- Email: [email protected]
Cerebrovascular disease in diabetes mellitus: The role of carotid intima-media thickness
Nutrition, Metabolism & Cardiovascular Diseases (2009) 19, 667e673
available at www.sciencedirect.com
journal homepage: www.elsevier.com/locate/nmcd
REVIEW
Cerebrovascular disease in diabetes mellitus: The role of carotid intima-media thickness S. Vigili de Kreutzenberg*, A. Tiengo, A. Avogaro Department of Clinical and Experimental Medicine, University of Padova, Via Giustiniani, 2, 35128 Padova, Italy Received 6 October 2008; received in revised form 14 January 2009; accepted 17 March 2009
KEYWORDS Carotid intima-media thickness; Diabetes mellitus; Cerebrovascular disease
Abstract Background and purpose: Cerebrovascular disease in diabetes appears to be less considered than coronary and peripheral disease, the reason being the intrinsic difficulty in finding available diagnostic tools for its early identification. Among these, carotid artery intima-media thickness (cIMT) represents the simplest measurable parameter for preatherosclerotic lesions in extra-cranic arteries. Methods: The role of cIMT as a surrogate marker of cerebral atherosclerosis and predictor of stroke, its relationship to microangiopathy and chronic inflammation, along with its role as an outcome parameter in anti-hyperglycemic therapeutical intervention trials in type 2 and 1 diabetes mellitus are discussed in this paper. Results and conclusions: Carotid IMT is increased in diabetes. It is an independent predictor of stroke, in particular of the ischemic subtype, and of stroke recurrence in diabetic, as well as in non-diabetic populations. A possible role of cIMT as a predictor of microangiopathy has also been suggested, but it needs further investigation. A weak association with chronic inflammation has been demonstrated in diabetic patients. Carotid IMT has been successfully employed as an outcome parameter for several anti-hyperglycemic therapeutic trials. However data on cIMT as a predictor of cerebrovascular disease are scarce in diabetic patients, particularly in type 1 diabetes, and more studies are needed to define the risk of cerebrovascular disease in diabetic patients. ª 2009 Elsevier B.V. All rights reserved.
Introduction
* Corresponding author. Tel.: þ39 049 821 2183; fax: þ39 049 875 4179. E-mail address: [email protected] (S. Vigili de Kreutzenberg).
Stroke remains the third cause of death in western countries [1], resulting in more than 160 000 deaths annually in the United States, and approximately 650 000 in Europe [2]. Type 1 and 2 diabetes are independent risk factors for stroke and its recurrence [3e5]. Thus, identifying diabetic
0939-4753/$ - see front matter ª 2009 Elsevier B.V. All rights reserved. doi:10.1016/j.numecd.2009.03.014
668 patients who are at high risk of developing stroke is of great clinical importance. The average risk of stroke in diabetic subjects compared to non-diabetic, ranges from 1.8- to nearly 6-fold, according to epidemiological studies [6]. In insulin treated diabetes, the relative risk for stroke mortality has been reported as 3.1 in men and 4.4 in women. The presence of other risk factors, which often cluster with diabetes, can further increase the risk. Among these, high blood pressure is a major independent predictor for stroke in diabetes [7], while cholesterol levels are not associated with the risk of stroke, as in the non-diabetic population. Arterial hypertension directly contributes to arterial wall alterations with one of the first being intimal-medial thickening [8]. Thickness of the arterial wall is an independent predictor of stroke in normotensive subjects [9]. The metabolic/insulin resistance syndrome is a well-documented predictor of cardiovascular disease (CVD) and stroke [10], as well as of diabetes.
Carotid intima-media thickness in type 2 diabetes Carotid IMT is a surrogate marker of subclinical atherosclerosis and a strong predictor of future cardiovascular events [11,12], asymptomatic myocardial ischemia [13], peripheral vascular disease [14], ischemic stroke [15] and cardiac dysfunction [16]. Hunt et al. [17] demonstrated that IMT of the internal carotid artery is significantly elevated in subjects who will subsequently develop diabetes. In newly diagnosed type 2 diabetic subjects, cIMT is significantly greater compared to normal glucose tolerant matched controls [18]. A weak relationship between genetic variants and carotid atherosclerosis has also been demonstrated [19]. The mean common carotid IMT is reported to range from 0.71 to 0.91 mm in diabetic patients who are middle-aged and without coronary artery disease (CAD), and from 0.66 to 0.74 mm in comparable control subjects [20]. An increase of IMT in type 2 diabetes, and to a lesser extent in impaired glucose tolerance, has been widely documented [20,21]. In a recent review, Brohall et al. [22] analyzed the mean cIMT value reported for type 2 diabetes and found that it was 0.13 mm thicker, compared to non-diabetic subjects. Lee et al. [23] and Haffner et al. [24] established that this increase was higher in diabetic subjects with overt macroangiopathic complications. In diabetic patients, the predictive value of cIMT for coronary events has been demonstrated to be similar and additive to that of the Framingham risk score [25]. This observation was not confirmed by the Rotterdam Study that did not find an incremental value of IMT in the prediction of CVD risk [26]. As well as hyperglycemia, metabolic abnormalities that cluster with diabetes and represent single risk factors for atherosclerosis, for example, insulin resistance, arterial hypertension, central obesity, and dyslipidemia contribute to the progression of cIMT in diabetes [7,9,27]. However, it is difficult to dissect the role of specific components of metabolic abnormalities in cIMT progression. Among these, the most important seems to be arterial hypertension, which, per se, determines functional and anatomical changes of arterial walls [9].
S. Vigili de Kreutzenberg et al. The specific role of cIMT as a predictor of stroke and stroke recurrence has been widely demonstrated in the general population [9,11,15]. Unfortunately, studies devoted to assessing diabetic subjects alone are scarce. Recently, Lee et al. found that an increased cIMT is associated with acute ischemic stroke in type 2 diabetes [28]. In a Japanese study, Matsumoto et al. [29] also observed this significant association in 438 type 2 diabetic patients.
Carotid intima-media thickness in type 1 diabetes As in adults with type 2 diabetes, cIMT is significantly increased in adult type 1 diabetic patients [30], suggesting a precocious development of atherosclerosis in this disease. The Epidemiology of Diabetes Intervention and Complications (EDIC) Study evaluated cIMT progression in type 1 diabetic subjects and found the IMT of the internal carotid artery significantly increased in both sexes, compared to matched non-diabetic controls, at year 6 of follow-up. The mean progression was significantly less in the group that had received intensive therapy. Therefore, hyperglycemia seems to influence atherosclerosis development in the long run, and the positive effect of intensive therapy efficiently reduces cIMT progression [30]. The Stockholm Diabetes Intervention Study also provided evidence of the favorable influence of glucose intensive treatment on carotid IMT and stiffening in a total of 59 type 1 diabetic patients [31]. In a small cohort of type 1 diabetic subjects (23 men; 16 women) a significant link between mean glycated hemoglobin and cIMT was found in women, but not in men, in an 18 year follow-up study [32]. In another cross-sectional study, major factors influencing common carotid artery cIMT in 148 type 1 diabetic patients were age, diabetes duration and hypertension while long-standing glycemic control played a minor role. Few other studies have evaluated the association of IMT and classical risk factors for atherosclerosis in type 1 diabetic patients [33]. The DCCT/EDIC trial [34] suggested that age, height, smoking and BMI were the most important predictors of common carotid IMT by multivariate analysis, whereas age, smoking and LDL cholesterol were the most important predictors of internal carotid IMT. This study also demonstrated that increased levels of modified ApoB-rich immune complexes are associated with an increased progression of internal carotid IMT [35]. A recent analysis of a patient subgroup of the DCCT/EDIC study demonstrated that among CRP, fibrinogen, soluble VCAM-1, ICAM-1, E-selectin and fibrinolytic markers, fibrinogen was the best predictor for progression of cIMT [36]. For type 1 diabetic children, only conflicting results are available, some confirming [37], and others denying [38] an increased cIMT in this population. The reason for this discrepancy could be the small number of patients included in the studies, and the lack of a well standardized method for cIMT measurement; further studies are therefore needed to answer this question. In type 1 diabetic children an increased IMT was associated with peripheral endothelial dysfunction [38], age of onset of diabetes, insulin dose requirement, systolic blood pressure and total cholesterol
Cerebrovascular disease in diabetes: role of carotid IMT levels [39]. In type 1 diabetes, no data are available on cIMT as a predictor of cerebrovascular disease (CD).
