Editorial Comment Cardiology 2015;131:162–164 DOI: 10.1159/000380878
Received: February 10, 2015 Accepted: February 10, 2015 Published online: May 6, 2015
Treating Atherosclerotic Disease: A Still-Unsolved Challenge Bernard Geudelin Mediante GmbH, Eptingen/Basel, Switzerland
© 2015 S. Karger AG, Basel 0008–6312/15/1313–0162$39.50/0 E-Mail [email protected] www.karger.com/crd
domized to receive glimepiride or pioglitazone for 18 months. Mean atheroma volume measured by intravascular ultrasound increased from baseline to study completion with glimepiride, but decreased significantly (p = 0.002) with pioglitazone. The author concluded that in patients with type 2 diabetes and coronary artery disease, treatment with pioglitazone results in a significantly lower rate of progression of coronary atherosclerosis [4]. A similar study was published recently by Christoph et al. [5], on 54 nondiabetic patients with acute coronary syndrome randomized to receive either 30 mg pioglitazone or placebo in a 9-month prospective, doubleblind, placebo-controlled study. The plaque size and composition were assessed by virtual-histology intravascular ultrasound. The authors concluded that treatment with a PPARγ agonist in nondiabetic patients results in a coronary artery plaque stabilization in addition to usual medical care. The pilot study investigates the effect of pioglitazone on the vessel wall function of large and small arteries. Fifty-four nondiabetic patients with unstable angina or nonST elevation myocardial infarction (NSTEMI) caused by coronary heart disease requiring stents, were observed in a 9-month, prospective, double-blind study, and were randomized to pioglitazone or placebo. The primary efficacy end points were changes in the following surrogate Dr. Bernhard Geudelin Mediante GmbH CH–4458 Eptingen/Basel (Switzerland) E-Mail bernard.geudelin @ bluewin.ch
Downloaded by: Washington University 198.143.32.1 - 1/27/2016 12:13:27 PM
The publication by Christoph et al. [1] in this issue of Cardiology refers to a double-blind, placebo-controlled study which addresses the effect of the insulin-sensitizing pioglitazone as a secondary prevention in nondiabetic patients with coronary artery disease. Atherosclerosis is a widespread disease affecting the large arteries like the aorta, the coronary arteries and small vessels like the retinal vessels, and causes pathological vessel wall stiffness. Despite advanced therapy with statins, antithrombotics and antihypertensive agents, the medical treatment of coronary artery disease is less than optimal. Therefore, additional therapeutic antiatherosclerotic options are desirable. Previous studies have shown that PPARγ agonists could reduce macrovascular complications in patients with type 2 diabetes [2]. In the PROactive study, 5,238 patients with type 2 diabetes and evidence of macrovascular disease were assigned to oral pioglitazone or matching placebo. The average time of observation was 34.5 months. The difference was statistically significant in favor of pioglitazone (p = 0.027) at the composite end point of all-cause mortality, nonfatal myocardial infarction and stroke [3]. The change in percent atheroma volume in coronary arteries was investigated in the PERISCOPE study, a double-blind, randomized, multicenter trial on 543 patients with coronary disease and type 2 diabetes, ran-
parameters: carotid-femoral pulse wave velocity (PWV), static and dynamic retinal vascular signs, and common carotid intima-media thickness, which are well-documented predictors of cardiovascular risk [6–8]. Comparative to the previous study on nondiabetic patients where plaque size was measured by virtual-histology intravascular ultrasound, the measure of the common carotid intima-media thickness was determined in the common carotid artery by using an ultrasound with a linear transducer, a well-evaluated surrogate parameter of cardiovascular mortality. The secondary end point was the correlation with cholesteryl ester transfer protein and other metabolic parameters, as it is speculated that a reduction in the activity of this protein inhibits the atherosclerotic plaque. Baseline characteristics were similar in the pioglitazone and placebo groups: hypertension was present in 81.5 and 77.8%, respectively, and dyslipidemia occurred in 77.8 and 77.8%, respectively. Of note, all patients received 20 mg of atorvastatin and an antiplatelet agent as the established standard of care for patients with cardiovascular disease, and a beta-blocker was administered to 92.6 and 96.3%, respectively. Compared to placebo, the treatment with pioglitazone was not able to influence the PWV, retinal vessel function or intima-media thickness in patients without diabetes. On the contrary, there