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The under-use of statin in type 2 diabetic patients attending diabetic clinics in Italy
Nutrition, Metabolism & Cardiovascular Diseases (2007) 17, 32e40
www.elsevier.com/locate/nmcd
The under-use of statin in type 2 diabetic patients attending diabetic clinics in Italy Angelo Avogaro*, Pietro Guida, Carlo Giorda, Edoardo Mannucci, Gerardo Medea, Marco Comaschi, Mario Velussi, Guglielmo Armienti, Roberta Zucchetti, on behalf of Progetto DIARIO (DIAbetic Register in Italian Offices) Department of Clinical and Experimental Medicine, University of Padova, School of Medicine, Via Giustiniani 2, 35128 Padova, Italy Received 7 June 2005; received in revised form 4 October 2005; accepted 1 December 2005
KEYWORDS Diabetes mellitus; Statins; Cholesterol; Vascular complications; Prescriptions
Abstract Background and aims: The greatest decrease in mortality from cardiovascular disease (CAD) that can be achieved with 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors (statins) is seen in patients with the highest risk for CAD, such as diabetics. Yet, there is evidence for inadequate use of drug therapies to achieve lipid goals. Our aims were to: (1) assess the prevalence of statin use in patients attending diabetic clinics and (2) correlate the use of statins with their risk and clinical status. Methods and results: Of 9921 patients included, only 20.4% of them were receiving statin therapy. Statins were more progressively prescribed in those with risk factors additional to that of diabetes. Patients under statin treatment were older, mostly type 2 diabetics, more hypertensive and hyperlipidemic, had a higher prevalence of both macro- and microvascular disease. Among those with a total cholesterol concentration above 252 mg/dl, statin treatment was given only to 60% of diabetic patients with prior myocardial infarction, 56% of those with angina, 66% of those having had prior revascularization procedure, 54% of those with cerebrovascular disease and 51% of those with peripheral artery disease. Conclusions: At least in Italy, statins are not prescribed to the majority of diabetic patients, and a substantial proportion of patients not treated with statins present significant macro- and microvascular complications. ª 2005 Elsevier B.V. All rights reserved.
* Corresponding author. Tel.: þ39 049 821 2178; fax: þ39 049 875 4179. E-mail address: [email protected] (A. Avogaro). 0939-4753/$ - see front matter ª 2005 Elsevier B.V. All rights reserved. doi:10.1016/j.numecd.2005.12.001
Under-use of statin in type 2 diabetic patients attending diabetic clinics
Introduction
Methods
Randomized clinical trials have established that low-density lipoprotein cholesterol (LDL-C) reduction is a key factor in preventing cardiovascular disease (CVD) [1e6]. The 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors, known as statins, are the most effective agents to reduce LDL-C. Interestingly, the greatest decrease in morbidity and mortality that can be achieved with these agents is seen in patients at the highest risk for CVD such as type 2 diabetic patients [7,8]. These patients are at increased risk of CVD: primary prevention studies using aspirin and statin have shown the beneficial effects of these two drugs in diabetes [9,10]. The National Institute for Clinical Excellence guidelines on lipid and blood pressure management in patients with type 2 diabetes mellitus recommended statin treatment for patients with a 15% CVD risk at 10 years, advocating more widespread prescription of statins [11]. The recent findings of the Heart Protection Study (HPS) suggest that all patients with diabetes aged between 40 and 80 years with total cholesterol of >3.5 mmol/l should be treated with statins, implying that CVD risk estimation is not necessary [8]. Patients with clinically established CVD are defined as the highest priority in the Joint European Societies’ guidelines for the prevention of CVD and clearly emphasize the high-risk status of diabetic patients [12e14]. The EUROASPIRE II, which covered 15 countries, showed a high prevalence of unhealthy lifestyles, modifiable risk factors and inadequate use of drug therapies to achieve blood pressure and lipid goals [15]. Among the patients on admission, at discharge and at interview the use of the lipid lowering drugs was under-used in 26%, 43% and 61%, respectively. Thus, this study showed that there is considerable potential throughout Europe to raise the standard of preventive cardiology through more effective lifestyle intervention, control of other risk factors and optimal use of prophylactic drug therapies in order to reduce coronary morbidity and mortality. Specifically in Italy, among patients suffering from coronary heart disease (CHD), the lipid lowering drugs were prescribed on admission, on discharge, and at interview to 10.1%, 45.5% and 59.7% of the patients, respectively. However, these figures were obtained from a selected subset of patients of whom only 21.8% had a self-reported diabetes. In the light of these premises we wished to assess the prevalence of statin use in patients attending diabetic clinics and to correlate the use of statins to their clinical status.
