International Journal of Cardiology 188 (2015) 13–15
Contents lists available at ScienceDirect
International Journal of Cardiology journal homepage: www.elsevier.com/locate/ijcard
Letter to the Editor
The effects and safety of vildagliptin on cardiac function after acute myocardial infarction Toshiyuki Nishikido a, Jun-ichi Oyama a,⁎, Hiroshi Ohira b, Koichi Node a a b
Department of Cardiovascular of Medicine, Saga University Hospital, Saga, Japan Department of Cardiovascular Medicine, Edogawa Hospital, Tokyo, Japan
a r t i c l e
i n f o
Article history: Received 30 March 2015 Accepted 31 March 2015 Available online 1 April 2015 Keywords: Vildagliptin Acute coronary syndrome Cardiac function
Type 2 diabetes mellitus (T2DM) is one of the high risk factors for acute coronary syndrome. Improved glycemic control made it possible to reduce the prevalence of diabetes-related complication such as a microvascular disease [1,2]. However, previous studies have showed that intensive use of insulin, sulfonylureas, and thiazolidinedione, was associated with severe hypoglycemia, and did not improve outcomes of cardiovascular disease despite lowering blood glucose levels substantially [3,4]. Dipeptidyl peptidase-4 (DPP-4) inhibitors are new anti-DM agents with possible protective effects for the cardiovascular system. Glucagon-like peptide-1 (GLP-1) reduced the infarct size in vivo, and improved left ventricular systolic dysfunction after myocardial infarction in a small single-center study. Furthermore, DPP-4 inhibitors have demonstrated to prevent cardiac remodeling after myocardial infarction [5–7]. In contrast, the rate of hospitalization for heart failure was increased by saxagliptin [8]. The purpose of this study was to evaluate the effects of DPP-4 inhibitors on cardiac function in patients with new onset acute myocardial infarction (AMI). We performed a multicenter, open-label, parallel-group comparison study between December 2011 and March 2014 in Japan. A total of 22 patients with T2DM with a HbA1c of N 6.5% despite conventional treatment (except incretin-related therapy) with diet, exercise and/or drugs were assigned to the vildagliptin treatment group and nonincretin treatment group randomly within 48 h after the onset of AMI. Other inclusion criteria included over 20 years of age, willingness to participate for the duration of the trial, and the provision of written in⁎ Corresponding author at: Department of Advanced Cardiology, Saga University, 5-1-1 Nabeshima, Saga 849-8501, Japan. E-mail address: [email protected] (J. Oyama).
http://dx.doi.org/10.1016/j.ijcard.2015.03.433 0167-5273/© 2015 Published by Elsevier Ireland Ltd.
formed consent. The exclusion criteria were the patients with insulin dependent diabetes mellitus including type 1 diabetes mellitus, a history of diabetic ketoacidosis or diabetic coma within three months, receiving insulin therapy, severe heart failure (NYHA functional class III or IV), serious renal or hepatic dysfunction, pregnancy, and judged to be ineligible for inclusion in the study. Twelve patients in the vildagliptin treatment group had been taking 50 mg of vildagliptin twice a day, and 10 patients in the non-incretin treatment group had been taking anti-DM agents without incretin agents. But, the combination use of other antihyperglycemic agents was permitted in the vildagliptin treatment group. We evaluated the effects of vildagliptin on cardiac function and safety for 6 months. Continuous variables are presented as the mean and standard error of the means. Categorical variables are expressed as numbers or percentages and were compared using the χ2 test. Statistically significant differences between two groups were compared by the