was a slight increase in PWV of similar magnitude in both groups. There were no relevant changes in CETP concentration and activity. There was a moderate weight increase in the pioglitazone group, which is consistent with data from the literature [9], and a slight decrease in systolic and diastolic blood pressure (not significant). The authors conclude that the treatment with a PPARγ agonist in nondiabetic patients could not improve the function of large and small peripheral vessels. These results are in some way in contradiction with the previous study by Christoph et al. [5] in nondiabetic patients, which showed a stabilization of the plaque size and composition in the coronary arteries, with a significant decrease of necrotic core and plaque volume when compared to placebo. Indeed, noninvasive measures of carotid-radial PWV were shown to correlate with the extent of coronary artery plaque volume and could be a useful noninvasive surrogate marker for the extent of coronary atherosclerosis [10]. In addition, it was found that pioglitazone reduced mortality, nonfatal myocardial infarction and stroke in diabetic patients, but the duration of the study was close to 3 years. The follow-up period of the current study (9 months) was too short to investigate the clinical out-
come. Another limitation of the study was the concomitant medication with atorvastatin and antiplatelet agents, which may influence the vessel function besides the effect of pioglitazone and lead to a masking effect of pioglitazone. On the other hand, surrogate end points may not always reflect therapeutic efficacy: statins are indicated for prevention of cardiovascular events, even though their effect on arterial stiffness, as estimated by PWV measurements, has been poorly documented with only a few randomized clinical trials and a limited number of patients [11]. Recent studies have shown a beneficial effect of pioglitazone on progression of atherosclerosis. During an average follow-up of 2.3 years, the mean unadjusted annual rate of carotid intima-media thickness (CIMT) progression was significantly (p = 0.01) lower with pioglitazone treatment than with placebo [12]. Even if the effect of pioglitazone on the progression of atherosclerosis in nondiabetic patients remains uncertain, its anti-inflammatory component could explain the antiatherosclerotic effect independently of the effects on dyslipidemia and glucose metabolism. Recently, pioglitazone was shown to inhibit the proliferation and promote the apoptosis of vascular smooth muscle cells via the modulation of caspase and cyclin signaling pathways in a PPARγ-dependent manner [13]. The apoptosis of these cells has been identified in physiological remodeling of the vasculature and in disease states such as atherosclerosis, leading to a compensatory arterial remodeling when atherosclerotic plaques narrow the arterial lumen [14]. In conclusion, the results of this study open the debate and the way to future investigations that include robust clinical end points, inflammatory markers and a sufficiently prolonged follow-up.
Treating Atherosclerotic Disease: A Still-Unsolved Challenge
Cardiology 2015;131:162–164 DOI: 10.1159/000380878
1 Christoph M, Herold J, Berg-Holldack A, et al: Effects of the peroxisome proliferator-activated receptor-γ agonist pioglitazone on peripheral vessel function and clinical parameters in non diabetic patients: a double-center, randomized controlled pilot trial. Cardiology 2015;131:165–171. 2 Kawamori R: Evidences demonstrating the effects of anti-atherosclerotic actions of pioglitazone – special emphasis on the PROactive study and PERISCOPE study. Nihon Rinsho 2010;68:235–241. 3 Dormandy JA, Charbonnel B, Eckland DJ, et al; PROactive Investigators: Secondary prevention of macrovascular events in patients with type 2 diabetes in the PROactive study (PROspective pioglitAzone Clinical Trial In macroVascular Events): a randomised controlled trial. Lancet 2005;366:1279–1289.
163
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References
164
7 Blacher J, Asmar R, Djane S, et al: Aortic pulse wave velocity as a marker of cardiovascular risk in hypertensive patients. Hypertension 1999;33:1111–1117. 8 Den Ruijter HM, Peters SA, Anderson TJ, et al: Common carotid intima-media thickness measurements in cardiovascular risk prediction: a meta-analysis. JAMA 2012; 308: 796– 803. 9 Kusunoki M, Tsutsumi K, Sato D, et al: Pioglitazone-induced body weight gain is prevented by combined administration with the lipoprotein lipase activator NO-1886. Eur J Pharmacol 2011;668:486–491. 10 McLeod AL, Uren NG, Wilkinson IB, et al: Non-invasive measures of pulse wave velocity correlate with coronary arterial plaque load in humans. J Hypertens 2004;22:363–368.