System context and system cohort
33
The Italian Health System provides free medical care for both type 1 and type 2 diabetic patients through outpatient diabetic care units. Seventy percent of type 2 diabetic patients refer to these clinics. The Progetto DIARIO (DIAbetic Register in Italian Offices) created a data base for statin prescriptions in type 1 and type 2 diabetic patients. The population consists of all patients seen at the participating units between July 2002 and September 2002. Type 1 and type 2 diabetes were diagnosed according to the 1985 criteria of the World Health Organization. To create a representative sample of the diabetic population referring to each clinic, patients were randomly chosen so that the data of patients seen in each of the 183 participating clinics in the first weeks of each month between July and September were analyzed. During the examination, for each patient included in the cohort, a standard questionnaire was used. The variables considered were: personal data and lifestyle habits; anthropometrical data; pharmacological therapies; laboratory data; clinical history and data on microvascular (retinopathy and chronic renal failure), and data on macrovascular complications (myocardial infarction, ischemic heart disease, coronary artery bypass, coronary angioplasty, cerebral and peripheral artery disease). Each patient had at least a: (1) plasma glucose, HbA1c and lipid profile, determined in the fasting state, no more than three months prior to the interview; (2) systolic and diastolic blood pressures measured during the visit with a sphygmomanometer after the patient had been seated for at least 5 min; and (3) a comprehensive eye examination by an ophthalmologist no more than six months before.
Definitions A patient was defined as hypertensive if he/she used an antihypertensive treatment or had a blood pressure 140/90 mm Hg. Patients were classified as having CHD if they had: (1) a positive history for hospital admission for either an acute myocardial infarction (AMI) or an episode of angina; (2) a positive 12-lead ECG for prior acute myocardial infarction or angina coded using the Minnesota coding system (criteria I 1e3,
34
A. Avogaro et al.
IV 1e3, V 1e2, and VII 1); (3) a positive history for coronary artery bypass graft (CABG); or (4) a positive history for percutaneous transluminal coronary angioplasty (PTCA) [14]. Patients were classified as hyperlipidemic if they had a total cholesterol 200 mg/dl, HDL cholesterol < 40 mg/dl for men and <50 mg/dl for women, or if they were on lipid lowering therapy [15]. Patients were classified as having cerebrovascular disease if they had had an episode of neurological dysfunction caused by a cerebral vascular episode associated either with temporary or permanent brain injury [16]. Patients were classified as having peripheral artery disease if they had a ratio of arm/foot systolic pressure 0.7 or a previous history of lower limb revascularization or evidence or a significant arterial stenosis detected either by angiography or by Doppler ultrasound [17]. Patients were classified as having a chronic renal failure if glomerular filtration rate was less than 30 cc/min according to the Cockroft formula [18]. Definition of the components of metabolic syndrome was derived from the NCEP-ATP III [19].
Statistical analysis Continuous variables were expressed as mean standard deviation and were compared with
Table 1
Results A total of 9921 patients were included for the analysis. For all participants, the data listed in the methods were collected; patients were excluded from the analysis if data on sex, age, HbA1c, glycaemia, and lipids were missing or implausible. The main characteristics of the study population are presented in Table 1. Diabetic women showed a higher severity of risk factors for CVD, a worse metabolic control, and a substantially lower prevalence of previous acute myocardial infarction than men, but a similar prevalence of history of angina. The revascularization procedures were less frequently performed in women than men. The burden of atherosclerotic disease in peripheral arteries was also more frequent in men than women, who had, at variance, higher prevalence of diabetic microangiopathy. As shown in Table 2, women were receiving more blockers of the renineangiotensin system than men, who at variance, were receiving more antiplatelet drugs. Diuretics and antidiabetic agents were more employed in women. Only
Anthropometric and clinical characteristics of the study population
Sex (male %) Age (years) Type 1 diabetic patients (%) Hypertension (%) Hyperlipidemia (%) Previous acute myocardial infarction (%) History of angina (%) Revascularization (PTCA/CABG) (%) Cerebrovascular disease (%) Peripheral vascular disease (%) Diabetic retinopathy (%) Chronic renal failure (%) Systolic blood pressure (mm Hg) Diastolic blood pressure (mm Hg) Total cholesterol (mg/dl) HDL cholesterol (mg/dl) LDL cholesterol (mg/dl) Triglycerides (mg/dl) Fasting plasma glucose (mg/dl) HbA1c (%) Mean SD.
analysis of variance. Categorical variables were expressed as percent frequency and compared with Pearson c2 test. Differences were considered statistically significant when p-value was <0.05.
