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Lancet Diabetes Endocrinol. Author manuscript; available in PMC 2017 July 29.
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Published in final edited form as:

Lancet Diabetes Endocrinol. 2017 May ; 5(5): 333–340. doi:10.1016/S2213-8587(17)30087-6.

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, MD, Brian Claggett, PhD, Sara B Seidelmann, MD, Ellen W Seely, MD,
Milton Packer, MD, Michael R Zile, MD, Jean L Rouleau, MD, Karl Swedberg, MD, Martin
Lefkowitz, MD, Victor C Shi, MD, Akshay S Desai, MD, John J V McMurray, MD, and Scott D
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Solomon, MD
Cardiovascular Division (J P Seferovic MD, B Claggett PhD, S B Seidelmann MD, A S Desai MD,
S D SolomonMD) and Endocrinology, Diabetes, and Hypertension Division (E W Seely MD),
Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA; Baylor University
Medical Center, Dallas, TX, USA (M Packer MD); The Medical University of South Carolina and
RHJ Department of Veterans Administration Medical Center, Charleston, SC, USA (M R Zile MD);
Université de Montréal, Institut de Cardiologie, Montréal, QC, Canada (J L Rouleau MD);
Department of Molecular and Clinical Medicine, Sahlgrenska University Hospital, Göteborg,
Sweden (K Swedberg MD); Novartis Pharmaceutical Corporation, East Hanover, NJ, USA (M
Lefkowitz MD, V C Shi MD); and BHF Cardiovascular Research Centre, University of Glasgow,
Glasgow, UK (J J V McMurray MD)
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Summary
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
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Correspondence to: Scott D Solomon, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02115, USA,
[email protected].
Contributors
All authors contributed to the interpretation of the results, writing or revision of the manuscript, and approved the decision to submit
the article for publication.
Declaration of interests
During the conduct of the PARADIGM-HF study, MP, MRZ, JLR, KS, ASD, JJVM, and SDS report either grant, personal, non-
financial, or other support from Novartis, the sponsor of the study. ML and VCS report personal fees as employees of Novartis.
Outside of the submitted work, MP reports personal fees from Amgen, BioControl, Cytokinetics, CardioKinetix, CardioMEMS,
Cardiorentis, Janssen, Novartis, Pfizer, and Sanofi. MRZ reports grant support and personal fees from Bayer, CVRx, Medtronic, and
Novartis; KS reports personal fees from Novartis, Amgen, and Servier. ASD reports personal fees from Novartis, Janssen, Sanofi,
Merck, St. Jude Medical, AstraZeneca, and Relypsa. JJVM reports non-financial and other support from Novartis. JPS, BC, SBS, and
EWS declare no competing interests.
 Seferovic et al. Page 2

randomly assigned to treatment with sacubitril/valsartan or enalapril. Of these patients, most

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(98%) had type 2 diabetes. We assessed changes in HbA1c, triglycerides, HDL cholesterol and
BMI in a mixed effects longitudinal analysis model. Times 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
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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.

Introduction
Heart failure and diabetes frequently coexist, with a prevalence of diabetes as high as 35–
40% in patients with heart failure, independent of the degree of impairment in ejection
fraction.1 Moreover, diabetes is considered to be a major comorbidity and strong
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independent risk factor for the progression of heart failure with either preserved or reduced
ejection fraction,2 with an attendant elevated risk of both admission to hospital for heart
failure and death, compared with patients without diabetes.3–5 The degree of risk has further
been related to the level of glycaemic control in patients with heart failure,6 and more severe
hyperglycaemia has been associated with worsening of cardiac structure and function.7,8

Compared with the angiotensin-converting enzyme inhibitor (ACEI) enalapril, sacubitril/

valsartan (formerly known as LCZ696), an angiotensin receptor-neprilysin inhibitor (ARNI),
improved morbidity and mortality in patients with heart failure and reduced ejection fraction
(HFrEF) in the Prospective Comparison of ARNI with ACEI to Determine Impact on Global
Mortality and morbidity in Heart Failure (PARADIGM-HF) trial, after a median follow-up
of 27 months.5
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Sacubitril/valsartan did not reduce the pre-specified exploratory outcome of new onset
diabetes in comparison with enalapril, although the number of patients with new-onset
diabetes during the course of the trial was very small.

