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No significant difference in risk of heart failure hospitalization with vildagliptin in diabetic patients with systolic
chronic heart failure: VIVIDD study
2
3
ABSTRACT
Recently, two large outcome trials with DPP-4 inhibitors (SAVOR-TIMI 53 & EXAMINE)
reported an increase in hospitalization for heart failure (HF) in patients with type 2
diabetes mellitus (T2DM) and high cardiovascular risk. This increase was particularly
noted in SAVOR-TIMI in patients with elevated plasma brain natriuretic peptide,
suggesting high risk for HF.
In order to determine whether this increase is also observed with other agents
in the class and in those patients at particularly high HF risk, we determined HF
hospitalizations in the VIVIDD study of patients with T2DM (HbA1c 6.5–10.0%)
who had systolic chronic HF (CHF) with ejection fraction (EF) <40%. Patients were
treated with vildagliptin (n=128) or placebo (n=124) for 52 weeks.
Key baseline demographic parameters were similar between the two groups. There
was no significant difference in the incidence of adjudicated hospitalization due
to worsening of HF between treatments, 10.2% with vildagliptin vs. 8.0% with
placebo, p=0.552. Adjudicated worsening of HF (vildagliptin 18.0% vs. placebo
17.6%, p=NS) was also not different between groups. The proportion of patients
with increased HF medication (adjudicated) was similar between groups (vildagliptin
26.6% vs. placebo 24.0%, p=0.640). All of the above are consistent with the
previously reported findings for the primary study endpoint, change in EF from
baseline between groups at 12 months, which was not different (vildagliptin +5.0%
vs. placebo +4.3%, p=0.667).
There was no significant difference in the incidence of adjudicated hospitalization
for HF with the DPP-4 inhibitor vildagliptin compared to placebo in patients with
T2DM and systolic CHF. These findings suggest that the increased risk of HF
hospitalization with other DPP-4 inhibitors, observed especially in high HF risk
patients, is not seen with vildagliptin in the VIVIDD population of CHF patients.
INTRODUCTION
• Diabetes and heart failure (HF) often co-exist and the prevalence of both is increasing
worldwide. However, there are limited data from clinical studies that specifically
assessed the effect of glucose-lowering agents in patients with diabetes and HF. 1
• Recently, two large cardiovascular (CV) outcome trials in patients with type 2 diabetes
mellitus (T2DM) and high CV risk reported an increase in hospitalizations for HF
with dipeptidyl peptidase-4 inhibitors (DPP-4i) compared to placebo, which was
statistically significant for saxagliptin (SAVOR-TIMI 53) and non-significant for alogliptin
(EXAMINE).2,3 The post-hoc analysis from the SAVOR-TIMI study suggested that the
increased risk for HF hospitalization might have been driven by patients with high
baseline plasma brain natriuretic peptide (BNP).
• We previously reported the key results from the Vildagliptin In VentrIcular Dysfunction
Diabetes (VIVIDD) study, a dedicated, placebo-controlled trial in patients with T2DM
and congestive heart failure (CHF), New York Heart Association (NYHA) class I–III,
evaluating the effect of the DPP-4i vildagliptin on left ventricular ejection fraction
(LVEF).4
• Here we focus on the study data related to the worsening of pre-existing HF in VIVIDD
patients, including hospitalizations for CHF, over the 52-week treatment period.
4
4
5
Monash University, Melbourne, Australia; 2Novartis Pharmaceuticals Corporation, East Hanover, NJ, USA; 3University Hospital Santa Maria della Misericordia, Perugia University School of Medicine, Umbriashire, Italy;
4
Novartis Pharma AG, Basel, Switzerland; 54th Military Hospital, Wroclaw, Poland
1
METHODS
• Patients aged 18–85 years with T2DM duration ≥3 months, HbA1c 6.5–10.0%,
estimated glomerular filtration rate (eGFR) ≥30 ml/min, LVEF <40% and CHF (NYHA
class I–III) were randomized to 52 weeks, treatment with placebo or vildagliptin 50
mg bid (or 50 mg qd if taking a sulfonylurea).
• The primary objective was to demonstrate that vildagliptin was non-inferior to placebo
with respect to change in LVEF from baseline to 52 weeks (lower 95% CI more than
–3.5%). The primary population (per protocol set, PPS) for analysis of LVEF included
any patient who had at least one follow-up echocardiogram recorded ≥22 weeks
after randomization. An ANCOVA model with treatment, region (pooled centers) and
NYHA class as the classification variables and baseline LVEF as the covariate was
used for analysis. The full analysis set (FAS) population was also analyzed to confirm
the robustness of the primary results.