Total, n ¼ 9921
Females, n ¼ 4943
Males, n ¼ 4978
p
50 65 12 8.3 56.6 34.3 7.4 5.6 4.1 4.2 8.8 21.4 4.1 141 19 81 9 207 40 51 14 126 34 151 102 163 69 7.5 1.6
0 66 12 8.2 61.5 36.3 4.7 5.9 2.4 3.8 6.8 22.6 3.2 142 19 81 9 211 40 53 15 128 35 149 94 166 79 7.6 1.6
100 64 12 8.5 51.7 32.3 10.1 5.2 5.8 4.6 10.8 20.2 5.0 140 19 81 9 202 40 48 13 124 33 154 109 161 58 7.4 1.6
e <0.001 0.635 <0.001 <0.001 <0.001 0.088 <0.001 0.047 <0.001 0.005 <0.001 <0.001 0.693 <0.001 <0.001 <0.001 0.005 0.004 <0.001
Under-use of statin in type 2 diabetic patients attending diabetic clinics 20.4% of diabetic patients were receiving statins which were more commonly prescribed in women than in men. Table 3 shows the anthropometric and clinical characteristics of diabetic patients without CVD as a function of the number of principal risk factors co-segregating with diabetes: patients with more risk factors, including diabetes, were older, had a higher atherosclerotic burden, a higher prevalence of diabetic microvascular disease, and worse metabolic and pressure controls. Statin therapy was more progressively prescribed in those with other risk factors in addition to diabetes. Table 4 reported the same analysis for diabetic patients with CVD: comparable results for these patients were obtained as for those without CVD. However, patients with CVD had higher prevalence of retinopathy, chronic renal failure, and had higher HbA1c than those without. Statins were significantly more prescribed in those with CVD than in those without. Among those who were not treated with statins, higher cholesterol levels were less likely to be associated with type 1 diabetes, prior acute myocardial infarction, and cerebrovascular disease (Table 5). As shown in Table 6, the patients treated with statins were more likely to have CHD, CVD
Table 2 Drug treatment in the entire cohort according to sex Totals, Females, Males, p n ¼ 9921 n ¼ 4943 n ¼ 4978 ACE-inhibitors 30.8 (%) ATII inhibitors 12.0 (%) Beta-blockers 8.5 (%) Antiplatelets 19.7 (%) Anticoagulants 2.2 (%) Ca-channel 17.6 blockers (%) Digitalis (%) 2.6 Antiarrhythmics 0.9 (%) Diuretics (%) 17.0 Nitrates (%) 5.4 Antidiabetics 84.8 agentsa (%) Fibrates (%) 2.9 Omega 3 (%) 1.0 Statins (%) 20.4
32.2
29.4
0.003
13.6
10.5
<0.001
8.7
8.4
0.59
17.3
22.2
<0.001
1.9
2.5
0.062
18.8
16.5
0.002
2.9 0.9
2.2 1.0
0.023 0.863
19.6 5.6 85.8
14.4 5.2 83.8
<0.001 0.31 0.006
2.5 0.7 21.8
3.2 1.3 19.1
0.036 0.003 <0.001
a Antidiabetic agents include oral hypoglycemic agents plus insulin.
35
and worse major risk factors for CVD. However, as shown in Fig. 1, only 60% of diabetic patients with prior myocardial infarction and total cholesterol higher than 252 mg/dl were on statin treatment, 56% of those with angina, 66% those with a prior revascularization procedure, 54% of those with cerebrovascular disease, and 51% of those with peripheral artery disease.
Discussion This study shows that: (1) statins are not prescribed to the majority of diabetic patients; (2) treatment with statins is more frequent in patients with increasing severity of cardiovascular burden; however, a major proportion of diabetic patients, irrespective of the presence of CVD, is not receiving statin therapy despite a clinically manifest peripheral artery disease. This study shows that the prevalence of CHD is 11% in women and 16% in men. The prevalence in women is comparable to that reported in a previous Italian study [14]; in contrast we found a higher prevalence of CHD in men. This discrepancy is not readily apparent. Either a different randomization strategy between the two studies or a different reperfusion attitude between participating centres may explain such a difference [20]. Women had lower prevalent CVD than men despite worse risk factor profile: this incongruity may be due to the fact that women were more treated than men; moreover women, despite similar treatment, appear to gain more protection in terms of primary end points [6]. Another potential caveat which could partially explain the observed results is that the reported lipid data were obtained in different laboratories with different procedures. Unfortunately, there was no possibility to assay biomarkers in a single core laboratory. Another potential limitation of this study is that the data collected in this survey relate to diabetic patients referring to the outpatient diabetic units; unfortunately, in some Italian regions, up to 60% of type 2 diabetic patients are followed by their general practitioner. Undoubtedly this may affect the information gained in the study which may not be representative of the whole Italian diabetic population. ATP III set the goal for LDL cholesterol lowering in high-risk patients to be <100 mg/dl, the practical limit endorsed by available clinical trials. This limit is further reduced to <70 mg/dl in patients at very high risk. Diabetes is a high-risk condition, and diabetes plus CHD is a very high-risk condition [21]. The data presented in this study demonstrate