Cardiology 2015;131:162–164 DOI: 10.1159/000380878
11 Rizos EC, Agouridis AP, Elisaf MS: The effect of statin therapy on arterial stiffness by measuring pulse wave velocity: a systematic review. Curr Vasc Pharmacol 2010;8:638–644. 12 Saremi A, Schwenke DC, Buchanan TA, et al: Pioglitazone slows progression of atherosclerosis in prediabetes independent of changes in cardiovascular risk factors. Arterioscler Thromb Vasc Biol 2013;33:393–399. 13 Wan J, Xiao Z, Chao S, et al: Pioglitazone modulates the proliferation and apoptosis of vascular smooth muscle cells via peroxisome proliferator-activated receptor-gamma. Diabetol Metab Syndr 2014;6:101. 14 Bennett MR: Apoptosis of vascular smooth muscle cells in vascular remodelling and atherosclerotic plaque rupture. Cardiovasc Res 1999;41:361–368.
Geudelin
Downloaded by: Washington University 198.143.32.1 - 1/27/2016 12:13:27 PM
4 Nissen SE, Nicholls SJ, Wolski K, et al; PERISCOPE Investigators: Comparison of pioglitazone vs. glimepiride on progression of coronary atherosclerosis in patients with type 2 diabetes: the PERISCOPE randomized controlled trial. JAMA 2008;299:1561–1573. 5 Christoph M, Herold J, Berg-Holldack A, et al: Effects of the PPARγ agonist pioglitazone on coronary atherosclerotic plaque composition and plaque progression in non-diabetic patients: a double-center, randomized controlled VH-IVUS pilot-trial. Heart Vessels 2014, Epub ahead of print. 6 Al-Fiadh AH, Farouque O, Kawasaki R, et al: Retinal microvascular structure and function in patients with risk factors of atherosclerosis and coronary artery disease. Atherosclerosis 2014;233:478–484.
Received: February 10, 2015 Accepted: February 10, 2015 Published online: May 6, 2015
Treating Atherosclerotic Disease: A Still-Unsolved Challenge Bernard Geudelin Mediante GmbH, Eptingen/Basel, Switzerland
© 2015 S. Karger AG, Basel 0008–6312/15/1313–0162$39.50/0 E-Mail [email protected] www.karger.com/crd
domized to receive glimepiride or pioglitazone for 18 months. Mean atheroma volume measured by intravascular ultrasound increased from baseline to study completion with glimepiride, but decreased significantly (p = 0.002) with pioglitazone. The author concluded that in patients with type 2 diabetes and coronary artery disease, treatment with pioglitazone results in a significantly lower rate of progression of coronary atherosclerosis [4]. A similar study was published recently by Christoph et al. [5], on 54 nondiabetic patients with acute coronary syndrome randomized to receive either 30 mg pioglitazone or placebo in a 9-month prospective, doubleblind, placebo-controlled study. The plaque size and composition were assessed by virtual-histology intravascular ultrasound. The authors concluded that treatment with a PPARγ agonist in nondiabetic patients results in a coronary artery plaque stabilization in addition to usual medical care. The pilot study investigates the effect of pioglitazone on the vessel wall function of large and small arteries. Fifty-four nondiabetic patients with unstable angina or nonST elevation myocardial infarction (NSTEMI) caused by coronary heart disease requiring stents, were observed in a 9-month, prospective, double-blind study, and were randomized to pioglitazone or placebo. The primary efficacy end points were changes in the following surrogate Dr. Bernhard Geudelin Mediante GmbH CH–4458 Eptingen/Basel (Switzerland) E-Mail bernard.geudelin @ bluewin.ch
Downloaded by: Washington University 198.143.32.1 - 1/27/2016 12:13:27 PM
The publication by Christoph et al. [1] in this issue of Cardiology refers to a double-blind, placebo-controlled study which addresses the effect of the insulin-sensitizing pioglitazone as a secondary prevention in nondiabetic patients with coronary artery disease. Atherosclerosis is a widespread disease affecting the large arteries like the aorta, the coronary arteries and small vessels like the retinal vessels, and causes pathological vessel wall stiffness. Despite advanced therapy with statins, antithrombotics and antihypertensive agents, the medical treatment of coronary artery disease is less than optimal. Therefore, additional therapeutic antiatherosclerotic options are desirable. Previous studies have shown that PPARγ agonists could reduce macrovascular complications in patients with type 2 diabetes [2]. In the PROactive study, 5,238 patients with type 2 diabetes and evidence of macrovascular disease were assigned to oral pioglitazone or matching placebo. The average time of observation was 34.5 months. The difference was statistically significant in favor of pioglitazone (p = 0.027) at the composite end point of all-cause mortality, nonfatal myocardial infarction and stroke [3]. The change in percent atheroma volume in coronary arteries was investigated in the PERISCOPE study, a double-blind, randomized, multicenter trial on 543 patients with coronary disease and type 2 diabetes, ran-