unpaired t-test with a 95% confidence interval for continuous variables. If the distribution was skewed, statically significant differences were analyzed using the nonparametric Mann–Whitney test for changes between 2 groups. The P values were two-sided in all analyses. We regarded a P value under 0.05 as being statistically significant and conducted all statistical analyses. There were no significant differences in the demographic and baseline characteristics or laboratory values (Table 1). All patients were Killip class I on admission, and they had not had severe hepatic disease, chronic kidney disease, and previous hospitalizations due to heart failure. Both groups received the standard medication for post-MI with aspirin, clopidogrel, ACE inhibitors or ARB, β-blockers, and statins. In all cases, those with the first attack of acute coronary syndrome in this time, the reperfusion of culprit lesions had been succeeded by percutaneous coronary interventions with stent implantation. But, other stenosis lesions had been left in some cases of both groups without significant differences. After 6 months, the change of the cardiac functions including ejection fraction (EF), the ratio of early to late peak diastolic filling velocity (E/A), deceleration time, and the ratio of early diastolic transmitral filling velocity (E) to early diastolic mitral annular velocity (e′) (E/e′) evaluated with transthoracic echocardiography in the vildagliptin treatment group was same as that in the non-incretin treatment group, but brain natriuretic peptide (BNP) levels decreased significantly in the vildagliptin treatment group (67.2 ± 40.7 pg/ml vs 93.7 ± 23.6 pg/ml; P = 0.02) (Fig. 1). The HbA1c levels were lower with vildagliptin (5.95 ± 0.94% vs 6.99 ± 1.63%; P = 0.04). There were no serious adverse events
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T. Nishikido et al. / International Journal of Cardiology 188 (2015) 13–15
Table 1 The demographic and baseline characteristics of the subjects. Variables
Vildagliptin treatment group (n = 12)
Non-incretin treatment group (n = 10)
P value
Age (years) Male no. (%) Weight (kg) BMI (kg/m2) Current smoking no. (%) Hypertension no. (%) Prior hypoglycemic therapy no. (%) Culprit lesion no. (%) LAD LCx RCA Multivessel coronary artery disease no. (%) Medication no. (%) ACE inhibitor ARB β-blocker Spironolactone Statin Creatine kinase peak (U/l) Creatine kinase-MB peak (ng/ml) Left ventricular mass index (g/m2) BNP (pg/ml) Fasting serum glucose (mg/dl) Glycated hemoglobin (%) 1.5-AG (μg/ml) eGFR (ml/min/1.73 m2)
59.7 ± 2.5 10 (83.3) 69.0 ± 2.3 25.2 ± 0.8 10 (83.3) 9 (75.0) 4 (33.3)
63.7 ± 4.3 8 (80.0) 71.3 ± 7.3 26.5 ± 1.9 6 (60.0) 3 (30.0) 2 (20.0)
0.41 0.84 0.74 0.53 0.04 0.08 0.65
7 (58.3) 1 (8.3) 2 (16.7) 5 (41.7)
7 (70.0) 3 (30.0) 0 5 (50.0)
0.9 0.29 0.47 0.97
7 (33.3) 1 (8.3) 7 (33.3) 0 10 (83.3) 1200.4 ± 182.4 184.4 ± 24.8 99.3 ± 8.3 170.1 ± 67.4 176.4 ± 25.4 7.48 ± 0.45 6.85 ± 1.15 69.7 ± 4.1
5 (50) 5 (50) 9 (90) 1 (10) 10 (100) 1749.0 ± 552.4 128.8 ± 62.1 111.8 ± 8.9 124.2 ± 39.6 207.9 ± 22.1 8.09 ± 0.58 5.89 ± 2.82 71.8 ± 6.4
0.97 0.06 0.16 0.45 0.32 0.5 0.19 0.58 0.36 0.4 0.73 0.78
Data were expressed as the mean and standard error of the means.
including hypoglycemia, pancreatitis, major cardiovascular events, and hospitalization for heart failure in either group. The liver and renal functions did not change in both groups after 6 months.
Our results suggest that vildagliptin did not improve the systolic and diastolic cardiac functions significantly. However, the level of BNP decreased in the vildagliptin treatment group significantly. Assumably,
Fig. 1. The changes of cardiac function and renal function during the study. *P b 0.05.