The effect of neprilysin inhibitors on insulin sensitivity has been investigated in several
studies. Sacubitril/valsartan improved peripheral insulin sensitivity in obese hypertensive
patients,9 whereas omapatrilat, a dual angiotensin-converting-enzyme–neprilysin inhibitor,

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 Seferovic et al. Page 3

has potent insulin-sensitising effects experimentally, increasing myocardial glucose uptake

in Zucker fatty rats,10 although there are no data on the effect of omapatrilat on insulin
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sensitivity and glycaemic control in humans. We therefore investigated the effect of

sacubitril/valsartan versus enalapril on HbA1c in patients with diabetes and HFrEF enrolled
in PARADIGM-HF, as well as the influence of these regimens on the initiation of oral
antihyperglycaemic and insulin therapy in patients with diabetes.

Methods
Study design and participants
We did a post-hoc analysis of the PARADIGM-HF study, a multicentre, double-blind,
parallel group, randomised active-controlled trial. Patients with HFrEF (left ventricular
ejection fraction [LVEF] ≤40%) and elevated natriuretic peptides5 were randomly assigned
to receive either sacubitril/valsartan 97 mg/103 mg twice a day or enalapril 10 mg twice a
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day. Full details of the trial design, entry criteria, and main results have been previously
reported.5,11,12 New-onset of diabetes was a prespecified exploratory outcome in
PARADIGM-HF and was diagnosed based on blood glucose levels meeting American
Diabetes Association criteria or initiation of oral hypoglycaemic drugs, insulin sensitisers,
insulin therapy, or HbA1c concentrations of 6·5% or more. The cases of new-onset of
diabetes were adjudicated by an independent adjudication committee. The trial was
approved by local ethics committees and all patients provided written informed consent.

In this study, the primary analysis was based on a subset of 3778 of the 8399 randomly
assigned patients who reported a history of diabetes, had HbA1c concentrations of 6·5% or
more, or both at screening.13 Among these patients, most (98%) had type 2 diabetes.
Patients diagnosed with HbA1c of 6·5% or more at screening visit were considered as having
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diabetes from that date. The date of diabetes diagnosis in patients with a previous history of
diabetes was assessed based on medical record review or self-report at the screening visit.
Glycaemic control was assessed by measuring HbA1c concentration at screening, 1-year, 2-
year, and 3-year visits. In order to further describe HbA1c changes from screening to the 1-
year visit, we created categories of HbA1c (<6·5%, 6·5%–6·9%, 7%–7·9%, and ≥8%).
Additionally, we analysed changes in triglycerides, HDL cholesterol, and body BMI during
the course of the study. We further analysed time to oral antihyperglycaemic and insulin
therapy initiation during follow-up. All assays included in this analysis were measured in a
central laboratory.

HbA1c concentrations were measured by the BioRad D-10 Haemoglobin A1c Program as the
percentage determination of HbA1c using ion-exchange high-performance liquid
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chromatography.14 The reportable range for this assay is 3·8%–18·5%, with any sample
greater than 15% being suspected as having a haemoglobin variant. HDL cholesterol and
triglycerides were measured with the Roche Boehringer Mannheim Diagnostics assay, by
enzymatic in-vitro methodology.15,16 The measuring range of HDL cholesterol was 0·08–
3·10 mmol/L and for triglycerides it was 0·05–11·4 mmol/L.

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Statistical analysis
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Descriptive data are presented as the mean (SD) for normally distributed variables and as
median (IQR) for non-normally distributed variables. Categorical variables are expressed as
proportions and were compared by the chi-square test. All continuous variables were
compared using t-tests, with the exception of the duration of diabetes and triglycerides,
which were compared using Wilcoxon rank-sum tests. Changes in HbA1c, triglycerides,
HDL cholesterol, and BMI were assessed and compared at 1 year, 2 years, and 3 years after
randomisation. Changes at annual visits were assessed via linear regression with adjustment
for screening values. Overall changes were assessed in a mixed effects longitudinal analysis
model. Time to initiation of oral antihyperglycaemic drugs and insulin in participants
previously not treated with these drugs was compared using survival analysis techniques,
including Kaplan-Meier estimates and Cox proportional hazards models. In order to assess
whether the difference in time to initiation of insulin between groups could be attributed to
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more frequent hospital admission, we did a sensitivity analysis that censored patient follow-
up at the time of the first post-randomisation hospital admission. Two-sided p values of
<0·05 were considered significant. Analyses were done with Stata (version 14.1).