36
A. Avogaro et al.
Table 3 Anthropometric and clinical variables and statin therapy according to the number of risk factorsa in addition to diabetes in patients without cardiovascular disease Sex (male %) Age (years) Type 1 diabetic patients (%) Diabetic retinopathy (%) Chronic renal failure (%) Systolic blood pressure (mm Hg) Diastolic blood pressure (mm Hg) Total cholesterol (mg/dl) HDL cholesterol (mg/dl) LDL cholesterol (mg/dl) Triglycerides (mg/dl) HbA1c Statin therapy
Diabetes, n ¼ 829
þ1, n ¼ 3252
þ2, n ¼ 2414
þ3, n ¼ 1214
p
53 56 16 27.3
51 64 12 10.2
46 64 11 4.8
37 64 11 2.6
<0.001 <0.001 <0.001
15.6 1.9
19.5 2.7
16.9 3.3
21.6 3.8
<0.001 0.058
117 7
142 18
144 18
148 16
<0.001
73 7
81 9
82 9
84 9
<0.001
198 35 59 13 121 30 90 29 7.3 1.6 10.9
204 36 57 14 126 31 107 55 7.4 1.5 14.0
210 44 46 11 130 36 179 115 7.6 1.7 18.3
214 40 38 6 128 38 244 112 7.8 1.7 22.6
<0.001 <0.001 <0.001 <0.001 <0.001 <0.001
Mean SD. a Risk factors considered were: blood pressure 140/90, HDL cholesterol < 40 mg/dl for men and <50 mg/dl for women, triglycerides 150 mg/dl, and total cholesterol 200 mg/dl.
that, not only baseline LDL cholesterol in diabetic patients is much higher than this recommended level, but also that LDL cholesterol increases in patients with more than one component of the metabolic syndrome as defined by ATP III. Based on available outcomes, statin therapy should by initiated in all diabetic patients as outlined by the HPS
trial, and recently by the CARDS trial [8,22]. These studies also emphasize the finding that risk charts are not useful in establishing future cardiovascular risk in type 2 diabetic patients in order to initiate statin therapy. Our data are meagre in the sense that only 20.4% of diabetic patients periodically referring
Table 4 Anthropometric and clinical variables and statin therapy according to the number of risk factorsa in addition to diabetes in patients with cardiovascular disease Sex (male %) Age (years) Type 1 diabetic patients (%) Diabetic retinopathy (%) Chronic renal failure (%) Systolic blood pressure (mm Hg) Diastolic blood pressure (mm Hg) Total cholesterol (mg/dl) HDL cholesterol (mg/dl) LDL cholesterol (mg/dl) Triglycerides (mg/dl) HbA1c Statin therapy
Diabetes, n¼153
þ1, n¼901
þ2, n¼726
þ3, n¼432
p
70 69 9 9.2
66 70 9 7.1
57 69 9 3.9
42 69 9 4.4
<0.001 0.024 0.005
26.8 3.3
31.2 6.7
28.9 9.9
36.1 9.5
117 6
144 19
145 17
148 16
<0.001
73 8
80 10
80 9
82 10
<0.001
195 35 56 11 120 31 99 27 7.3 1.4 32.7
203 44 56 14 123 32 109 39 7.4 1.4 31.5
206 45 45 10 126 35 177 102 7.8 1.5 36.1
216 40 38 6 131 38 252 134 8.2 1.7 39.8
<0.001 <0.001 0.006 <0.001 <0.001 0.019
0.046 0.008
Mean SD. a Risk factors considered were: blood pressure 140/90, HDL cholesterol < 40 mg/dl for men and <50 mg/dl for women, triglycerides 150 mg/dl, and total cholesterol 200 mg/dl.