• The incidence of hypoglycemia was similar between the two treatment groups: 4.7%
with vildagliptin versus 5.6% with placebo.
• Vildagliptin was superior to placebo with regard to the mean HbA1c change, with a
placebo-subtracted difference of –0.6% (p<0.001) at week 16 and –0.4% (p=0.040)
at week 52.
Table 1. Baseline characteristics of patients (randomized set)
Placebo
n=126
Age, years
62.9 (8.5)
63.4 (10.2)
• Safety was evaluated by conventional adverse event (AE) reporting. Prospectively
selected CV events of interest, including worsening of CHF with or without hospitalization,
were assessed in a blinded manner by an independent adjudication committee of
CV experts.
Women, n (%)
29 (22.7)
30 (23.8)
BMI, kg/m2
29.6 (4.6)
29.3 (4.7)
Obese (BMI ≥30 kg/m2), n (%)
54 (42.2)
50 (39.7)
Current smoker, n (%)
21 (16.4)
9 (7.1)
• Change in HbA1c from baseline to 16 weeks was a secondary efficacy variable.
An ANCOVA model with treatment and region (pooled center) as the classification
variables and baseline HbA1c as the covariate was used to analyze change in HbA1c.
eGFR (mL/min/1.73m2)
66.9 (22.6)
64.3 (20.7)
Mild RI (≥50 – ≤80), n (%)
64 (50.0)
61 (48.4)
Moderate RI (≥30 – <50), n (%)
30 (23.4)
33 (26.2)
2 (1.6)
4 (3.2)
7.8 (1.0)
7.8 (1.1)
RESULTS
Systolic BP, mmHg
130.4 (16.3)
127.9 (15.3)
Diastolic BP, mmHg
77.6 (8.9)
77.2 (8.7)
• A total of 254 patients (vildagliptin, n=128; placebo, n=126) were randomized.
Urine albumin to creatinine ratio*, mg/mmol
4.6
2.6
• Patient baseline characteristics were, overall, balanced between the two groups;
however, there were some imbalances in the medical history (Tables 1 and 2).
A higher percentage of patients in the vildagliptin group presented with a history of
smoking, chronic obstructive pulmonary disease, albuminuria, hospitalization for HF, and
greater median values of BNP and values of urine albumin-to-creatinine ratio at baseline.
Medical history, n (%)
Myocardial infarction
80 (62.5)
79 (62.7)
Angina pectoris
55 (43.0)
Stroke
• In the PPS, the mean LVEF increased by 4.95% and 4.33% in the vildagliptin
and placebo groups, respectively, with a between-treatment difference of 0.62%
(95% CI: –2.21 to 3.44), confirming the non-inferiority of vildagliptin versus placebo
(Figure 1). The analysis of the FAS supported the primary analysis in the PPS.
• The incidence of adjudicated CV events was similar between the two treatment
groups (Table 3).
• There was no difference in adjudicated worsening of CHF events (with or without
hospitalization) between vildagliptin and placebo groups (18.0% versus 17.6%,
respectively; p=0.939). The incidence of hospitalization due to CHF was similar
between the two treatment groups (vildagliptin, 10.2% versus placebo, 8.0%; p=0.552).
n=
BL=
• The slight increase in mean body weight was similar between vildagliptin and placebo
groups. The mean body weight was 84.6 kg versus 81.4 kg at baseline and 85.8 kg
versus 82.7 kg at study endpoint in the vildagliptin and placebo groups, respectively.
Vildagliptin
n=128
• BNP was an exploratory endpoint. An ANCOVA analysis was performed on the change
from baseline to end of study with log-transformed data.
Figure 1. Adjusted mean change in LVEF (per protocol set)
Severe RI (<30), n (%)
HbA1c, %
89
30.5%
Table 3. Adjudicated CV events and other significant adverse events
(safety set)
90
29.8%
Placebo
n=125
p-value*
35 (27.3)
31 (24.8)
0.646
7 (5.5)
4 (3.2)
0.377
Heart failure
23 (18.0)
22 (17.6)
0.939
Heart failure hospitalizations
13 (10.2)
10 (8.0)
0.552
Any adjudicated CV event
4.95
6.0
CV death
4.33
5.0
4.0
*p-values were based on CMH test (or Fisher exact test if 25% of the expected frequency is <5). CV, cardiovascular
3.0
CONCLUSIONS
2.0
• Vildagliptin was not associated with worsening of pre-existing CHF or increase
in hospitalizations for CHF in patients with NYHA class I–III compared with
placebo. The changes in LVEF, BNP and CHF medications were consistent with
these findings.
1.0
0.0
Vildagliptin
• The overall incidence of adjudicated CV events was similar between the two
treatment groups.