Role of the funding source

The funder of the study was involved in the PARADIGM-HF study design and protocol
development, and data collection. The presented analysis was prepared jointly by all authors.
The data analysis was done by the academic authors (SDS, BC, JPS) at Brigham and
Women’s Hospital. The corresponding and coauthors had full access to the data in the study,
contributed to the writing of the manuscript, and had final responsibility for the decision to
submit for publication.
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Results
Of the 8399 patients with HFrEF enrolled in PARADIGM-HF, 3778 (45%) patients were
identified at screening as having diabetes based on their medical history (n=2896 [34%]) or
a screening HbA1c concentration of 6·5% or higher without a reported diagnosis of diabetes
(n=882 [11%]). Characteristics of patients with diabetes at screening are presented in table
1. The mean age of patients was 64 years (SD 11), and the majority were men (2970 [79%]
of 3778) and white (2533 [67%] of 3778). The mean BMI was 29·03 kg/m2 (SD 5·78), and
mean systolic and diastolic blood pressure were 129 mm Hg (SD 17) and 78 mm Hg (SD
11), respectively. Most patients were New York Heart Association (NYHA) functional class
2 (2321 [61%]) or 3 (1376 [36%]).17 2896 (77%) patients had a previous diagnosis of
diabetes with a median duration of 3·5 years, and a screening mean HbA1c of 7·44% (SD
1·55). More than half of the patients (57%) used antihyperglycaemic therapy at screening,
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mostly metformin, sulfonylureas, and insulin. Among the participants with diabetes, there
were no significant differences between the two treatment groups in baseline characteristics,
except for triglycerides, which were lower in the sacubitril/valsartan group (table 1).
Comparison of baseline characteristics of patients with diabetes and those without diabetes
at screening is presented in the appendix (p 2).

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In PARADIGM-HF, there were 39 of 2741 (1%) cases of incident diabetes reported in the
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sacubitril/valsartan group and 44 of 2762 (2%) in the enalapril group among those with no
known history of diabetes at screening (p=0·63). After excluding 912 patients who were
identified as having HbA1c concentrations of 6·5% or greater (440 in the enalapril group and
472 in the sacubitril/valsartan group), there were 33 (1·4%) cases of incident diabetes in the
sacubitril/valsartan group and 31 cases (1·3%) in the enalapril group (p=0·73). Among
patients with diabetes at screening, there were no significant differences in HbA1c
concentrations between randomised groups (table 2). During the first year of follow-up,
HbA1c 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
compared with baseline), and the estimated reduction was similar at years 2 and 3.

Over the full duration of follow-up, the decrease in HbA1c was significantly greater in
patients receiving sacubitril/valsartan compared with those receiving enalapril (overall
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reduction 0·14%, 95% CI 0·06–0·23, p=0·0055; table 2, figure 1). The HbA1c reduction from
sacubitril/valsartan was apparent only in patients identified as having diabetes at screening,
with no treatment effect seen in patients without diabetes (appendix p 3). However, within
the diabetes cohort, there was no significant relationship between screening HbA1c
concentrations and the magnitude of the treatment effect. For patients with HbA1c
concentrations of 8% or higher at screening, those in the sacubitril/valsartan group were
more likely to change to a lower HbA1c category at the 1-year visit than those in the
enalapril group (41% vs 33%, p=0·025; appendix, p 5). For patients with a 6·5%–6·9% or 7–
7·9% concentration at screening, patients in the sacubitril/valsartan group were more likely
to have moved to a lower HbA1c category and less likely to have moved to a higher HbA1c
category compared to those receiving enalapril (net difference 11%, p=0·020 and 14%,
p=0·017, respectively; appendix p 5). In a landmark analysis at 1 year considering the
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change in HbA1c and the screening value, we observed no significant relationship between
change in HbA1c and the composite primary outcome of cardiovascular death or first
hospital admission for heart failure in the entire cohort of patients with diabetes (hazard ratio
[HR] 0·99, 95% CI 0·91–1·06 per HbA1c unit, p=0·70), suggesting that the potential benefit
on heart failure outcomes and on HbA1c were independent of one another.