Under-use of statin in type 2 diabetic patients attending diabetic clinics to the diabetes unit are under statin treatment. Furthermore, a substantial proportion of diabetic patients with prevalent artery disease, i.e. very high-risk patients, do not receive appropriate statin therapy. Yet, among those who are receiving appropriate treatment, both total cholesterol and LDL cholesterol are still unacceptably high. These data not only emphasize the poor receptiveness of physicians to adhere to guideline recommendations but also support the findings of both EUROASPIRE I and II which demonstrated that most CHD patients are still not achieving the cholesterol goal, and that there is a considerable potential to raise the standards for preventive cardiology [13,23]. This analysis confirms the findings of another survey performed in Italy in which it was shown that in diabetic patients there is a substantial gap between therapeutic guidelines and actual treatment [24]. Since a positive correlation between the number of treatments taken and the assumption of statins was found using a multivariate model, physicians’ prescription attitudes were proposed as a possible reason for this behaviour. However, it must be kept in mind that our survey includes not the entire diabetic population but only a portion of it; there are indeed some Italian regions where more than
37
half of diabetic patients are seen by the general practitioners. Our data not only emphasize these concepts but also underpin another major negative aspect in treating the atherosclerotic burden in diabetic patients, i.e., statin therapy is only partially globally risk-driven; instead it appears to be organdamage driven. As shown in Fig. 1, it is indeed clear that there is a significant discrepancy in statin treatment between those who receive a coronary revascularization and those who show clinically evident peripheral or cerebrovascular artery disease. This is clinically unacceptable since it is evident that the presence of peripheral artery disease is not only itself a mirror of ongoing atherosclerotic vascular disease but coexists with atherosclerotic disease in other sections of the vascular tree [25]. As regards secondary prevention, until November 2004 in Italy, the National Health Service provided statins free of charge only to patients who experienced a coronary event. This may explain why patients with peripheral and cerebral artery diseases show such low rates of treatment. Statins have been shown to lower not only plasma LDL cholesterol and triglyceride levels in type 2 diabetic patients, but also small dense LDL
Table 5 Anthropometric and clinical variables of patients not treated with statins stratified according total cholesterol concentration
Sex (males %) Age (years) Tipe 1 diabetes (%) Hypertension (%) Hyperlipidemia (%) Prior acute myocardial infarction (%) Angina (%) Revascularization (%) Cerebrovascular disease (%) Peripheral artery disease (%) Chronic renal failure (%) Systolic blood pressure (mm Hg) Diastolic blood pressure (mm Hg) HDL cholesterol (mg/dl) LDL cholesterol (mg/dl) Triglycerides (mg/dl) Fasting plasma glucose (mg/dl) HbA1c (%) Mean SD.
n ¼ 7893
173, n ¼ 1612
174e212, n ¼ 3360
213e251, n ¼ 2207
252, n ¼ 714
p
51 65 12 9.4 53.6 21.6 5.4
58 64 14 13.0 49.3 10.5 5.2
53 64 12 9.6 53.0 13.1 6.3
47 66 12 6.8 56.5 30.4 4.5
39 64 11 8.3 57.3 58.8 4.5
<0.001 <0.001 <0.001 <0.001 <0.001 0.022
4.3 2.5 3.5 7.8 3.8 141 19
4.5 2.8 4.3 7.4 4.2 138 19
4.4 2.8 3.8 7.1 3.5 140 18
3.9 2.0 2.7 9.1 3.5 143 19
4.2 1.8 3.4 8.0 4.9 145 20
0.713 0.167 0.041 0.055 0.242 <0.001
81 9
79 9
81 9
82 9
83 10
<0.001
51 15 124 19 146 102 164 85
46 12 88 17 114 63 158 60
50 13 117 17 137 79 160 57
54 15 144 19 162 102 168 85
56 17 175 29 214 175 182 93
<0.001 <0.001 <0.001 <0.001
7.5 1.6
7.4 1.7
7.4 1.5
7.6 1.6
8.0 2.0
<0.001
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A. Avogaro et al.
Table 6 Anthropometric and clinical variables of patients treated with statins stratified according total cholesterol concentration
Sex (males %) Age (years) Type 1 diabetes (%) Hypertension (%) Hyperlipidemia (%) Prior acute myocardial infarction (%) Angina (%) Revascularization (%) Cerebrovascular disease (%) Peripheral artery disease (%) Chronic renal failure (%) Systolic blood pressure (mm Hg) Diastolic blood pressure (mm Hg) HDL cholesterol (mg/dl) LDL cholesterol (mg/dl) Triglycerides (mg/dl) Fasting plasma glucose (mg/dl) HbA1c (%)
n ¼ 2028
173, n ¼ 305
174e212, n ¼ 602
213e251, n ¼ 636
252, n ¼ 485
p
47 66 12 4.3 68.1 83.7 15.2
58 66 9 4.6 72.5 77.7 27.2
50 66 9 4.5 70.6 82.1 16.8
45 66 9 4.1 64.6 83.5 11.9
39 65 10 4.3 66.8 89.9 9.9
<0.001 0.080 0.982 0.040 <0.001 <0.001
10.6 10.4 6.7
12.8 17 5.2
13 12.8 8.6
9.4 9 6.1
7.8 5.2 5.8
0.019 <0.001 0.129
12.8
13.1
14.3
11.6
12.4
0.559
5.3
8.5
4.7
4.4
5.2
0.048
142 19
140 17
142 18
141 18
145 19
<0.001
81 9
80 9
81 10
81 9
82 10
0.008
50 15
46 12
50 12
50 14
52 15
<0.001
135 19 171 102 162 85
85 19 137 75 153 48
114 19 153 80 156 51
147 21 173 95 164 85
183 29 212 155 171 57
<0.001 <0.001 <0.001
7.6 1.6
7.4 1.4
7.4 1.4
7.5 1.5
8.0 1.8
<0.001
Mean SD.