parameters: carotid-femoral pulse wave velocity (PWV), static and dynamic retinal vascular signs, and common carotid intima-media thickness, which are well-documented predictors of cardiovascular risk [6–8]. Comparative to the previous study on nondiabetic patients where plaque size was measured by virtual-histology intravascular ultrasound, the measure of the common carotid intima-media thickness was determined in the common carotid artery by using an ultrasound with a linear transducer, a well-evaluated surrogate parameter of cardiovascular mortality. The secondary end point was the correlation with cholesteryl ester transfer protein and other metabolic parameters, as it is speculated that a reduction in the activity of this protein inhibits the atherosclerotic plaque. Baseline characteristics were similar in the pioglitazone and placebo groups: hypertension was present in 81.5 and 77.8%, respectively, and dyslipidemia occurred in 77.8 and 77.8%, respectively. Of note, all patients received 20 mg of atorvastatin and an antiplatelet agent as the established standard of care for patients with cardiovascular disease, and a beta-blocker was administered to 92.6 and 96.3%, respectively. Compared to placebo, the treatment with pioglitazone was not able to influence the PWV, retinal vessel function or intima-media thickness in patients without diabetes. On the contrary, there was a slight increase in PWV of similar magnitude in both groups. There were no relevant changes in CETP concentration and activity. There was a moderate weight increase in the pioglitazone group, which is consistent with data from the literature [9], and a slight decrease in systolic and diastolic blood pressure (not significant). The authors conclude that the treatment with a PPARγ agonist in nondiabetic patients could not improve the function of large and small peripheral vessels. These results are in some way in contradiction with the previous study by Christoph et al. [5] in nondiabetic patients, which showed a stabilization of the plaque size and composition in the coronary arteries, with a significant decrease of necrotic core and plaque volume when compared to placebo. Indeed, noninvasive measures of carotid-radial PWV were shown to correlate with the extent of coronary artery plaque volume and could be a useful noninvasive surrogate marker for the extent of coronary atherosclerosis [10]. In addition, it was found that pioglitazone reduced mortality, nonfatal myocardial infarction and stroke in diabetic patients, but the duration of the study was close to 3 years. The follow-up period of the current study (9 months) was too short to investigate the clinical out-
come. Another limitation of the study was the concomitant medication with atorvastatin and antiplatelet agents, which may influence the vessel function besides the effect of pioglitazone and lead to a masking effect of pioglitazone. On the other hand, surrogate end points may not always reflect therapeutic efficacy: statins are indicated for prevention of cardiovascular events, even though their effect on arterial stiffness, as estimated by PWV measurements, has been poorly documented with only a few randomized clinical trials and a limited number of patients [11]. Recent studies have shown a beneficial effect of pioglitazone on progression of atherosclerosis. During an average follow-up of 2.3 years, the mean unadjusted annual rate of carotid intima-media thickness (CIMT) progression was significantly (p = 0.01) lower with pioglitazone treatment than with placebo [12]. Even if the effect of pioglitazone on the progression of atherosclerosis in nondiabetic patients remains uncertain, its anti-inflammatory component could explain the antiatherosclerotic effect independently of the effects on dyslipidemia and glucose metabolism. Recently, pioglitazone was shown to inhibit the proliferation and promote the apoptosis of vascular smooth muscle cells via the modulation of caspase and cyclin signaling pathways in a PPARγ-dependent manner [13]. The apoptosis of these cells has been identified in physiological remodeling of the vasculature and in disease states such as atherosclerosis, leading to a compensatory arterial remodeling when atherosclerotic plaques narrow the arterial lumen [14]. In conclusion, the results of this study open the debate and the way to future investigations that include robust clinical end points, inflammatory markers and a sufficiently prolonged follow-up.