In addition, the sacubitril/valsartan treatment effect HR for the primary PARADIGM-HF

outcome in participants with diabetes was 0·84 (95% CI 0·74–0·95, p=0·0043)—similar to
the overall treatment effect for the entire cohort (HR 0·80, 95% CI 0·73–0·87, p<0·001).5 As
previously reported, we observed a marginal interaction between known diabetes status and
the secondary endpoint of cardiovascular death, suggesting an attenuated benefit in patients
with diabetes (pinteraction=0·052). Nevertheless, cardiovascular deaths were reduced in the
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sacubitril/valsartan group among patients with diabetes (appendix p 6).

Among patients with diabetes who were insulin-naive at the time of randomisation, 153
(10%) patients in the enalapril group and 114 (7%) in the sacubitril/valsartan group were
initiated on insulin therapy (HR 0·71, 95% CI 0·56–0·90, p=0·0052; table 3, figure 2). In a
sensitivity analysis that censored patient follow-up at the time of the first post-randomisation
hospital admission, the reduction in insulin initiation in the sacubitril/valsartan group (HR
0·69, 95% CI 0·50–0·97, p=0·031) remained consistent with the overall results. Similarly,

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fewer patients were started on oral antihyperglycaemic therapy (HR 0·77, 95% CI 0·58–1·02,
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p=0·073) in the sacubitril/valsartan group, although the difference did not reach statistical
significance. Of those patients not identified as having diabetes at screening, the percentages
of patients initiating antihyperglycaemic therapy post-randomisation were not significantly
different between the enalapril and sacubitril/valsartan groups (insulin: 21 [0·9%] vs 15
[0·7%] p=0·35; oral antihyperglycaemic agents: 44 [1·9%] vs 50 [2·2%] p=0·46; either: 57
[2·4%] vs 63 [2·8%], p=0·49).

During the trial follow-up, there were 97 hypoglycaemic events in patients with diabetes at
screening, with 44 events occurring in patients receiving enalapril and 53 events in patients
receiving sacubitril/valsartan (HR 1·18, 95% CI 0·79–1·76, p=0·42).

There was no consistent difference in triglyceride levels throughout the study. However,
HDL cholesterol levels increased significantly by 0·02 mmol/L (95% CI 0·00–0·03) during
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the course of the trial in patients using sacubitril/valsartan compared with those using
enalapril (p=0·043, table 4). BMI increased by an average of 0·28 kg/m2 (95% CI 0·14–0·41)
over the course of follow-up in patients randomly assigned to sacubitril/valsartan, compared
with those receiving enalapril (p<0·0001; table 4).

Discussion
In this post-hoc analysis of patients with mostly type 2 diabetes and HFrEF from the
PARADIGM-HF study, we found that treatment with sacubitril/valsartan was associated
with greater reductions in HbA1c concentrations than treatment with enalapril. Sacubitril/
valsartan was shown in PARADIGM-HF to reduce the risk of cardiovascular death, hospital
admission for heart failure, and all-cause mortality compared with enalapril in patients with
heart failure, and this benefit was observed in both those with and without diabetes at
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screening.5 The rates of these outcomes increased with increasing HbA1c at baseline6. In this
post-hoc analysis of patients with diabetes and HFrEF from the PARADIGM-HF study, we
found that treatment with sacubitril/valsartan was associated with greater reductions in
HbA1c concentrations than treatment with enalapril. Moreover, during the 3-year course of
the study, fewer participants in the sacubitril/valsartan group required initiation of insulin
therapy for glycaemic control. These data suggest that in addition to the heart failure
benefits previously shown, sacubitril/valsartan might have favourable metabolic effects in
patients with heart failure and diabetes.