IMT, inflammation and microangiopathy The association between pre-atherosclerosis, as measured by cIMT, and a low-grade inflammation shows conflicting results. The prospective Carotid Atherosclerosis Progression Study demonstrated a highly significant association between IMT and hs-CRP, in a total of 3122 subjects (2.5% were diabetic); however, this association disappeared after controlling for other cardiovascular risk factors [40]. The data analysis of the Intervention Project on Cerebrovascular Diseases and Dementia in the Community of Ebersberg, Bavaria (INVADE), a prospective, population-based study enrolling 3534 subjects (mean age 69 years), of which 882 were diabetic, showed that cIMT progression was not significantly related to hsCRP (P Z 0.06), after adjustment for risk factors [41]. Similarly, studies carried out in smaller cohorts of type 2 diabetic patients failed to find such an association [42] or found it, but only by applying linear regression analysis [43]. On the other hand, CRP appeared to be significantly related to cIMT in small cohorts of type 1 diabetic subjects [44], suggesting that lowgrade inflammation could be a more important risk factor in young patients with type 1 diabetes. Serum concentrations of ICAM-1, VCAM-1, and E-selectin have been demonstrated to strongly predict microangiopathy, but to have a lesser value in macroangiopathy prediction when this is accompanied by an increased cIMT (>1.1 mm) [45]. Interleukin 18 showed an association with cIMT in type 2 diabetes [46]. A positive association between cell adhesion molecules and IMT was also present in a general population sample, of which 18% were diabetic subjects [47]. These data suggest a weak association between chronic inflammation and pre-atherosclerosis. A significant correlation between cIMT and functional changes of the arterial wall, such as arterial stiffness and brachial artery flow-mediated vasodilatation, was observed in type 2 diabetic patients in the SMART study [48] and in the Chennai Urban Population Study [49], underlying the link between endothelial dysfunction and atherogenesis. A common pathogenesis for both micro- and macrovascular complications of diabetes has been suggested. However this issue remains controversial and is still under debate. A significant association between retinal microangiopathy and IMT was found in the diabetic population of the Atherosclerosis Risk in Communities Study [50] and in that of the Chennai Urban Rural Epidemiology Study [51] and was independent of age, diabetes duration and glycemic control. Different conclusions were drawn in the Cardiovascular Health Study (CHS), in which no association between early atherosclerosis and diabetic retinopathy was found. However, in CHS, only a small number of patients was affected by retinopathy (n Z 80) and the age of these subjects was quite elevated (>69 years) [52], invalidating these conclusions. The same results were obtained in a subgroup of 256 participants of the Hoorn Study [53], of which 42% were diabetic; this study does not uphold the hypothesis that subclinical atherosclerosis is associated with retinal microangiopathy. Instead, a significant association has been extensively demonstrated between
669 microalbuminuria and cIMT in type 2 diabetic subjects in IRAS [54], in the Multi Ethnic Study of Atherosclerosis [55] and in other studies. Furthermore, in a subgroup of the Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) study, this association was demonstrated even for microalbuminuria levels still in the normal range [56]. A recent analysis of the SMART study suggested a different pathogenesis between small- and large-vessel disease [57]. In this study, common carotid artery (CCA) IMT was higher in patients with large-vessel disease (1.08 vs 0.92 mm), and the difference remained significant after adjustment for age, sex and hypertension (0.11 mm; 95% CI, 0.05e0.18). Similar results were obtained by Cupini et al. [58]. On the other hand, the GENIC Investigators and others researchers did not find any difference in CCA IMT between patients with large- or small-vessel disease [59,60]. Finally, no conclusive remarks about a common pathogenesis for micro- and macroangiopathy can yet be made. In type 1 diabetes, endothelial dysfunction [37] and nephropathy [61] are associated with cIMT. Altogether, these data strongly support the hypothesis of a common ground in the development of both micro- and macrovascular complications both in type 2 and type 1 diabetes.
Effects of therapeutic intervention on IMT in diabetes Carotid IMT measurement has been extensively employed as an outcome parameter in several clinical trials. Lifestyle changes favorably influence cIMT progression in patients affected by diabetes. Kim et al. observed a significant reduction of cIMT progression in a small sample of type 2 diabetic patients after 6 months of intensive lifestyle modification [62]. The amelioration of glucose metabolism, as demonstrated by better glycated hemoglobin, as well as fasting and post-prandial glycemic levels could play an important role in IMT regression, as demonstrated by Esposito et al. [63] and Yamasaki et al. [64]. In a Japanese study, metformin therapy was able to attenuate IMT progression of the common carotid artery in type 2 diabetic patients [65]. The most probable primary mechanism of action is attributed to the anti-oxidant effects of this drug. In a comparison between metformin, gliclazide and glibenclamide, the two anti-hypoglycemic agents, rather than glibenclamide were effective in slowing the progression of cIMT [66]. Glitazones have shown important and rapid (months) effects in either reducing the progression or determining regression of IMT in type 2 diabetic patients [67], as in nondiabetic subjects [68]. These agents act by improving endothelial function through anti-inflammatory mechanisms and through positive direct effects on the arterial wall, glucose and lipid metabolism and reducing arterial pressure. The Carotid Intima-Media Thickness in Atherosclerosis Using Pioglitazone (CHICAGO ) trial, which randomized 462 type 2 diabetic patients, demonstrated that, over an 18-month treatment period, pioglitazone slowed the progression of carotid IMT, in comparison with glimepiride [69]. Recently, Davidson et al. have suggested that this action is mediated by an increase of HDL
670
S. Vigili de Kreutzenberg et al.
cholesterol due to this glitazone [70]. Nakamura et al. demonstrated that pioglitazone treatment significantly reduced carotid IMT in type 2 diabetic patients, after 6 and 12 months of treatment compared with glibencalmide or voglibose [71]. The reduction of carotid IMT seems to be independent of glycemic control [72]. Similarly, rosiglitazone significantly reduces IMT progression in type 2 diabetic patients [73]. The magnitude of IMT reduction with glitazones is similar to that obtained with high-dose statin therapy in hypercholesterolemic patients. In the STOP-NIDDM trial, acarbose treatment determined a significant reduction of the progression of IMT versus placebo, with a mean IMT increment of 0.02 mm and 0.05 mm, respectively (P Z 0.027), after an average period of 3.9 years in patients with impaired glucose tolerance [74]. Oyama et al. also found a reduction of cIMT in type 2 diabetic patients treated with sulfonylurea, after its association with acarbose [75]. Table 1 summarizes the main studies on cIMT modifications induced by anti-hyperglycemic therapy. Finally, in type 1 diabetic patients a reduction of cIMT progression has also been documented in those who underwent pancreas transplantation [76].
Summary and conclusions Stroke is one of the facets of cardiovascular disease that represents the first cause of mortality in both type 1
and type 2 diabetic patients. Nevertheless, this complication is poorly recognized as a specific target for primary and secondary prevention in diabetes, and no guidelines dedicated to cerebrovascular disease risk evaluation/diagnosis/treatment exist. Carotid IMT measurement is a relatively simple and cost-effective method for the identification of pre-atherosclerosis in the extra-cranic area. It has been demonstrated that diabetic patients show a significantly higher cIMT than non-diabetic subjects. Carotid IMT progression is due not only to diabetes per se, but also to other metabolic abnormalities that cluster with diabetes, in particular arterial hypertension. Many population-based studies have emphasized the role of cIMT as a marker for ischemic stroke and stroke recurrence. Data obtained in diabetic populations, even if scarce, have confirmed such an association, and cIMT determination should probably become a default examination in the assessment of the CD risk in diabetic patients. A possible link between pre-atherosclerosis, as defined by increased cIMT, and microvascular damage has also been suggested in diabetes, but experimental data are inconclusive. Also, the association with chronic subclinical inflammation seems weak. Finally, further studies are needed in this at risk population, in order to fully define the role of cIMT measurement and, possibly, more diagnostic tests for CD in diabetic subjects should be proposed.
Table 1 Main studies of carotid IMT value (*), progression (þ), or regression () due to anti-hyperglycemic therapy or lifestyle intervention in type 2 diabetic subjects. Author, year (site of IMT measurement)
Drug/intervention (mg/day)
Katakami et al., 2004 [62] (CCA, ICA)
Glibenclamide (1.25e7.5) Gliclazide (20e120) Glibenclamide (1.25e5) þ metformin (500e750) Pioglitazone (30) Glibenclamide (5) Vogliose (0.6) Pioglitazone (45) Glimepride 2.7 1.6 Repaglinide (1,5e12) Glyburide (5e20) With Voglibose (0.4e0.6) Without Voglibose Metformin (500e750) Sulfonylurea/diet Lifestyle Controls Troglitazone (400) Placebo Pioglitazone (15e45) Glimepiride (1e4) Rosiglitazone (4) Metformin (1700) Acarbose (300) Placebo
Nakamura et al., 2004 [67] (CCA)
Langenfeld et al., 2005 [68] (CCA) Esposito et al., 2005 [59] (CCA) Yamasaki et al., 2005 [60] (CCA, ICA) Matsumoto et al., 2004 [61] (CCA) Kim et al., 2006 [58] (CCA) Hodis et al. (subjects with IMT 0.8 mm) 2006 [63] (CCA) Mazzone et al., 2006 [65] (CCA) Stocker et al., 2007 [69] (CCA) Oyama et al., 2008 [71] (CCA)
Subject number 59 30 29 15 15 15 89 84 88 87 51 50 36 56 32 26 97 91 175 186 35 38 41 43
Follow-up period
IMT progression /regression (mm)
3 years
þ0.064 0.045 þ0.032 0.036 þ0.003 0.048
12 months
24 weeks 12 months 3 years 2 years 6 months 2 years 18 months 6 months 12 months
0.68 0.09* 0.78 0.09* 0.77 0.12* 0.054 0.059 0.011 0.058 0.029 0.021 0.005 0.01 0.024 0.047 þ0.056 0.046 þ0.02 0.08 þ0.07 0.08 0.040 0.136 þ0.083 0.167 þ0.0013 mm/year þ0.0084 mm/year 0.001 þ0.012 0.037 0.031 þ0.084 0.038 0.60 0.060 þ11.5 0.038
P
0.05 0.05
0.05 0.05 0.005 0.02 0.0001 0.01 0.007 0.03 0.02 0.02 0.05
When progressive evaluations are performed, the longest follow-up period is considered. ICA, internal carotid artery; CCA, common carotid artery.