Placebo
BL, baseline; LVEF, left ventricular ejection fraction
• There was a higher incidence of CV deaths with vildagliptin; however, interpretation
of these data is limited by the small number of events.
Table 2. Baseline background therapy (randomized set)
• Vildagliptin demonstrated clinically relevant and statistically significant
glucose-lowering efficacy versus placebo without increased risk of
hypoglycemia or body weight gain.
Vildagliptin
n=128
Placebo
n=126
ACE inhibitor
71.8
61.9
49 (38.9)
ARB
23.4
28.6
12 (9.4)
11 (8.7)
Beta-blocker
79.7
76.2
Atrial fibrillation
29 (22.7)
34 (27.0)
MRA
46.1
37.3
Hypertension
112 (87.5)
108 (85.7)
Prior hospitalization for HF
66 (51.6)
55 (43.7)
Digitalis glycoside
28.9
23.0
COPD
16 (12.5)
8 (6.3)
Diuretic (loop)
71.1
70.7
ICD
9.4
7.9
CRT
10.2
11.9
Disclosures
This study was funded by Novartis. HK has been consultant for Novartis Pharmaceuticals Corporation. GB
has been consultant for Sanofi Aventis and has received honoraria for lectures from Sanofi Aventis, Novartis
Pharma AG, Eli Lilly and Company, and AstraZeneca/Bristol-Myers Squibb. PP has been consultant for Novartis
Pharma AG and has received speaker honoraria from Novartis Pharma AG. VL, PK and WK are employees of
Novartis and own shares or stock options.
Heart failure status
NYHA class, n (%)
I
13 (10.2)
12 (9.5)
II
68 (53.1)
66 (52.4)
III
47 (36.7)
48 (38.1)
244.0
217.0
BNP**, pg/mL
Echocardiography parameters
30.6 (6.8)
29.6 (7.7)
Treatment (%)
Insulin
Monotherapy
24.2
24.6
Any
35.2
33.3
Oral anti-diabetes therapy
Sulfonylurea
46.9
53.2
Metformin
36.7
32.5
0.8
2.4
• The proportion of patients with an increase in CHF medication during the study was
similar in both the groups (vildagliptin, 26.6% versus placebo, 24.0%; p=0.640).
LVEF, %
LVEDV, mL
178.8 (59.1)
168.2 (66.2)
AGI
• Vildagliptin demonstrated numerically, but not statistically, greater reduction in the
ratio of geometric means (endpoint/baseline) for BNP, compared with placebo,
corresponding to 24% versus 8% BNP reduction from baseline, respectively.
LVESV, mL
124.5 (44.5)
120.2 (55.7)
Glinide
1.6
0.8
Any oral therapy
63.3
68.3
12.5
7.1
• More deaths were reported with vildagliptin. Adjudicated CV death was reported in
7 vildagliptin- and 4 placebo-treated patients (Table 3).
Vildagliptin
n=128
Patients with event, n (%)
7.0
Adjusted mean change (SE) in LVEF, %
Henry Krum , Valentina Lukashevich , Geremia B. Bolli , Plamen Kozlovski , Wolfgang Kothny , Piotr Ponikowski
1
1028-P
All values are mean (standard deviation) unless indicated otherwise.
BMI, body mass index; BNP, brain natriuretic peptide; BP, blood pressure; bpm, beats per minute; NYHA, New York
Heart Association; COPD, chronic obstructive pulmonary disease; CRT, cardiac resynchronization therapy;
eGFR, estimated glomerular filtration rate; HF, heart failure; LVEF, left ventricular ejection fraction; LVEDV, left
ventricular end diastolic volume; LVESV, left ventricular end systolic volume; RI, renal impairment
*geometric mean shown; **median shown
Diet only
ACE, angiotensin converting enzyme; ARB, angiotensin receptor blocker; AGI, alpha-glucosidase inhibitor;
CRT, cardiac resynchronization therapy; ICD, implantable cardioverter-defibrillator; MRA, mineralocorticoid receptor
antagonist
Poster presented at the 74th Scientific Sessions of the American Diabetes Association (ADA), June 13–17, 2014, San Francisco, CA, USA
•
REFERENCES
1. Voors AA et al. Heart. 2011;97:774–80.
2. Scirica SM et al. N Engl J Med. 2013;369:1317–26.
3. White WB et al. N Engl J Med. 2013;369:1327–35.
4. McMurray JJV et al. Heart Failure. 2013;12(Suppl 1):99.
Acknowledgments
The authors thank Anuja Shah, Novartis Healthcare Pvt. Ltd., Hyderabad, India, for editorial assistance, and
Vinod Goshamahal, Novartis Healthcare Pvt. Ltd., Hyderabad, India, for graphic design support.
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