Sacubitril/valsartan blocks both the renin-angiotensin system and inhibits neprilysin, an

enzyme expressed in a wide variety of tissues (endothelial, epithelial and smooth muscle
cells, cardiac myocytes, and adipocytes)18,19 and which is responsible for the breakdown of
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a number of vasoactive peptides, including the biologically active natriuretic peptides, as

well as bradykinin, angiotensin I and II, and glucagon-like peptide 1 (GLP-1).20 There are
several potential mechanisms by which inhibition of neprilysin might lead to improvement
in glycaemic control. Natriuretic peptides, which are increased by neprilysin inhibition,
might have a crucial role in insulin sensitivity and metabolism. Neprilysin is known to
promote lipid mobilisation from adipose tissue,21 increase postprandial lipid oxidation,22
promote adiponectin release,23 and enhance muscular oxidative capacity.24 Blood glucose

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concentrations have been shown to decrease after infusion of B-type natriuretic peptide
(BNP).25
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In the Atherosclerosis Risk in Communities study (n=7822) with a median follow-up of 12

years, higher concentrations of N-terminal proBNP were associated with a significantly
decreased risk of diabetes, even after adjustment for traditional risk factors and fasting
glucose.26 Augmentation of other neprilysin substrates by neprilysin inhibition might also
play a part in glycaemic control. Bradykinin, a neprilysin substrate, can improve insulin
sensitivity and attenuate lipolysis.27 Cyclic guanosine monophosphate, also increased by
neprilysin inhibition, has known vasodilatory effects in skeletal muscle and facilitates
lipolysis.20 Moreover, GLP-1, a neuropeptide of the incretin family and potent
antihyperglycaemic hormone with a very short circulating half-life, is partially degraded by
neprilysin.28 In high-fat-fed neprilysin deficient mice, improved glycaemic status was
associated with elevated active GLP-1 concentrations, reduced plasma dipeptidyl peptidase 4
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(DPP-4) activity and improved beta cell function, suggesting beneficial metabolic effects of
neprilysin inhibition.29 Inhibition of the renin-angiotensin system has also improved
glycaemic control,30,31 and angiotensin II promotes insulin resistance, while angiotensin-1-
receptor blockade modestly improves insulin sensitivity.32 Nevertheless, the improvement of
glucose metabolism by renin-angiotensin system inhibition alone is most likely to be
modest.

Dual ACE-neprilysin inhibitors improve insulin sensitivity in preclinical studies. Inhibition

of neprilysin with the dual ACE-neprilysin inhibitor omapatrilat improved whole-body
insulin-mediated glucose disposal, induced profound insulin sensitisation, and increased
myocardial glucose uptake in obese insulin-resistant Zucker rats.10 Also, both acute and
long-term dual ACE-neprilysin inhibition with mixanpril improved whole-body insulin-
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mediated glucose disposal and insulin sensitivity in obese Zucker rats.33 In a study
comparing the effects of sacubitril/valsartan and amlodipine on insulin resistance in 92
obese hypertensive patients treated for 8 weeks, those treated with sacubitril/valsartan
showed a significant increase in insulin sensitivity using the hyperinsulinaemic-euglycaemic
clamp technique.9

The magnitude of HbA1c reduction seen with sacubitril/valsartan in the patients with
diabetes enrolled in PARADIGM-HF was smaller compared with that observed in studies of
DPP-4 inhibitors,34–36 GLP-1 receptor agonists,37–39 and SGLT-2 inhibitors,40 in which
investigators were also able to modify standard of care for diabetes at will. However, in all
of these trials, these novel drugs were compared with placebo. By contrast, PARADIGM-HF
was an active-controlled study comparing sacubitril/valsartan with an ACE inhibitor.
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Whether the magnitude of reduction in HbA1c would have been greater if the drug were
compared with placebo is unknown. Moreover, our protocol allowed for individual
physicians to adjust the doses of antihyperglycaemic therapy at will, and more patients in the
enalapril group initiated use of oral antihyperglycaemic drugs including insulin, which
would be expected to attenuate treatment differences. Because patients treated with
sacubitril/valsartan had a greater increase in BMI, the reduction in HbA1c is unlikely to be
due to weight loss. Of note, 23% of patients included in this cohort were diagnosed with a
screening HbA1c concentration of 6·5% or more and did not have previous history of

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diabetes. This finding highlights the high prevalence of undiagnosed diabetes in patients
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with heart failure.