Cerebrovascular disease in diabetes: role of carotid IMT
671
Conflict of interest The authors have no conflict of interest
[18]
References [19] [1] Goldstein LB, Adams R, Alberts MJ, Appel LJ, Brass LM, Bushnell CD, et al. Primary Prevention of Ischemic Stroke. Stroke 2006;37:1583e633. [2] http://www.euro.who.int/InformationSources/Data/ 20011017_1 (22 May 2007). [3] Kuusisto J, Mykkanen L, Pyorala K, Laakso M. Non insulin-dependent diabetes and its metabolic control are important predictors of stroke in elderly subjects. Stroke 1994;25: 1157e64. [4] Sundquist K, Li X. Type 1 diabetes as a risk factor for stroke in men and woman aged 15e49: a nationwide study from Sweden. Diabet Med 2006;23:1261e7. [5] Rothwell PM, Giles MF, Flossmann E, Lovelock CE, Redgrave JNE, Warlow CP, et al. A simple score (ABCD) to identify individuals at high early risk of stroke after a transient ischaemic attack. Lancet 2005;366:29e36. [6] Kissela BM, Khoury J, Kleindorfer D, Woo D, Schneider A, Alwell K, et al. Epidemiology of ischemic stroke in patients with diabetes. The greater Cincinnati/Northern Kentucky Stroke Study. Diabetes Care 2005;28:355e9. [7] Davis TM, Millns H, Stratton IM, Holman RR, Turner RC. for the UK Prospective Study Group. Risk factors for stroke in type 2 diabetes mellitus (UKPDS 29). Arch Intern Med 1999;159:1097e103. [8] Femia R, Kozakova M, Nannipieri M, Gonzales-Villalpando C, Stern MP, Haffner SM, et al. Carotid Intima-media thickness in confirmed prehypertensive subjects: predictors and progression. Arterioscler Thromb Vasc Biol 2007;27:2244e9. [9] Li C, Engstro ¨m G, Berglund G, Janzon L, Hedblad B. Incidence of ischemic stroke in relation to asymptomatic carotid artery atherosclerosis in subjects with normal blood pressure. A prospective cohort study. Cerebrovasc Dis 2008;26:297e303. [10] Bonora E, Kiechl S, Willeit J, Oberhollenzer F, Egger G, Bonadonna RC, et al. Carotid atherosclerosis and coronary heart disease in the metabolic syndrome: prospective data from the Bruneck Study. Diabetes Care 2003;26:1251e7. [11] O’Leary DH, Polak JF, Kronmal RA, Manolio TA, Burke GL, Wolfson Jr SK. Carotid-artery intima and media thickness as a risk factor for myocardial infarction and stroke in older adults. Cardiovascular Health Study Collaborative Research Group. N Engl J Med 1999;340:14e22. [12] Chambless LE, Folsom AR, Davis V, Sharrett R, Heiss G, Sorlie P, et al. Risk factors for progression of common carotid atherosclerosis: the Atheroslerosis Risk in Communities Study 1987-1998. Am J Epidemiol 2002;155:38e47. [13] Nagai Y, Metter EJ, Earley CJ, Kemper MK, Becker LC, Lakatta EG, et al. Increased carotid artery intimal-medial thickness in asymptomatic older subject with exerciseinduced myocardial ischemia. Circulation 1998;98:1504e9. [14] Allison MA, Laughlin GA, Barrett-Connor E. Association between the ankleebrachial index and carotid intimal medial thickness in the Rancho Bernardo Study. Am J Cardiol 2006;98:1105e9. [15] Bots ML, Hoes AW, Koudstaal PJ, Hofman A, Grobbee DE. Common carotid intima-media thickness and risk of stroke and myocardial infarction: The Rotterdam Study. Circulation 1997;96:1432e7. [16] Fernandes VRS, Polak JF, Edvardsen T, Carvalho B, Gomes A, Bluemke DA, et al. Subclinical atherosclerosis and incipient regional myocardial dysfunction in asymptomatic individuals. The Multi-Ethnic Study of Atherosclerosis (MESA). J Am Coll Cardiol 2006;47:2420e8. [17] Hunt KJ, Williams K, Rivera D, O’Leary DH, Haffner SM, Stern MP, et al. Elevated carotid artery intima-media
[20]
[21]
[22]
[23]
[24]
[25]
[26]
[27]
[28]
[29]
[30]
[31]
[32]
[33]
thickness levels in individuals who subsequently develop type 2 diabetes. Arterioscler Thromb Vasc Biol 2003;23:1845e50. Temelkova-Kurktschiev TS, Koehler C, Leonhardt W, Schaper F, Henkel E, Siegert G, et al. Increased intimal-medial thickness in newly detected type 2 diabetes: risk factors. Diabetes Care 1999;22:333e8. Lange LA, Bowden DW, Langefeld CD, Wagenknechnect LE, Carr JJ, Rich SS, et al. Heritability of carotid artery intimamedial thickness in type 2 diabetes. Stroke 2002;33:1876e81. Niskanen L, Rauramaa R, Miettinen H, Haffner SM, Mercuri M, Uusitupa M. Carotid artery intima-media thickness in elderly patients with NIDDM and in nondiabetic subjects. Stroke 1996; 27:1986e92. Wagenknecht L, DE’Agostino R, Haffner S, Savage PJ, Rewers M. Impaired glucose tolerance, type 2 diabetes, and carotid wall thickness. Diabetes Care 1998;21:1812e8. Brohall G, Ode ´n A, Fagerberg B. Carotid artery intima-media thickness in patients with type 2 diabetes mellitus and impaired glucose tolerance: a systemic review. Diabet Med 2006;23:609e16. Lee CD, Folsom AR, Pankow JS, Brancati FL. for the Atherosclerosis Risk in Communities (ARIC) Study Investigators. Cardiovascular events in diabetic and nondiabetic adults with or without history of myocardial infarction. Circulation 2004;109:855e60. Haffner SM, D’Agostino RA, Saad MF, O’Leary DH, Savage PJ, Rewers M, et al. Carotid artery atherosclerosis in type-2 diabetic and nondiabetic subjects with and without symptomatic coronary artery disease (The Insulin Resistance Atherosclerosis Study). Am J Cardiol 2000;85:1395e400. Bernard S, Serusclat A, Targe F, Charriere S, Roth O, Beaune UJ, et al. Incremental predictive value of carotid ultrasonography in the assessment of coronary risk in a cohort of asymptomatic type 2 diabetic subjects. Diabetes Care 2005;28:1158e62. van der Meer IM, Iglesias del Sol A, Hak AE, Bots ML, Hofman A, Witteman JC. Risk factors for progression of atherosclerosis measured at multiple sites in the arterial tree: the Rotterdam Study. Stroke 2003;34:2374e9. Bonora E, Tessari R, Micciolo R, Zenere M, Targher G, Padovani R, et al. Intimal-medial thickness of the carotid artery in nondiabetic and NIDDM patients. Relationship with insulin resistance. Diabetes Care 1997;20:627e31. Lee EJ, Kim HJ, Bae JM, Kim JC, Han HJ, Park CS, et al. Relevance of common carotid intima-media thickness and carotid plaque as risk factors for ischemic stroke in patients with type 2 diabetes mellitus. Am J Neuroradiol 2007;28:916e9. Matsumoto K, Sera Y, Nakamura H, Ueki Y, Miyake S. Correlation between common carotid arterial wall thickness and ischemic stroke in patients with type 2 diabetes mellitus. Metabolism 2002;51:244e7. Nathan DM, Lachin J, Cleary P, Orchard T, Brillon DJ, Backlund JY, et al. Diabetes Control and Complication Trial; Epidemiology of Diabetes Interventions and Complications Research Group. Intensive diabetes therapy and carotid intima-media thickness in type 1 diabetes mellitus. N Engl J Med 2003;348:2294e303. Jensen-Urstad KJ, Reichard PG, Rosfors JJS, Lindblad LEL, Jensen-Urstad MT. Early atherosclerosis is retarded by improved long-term blood glucose control in patients with IDDM. Diabetes 1996;454:1253e8. Larsen JR, Brekke M, Bergengen L, Sandvik L, Arnesen H, Hanssen KF, et al. Mean HbA1c over 18 years predicts carotid intima media thickness in women with type 1 diabetes. Diabetologia 2005;48:776e9. Distiller LA, Joffe BI, Melville V, Welman T, Distiller GB. Carotid artery intima-media complex thickening in patients with long-surviving type 1 diabetes mellitus. J Diabetes Complications 2006;20:280e4.