T. Nishikido et al. / International Journal of Cardiology 188 (2015) 13–15
if the tendency with these results will be sustained, a large scale clinical trial for patients with AMI may elicit the significant protective effects of vildagliptin on cardiac function. Conflict of interest No potential conflicts of interest relevant to this article were reported. References [1] UK Prospective Diabetes Study (UKPDS) Group, Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33), Lancet 352 (1998) 837–853. [2] Action to Control Cardiovascular Risk in Diabetes Study Group, Effects of intensive glucose lowering in type 2 diabetes, N. Engl. J. Med. 358 (2008) 2545–2559.
15
[3] ADVANCE Collaborative Group, Intensive blood glucose control and vascular outcomes in patients with type 2 diabetes, N. Engl. J. Med. 358 (2008) 2560–2572. [4] D. Sun, N. Nguyen, T.R. DeGrado, M. Schwaiger, F.C. Brosius III, Ischemia induces translocation of the insulin-responsive glucose transporter GLUT4 to the plasma membrane of cardiac myocytes, Circulation 89 (1994) 793–798. [5] Lazaros A. Nikolaidis, Sunil Mankad, et al., Effects of glucagon-like peptide-1 in patients with acute myocardial infarction and left ventricular dysfunction after success reperfusion, Circulation 109 (2004) 962–965. [6] Que Liu, Christen Anderson, Anatoly Broyde, Clara Polizzi, Rayne Fernandez, Alain Baron, David G. Parkes, Glucagon-like peptide-1 and the exenatide analogue AC3174 improve cardiac function, cardiac remodeling, and survival in rats with chronic heart failure, Cardiovasc. Diabetol. 9 (2010) 76. [7] K.A. Connelly, Y. Zhang, A. Advani, S.L. Advani, K. Thai, D.A. Yuen, R.E. Gilbert, DPP-4 inhibition attenuates cardiac dysfunction and adverse remodeling following myocardial infarction in rats with experimental diabetes, Cardiovasc. Ther. 31 (2013) 259–267. [8] SAVOR-TIMI 53 Steering Committee and Investigators, Saxagliptin and cardiovascular outcomes in patients with type 2 diabetes mellitus, N. Engl. J. Med. 369 (2013) 1317–1326.
Contents lists available at ScienceDirect
International Journal of Cardiology journal homepage: www.elsevier.com/locate/ijcard
Letter to the Editor
The effects and safety of vildagliptin on cardiac function after acute myocardial infarction Toshiyuki Nishikido a, Jun-ichi Oyama a,⁎, Hiroshi Ohira b, Koichi Node a a b
Department of Cardiovascular of Medicine, Saga University Hospital, Saga, Japan Department of Cardiovascular Medicine, Edogawa Hospital, Tokyo, Japan
a r t i c l e
i n f o
Article history: Received 30 March 2015 Accepted 31 March 2015 Available online 1 April 2015 Keywords: Vildagliptin Acute coronary syndrome Cardiac function
Type 2 diabetes mellitus (T2DM) is one of the high risk factors for acute coronary syndrome. Improved glycemic control made it possible to reduce the prevalence of diabetes-related complication such as a microvascular disease [1,2]. However, previous studies have showed that intensive use of insulin, sulfonylureas, and thiazolidinedione, was associated with severe hypoglycemia, and did not improve outcomes of cardiovascular disease despite lowering blood glucose levels substantially [3,4]. Dipeptidyl peptidase-4 (DPP-4) inhibitors are new anti-DM agents with possible protective effects for the cardiovascular system. Glucagon-like peptide-1 (GLP-1) reduced the infarct size in vivo, and improved left ventricular systolic dysfunction after myocardial infarction in a small single-center study. Furthermore, DPP-4 inhibitors have demonstrated to prevent cardiac remodeling after myocardial infarction [5–7]. In contrast, the rate of hospitalization for heart failure was increased by saxagliptin [8]. The purpose of this study was to evaluate the effects of DPP-4 inhibitors on cardiac function in patients with new onset acute myocardial infarction (AMI). We performed a multicenter, open-label, parallel-group comparison study between December 2011 and March 2014 in Japan. A total of 22 patients with T2DM with a HbA1c of N 6.5% despite conventional treatment (except incretin-related therapy) with diet, exercise and/or drugs were assigned to the vildagliptin treatment group and nonincretin treatment group randomly within 48 h after the onset of AMI. Other inclusion criteria included over 20 years of age, willingness to participate for the duration of the trial, and the provision of written in⁎ Corresponding author at: Department of Advanced Cardiology, Saga University, 5-1-1 Nabeshima, Saga 849-8501, Japan. E-mail address: [email protected] (J. Oyama).