Several limitations of this analysis should be noted. Despite positive effects on glycaemic
control shown in this analysis, sacubitril/valsartan did not reduce the pre-specified
exploratory outcome of new-onset diabetes in comparison with enalapril, probably due to a
very small number of new-onset diabetes cases (n=84) during the course of the trial.
However, we believe that this endpoint might have been less sensitive to the effect of
sacubitril/valsartan on glycaemic control for several reasons. First, this population would not
be expected to be at especially high risk for developing diabetes, and indeed less than 2% of
patients in the trial without diabetes at screening developed diabetes. Based on the limited
number of events actually observed in the trial, the study would have been sufficiently
powered only to detect reductions of approximately 50% or greater. Second, the
determination of new-onset diabetes was clinical, and not based on periodic assessment.
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Although plasma glucose was later included in the routine biochemistry panel in
PARADIGM-HF, this was not necessarily fasting by protocol, and we were less able to
discern the effect of sacubitril/valsartan on this measure of glycaemic control. Nevertheless,
HbA1c is considered to be a more stable and accurate measure of long-term glycaemia,
correlating best with mean blood glucose over the previous 8–12 weeks, and also reflecting
glycaemic changes during the day. We had no direct or indirect measures of insulin
resistance in PARADIGM-HF. Whether sacubitril/valsartan would have a similar effect in
patients with insulin resistance and earlier phases of glycaemic impairment remains
unknown. Although we have start and stop data for antihyperglycaemic drugs, dosage was
not assessed by protocol, therefore we were not able to determine dose changes in diabetes
regimens. Finally, HbA1c assays can be confounded by haemoglobinopathies and therefore
perform less accurately in ethnic minority populations. Nevertheless, any reduction in
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precision induced by the specific assay or the characteristics of the patient population would
be expected to weaken the observed effects of therapy, which was randomised, and therefore
not differentially affected by any of these factors.

In summary, we found that treatment with sacubitril/valsartan resulted in improved

glycaemic control as shown by lower HbA1c concentrations compared with patients treated
with enalapril for patients with diabetes and HFrEF. This beneficial metabolic effect is most
likely secondary to the inhibition of neprilysin and consequent modulation of its circulating
substrates. These post-hoc findings should be considered hypothesis-generating and should
help inform clinicians who will be using sacubitril/valsartan in patients with heart failure,
especially because doses of insulin or other antihyperglycaemic drugs might need to be
adjusted if HbA1c concentrations decrease. Moreover, these data might encourage additional
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research into the beneficial metabolic properties of drugs of this class.

Acknowledgments
Funding Novartis.

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Research in context
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Evidence before this study

We searched PubMed for articles published up to Oct 11, 2016, using terms related to
neprilysin inhibition, diabetes, and insulin resistance, with no language restrictions, to
identify possible effects of this class of drugs on glycaemic control. There is evidence
from both preclinical and human studies on the effect of neprilysin inhibitors on insulin
sensitivity. Both omapatrilat and mixanpril, dual inhibitors of neprilysin and angiotensin-
converting enzyme, improved insulin sensitivity in obese insulin-resistant Zucker rats,
and sacubitril/valsartan (an angiotensin receptor neprilysin inhibitor) improved peripheral
insulin sensitivity in obese hypertensive patients, compared with patients treated with
amlodipine.

Added value of this study

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To our knowledge, this is the first study investigating the effect of sacubitril/valsartan on
glycaemic control. Our results showed that in patients with diabetes and heart failure with
reduced ejection fraction, treatment with sacubitril/valsartan resulted in improved
glycaemic control compared with enalapril. Also, fewer participants in the sacubitril/
valsartan group required initiation of insulin therapy throughout the course of the study.
Our findings suggest that sacubitril/valsartan, which has already been proven to reduce
morbidity and mortality in heart failure, might provide additional metabolic benefits in
patients with diabetes. Moreover, these data might suggest that patients with diabetes
taking sacubitril/valsartan for treatment of heart failure might require dose adjustment of
antihyperglycaemic therapy.