672 [34] Epidemiology of Diabetes Interventions and Complications (EDIC) Research Group. Effect of intensive diabetes treatment on carotid artery wall thickness in the epidemiology of diabetes interventions and complications. Diabetes 1999;48:383e90. [35] Lopes-Virella MF, McHenry MB, Lipsitz S, Yim E, Wilson PF, Lackland DT, et al. The DCCT/EDIC Research Group. Immune complexes containing modified lipoproteins are related to the progression of internal carotid intima-media thickness in patients with type 1 diabetes. Atherosclerosis 2007;190: 359e69. [36] Lopes-Virella MF, Carter RE, Gilbert GE, Klein RL, Jaffa M, Jenkins AJ, et al. Risk Factors related to inflammation and endothelial dysfunction in the DCCT/EDIC cohort and their relationship with nephropathy and macrovascular complications. Diabetes Care 2008;31:2006e12. [37] Jarvisalo MJ, Raitakari M, Toikka JO, Putto-Laurila A, Riikka R, Laine S, et al. Endothelial dysfunction and increased arterial intima-media thickness in children with type 1 diabetes. Circulation 2004;109:1750e5. [38] Singh TP, Groehn H, Kazmers A. Vascular function and carotid intimal-medial thickness in children with insulin-dependent diabetes mellitus. J Am Coll Cardiol 2003;41:661e5. [39] Dalla Pozza R, Bechtold S, Bonfig W, Putzker S, KozlikFeldmann R, Netz H, et al. Age of onset of type 1 diabetes in children and carotid intima medial thickness. J Clin Endocrinol Metab 2007;92:2053e7. [40] Lorenz MW, Karbstein P, Markus HS, Sitzer M. High-sensitivity C-reactive protein is not associated with carotid intima-media progression: the carotid atherosclerosis progression study. Stroke 2007;38:1774e9. [41] Sander D, Schulze-Horn C, Bickel H, Gnahn H, Bartels E, Conrad B. Combined effects of hemoglobin A1c and C-reactive protein on the progression of subclinical carotid atherosclerosis: the INVADE study. Stroke 2006;37:351e7. [42] Bowden DW, Lange LA, Langefeld CD, Brosnihan KB, Freedman BI, Carr JJ, et al. The relationship between Creactive protein and subclinical cardiovascular disease in the Diabetes Heart Study (DHS). Am Heart J 2005;150:1032e8. [43] Mita T, Watada H, Uchino H, Shimizu T, Hirose T, Tanaka Y, et al. Association of C-reactive protein with early-stage carotid atherosclerosis in Japanese patients with early-state type 2 diabetes mellitus. Endocr J 2006;53:693e8. [44] Mangge H, Schauenstein K, Stroedter L, Griesl A, Maerz W, Borkenstein M. Low grade inflammation in juvenile obesity and type 1 diabetes associated with early signs of atherosclerosis. Exp Clin Endocrinol Diabetes 2004;112:378e82. [45] Matsumoto K, Sera Y, Ueki Y, Inukai G, Niiro E, Miyake S. Comparison of serum concentrations of soluble adhesion molecules in diabetic microangiopathy and macroangiopathy. Diabet Med 2002;19:822e6. [46] Aso Y, Okumura K, Takebayashi K, Wakabayashi K, Inukai T. Relationship of plasma interleukin-18 concentrations to hyperhomocysteinemia and carotid intimal-medial wall thickness in patients with type 2 diabetes. Diabetes Care 2003;26:2622e7. [47] Rohde LE, Lee RT, Rivero J, Jamacochian M, Arroyo LH, Briggs W, et al. Circulating cell adhesion molecules are correlated with ultrasound-based assessment of carotid atherosclerosis. Arterioscler Thromb Vasc Biol 1998;18:1765e70. [48] Simons PC, Algra A, Bots ML, Grobbee DE, van der Graf Y. Common carotid intima media thickness and arterial stiffness: indicators of cardiovascular risk in high risk patients. The SMART Study (Second Manifestations of ARTerial disease). Circulation 1999;100:951e7. [49] Ravikumar R, Deepa R, Shanthirani CS, Mohan V. Comparison of carotid intima-media thickness, arterial stiffness, and brachial artery flow mediated dilatation in diabetic and nondiabetic subjects (The Chennai Urban Population Study[CUPS-9]). Am J Cardiol 2002;90:702e7.
S. Vigili de Kreutzenberg et al. [50] Klein R, Sharrett AR, Klein BE, Moss SE, Folsom AR, Wong TY, et al. The association of atherosclerosis, vascular risk factors, and retinopathy in adults with diabetes: the atherosclerosis risk in communities study. Ophthalmology 2002;109:1225e34. [51] Rema M, Mohan V, Deepa R, Ravikumar R. Chennai Urban Rural Epidemiology Study-2. Association of carotid intima-media thickness and arterial stiffness with diabetic retinopathy: the Chennai Urban Rural Epidemiology Study (CURES-2). Diabetes Care 2004;27:1962e7. [52] Klein R, Marino EK, Kuller LH, Polak JF, Tracy RP, Gottdiener JS, et al. The relation of atherosclerotic cardiovascular disease to retinopathy in people with diabetes in the Cardiovascular Health Study. Br J Ophthalmol 2002;86:84e90. [53] van Hecke MV, Dekker JM, Nijpels G, Stolk RP, Henry RM, Heine RJ, et al. Are retinal microvascular abnormalities associated with large artery endothelial dysfunction and intimamedia thickness? The Hoorn Study. Clin Sci 2006;110:597e604. [54] Mykkanen L, Zaccaro DJ, O’Leary DH, Howard G, Robbins DC, Haffner SM. Microalbuminuria and carotid artery intima-media thickness in nondiabetic and NIDDM subjects. The Insulin Resistance Atherosclerosis Study (IRAS). Stroke 1997;28:1710e6. [55] Kramer H, Jacobs DR, Bild D, Post W, Saad MF, Detrano R, et al. Urine albumin excretion and subclinical cardiovascular disease. The Multi-Ethnic Study of Atherosclerosis. Hypertension 2005;46:38e43. [56] Keech AC, Grieve SM, Patel A, Griffiths K, Skilton M, Watts GF, et al. Urinary albumin levels in the normal range determine arterial wall thickness in adults with Type 2 diabetes: a FIELD substudy. Diabet Med 2005;22:1558e65. [57] Pruissen DM, Gerritsen SA, Prinsen TJ, Dijk JM, Kappelle LJ, Algra A, et al. Carotid intima-media thickness is different in large- and small-vessel ischemic stroke: the SMART study. Stroke 2007;38:1371e3. [58] Cupini LM, Pasqualetti P, Diomedi M, Vernieri F, Silvestrini M, Rizzato B, et al. Carotid artery intima-media thickness and lacunar versus nonlacunar infarcts. Stroke 2002;33:689e94. [59] Touboul PJ, Elbaz A, Koller C, Lucas C, Adraı¨ V, Che ´dru F, et al. Common carotid artery intima-media thickness and brain infarction: the Etude du Profil Genetique de l’Infarctus Cerebral (GENIC) casecontrol study. The GENIC Investigators. Circulation 2000;102:313e8. [60] Nagai Y, Kitagawa K, Yamagami H, Kondo K, Hougaku H, Hori M, et al. Carotid artery intima-media thickness and plaque score for the risk assessment of stroke subtypes. Ultrasound Med Biol 2002;28:1239e43. [61] Frost D, Beischer W. Determinants of carotid artery wall thickening in young patients with Type 1 diabetes mellitus. Diabet Med 1998;15:851e7. [62] Kim SH, Lee SJ, Kang ES, Kang S, Hur KY, Lee HJ, et al. Effects of lifestyle modification on metabolic parameters and carotid intima-media thickness in patients with type 2 diabetes mellitus. Metabolism 2006;55:1053e9. [63] Esposito K, Giugliano D, Nappo F, Marfella R. Regression of carotid atherosclerosis by control of postprandial hyperglycemia in type 2 diabetes mellitus. Circulation 2004;110:214e9. [64] Yamasaki Y, Katakami N, Hayaishi-Okano R, Matsuhisa M, Kajimoto Y, Kosugi K, et al. alpha-Glucosidase inhibitor reduces the progression of carotid intima-media thickness. Diabetes Res Clin Pract 2005;67:204e10. [65] Matsumoto K, Sera Y, Abe Y, Tominaga T, Yeki Y, Miyake S. Metformin attenuates progression of carotid arterial wall thickness in patients with type 2 diabetes. Diabetes Res Clin Pract 2004;64:225e8. [66] Katakami N, Yamasaki Y, Hayaishi-Okano R, Ohtoshi K, Kaneto H, Matsuhisa M, et al. Metformin or gliclazide, rather than glibenclamide, attenuate progression of carotid intimamedia thickness in subjects with type 2 diabetes. Diabetologia 2004;47:1906e13.
Cerebrovascular disease in diabetes: role of carotid IMT [67] Hodis HN, Mack WJ, Zheng L, Li Y, Torres M, Sevilla D, et al. Effect of peroxisome proliferator-activated receptor gamma agonist treatment on subclinical atherosclerosis in patients with insulinrequiring type 2 diabetes. Diabetes Care 2006;29:1545e53. [68] Sidhu JS, Kaposzta Z, Markus HS, Kaski JC. Effect of rosiglitazone on common carotid intima-media thickness progression in coronary artery disease patients without diabetes mellitus. Arterioscler Thromb Vasc Biol 2004;24:930e4. [69] Mazzone T, Meyer PM, Feinstein SB, Davidson MH, Kondos GT, D’Agostino RB, et al. Effect of pioglitazone compared with glimepiride on carotid intima-media thickness in type 2 diabetes: a randomized trial. JAMA 2006;296:2572e81. [70] Davidson M, Meyer PM, Haffner S, Feinstein S, D’Agostino R, Kondos GT, et al. Increased high-density lipoprotein cholesterol predicts the pioglitazone mediated reduction of carotid intima-media thickness progression in patients with type 2 diabetes mellitus. Circulation 2008;117:2123e30. [71] Nakamura T, Matsuda T, Kawagoe Y, Ogawa H, Takahashi Y, Sekizuka K, et al. Effect of pioglitazone on carotid intimamedia thickness and arterial stiffness in type 2 diabetic nephropathy patients. Metabolism 2004;53:1382e6.
