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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. Text Message (SMS) Text : Qff886 To : 8NOVA (86682) US Only +18324604729 North, Central and South Americas; Caribbean; China +447860024038 UK, Europe & Russia +46737494608 Sweden, Europe Standard data or message rates may apply Download document at the following URL: http://novartis.medicalcongressposters.com/Default.aspx?doc=ff886 Scan to download a reprint of this poster