Patients treated with statins (%)
70
Revasc AMI
60
Angina
Revasc
CVD
Revasc
50
PVD
AMI Revasc
AMI
Angina
CVD
40 Angina
Angina
AMI CVD
30
PVD
PVD
PVD CVD
20
10
0 <173
174-212
213-251
>252
Total Cholesterol (mg/dl)
Figure 1 The percentage of diabetic patients treated with statins according to total cholesterol levels and to atherosclerotic disease. Black bars represent those with a history of acute myocardial infarction (AMI), the dark grey bars those with angina, the light bars those who had revascularization procedure (Revasc), the light squared bars (blue in web version) those with cerebrovascular disease (CVD), and the white bars those with peripheral vascular disease (PVD).
Under-use of statin in type 2 diabetic patients attending diabetic clinics levels [26]. It was shown that atorvastatin can positively modify LDL particle density in type 2 diabetic patients [27]. Similarly, fluvastatin reduces small dense LDL subfractions more effectively than more buoyant fractions in type 2 diabetic patients [28]. In contrast, simvastatin decreased cholesterol concentrations uniformly across all LDL subfractions in these patients [29]. In this study we do not report either the type of statin prescribed or the dose prescribed: this may explain why, even in those receiving statin therapy, adequate LDL cholesterol level is not achieved. However, as recently emphasized, most diabetic patients benefit from moderate doses of these drugs [30]. We also found that patients receiving statin treatment have a similar metabolic control to those who are not receiving the treatment: neither the CARDS nor the HPS assessed the impact of statin treatment of glycemic control, although some studies in nondiabetic patients showed that statins are able to decrease the onset of new diabetes and delay the start of insulin therapy [31e33]. The use of statin therapy has also been proposed for nonmacrovascular disease such as diabetic retinopathy and nephropathy. In this study 13.4% of patients had diabetic retinopathy among those without CVD vs. 30.7% among those with CVD: these data emphasize the tight association between micro- and macrovascular complication in type 2 diabetic patients [34]. We also show that 20.8% of those not treated with statin had evidence of diabetic retinopathy and 3.8% of chronic renal failure. Observational studies of patients with diabetes have shown an association between diabetic retinopathy and plasma cholesterol levels [35e37]. The presence of retinopathy was associated with higher cholesterol levels. In another study the severity of visual loss correlated with the severity of retinopathy [38]: by inference, reduction in cholesterol may favourably affect retinopathy. In conclusion we show that statins are not prescribed for the majority of diabetic patients and that a substantial proportion of patients not treated with statins present significant macro- and microvascular complications. Although optimal LDL-C levels have been set at <100 mg/dl for high-risk patients, this nationwide Italian study in ambulatory diabetic patients, as other recent studies, shows that only about 20% of such patients are under appropriate treatment. Thus, a large treatment gap remains which needs to be overcome if we are to continue to make significant inroads into preventing further morbidity and mortality in high-risk diabetic subjects.
39
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A. Avogaro et al. for the National Cholesterol Education Program Adult Treatment Panel III Guidelines. J Am Coll Cardiol 2004; 44:720e32. Morey SS. American Heart Association issues guidelines on imaging in transient ischemic attacks and stroke. Am Fam Physician 1998;57:1685e6. Sacks D, Bakal CW, Beatty PT, Becker GJ, Cardella JF, Raabe RD, et al. Position statement on the use of the anklee brachial index in the evaluation of patients with peripheral vascular disease: a consensus statement developed by the standards division of the society of cardiovascular & interventional radiology. J Vasc Interv Radiol 2002;13:353. Hakim RM, Lazarus JM. Initiation of dialysis. J Am Soc Nephrol 1995;6:1319e28. National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III). Third report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III) final report. Circulation 2002;106: 3143e421. Filardo G, Maggioni AP, Mura G, Valagussa F, Valagussa L, Schweiger C, et al. The consequences of under-use of coronary revascularization; results of a cohort study in Northern Italy. Eur Heart J 2001;22:654e62. Grundy SM, Cleeman JI, Merz CN, Brewer Jr HB, Clark LT, Hunninghake DB, et al. Implications of recent clinical trials for the National Cholesterol Education Program Adult Treatment Panel III Guidelines. Arterioscler Thromb Vasc Biol 2004;24:e149e61. Colhoun HM, Betteridge DJ, Durrington PN, Hitman GA, Neil HA, Livingstone SJ, et al. Primary prevention of cardiovascular disease with atorvastatin in type 2 diabetes in the Collaborative Atorvastatin Diabetes Study (CARDS): multicentre randomised placebo-controlled trial. Lancet 2004;364:685e96. EUROASPIRE. A European Society of Cardiology survey of secondary prevention of coronary heart disease: principal results. EUROASPIRE Study Group. European action on secondary prevention through intervention to reduce events. Eur Heart J 1997;18:1569e82. Erratum in: Eur Heart J 1998;19:356e7. Giorda C, Maggini M, Spila S, Turco S, Raschetti R, the DAI Study Group. Secondary prevention for coronary artery desease in high risk diabetic patients. Nutr Metab Cardiovasc Dis 2003;13:238e43. Sukhija R, Aronow WS, Yalamanchili K, Sinha N, Babu S. Prevalence of coronary artery disease, lower extremity peripheral arterial disease, and cerebrovascular disease in 110 men with an abdominal aortic aneurysm. Am J Cardiol 2004;94:1358e9.