673 [72] Langenfeld MR, Forst T, Hohberg C, Kann P, Lubben G, Konrad T, et al. Pioglitazone decreases carotid intima-media thickness independently of glycemic control in patients with type 2 diabetes mellitus: results from a controlled randomized study. Circulation 2005;111:2525e31. [73] Stocker DJ, Taylor AJ, Langley RW, Jezior MR, Vigersky RA. A randomized trial of the effects of rosiglitazone and metformin on inflammation and subclinical atherosclerosis in patients with type 2 diabetes. Am Heart J 2007;153:445. e1-6. [74] Hanefeld M, Chiasson JL, Koehler C, Henkel E, Schaper F, Temelkova-Kurktschiev T. Acarbose slows progression of intima-media thickness of the carotid arteries in subjects with impaired glucose tolerance. Stroke 2004;35:1073e8. [75] Oyama T, Saiki A, Endoh K, Ban N, Nagayama D, Ohhira M, et al. Effect of acarbose, an alpha-glucosidase inhibitor, on serum lipoprotein lipase mass levels and common carotid artery intima-media thickness in type 2 diabetes mellitus treated by sulfonylurea. J Atheroscler Thromb 2008;15:154e9. [76] Larsen JL, Ratansuwan T, Burkman T, Lynch T, Erickson J, Colling C, et al. Carotid intima media thickness decreases after pancreas transplantation. Transplantation 2002;73:936e40.
available at www.sciencedirect.com
journal homepage: www.elsevier.com/locate/nmcd
REVIEW
Cerebrovascular disease in diabetes mellitus: The role of carotid intima-media thickness S. Vigili de Kreutzenberg*, A. Tiengo, A. Avogaro Department of Clinical and Experimental Medicine, University of Padova, Via Giustiniani, 2, 35128 Padova, Italy Received 6 October 2008; received in revised form 14 January 2009; accepted 17 March 2009
KEYWORDS Carotid intima-media thickness; Diabetes mellitus; Cerebrovascular disease
Abstract Background and purpose: Cerebrovascular disease in diabetes appears to be less considered than coronary and peripheral disease, the reason being the intrinsic difficulty in finding available diagnostic tools for its early identification. Among these, carotid artery intima-media thickness (cIMT) represents the simplest measurable parameter for preatherosclerotic lesions in extra-cranic arteries. Methods: The role of cIMT as a surrogate marker of cerebral atherosclerosis and predictor of stroke, its relationship to microangiopathy and chronic inflammation, along with its role as an outcome parameter in anti-hyperglycemic therapeutical intervention trials in type 2 and 1 diabetes mellitus are discussed in this paper. Results and conclusions: Carotid IMT is increased in diabetes. It is an independent predictor of stroke, in particular of the ischemic subtype, and of stroke recurrence in diabetic, as well as in non-diabetic populations. A possible role of cIMT as a predictor of microangiopathy has also been suggested, but it needs further investigation. A weak association with chronic inflammation has been demonstrated in diabetic patients. Carotid IMT has been successfully employed as an outcome parameter for several anti-hyperglycemic therapeutic trials. However data on cIMT as a predictor of cerebrovascular disease are scarce in diabetic patients, particularly in type 1 diabetes, and more studies are needed to define the risk of cerebrovascular disease in diabetic patients. ª 2009 Elsevier B.V. All rights reserved.
Introduction
* Corresponding author. Tel.: þ39 049 821 2183; fax: þ39 049 875 4179. E-mail address: [email protected] (S. Vigili de Kreutzenberg).
Stroke remains the third cause of death in western countries [1], resulting in more than 160 000 deaths annually in the United States, and approximately 650 000 in Europe [2]. Type 1 and 2 diabetes are independent risk factors for stroke and its recurrence [3e5]. Thus, identifying diabetic
0939-4753/$ - see front matter ª 2009 Elsevier B.V. All rights reserved. doi:10.1016/j.numecd.2009.03.014
668 patients who are at high risk of developing stroke is of great clinical importance. The average risk of stroke in diabetic subjects compared to non-diabetic, ranges from 1.8- to nearly 6-fold, according to epidemiological studies [6]. In insulin treated diabetes, the relative risk for stroke mortality has been reported as 3.1 in men and 4.4 in women. The presence of other risk factors, which often cluster with diabetes, can further increase the risk. Among these, high blood pressure is a major independent predictor for stroke in diabetes [7], while cholesterol levels are not associated with the risk of stroke, as in the non-diabetic population. Arterial hypertension directly contributes to arterial wall alterations with one of the first being intimal-medial thickening [8]. Thickness of the arterial wall is an independent predictor of stroke in normotensive subjects [9]. The metabolic/insulin resistance syndrome is a well-documented predictor of cardiovascular disease (CVD) and stroke [10], as well as of diabetes.
Carotid intima-media thickness in type 2 diabetes Carotid IMT is a surrogate marker of subclinical atherosclerosis and a strong predictor of future cardiovascular events [11,12], asymptomatic myocardial ischemia [13], peripheral vascular disease [14], ischemic stroke [15] and cardiac dysfunction [16]. Hunt et al. [17] demonstrated that IMT of the internal carotid artery is significantly elevated in subjects who will subsequently develop diabetes. In newly diagnosed type 2 diabetic subjects, cIMT is significantly greater compared to normal glucose tolerant matched controls [18]. A weak relationship between genetic variants and carotid atherosclerosis has also been demonstrated [19]. The mean common carotid IMT is reported to range from 0.71 to 0.91 mm in diabetic patients who are middle-aged and without coronary artery disease (CAD), and from 0.66 to 0.74 mm in comparable control subjects [20]. An increase of IMT in type 2 diabetes, and to a lesser extent in impaired glucose tolerance, has been widely documented [20,21]. In a recent review, Brohall et al. [22] analyzed the mean cIMT value reported for type 2 diabetes and found that it was 0.13 mm thicker, compared to non-diabetic subjects. Lee et al. [23] and Haffner et al. [24] established that this increase was higher in diabetic subjects with overt macroangiopathic complications. In diabetic patients, the predictive value of cIMT for coronary events has been demonstrated to be similar and additive to that of the Framingham risk score [25]. This observation was not confirmed by the Rotterdam Study that did not find an incremental value of IMT in the prediction of CVD risk [26]. As well as hyperglycemia, metabolic abnormalities that cluster with diabetes and represent single risk factors for atherosclerosis, for example, insulin resistance, arterial hypertension, central obesity, and dyslipidemia contribute to the progression of cIMT in diabetes [7,9,27]. However, it is difficult to dissect the role of specific components of metabolic abnormalities in cIMT progression. Among these, the most important seems to be arterial hypertension, which, per se, determines functional and anatomical changes of arterial walls [9].
S. Vigili de Kreutzenberg et al. The specific role of cIMT as a predictor of stroke and stroke recurrence has been widely demonstrated in the general population [9,11,15]. Unfortunately, studies devoted to assessing diabetic subjects alone are scarce. Recently, Lee et al. found that an increased cIMT is associated with acute ischemic stroke in type 2 diabetes [28]. In a Japanese study, Matsumoto et al. [29] also observed this significant association in 438 type 2 diabetic patients.
Carotid intima-media thickness in type 1 diabetes As in adults with type 2 diabetes, cIMT is significantly increased in adult type 1 diabetic patients [30], suggesting a precocious development of atherosclerosis in this disease. The Epidemiology of Diabetes Intervention and Complications (EDIC) Study evaluated cIMT progression in type 1 diabetic subjects and found the IMT of the internal carotid artery significantly increased in both sexes, compared to matched non-diabetic controls, at year 6 of follow-up. The mean progression was significantly less in the group that had received intensive therapy. Therefore, hyperglycemia seems to influence atherosclerosis development in the long run, and the positive effect of intensive therapy efficiently reduces cIMT progression [30]. The Stockholm Diabetes Intervention Study also provided evidence of the favorable influence of glucose intensive treatment on carotid IMT and stiffening in a total of 59 type 1 diabetic patients [31]. In a small cohort of type 1 diabetic subjects (23 men; 16 women) a significant link between mean glycated hemoglobin and cIMT was found in women, but not in men, in an 18 year follow-up study [32]. In another cross-sectional study, major factors influencing common carotid artery cIMT in 148 type 1 diabetic patients were age, diabetes duration and hypertension while long-standing glycemic control played a minor role. Few other studies have evaluated the association of IMT and classical risk factors for atherosclerosis in type 1 diabetic patients [33]. The DCCT/EDIC trial [34] suggested that age, height, smoking and BMI were the most important predictors of common carotid IMT by multivariate analysis, whereas age, smoking and LDL cholesterol were the most important predictors of internal carotid IMT. This study also demonstrated that increased levels of modified ApoB-rich immune complexes are associated with an increased progression of internal carotid IMT [35]. A recent analysis of a patient subgroup of the DCCT/EDIC study demonstrated that among CRP, fibrinogen, soluble VCAM-1, ICAM-1, E-selectin and fibrinolytic markers, fibrinogen was the best predictor for progression of cIMT [36]. For type 1 diabetic children, only conflicting results are available, some confirming [37], and others denying [38] an increased cIMT in this population. The reason for this discrepancy could be the small number of patients included in the studies, and the lack of a well standardized method for cIMT measurement; further studies are therefore needed to answer this question. In type 1 diabetic children an increased IMT was associated with peripheral endothelial dysfunction [38], age of onset of diabetes, insulin dose requirement, systolic blood pressure and total cholesterol
Cerebrovascular disease in diabetes: role of carotid IMT levels [39]. In type 1 diabetes, no data are available on cIMT as a predictor of cerebrovascular disease (CD).
