0.80) HR, 95% confidence interval (CI)), significantly higher in the pre-diabetes mellitus category (0.76 (0.61-0.96) HR 95% CI) and the highest in individuals with undiagnosed and known diabetes mellitus (0.86 (0.65-1.15) and (0.092 (0.77-1.09) – HR 95% CI respectively) with a p value for interaction of 0.09. In addition patients with a history of diabetes mellitus were at higher risk of the primary composite outcome of heart failure hospitalization and cardiovascular mortality compared to those with normal HbA1c with the adjusted hazard ratio (HR), 1.64, 95% CI, 1.44 to 1.88, p < 0.001. The HR for undiagnosed diabetes mellitus (HbA1c,
> 6.5%) compared with those whose HbA1c < 6.0% was 1.39 (1.18-1.64) 95% CI, p < 0.001.

LCZ696 reduced the occurrence of the primary composite outcome compared with enalapril, in all glycemic categories.

Adverse Events Common Adverse Events: symptomatic hypotension (45%), serum creatinine >= 2.5 mg/dL (31%), hyperkalemia > 5.5 mmol/L (65.5%)          
Serious Adverse Events: symptomatic hypotension SBP < 90 mm Hg (6%)        
Percentage that Discontinued due to Adverse Events: 22.5%          
Study Author Conclusions The presence of non-diabetic dysglycemia (pre-diabetes) is associated with an increased risk of adverse events associated with HF-REF.  In addition, pre-diabetes mellitus and diabetes mellitus was associated with worse symptom status, reduced exercise tolerance and neurohormonal activation.  In addition, individuals with lower HbA1c in patients without known diabetes mellitus corresponded with a better prognosis when compared with patients with known and treated diabetes mellitus.  This study is important because it demonstrates that dysglycemia is a risk factor in advsere outcomes in patients with heart failure.  This study removed the confounding variable of hyperglycemic drugs so that the effects of hyperglycemia could be readily observed.  However, this study demonstrates an association and not a causative relationship between dysglycemia and heart failure outcomes.  It was also noted that the prevalence of dysglycemia is common in HF-REF patients and the effects of the LCZ696 drug therapy had beneficial effects on all populations when compared to enalapril.  


Though the association with lower elevated glycosylated hemoglobin (HbA1c) goal of 7% and an increase in mortality was demonstrated with the Action to Control Cardiovascular Risk in Diabetes (ACCORD) study group, further studies are warranted [1,4].  With further studies of heart failure groups, this study and others are demonstrating an increased association of advanced heart failure and elevated HbA1c levels.





  1. Kostis JB, Sanders M. The association of heart failure with insulin resistance and the development of type 2 diabetes.  Am J Hypertens.  2005; 18:731–737.  [PubMed: 15882558] Accessed 15 Jan 2016.


  1. Tomova, G., Vani Nimbal, and Tamara Horwich.  Relation between hemoglobin A1c and outcomes in heart failure patients with and without diabetes mellitus.  American Journal of Cardiology 109(12): 1767-1773, 15 Jun 2012.   Accessed 15 Jan 2016.


  1. Kristensen, S., David Preiss, Pardeep Jhund, et al. Risk related to pre-diabetes mellitus and diabetes mellitus in heart failure with reduced ejection fraction.  Circulation Heart Failure, Issue 9:1-12, Jan 2016.  Accessed 15 Jan 2016.


  1. Held, C. H.  Gersteine, S.  Yusuf, et al.  Glucose levels predict hospitalization for congestive heart failure in patients at high cardiovascular risk.  American Heart Association Circulation 115:1371-1375, Mar 2007.  Accessed 15 Jan 2016.


  1. Iribarren C, Karter AJ, Go AS, Ferrara A, Liu JY, Sidney S, Selby JV. Glycemic control and heart failure among adult patients with diabetes.  Circulation.  2001; 103:2668–2673.  [PubMed: 11390335] Accessed 15 Jan 2016.




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