Treating Atherosclerotic Disease: A Still-Unsolved Challenge
Cardiology 2015;131:162–164 DOI: 10.1159/000380878
1 Christoph M, Herold J, Berg-Holldack A, et al: Effects of the peroxisome proliferator-activated receptor-γ agonist pioglitazone on peripheral vessel function and clinical parameters in non diabetic patients: a double-center, randomized controlled pilot trial. Cardiology 2015;131:165–171. 2 Kawamori R: Evidences demonstrating the effects of anti-atherosclerotic actions of pioglitazone – special emphasis on the PROactive study and PERISCOPE study. Nihon Rinsho 2010;68:235–241. 3 Dormandy JA, Charbonnel B, Eckland DJ, et al; PROactive Investigators: Secondary prevention of macrovascular events in patients with type 2 diabetes in the PROactive study (PROspective pioglitAzone Clinical Trial In macroVascular Events): a randomised controlled trial. Lancet 2005;366:1279–1289.
163
Downloaded by: Washington University 198.143.32.1 - 1/27/2016 12:13:27 PM
References
164
7 Blacher J, Asmar R, Djane S, et al: Aortic pulse wave velocity as a marker of cardiovascular risk in hypertensive patients. Hypertension 1999;33:1111–1117. 8 Den Ruijter HM, Peters SA, Anderson TJ, et al: Common carotid intima-media thickness measurements in cardiovascular risk prediction: a meta-analysis. JAMA 2012; 308: 796– 803. 9 Kusunoki M, Tsutsumi K, Sato D, et al: Pioglitazone-induced body weight gain is prevented by combined administration with the lipoprotein lipase activator NO-1886. Eur J Pharmacol 2011;668:486–491. 10 McLeod AL, Uren NG, Wilkinson IB, et al: Non-invasive measures of pulse wave velocity correlate with coronary arterial plaque load in humans. J Hypertens 2004;22:363–368.
Cardiology 2015;131:162–164 DOI: 10.1159/000380878
11 Rizos EC, Agouridis AP, Elisaf MS: The effect of statin therapy on arterial stiffness by measuring pulse wave velocity: a systematic review. Curr Vasc Pharmacol 2010;8:638–644. 12 Saremi A, Schwenke DC, Buchanan TA, et al: Pioglitazone slows progression of atherosclerosis in prediabetes independent of changes in cardiovascular risk factors. Arterioscler Thromb Vasc Biol 2013;33:393–399. 13 Wan J, Xiao Z, Chao S, et al: Pioglitazone modulates the proliferation and apoptosis of vascular smooth muscle cells via peroxisome proliferator-activated receptor-gamma. Diabetol Metab Syndr 2014;6:101. 14 Bennett MR: Apoptosis of vascular smooth muscle cells in vascular remodelling and atherosclerotic plaque rupture. Cardiovasc Res 1999;41:361–368.
Geudelin
Downloaded by: Washington University 198.143.32.1 - 1/27/2016 12:13:27 PM
4 Nissen SE, Nicholls SJ, Wolski K, et al; PERISCOPE Investigators: Comparison of pioglitazone vs. glimepiride on progression of coronary atherosclerosis in patients with type 2 diabetes: the PERISCOPE randomized controlled trial. JAMA 2008;299:1561–1573. 5 Christoph M, Herold J, Berg-Holldack A, et al: Effects of the PPARγ agonist pioglitazone on coronary atherosclerotic plaque composition and plaque progression in non-diabetic patients: a double-center, randomized controlled VH-IVUS pilot-trial. Heart Vessels 2014, Epub ahead of print. 6 Al-Fiadh AH, Farouque O, Kawasaki R, et al: Retinal microvascular structure and function in patients with risk factors of atherosclerosis and coronary artery disease. Atherosclerosis 2014;233:478–484.