Implications of all the available evidence

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Although our findings were post-hoc and hypothesis-generating, they should help to
inform clinicians using sacubitril/valsartan in patients with heart failure of its potential
beneficial effect on glycaemic control. Moreover, these data might encourage additional
research into the beneficial metabolic properties of drugs of this class.
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Figure 1.
Changes in mean HbA1c and confidence intervals by treatment group at screening,
randomisation, 1-year, 2-year, and 3-year visits
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Figure 2.
Kaplan-Meier curve showing time to insulin initiation in the sacubitril/valsartan and
enalapril groups, in patients previously not treated with insulin
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Table 1

Baseline characteristics of patients with diabetes overall and by treatment groups, at screening
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All patients with diabetes Patients receiving enalapril Patients receiving sacubitril/
(n=3778) (n=1874) valsartan (n=1904)
Age (years) 64·1 (10·6) 63·8 (10·4) 64·4 (10·7)

Sex
Women 808 (21%) 416 (22%) 392 (21%)
Men 2970 (79%) 1458 (78%) 1512 (79%)

Race
White 2533 (67%) 1254 (67%) 1279 (67%)
Black 176 (5%) 86 (45%) 90 (5%)
Asian 740 (20%) 367 (20%) 373 (20%)
Other 329 (9%) 167 (9%) 162 (9%)
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Previous history of diabetes 2896 (77%) 1450 (77%) 1446 (76%)

Duration of diabetes (years) 3·5 (0–10·3) 3·7 (0–10·4) 3·2 (0–10·2)

BMI (kg/m2) 29·03 (5·78) 29·01 (5·69) 29·05 (5·87)

Systolic blood pressure (mm Hg) 129 (17) 129 (17) 129 (17)

Diastolic blood pressure (mm Hg) 78 (11) 78 (11) 78 (10)

NYHA functional class

1 12 (<1%) 6 (<1%) 6 (<1%)
2 2321 (61%) 1157 (62%) 1164 (61%)
3 1376 (36%) 679 (36%) 697 (37%)
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4 64 (2%) 31 (2%) 33 (2%)

HbA1c (%) 7·44 (1·55) 7·48 (1·58) 7·41 (1·51)

Total cholesterol (mmol/L) 4·4 (1·2) 4·4 (1·2) 4·3 (1·2)

LDL cholesterol( mmol/L) 2·4 (1·0) 2·4 (1·0) 2·4 (0·9)

HDL cholesterol (mmol/L) 1·15 (0·34) 1·16 (0·34) 1·15 (0·33)

Triglycerides (mmol/L) 1·51 (1·07–2·18) 1·55 (1·10–2·23) 1·47 (1·05–2·11)

Creatinine (μmol/L) 100·3 (26·2) 99·8 (26·2) 100·9 (26·2)

eGFR (mL/min per 1·73m2) 66·7 (19·3) 67·1 (19·6) 66·4 (19·0)
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Medical history
Hypertension 2922 (77%) 1446 (77%) 1476 (78%)
Atrial fibrillation 1407 (37%) 715 (38%) 692 (36%)
Hospital admission for heart failure 2474 (65%) 1233 (66%) 1241 (65%)

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All patients with diabetes Patients receiving enalapril Patients receiving sacubitril/
(n=3778) (n=1874) valsartan (n=1904)
Myocardial infarction 1781(47%) 880 (47%) 901 (47%)
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Stroke 336 (9%) 176 (9%) 160 (8%)

Treatment
ACE inhibitor 2876 (76%) 1416 (76%) 1460 (77%)
Angiotensin-receptor blocker 917 (24%) 466 (25%) 451 (24%)
Diuretic 3181 (84%) 1570 (84%) 1611 (85%)
β-blocker 3504 (93%) 1738 (93%) 1766 (93%)
Antihyperglycaemic drugs (total) 2164 (57%) 1093 (58%) 1072 (56%)
Metformin 868 (23%) 416 (22%) 452 (24%)
Sulfonylurea 799 (21%) 396 (21%) 403 (21%)
Thiazolidinediones 28 (1%) 18 (1%) 10 (1%)
Alpha-glucosidase inhibitors 74 (2%) 38 (2%) 36 (2%)
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Glinides 43 (1%) 18 (1%) 25 (1%)