http://dx.doi.org/10.1016/j.ijcard.2015.03.433 0167-5273/© 2015 Published by Elsevier Ireland Ltd.
formed consent. The exclusion criteria were the patients with insulin dependent diabetes mellitus including type 1 diabetes mellitus, a history of diabetic ketoacidosis or diabetic coma within three months, receiving insulin therapy, severe heart failure (NYHA functional class III or IV), serious renal or hepatic dysfunction, pregnancy, and judged to be ineligible for inclusion in the study. Twelve patients in the vildagliptin treatment group had been taking 50 mg of vildagliptin twice a day, and 10 patients in the non-incretin treatment group had been taking anti-DM agents without incretin agents. But, the combination use of other antihyperglycemic agents was permitted in the vildagliptin treatment group. We evaluated the effects of vildagliptin on cardiac function and safety for 6 months. Continuous variables are presented as the mean and standard error of the means. Categorical variables are expressed as numbers or percentages and were compared using the χ2 test. Statistically significant differences between two groups were compared by the unpaired t-test with a 95% confidence interval for continuous variables. If the distribution was skewed, statically significant differences were analyzed using the nonparametric Mann–Whitney test for changes between 2 groups. The P values were two-sided in all analyses. We regarded a P value under 0.05 as being statistically significant and conducted all statistical analyses. There were no significant differences in the demographic and baseline characteristics or laboratory values (Table 1). All patients were Killip class I on admission, and they had not had severe hepatic disease, chronic kidney disease, and previous hospitalizations due to heart failure. Both groups received the standard medication for post-MI with aspirin, clopidogrel, ACE inhibitors or ARB, β-blockers, and statins. In all cases, those with the first attack of acute coronary syndrome in this time, the reperfusion of culprit lesions had been succeeded by percutaneous coronary interventions with stent implantation. But, other stenosis lesions had been left in some cases of both groups without significant differences. After 6 months, the change of the cardiac functions including ejection fraction (EF), the ratio of early to late peak diastolic filling velocity (E/A), deceleration time, and the ratio of early diastolic transmitral filling velocity (E) to early diastolic mitral annular velocity (e′) (E/e′) evaluated with transthoracic echocardiography in the vildagliptin treatment group was same as that in the non-incretin treatment group, but brain natriuretic peptide (BNP) levels decreased significantly in the vildagliptin treatment group (67.2 ± 40.7 pg/ml vs 93.7 ± 23.6 pg/ml; P = 0.02) (Fig. 1). The HbA1c levels were lower with vildagliptin (5.95 ± 0.94% vs 6.99 ± 1.63%; P = 0.04). There were no serious adverse events
14
T. Nishikido et al. / International Journal of Cardiology 188 (2015) 13–15
Table 1 The demographic and baseline characteristics of the subjects. Variables
Vildagliptin treatment group (n = 12)
Non-incretin treatment group (n = 10)
P value