IMT, inflammation and microangiopathy The association between pre-atherosclerosis, as measured by cIMT, and a low-grade inflammation shows conflicting results. The prospective Carotid Atherosclerosis Progression Study demonstrated a highly significant association between IMT and hs-CRP, in a total of 3122 subjects (2.5% were diabetic); however, this association disappeared after controlling for other cardiovascular risk factors [40]. The data analysis of the Intervention Project on Cerebrovascular Diseases and Dementia in the Community of Ebersberg, Bavaria (INVADE), a prospective, population-based study enrolling 3534 subjects (mean age 69 years), of which 882 were diabetic, showed that cIMT progression was not significantly related to hsCRP (P Z 0.06), after adjustment for risk factors [41]. Similarly, studies carried out in smaller cohorts of type 2 diabetic patients failed to find such an association [42] or found it, but only by applying linear regression analysis [43]. On the other hand, CRP appeared to be significantly related to cIMT in small cohorts of type 1 diabetic subjects [44], suggesting that lowgrade inflammation could be a more important risk factor in young patients with type 1 diabetes. Serum concentrations of ICAM-1, VCAM-1, and E-selectin have been demonstrated to strongly predict microangiopathy, but to have a lesser value in macroangiopathy prediction when this is accompanied by an increased cIMT (>1.1 mm) [45]. Interleukin 18 showed an association with cIMT in type 2 diabetes [46]. A positive association between cell adhesion molecules and IMT was also present in a general population sample, of which 18% were diabetic subjects [47]. These data suggest a weak association between chronic inflammation and pre-atherosclerosis. A significant correlation between cIMT and functional changes of the arterial wall, such as arterial stiffness and brachial artery flow-mediated vasodilatation, was observed in type 2 diabetic patients in the SMART study [48] and in the Chennai Urban Population Study [49], underlying the link between endothelial dysfunction and atherogenesis. A common pathogenesis for both micro- and macrovascular complications of diabetes has been suggested. However this issue remains controversial and is still under debate. A significant association between retinal microangiopathy and IMT was found in the diabetic population of the Atherosclerosis Risk in Communities Study [50] and in that of the Chennai Urban Rural Epidemiology Study [51] and was independent of age, diabetes duration and glycemic control. Different conclusions were drawn in the Cardiovascular Health Study (CHS), in which no association between early atherosclerosis and diabetic retinopathy was found. However, in CHS, only a small number of patients was affected by retinopathy (n Z 80) and the age of these subjects was quite elevated (>69 years) [52], invalidating these conclusions. The same results were obtained in a subgroup of 256 participants of the Hoorn Study [53], of which 42% were diabetic; this study does not uphold the hypothesis that subclinical atherosclerosis is associated with retinal microangiopathy. Instead, a significant association has been extensively demonstrated between
669 microalbuminuria and cIMT in type 2 diabetic subjects in IRAS [54], in the Multi Ethnic Study of Atherosclerosis [55] and in other studies. Furthermore, in a subgroup of the Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) study, this association was demonstrated even for microalbuminuria levels still in the normal range [56]. A recent analysis of the SMART study suggested a different pathogenesis between small- and large-vessel disease [57]. In this study, common carotid artery (CCA) IMT was higher in patients with large-vessel disease (1.08 vs 0.92 mm), and the difference remained significant after adjustment for age, sex and hypertension (0.11 mm; 95% CI, 0.05e0.18). Similar results were obtained by Cupini et al. [58]. On the other hand, the GENIC Investigators and others researchers did not find any difference in CCA IMT between patients with large- or small-vessel disease [59,60]. Finally, no conclusive remarks about a common pathogenesis for micro- and macroangiopathy can yet be made. In type 1 diabetes, endothelial dysfunction [37] and nephropathy [61] are associated with cIMT. Altogether, these data strongly support the hypothesis of a common ground in the development of both micro- and macrovascular complications both in type 2 and type 1 diabetes.
Effects of therapeutic intervention on IMT in diabetes Carotid IMT measurement has been extensively employed as an outcome parameter in several clinical trials. Lifestyle changes favorably influence cIMT progression in patients affected by diabetes. Kim et al. observed a significant reduction of cIMT progression in a small sample of type 2 diabetic patients after 6 months of intensive lifestyle modification [62]. The amelioration of glucose metabolism, as demonstrated by better glycated hemoglobin, as well as fasting and post-prandial glycemic levels could play an important role in IMT regression, as demonstrated by Esposito et al. [63] and Yamasaki et al. [64]. In a Japanese study, metformin therapy was able to attenuate IMT progression of the common carotid artery in type 2 diabetic patients [65]. The most probable primary mechanism of action is attributed to the anti-oxidant effects of this drug. In a comparison between metformin, gliclazide and glibenclamide, the two anti-hypoglycemic agents, rather than glibenclamide were effective in slowing the progression of cIMT [66]. Glitazones have shown important and rapid (months) effects in either reducing the progression or determining regression of IMT in type 2 diabetic patients [67], as in nondiabetic subjects [68]. These agents act by improving endothelial function through anti-inflammatory mechanisms and through positive direct effects on the arterial wall, glucose and lipid metabolism and reducing arterial pressure. The Carotid Intima-Media Thickness in Atherosclerosis Using Pioglitazone (CHICAGO ) trial, which randomized 462 type 2 diabetic patients, demonstrated that, over an 18-month treatment period, pioglitazone slowed the progression of carotid IMT, in comparison with glimepiride [69]. Recently, Davidson et al. have suggested that this action is mediated by an increase of HDL
670
S. Vigili de Kreutzenberg et al.
cholesterol due to this glitazone [70]. Nakamura et al. demonstrated that pioglitazone treatment significantly reduced carotid IMT in type 2 diabetic patients, after 6 and 12 months of treatment compared with glibencalmide or voglibose [71]. The reduction of carotid IMT seems to be independent of glycemic control [72]. Similarly, rosiglitazone significantly reduces IMT progression in type 2 diabetic patients [73]. The magnitude of IMT reduction with glitazones is similar to that obtained with high-dose statin therapy in hypercholesterolemic patients. In the STOP-NIDDM trial, acarbose treatment determined a significant reduction of the progression of IMT versus placebo, with a mean IMT increment of 0.02 mm and 0.05 mm, respectively (P Z 0.027), after an average period of 3.9 years in patients with impaired glucose tolerance [74]. Oyama et al. also found a reduction of cIMT in type 2 diabetic patients treated with sulfonylurea, after its association with acarbose [75]. Table 1 summarizes the main studies on cIMT modifications induced by anti-hyperglycemic therapy. Finally, in type 1 diabetic patients a reduction of cIMT progression has also been documented in those who underwent pancreas transplantation [76].
Summary and conclusions Stroke is one of the facets of cardiovascular disease that represents the first cause of mortality in both type 1
and type 2 diabetic patients. Nevertheless, this complication is poorly recognized as a specific target for primary and secondary prevention in diabetes, and no guidelines dedicated to cerebrovascular disease risk evaluation/diagnosis/treatment exist. Carotid IMT measurement is a relatively simple and cost-effective method for the identification of pre-atherosclerosis in the extra-cranic area. It has been demonstrated that diabetic patients show a significantly higher cIMT than non-diabetic subjects. Carotid IMT progression is due not only to diabetes per se, but also to other metabolic abnormalities that cluster with diabetes, in particular arterial hypertension. Many population-based studies have emphasized the role of cIMT as a marker for ischemic stroke and stroke recurrence. Data obtained in diabetic populations, even if scarce, have confirmed such an association, and cIMT determination should probably become a default examination in the assessment of the CD risk in diabetic patients. A possible link between pre-atherosclerosis, as defined by increased cIMT, and microvascular damage has also been suggested in diabetes, but experimental data are inconclusive. Also, the association with chronic subclinical inflammation seems weak. Finally, further studies are needed in this at risk population, in order to fully define the role of cIMT measurement and, possibly, more diagnostic tests for CD in diabetic subjects should be proposed.
Table 1 Main studies of carotid IMT value (*), progression (þ), or regression () due to anti-hyperglycemic therapy or lifestyle intervention in type 2 diabetic subjects. Author, year (site of IMT measurement)
Drug/intervention (mg/day)
Katakami et al., 2004 [62] (CCA, ICA)
Glibenclamide (1.25e7.5) Gliclazide (20e120) Glibenclamide (1.25e5) þ metformin (500e750) Pioglitazone (30) Glibenclamide (5) Vogliose (0.6) Pioglitazone (45) Glimepride 2.7 1.6 Repaglinide (1,5e12) Glyburide (5e20) With Voglibose (0.4e0.6) Without Voglibose Metformin (500e750) Sulfonylurea/diet Lifestyle Controls Troglitazone (400) Placebo Pioglitazone (15e45) Glimepiride (1e4) Rosiglitazone (4) Metformin (1700) Acarbose (300) Placebo
Nakamura et al., 2004 [67] (CCA)
Langenfeld et al., 2005 [68] (CCA) Esposito et al., 2005 [59] (CCA) Yamasaki et al., 2005 [60] (CCA, ICA) Matsumoto et al., 2004 [61] (CCA) Kim et al., 2006 [58] (CCA) Hodis et al. (subjects with IMT 0.8 mm) 2006 [63] (CCA) Mazzone et al., 2006 [65] (CCA) Stocker et al., 2007 [69] (CCA) Oyama et al., 2008 [71] (CCA)
Subject number 59 30 29 15 15 15 89 84 88 87 51 50 36 56 32 26 97 91 175 186 35 38 41 43
Follow-up period
IMT progression /regression (mm)
3 years
þ0.064 0.045 þ0.032 0.036 þ0.003 0.048
12 months
24 weeks 12 months 3 years 2 years 6 months 2 years 18 months 6 months 12 months
0.68 0.09* 0.78 0.09* 0.77 0.12* 0.054 0.059 0.011 0.058 0.029 0.021 0.005 0.01 0.024 0.047 þ0.056 0.046 þ0.02 0.08 þ0.07 0.08 0.040 0.136 þ0.083 0.167 þ0.0013 mm/year þ0.0084 mm/year 0.001 þ0.012 0.037 0.031 þ0.084 0.038 0.60 0.060 þ11.5 0.038
P
0.05 0.05
0.05 0.05 0.005 0.02 0.0001 0.01 0.007 0.03 0.02 0.02 0.05
When progressive evaluations are performed, the longest follow-up period is considered. ICA, internal carotid artery; CCA, common carotid artery.