[26] Corsini A. The safety of HMG-CoA reductase inhibitors in special populations at high cardiovascular risk. Cardiovasc Drugs Ther 2003;17:265e85. [27] Pontrelli L, Parris W, Adeli K, Cheung RC. Atorvastatin treatment beneficially alters the lipoprotein profile and increases low-density lipoprotein particle diameter in patients with combined dyslipidemia and impaired fasting glucose/type 2 diabetes. Metabolism 2002;51: 334e42. [28] Winkler K, Abletshauser C, Hoffmann MM, Friedrich I, Baumstark MW, Wieland H, et al. Effect of fluvastatin slow-release on low-density lipoprotein (LDL) subfractions in patients with type 2 diabetes mellitus: baseline LDL profile determines specific mode of action. J Clin Endocrinol Metab 2002;87:5485e90. [29] Sbarouni E, Kyriakides ZS, Kremastinos D. The effect of hormone replacement therapy alone and in combination with simvastatin on plasma lipids of hypercholesterolemic postmenopausal women with coronary artery disease. J Am Coll Cardiol 1998;32:1244e50. [30] Vijan S, Hayward RA, American College of Physicians. Pharmacologic lipid-lowering therapy in type 2 diabetes mellitus: background paper for the American College of Physicians. Ann Intern Med 2004;140:650e8. [31] Auer J, Berent R, Weber T, Eber B. Clinical significance of pleiotropic effects of statins: lipid reduction and beyond. Curr Med Chem 2002;9:1831e50. [32] Yee A, Majumdar SR, Simpson SH, McAlister FA, Tsuyuki RT, Johnson JA. Statin use in type 2 diabetes mellitus is associated with a delay in starting insulin. Diabet Med 2004; 21:962e7. [33] Jick SS, Bradbury BD. Statins and newly diagnosed diabetes. Br J Clin Pharmacol 2004;58:303e9. [34] Klein BE, Moss SE, Klein R, Surawicz TS. The Wisconsin Epidemiologic Study of diabetic retinopathy. XIII. Relationship of serum cholesterol to retinopathy and hard exudate. Ophthalmology 1991;98:1261e5. [35] Wong TY, Klein R, Sharrett AR, Duncan BB, Couper DJ, Tielsch JM, et al. Retinal arteriolar narrowing and risk of coronary heart disease in men and women. The atherosclerosis risk in communities study. JAMA 2002;287:1153e9. [36] Chew EY, Klein ML, Ferris III FL, Remaley NA, Murphy RP, Chantry K, et al. Association of elevated serum lipid levels with retinal hard exudates in diabetic retinopathy. Early Treatment Diabetic Retinopathy Study (ETDRS) report 22. Arch Ophthalmol 1996;114:1079e84. [37] Ferris III FL, Chew EY, Hoogwerf BJ. Serum lipids and diabetic retinopathy. Early Treatment Diabetic Retinopathy Study Research Group. Diabetes Care 1996;19:1291e3. [38] Gordon B, Chang S, Kavanagh M, Berrocal M, Yannuzzi L, Robertson C, et al. The effects of lipid lowering on diabetic retinopathy. Am J Ophthalmol 1991;112:385e91.