Age (years) Male no. (%) Weight (kg) BMI (kg/m2) Current smoking no. (%) Hypertension no. (%) Prior hypoglycemic therapy no. (%) Culprit lesion no. (%) LAD LCx RCA Multivessel coronary artery disease no. (%) Medication no. (%) ACE inhibitor ARB β-blocker Spironolactone Statin Creatine kinase peak (U/l) Creatine kinase-MB peak (ng/ml) Left ventricular mass index (g/m2) BNP (pg/ml) Fasting serum glucose (mg/dl) Glycated hemoglobin (%) 1.5-AG (μg/ml) eGFR (ml/min/1.73 m2)
59.7 ± 2.5 10 (83.3) 69.0 ± 2.3 25.2 ± 0.8 10 (83.3) 9 (75.0) 4 (33.3)
63.7 ± 4.3 8 (80.0) 71.3 ± 7.3 26.5 ± 1.9 6 (60.0) 3 (30.0) 2 (20.0)
0.41 0.84 0.74 0.53 0.04 0.08 0.65
7 (58.3) 1 (8.3) 2 (16.7) 5 (41.7)
7 (70.0) 3 (30.0) 0 5 (50.0)
0.9 0.29 0.47 0.97
7 (33.3) 1 (8.3) 7 (33.3) 0 10 (83.3) 1200.4 ± 182.4 184.4 ± 24.8 99.3 ± 8.3 170.1 ± 67.4 176.4 ± 25.4 7.48 ± 0.45 6.85 ± 1.15 69.7 ± 4.1
5 (50) 5 (50) 9 (90) 1 (10) 10 (100) 1749.0 ± 552.4 128.8 ± 62.1 111.8 ± 8.9 124.2 ± 39.6 207.9 ± 22.1 8.09 ± 0.58 5.89 ± 2.82 71.8 ± 6.4
0.97 0.06 0.16 0.45 0.32 0.5 0.19 0.58 0.36 0.4 0.73 0.78
Data were expressed as the mean and standard error of the means.
including hypoglycemia, pancreatitis, major cardiovascular events, and hospitalization for heart failure in either group. The liver and renal functions did not change in both groups after 6 months.
Our results suggest that vildagliptin did not improve the systolic and diastolic cardiac functions significantly. However, the level of BNP decreased in the vildagliptin treatment group significantly. Assumably,
Fig. 1. The changes of cardiac function and renal function during the study. *P b 0.05.
T. Nishikido et al. / International Journal of Cardiology 188 (2015) 13–15
if the tendency with these results will be sustained, a large scale clinical trial for patients with AMI may elicit the significant protective effects of vildagliptin on cardiac function. Conflict of interest No potential conflicts of interest relevant to this article were reported. References [1] UK Prospective Diabetes Study (UKPDS) Group, Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33), Lancet 352 (1998) 837–853. [2] Action to Control Cardiovascular Risk in Diabetes Study Group, Effects of intensive glucose lowering in type 2 diabetes, N. Engl. J. Med. 358 (2008) 2545–2559.
15
[3] ADVANCE Collaborative Group, Intensive blood glucose control and vascular outcomes in patients with type 2 diabetes, N. Engl. J. Med. 358 (2008) 2560–2572. [4] D. Sun, N. Nguyen, T.R. DeGrado, M. Schwaiger, F.C. Brosius III, Ischemia induces translocation of the insulin-responsive glucose transporter GLUT4 to the plasma membrane of cardiac myocytes, Circulation 89 (1994) 793–798. [5] Lazaros A. Nikolaidis, Sunil Mankad, et al., Effects of glucagon-like peptide-1 in patients with acute myocardial infarction and left ventricular dysfunction after success reperfusion, Circulation 109 (2004) 962–965. [6] Que Liu, Christen Anderson, Anatoly Broyde, Clara Polizzi, Rayne Fernandez, Alain Baron, David G. Parkes, Glucagon-like peptide-1 and the exenatide analogue AC3174 improve cardiac function, cardiac remodeling, and survival in rats with chronic heart failure, Cardiovasc. Diabetol. 9 (2010) 76. [7] K.A. Connelly, Y. Zhang, A. Advani, S.L. Advani, K. Thai, D.A. Yuen, R.E. Gilbert, DPP-4 inhibition attenuates cardiac dysfunction and adverse remodeling following myocardial infarction in rats with experimental diabetes, Cardiovasc. Ther. 31 (2013) 259–267. [8] SAVOR-TIMI 53 Steering Committee and Investigators, Saxagliptin and cardiovascular outcomes in patients with type 2 diabetes mellitus, N. Engl. J. Med. 369 (2013) 1317–1326.