Cerebrovascular disease in diabetes: role of carotid IMT
671
Conflict of interest The authors have no conflict of interest
[18]
References [19] [1] Goldstein LB, Adams R, Alberts MJ, Appel LJ, Brass LM, Bushnell CD, et al. Primary Prevention of Ischemic Stroke. Stroke 2006;37:1583e633. [2] http://www.euro.who.int/InformationSources/Data/ 20011017_1 (22 May 2007). [3] Kuusisto J, Mykkanen L, Pyorala K, Laakso M. Non insulin-dependent diabetes and its metabolic control are important predictors of stroke in elderly subjects. Stroke 1994;25: 1157e64. [4] Sundquist K, Li X. Type 1 diabetes as a risk factor for stroke in men and woman aged 15e49: a nationwide study from Sweden. Diabet Med 2006;23:1261e7. [5] Rothwell PM, Giles MF, Flossmann E, Lovelock CE, Redgrave JNE, Warlow CP, et al. A simple score (ABCD) to identify individuals at high early risk of stroke after a transient ischaemic attack. Lancet 2005;366:29e36. [6] Kissela BM, Khoury J, Kleindorfer D, Woo D, Schneider A, Alwell K, et al. Epidemiology of ischemic stroke in patients with diabetes. The greater Cincinnati/Northern Kentucky Stroke Study. Diabetes Care 2005;28:355e9. [7] Davis TM, Millns H, Stratton IM, Holman RR, Turner RC. for the UK Prospective Study Group. Risk factors for stroke in type 2 diabetes mellitus (UKPDS 29). Arch Intern Med 1999;159:1097e103. [8] Femia R, Kozakova M, Nannipieri M, Gonzales-Villalpando C, Stern MP, Haffner SM, et al. Carotid Intima-media thickness in confirmed prehypertensive subjects: predictors and progression. Arterioscler Thromb Vasc Biol 2007;27:2244e9. [9] Li C, Engstro ¨m G, Berglund G, Janzon L, Hedblad B. Incidence of ischemic stroke in relation to asymptomatic carotid artery atherosclerosis in subjects with normal blood pressure. A prospective cohort study. Cerebrovasc Dis 2008;26:297e303. [10] Bonora E, Kiechl S, Willeit J, Oberhollenzer F, Egger G, Bonadonna RC, et al. Carotid atherosclerosis and coronary heart disease in the metabolic syndrome: prospective data from the Bruneck Study. Diabetes Care 2003;26:1251e7. [11] O’Leary DH, Polak JF, Kronmal RA, Manolio TA, Burke GL, Wolfson Jr SK. Carotid-artery intima and media thickness as a risk factor for myocardial infarction and stroke in older adults. Cardiovascular Health Study Collaborative Research Group. N Engl J Med 1999;340:14e22. [12] Chambless LE, Folsom AR, Davis V, Sharrett R, Heiss G, Sorlie P, et al. Risk factors for progression of common carotid atherosclerosis: the Atheroslerosis Risk in Communities Study 1987-1998. Am J Epidemiol 2002;155:38e47. [13] Nagai Y, Metter EJ, Earley CJ, Kemper MK, Becker LC, Lakatta EG, et al. Increased carotid artery intimal-medial thickness in asymptomatic older subject with exerciseinduced myocardial ischemia. Circulation 1998;98:1504e9. [14] Allison MA, Laughlin GA, Barrett-Connor E. Association between the ankleebrachial index and carotid intimal medial thickness in the Rancho Bernardo Study. Am J Cardiol 2006;98:1105e9. [15] Bots ML, Hoes AW, Koudstaal PJ, Hofman A, Grobbee DE. Common carotid intima-media thickness and risk of stroke and myocardial infarction: The Rotterdam Study. Circulation 1997;96:1432e7. [16] Fernandes VRS, Polak JF, Edvardsen T, Carvalho B, Gomes A, Bluemke DA, et al. Subclinical atherosclerosis and incipient regional myocardial dysfunction in asymptomatic individuals. The Multi-Ethnic Study of Atherosclerosis (MESA). J Am Coll Cardiol 2006;47:2420e8. [17] Hunt KJ, Williams K, Rivera D, O’Leary DH, Haffner SM, Stern MP, et al. Elevated carotid artery intima-media
[20]
[21]
[22]
[23]
[24]
[25]
[26]
[27]
[28]
[29]
[30]
[31]
[32]
[33]
thickness levels in individuals who subsequently develop type 2 diabetes. Arterioscler Thromb Vasc Biol 2003;23:1845e50. Temelkova-Kurktschiev TS, Koehler C, Leonhardt W, Schaper F, Henkel E, Siegert G, et al. Increased intimal-medial thickness in newly detected type 2 diabetes: risk factors. Diabetes Care 1999;22:333e8. Lange LA, Bowden DW, Langefeld CD, Wagenknechnect LE, Carr JJ, Rich SS, et al. Heritability of carotid artery intimamedial thickness in type 2 diabetes. Stroke 2002;33:1876e81. Niskanen L, Rauramaa R, Miettinen H, Haffner SM, Mercuri M, Uusitupa M. Carotid artery intima-media thickness in elderly patients with NIDDM and in nondiabetic subjects. Stroke 1996; 27:1986e92. Wagenknecht L, DE’Agostino R, Haffner S, Savage PJ, Rewers M. Impaired glucose tolerance, type 2 diabetes, and carotid wall thickness. Diabetes Care 1998;21:1812e8. Brohall G, Ode ´n A, Fagerberg B. Carotid artery intima-media thickness in patients with type 2 diabetes mellitus and impaired glucose tolerance: a systemic review. Diabet Med 2006;23:609e16. Lee CD, Folsom AR, Pankow JS, Brancati FL. for the Atherosclerosis Risk in Communities (ARIC) Study Investigators. Cardiovascular events in diabetic and nondiabetic adults with or without history of myocardial infarction. Circulation 2004;109:855e60. Haffner SM, D’Agostino RA, Saad MF, O’Leary DH, Savage PJ, Rewers M, et al. Carotid artery atherosclerosis in type-2 diabetic and nondiabetic subjects with and without symptomatic coronary artery disease (The Insulin Resistance Atherosclerosis Study). Am J Cardiol 2000;85:1395e400. Bernard S, Serusclat A, Targe F, Charriere S, Roth O, Beaune UJ, et al. Incremental predictive value of carotid ultrasonography in the assessment of coronary risk in a cohort of asymptomatic type 2 diabetic subjects. Diabetes Care 2005;28:1158e62. van der Meer IM, Iglesias del Sol A, Hak AE, Bots ML, Hofman A, Witteman JC. Risk factors for progression of atherosclerosis measured at multiple sites in the arterial tree: the Rotterdam Study. Stroke 2003;34:2374e9. Bonora E, Tessari R, Micciolo R, Zenere M, Targher G, Padovani R, et al. Intimal-medial thickness of the carotid artery in nondiabetic and NIDDM patients. Relationship with insulin resistance. Diabetes Care 1997;20:627e31. Lee EJ, Kim HJ, Bae JM, Kim JC, Han HJ, Park CS, et al. Relevance of common carotid intima-media thickness and carotid plaque as risk factors for ischemic stroke in patients with type 2 diabetes mellitus. Am J Neuroradiol 2007;28:916e9. Matsumoto K, Sera Y, Nakamura H, Ueki Y, Miyake S. Correlation between common carotid arterial wall thickness and ischemic stroke in patients with type 2 diabetes mellitus. Metabolism 2002;51:244e7. Nathan DM, Lachin J, Cleary P, Orchard T, Brillon DJ, Backlund JY, et al. Diabetes Control and Complication Trial; Epidemiology of Diabetes Interventions and Complications Research Group. Intensive diabetes therapy and carotid intima-media thickness in type 1 diabetes mellitus. N Engl J Med 2003;348:2294e303. Jensen-Urstad KJ, Reichard PG, Rosfors JJS, Lindblad LEL, Jensen-Urstad MT. Early atherosclerosis is retarded by improved long-term blood glucose control in patients with IDDM. Diabetes 1996;454:1253e8. Larsen JR, Brekke M, Bergengen L, Sandvik L, Arnesen H, Hanssen KF, et al. Mean HbA1c over 18 years predicts carotid intima media thickness in women with type 1 diabetes. Diabetologia 2005;48:776e9. Distiller LA, Joffe BI, Melville V, Welman T, Distiller GB. Carotid artery intima-media complex thickening in patients with long-surviving type 1 diabetes mellitus. J Diabetes Complications 2006;20:280e4.