Dipeptidyl peptidase 4 inhibitors 107 (3%) 62 (3%) 45 (2%)
GLP-1 receptor agonists 11 (<1%) 7 (<1%) 4 (<1%)
Insulin 715 (19%) 375 (20%) 340 (18%)

Data are n (%), mean (SD), or median (IQR). There were no significant differences between groups at screening, except for triglycerides (p=0·016).
eGFR=estimated glomerular filtration rate. ACE=angiotensin-converting-enzyme. GLP=glucagon-like peptide. HbA1c=glycated haemoglobin.
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Table 2

HbA1c concentrations (%) by treatment groups, over the course of four visits
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Enalapril (n=1874) Sacubitril/valsartan (n=1904) Adjusted for screening values

Difference (95% CI) p value

Screening 7·48 (1·58) 7·41 (1·51) ·· ··

1-year 7·30 (1·66) 7·09 (1·60) −0·13 (−0·22 to −0·05) 0·0023

2-year 7·31 (1·78) 7·08 (1·61) −0·17 (−0·28 to −0·05) 0·0040

3-year 7·16 (1·61) 6·97 (1·58) −0·15 (−0·32 to 0·01) 0·072

Overall* ·· ·· −0·14 (−0·23 to −0·06) 0·0055

Data mean (SD). Number of patients with measurements of HbA1c at screening=3765, 1-year=3160, 2-year=2219, and 3-year=1040.

*
Longitudinal model.
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Table 3

Cumulative incidence of new initiation of insulin therapy in patients with diabetes not on insulin at screening
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during the course of follow-up in PARADIGM-HF, by treatment assignment

Enalapril (n=1490) Sacubitril/valsartan (n=1550) p value

Overall 153 (10%) 114 (7%) 0·0050

Cumulative incidence over time

1-year visit 5·5% (4·4–6·8) 3·8% (2·9–4·9) 0·025
2-year visit 9·3% (7·8–11·0) 7·2% (5·9–8·7) 0·057
3-year visit 13·3% (11·2–15·7) 9·1% (7·5–11·0) 0·0037

Incidence rate (per 100 person-years) 5·0 (4·2–5·8) 3·5 (2·9–4·2) ··

Hazard ratio Reference 0·71 (0·56–0·90) 0·0052

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Data are n (%) and 95% CI.

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Table 4

Changes in triglycerides and HDL-cholesterol concentrations, and body-mass index by treatment groups, over
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the course of four visits

Enalapril (n=1874) Sacubitril/valsartan (n=1904) Adjusted for screening values

Difference (95% CI) p value

Triglycerides (mmol/L)

Screening 1·88 (1·56) 1·79 (1·15) ·· ··

1-year 1·93 (1·46) 1·95 (1·52) 0·08 (−0·01 to 0·17) 0·094
2-year 2·04 (1·82) 1·87 (1·22) −0·16 (−0·27 to −0·04) 0·0083
3-year 1·92 (1·28) 1·84 (1·57) −0·06 (−0·22 to 0·10) 0·46

Overall* ·· ·· −0·01 (−0·09 to 0·07) 0·83

HDL cholesterol (mmol/L)

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Screening 1·16 (0·34) 1·15 (0·33) ·· ··

1-year 1·15 (0·35) 1·16 (0·35) 0·01 (−0·01 to 0·02) 0·50
2-year 1·15 (0·34) 1·17 (0·36) 0·03 (0·01 to 0·05) 0·0073
3-year 1·15 (0·33) 1·21 (0·38) 0·06 (0·02 to 0·09) 0·0011

Overall* ·· ·· 0·02 (0·00 to 0·03) 0·043

BMI (kg/m2)

Screening 29·01 (5·69) 29·05 (5·87) ·· ··

1-year 29·23 (5·70) 29·58 (5·83) 0·26 (0·13 to 0·40) 0·0001
2-year 29·07 (5·77) 29·68 (5·72) 0·31 (0·12 to 0·49) 0·0012
3-year 29·57 (6·07) 29·65 (5·67) 0·27 (−0·02 to 0·57) 0·065
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Overall* ·· ·· 0·28 (0·14 to 0·41) <0·0001

Data are mean (SD).

*
Longitudinal model.
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