672 [34] Epidemiology of Diabetes Interventions and Complications (EDIC) Research Group. Effect of intensive diabetes treatment on carotid artery wall thickness in the epidemiology of diabetes interventions and complications. Diabetes 1999;48:383e90. [35] Lopes-Virella MF, McHenry MB, Lipsitz S, Yim E, Wilson PF, Lackland DT, et al. The DCCT/EDIC Research Group. Immune complexes containing modified lipoproteins are related to the progression of internal carotid intima-media thickness in patients with type 1 diabetes. Atherosclerosis 2007;190: 359e69. [36] Lopes-Virella MF, Carter RE, Gilbert GE, Klein RL, Jaffa M, Jenkins AJ, et al. Risk Factors related to inflammation and endothelial dysfunction in the DCCT/EDIC cohort and their relationship with nephropathy and macrovascular complications. Diabetes Care 2008;31:2006e12. [37] Jarvisalo MJ, Raitakari M, Toikka JO, Putto-Laurila A, Riikka R, Laine S, et al. Endothelial dysfunction and increased arterial intima-media thickness in children with type 1 diabetes. Circulation 2004;109:1750e5. [38] Singh TP, Groehn H, Kazmers A. Vascular function and carotid intimal-medial thickness in children with insulin-dependent diabetes mellitus. J Am Coll Cardiol 2003;41:661e5. [39] Dalla Pozza R, Bechtold S, Bonfig W, Putzker S, KozlikFeldmann R, Netz H, et al. Age of onset of type 1 diabetes in children and carotid intima medial thickness. J Clin Endocrinol Metab 2007;92:2053e7. [40] Lorenz MW, Karbstein P, Markus HS, Sitzer M. High-sensitivity C-reactive protein is not associated with carotid intima-media progression: the carotid atherosclerosis progression study. Stroke 2007;38:1774e9. [41] Sander D, Schulze-Horn C, Bickel H, Gnahn H, Bartels E, Conrad B. Combined effects of hemoglobin A1c and C-reactive protein on the progression of subclinical carotid atherosclerosis: the INVADE study. Stroke 2006;37:351e7. [42] Bowden DW, Lange LA, Langefeld CD, Brosnihan KB, Freedman BI, Carr JJ, et al. The relationship between Creactive protein and subclinical cardiovascular disease in the Diabetes Heart Study (DHS). Am Heart J 2005;150:1032e8. [43] Mita T, Watada H, Uchino H, Shimizu T, Hirose T, Tanaka Y, et al. Association of C-reactive protein with early-stage carotid atherosclerosis in Japanese patients with early-state type 2 diabetes mellitus. Endocr J 2006;53:693e8. [44] Mangge H, Schauenstein K, Stroedter L, Griesl A, Maerz W, Borkenstein M. Low grade inflammation in juvenile obesity and type 1 diabetes associated with early signs of atherosclerosis. Exp Clin Endocrinol Diabetes 2004;112:378e82. [45] Matsumoto K, Sera Y, Ueki Y, Inukai G, Niiro E, Miyake S. Comparison of serum concentrations of soluble adhesion molecules in diabetic microangiopathy and macroangiopathy. Diabet Med 2002;19:822e6. [46] Aso Y, Okumura K, Takebayashi K, Wakabayashi K, Inukai T. Relationship of plasma interleukin-18 concentrations to hyperhomocysteinemia and carotid intimal-medial wall thickness in patients with type 2 diabetes. Diabetes Care 2003;26:2622e7. [47] Rohde LE, Lee RT, Rivero J, Jamacochian M, Arroyo LH, Briggs W, et al. Circulating cell adhesion molecules are correlated with ultrasound-based assessment of carotid atherosclerosis. Arterioscler Thromb Vasc Biol 1998;18:1765e70. [48] Simons PC, Algra A, Bots ML, Grobbee DE, van der Graf Y. Common carotid intima media thickness and arterial stiffness: indicators of cardiovascular risk in high risk patients. The SMART Study (Second Manifestations of ARTerial disease). Circulation 1999;100:951e7. [49] Ravikumar R, Deepa R, Shanthirani CS, Mohan V. Comparison of carotid intima-media thickness, arterial stiffness, and brachial artery flow mediated dilatation in diabetic and nondiabetic subjects (The Chennai Urban Population Study[CUPS-9]). Am J Cardiol 2002;90:702e7.
S. Vigili de Kreutzenberg et al. [50] Klein R, Sharrett AR, Klein BE, Moss SE, Folsom AR, Wong TY, et al. The association of atherosclerosis, vascular risk factors, and retinopathy in adults with diabetes: the atherosclerosis risk in communities study. Ophthalmology 2002;109:1225e34. [51] Rema M, Mohan V, Deepa R, Ravikumar R. Chennai Urban Rural Epidemiology Study-2. Association of carotid intima-media thickness and arterial stiffness with diabetic retinopathy: the Chennai Urban Rural Epidemiology Study (CURES-2). Diabetes Care 2004;27:1962e7. [52] Klein R, Marino EK, Kuller LH, Polak JF, Tracy RP, Gottdiener JS, et al. The relation of atherosclerotic cardiovascular disease to retinopathy in people with diabetes in the Cardiovascular Health Study. Br J Ophthalmol 2002;86:84e90. [53] van Hecke MV, Dekker JM, Nijpels G, Stolk RP, Henry RM, Heine RJ, et al. Are retinal microvascular abnormalities associated with large artery endothelial dysfunction and intimamedia thickness? The Hoorn Study. Clin Sci 2006;110:597e604. [54] Mykkanen L, Zaccaro DJ, O’Leary DH, Howard G, Robbins DC, Haffner SM. Microalbuminuria and carotid artery intima-media thickness in nondiabetic and NIDDM subjects. The Insulin Resistance Atherosclerosis Study (IRAS). Stroke 1997;28:1710e6. [55] Kramer H, Jacobs DR, Bild D, Post W, Saad MF, Detrano R, et al. Urine albumin excretion and subclinical cardiovascular disease. The Multi-Ethnic Study of Atherosclerosis. Hypertension 2005;46:38e43. [56] Keech AC, Grieve SM, Patel A, Griffiths K, Skilton M, Watts GF, et al. Urinary albumin levels in the normal range determine arterial wall thickness in adults with Type 2 diabetes: a FIELD substudy. Diabet Med 2005;22:1558e65. [57] Pruissen DM, Gerritsen SA, Prinsen TJ, Dijk JM, Kappelle LJ, Algra A, et al. Carotid intima-media thickness is different in large- and small-vessel ischemic stroke: the SMART study. Stroke 2007;38:1371e3. [58] Cupini LM, Pasqualetti P, Diomedi M, Vernieri F, Silvestrini M, Rizzato B, et al. Carotid artery intima-media thickness and lacunar versus nonlacunar infarcts. Stroke 2002;33:689e94. [59] Touboul PJ, Elbaz A, Koller C, Lucas C, Adraı¨ V, Che ´dru F, et al. Common carotid artery intima-media thickness and brain infarction: the Etude du Profil Genetique de l’Infarctus Cerebral (GENIC) casecontrol study. The GENIC Investigators. Circulation 2000;102:313e8. [60] Nagai Y, Kitagawa K, Yamagami H, Kondo K, Hougaku H, Hori M, et al. Carotid artery intima-media thickness and plaque score for the risk assessment of stroke subtypes. Ultrasound Med Biol 2002;28:1239e43. [61] Frost D, Beischer W. Determinants of carotid artery wall thickening in young patients with Type 1 diabetes mellitus. Diabet Med 1998;15:851e7. [62] Kim SH, Lee SJ, Kang ES, Kang S, Hur KY, Lee HJ, et al. Effects of lifestyle modification on metabolic parameters and carotid intima-media thickness in patients with type 2 diabetes mellitus. Metabolism 2006;55:1053e9. [63] Esposito K, Giugliano D, Nappo F, Marfella R. Regression of carotid atherosclerosis by control of postprandial hyperglycemia in type 2 diabetes mellitus. Circulation 2004;110:214e9. [64] Yamasaki Y, Katakami N, Hayaishi-Okano R, Matsuhisa M, Kajimoto Y, Kosugi K, et al. alpha-Glucosidase inhibitor reduces the progression of carotid intima-media thickness. Diabetes Res Clin Pract 2005;67:204e10. [65] Matsumoto K, Sera Y, Abe Y, Tominaga T, Yeki Y, Miyake S. Metformin attenuates progression of carotid arterial wall thickness in patients with type 2 diabetes. Diabetes Res Clin Pract 2004;64:225e8. [66] Katakami N, Yamasaki Y, Hayaishi-Okano R, Ohtoshi K, Kaneto H, Matsuhisa M, et al. Metformin or gliclazide, rather than glibenclamide, attenuate progression of carotid intimamedia thickness in subjects with type 2 diabetes. Diabetologia 2004;47:1906e13.
Cerebrovascular disease in diabetes: role of carotid IMT [67] Hodis HN, Mack WJ, Zheng L, Li Y, Torres M, Sevilla D, et al. Effect of peroxisome proliferator-activated receptor gamma agonist treatment on subclinical atherosclerosis in patients with insulinrequiring type 2 diabetes. Diabetes Care 2006;29:1545e53. [68] Sidhu JS, Kaposzta Z, Markus HS, Kaski JC. Effect of rosiglitazone on common carotid intima-media thickness progression in coronary artery disease patients without diabetes mellitus. Arterioscler Thromb Vasc Biol 2004;24:930e4. [69] Mazzone T, Meyer PM, Feinstein SB, Davidson MH, Kondos GT, D’Agostino RB, et al. Effect of pioglitazone compared with glimepiride on carotid intima-media thickness in type 2 diabetes: a randomized trial. JAMA 2006;296:2572e81. [70] Davidson M, Meyer PM, Haffner S, Feinstein S, D’Agostino R, Kondos GT, et al. Increased high-density lipoprotein cholesterol predicts the pioglitazone mediated reduction of carotid intima-media thickness progression in patients with type 2 diabetes mellitus. Circulation 2008;117:2123e30. [71] Nakamura T, Matsuda T, Kawagoe Y, Ogawa H, Takahashi Y, Sekizuka K, et al. Effect of pioglitazone on carotid intimamedia thickness and arterial stiffness in type 2 diabetic nephropathy patients. Metabolism 2004;53:1382e6.
673 [72] Langenfeld MR, Forst T, Hohberg C, Kann P, Lubben G, Konrad T, et al. Pioglitazone decreases carotid intima-media thickness independently of glycemic control in patients with type 2 diabetes mellitus: results from a controlled randomized study. Circulation 2005;111:2525e31. [73] Stocker DJ, Taylor AJ, Langley RW, Jezior MR, Vigersky RA. A randomized trial of the effects of rosiglitazone and metformin on inflammation and subclinical atherosclerosis in patients with type 2 diabetes. Am Heart J 2007;153:445. e1-6. [74] Hanefeld M, Chiasson JL, Koehler C, Henkel E, Schaper F, Temelkova-Kurktschiev T. Acarbose slows progression of intima-media thickness of the carotid arteries in subjects with impaired glucose tolerance. Stroke 2004;35:1073e8. [75] Oyama T, Saiki A, Endoh K, Ban N, Nagayama D, Ohhira M, et al. Effect of acarbose, an alpha-glucosidase inhibitor, on serum lipoprotein lipase mass levels and common carotid artery intima-media thickness in type 2 diabetes mellitus treated by sulfonylurea. J Atheroscler Thromb 2008;15:154e9. [76] Larsen JL, Ratansuwan T, Burkman T, Lynch T, Erickson J, Colling C, et al. Carotid intima media thickness decreases after pancreas transplantation. Transplantation 2002;73:936e40.