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The under-use of statin in type 2 diabetic patients attending diabetic clinics in Italy Angelo Avogaro*, Pietro Guida, Carlo Giorda, Edoardo Mannucci, Gerardo Medea, Marco Comaschi, Mario Velussi, Guglielmo Armienti, Roberta Zucchetti, on behalf of Progetto DIARIO (DIAbetic Register in Italian Offices) Department of Clinical and Experimental Medicine, University of Padova, School of Medicine, Via Giustiniani 2, 35128 Padova, Italy Received 7 June 2005; received in revised form 4 October 2005; accepted 1 December 2005
KEYWORDS Diabetes mellitus; Statins; Cholesterol; Vascular complications; Prescriptions
Abstract Background and aims: The greatest decrease in mortality from cardiovascular disease (CAD) that can be achieved with 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors (statins) is seen in patients with the highest risk for CAD, such as diabetics. Yet, there is evidence for inadequate use of drug therapies to achieve lipid goals. Our aims were to: (1) assess the prevalence of statin use in patients attending diabetic clinics and (2) correlate the use of statins with their risk and clinical status. Methods and results: Of 9921 patients included, only 20.4% of them were receiving statin therapy. Statins were more progressively prescribed in those with risk factors additional to that of diabetes. Patients under statin treatment were older, mostly type 2 diabetics, more hypertensive and hyperlipidemic, had a higher prevalence of both macro- and microvascular disease. Among those with a total cholesterol concentration above 252 mg/dl, statin treatment was given only to 60% of diabetic patients with prior myocardial infarction, 56% of those with angina, 66% of those having had prior revascularization procedure, 54% of those with cerebrovascular disease and 51% of those with peripheral artery disease. Conclusions: At least in Italy, statins are not prescribed to the majority of diabetic patients, and a substantial proportion of patients not treated with statins present significant macro- and microvascular complications. ª 2005 Elsevier B.V. All rights reserved.
* Corresponding author. Tel.: þ39 049 821 2178; fax: þ39 049 875 4179. E-mail address: [email protected] (A. Avogaro). 0939-4753/$ - see front matter ª 2005 Elsevier B.V. All rights reserved. doi:10.1016/j.numecd.2005.12.001
Under-use of statin in type 2 diabetic patients attending diabetic clinics
Introduction
Methods
Randomized clinical trials have established that low-density lipoprotein cholesterol (LDL-C) reduction is a key factor in preventing cardiovascular disease (CVD) [1e6]. The 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors, known as statins, are the most effective agents to reduce LDL-C. Interestingly, the greatest decrease in morbidity and mortality that can be achieved with these agents is seen in patients at the highest risk for CVD such as type 2 diabetic patients [7,8]. These patients are at increased risk of CVD: primary prevention studies using aspirin and statin have shown the beneficial effects of these two drugs in diabetes [9,10]. The National Institute for Clinical Excellence guidelines on lipid and blood pressure management in patients with type 2 diabetes mellitus recommended statin treatment for patients with a 15% CVD risk at 10 years, advocating more widespread prescription of statins [11]. The recent findings of the Heart Protection Study (HPS) suggest that all patients with diabetes aged between 40 and 80 years with total cholesterol of >3.5 mmol/l should be treated with statins, implying that CVD risk estimation is not necessary [8]. Patients with clinically established CVD are defined as the highest priority in the Joint European Societies’ guidelines for the prevention of CVD and clearly emphasize the high-risk status of diabetic patients [12e14]. The EUROASPIRE II, which covered 15 countries, showed a high prevalence of unhealthy lifestyles, modifiable risk factors and inadequate use of drug therapies to achieve blood pressure and lipid goals [15]. Among the patients on admission, at discharge and at interview the use of the lipid lowering drugs was under-used in 26%, 43% and 61%, respectively. Thus, this study showed that there is considerable potential throughout Europe to raise the standard of preventive cardiology through more effective lifestyle intervention, control of other risk factors and optimal use of prophylactic drug therapies in order to reduce coronary morbidity and mortality. Specifically in Italy, among patients suffering from coronary heart disease (CHD), the lipid lowering drugs were prescribed on admission, on discharge, and at interview to 10.1%, 45.5% and 59.7% of the patients, respectively. However, these figures were obtained from a selected subset of patients of whom only 21.8% had a self-reported diabetes. In the light of these premises we wished to assess the prevalence of statin use in patients attending diabetic clinics and to correlate the use of statins to their clinical status.
System context and system cohort
33
The Italian Health System provides free medical care for both type 1 and type 2 diabetic patients through outpatient diabetic care units. Seventy percent of type 2 diabetic patients refer to these clinics. The Progetto DIARIO (DIAbetic Register in Italian Offices) created a data base for statin prescriptions in type 1 and type 2 diabetic patients. The population consists of all patients seen at the participating units between July 2002 and September 2002. Type 1 and type 2 diabetes were diagnosed according to the 1985 criteria of the World Health Organization. To create a representative sample of the diabetic population referring to each clinic, patients were randomly chosen so that the data of patients seen in each of the 183 participating clinics in the first weeks of each month between July and September were analyzed. During the examination, for each patient included in the cohort, a standard questionnaire was used. The variables considered were: personal data and lifestyle habits; anthropometrical data; pharmacological therapies; laboratory data; clinical history and data on microvascular (retinopathy and chronic renal failure), and data on macrovascular complications (myocardial infarction, ischemic heart disease, coronary artery bypass, coronary angioplasty, cerebral and peripheral artery disease). Each patient had at least a: (1) plasma glucose, HbA1c and lipid profile, determined in the fasting state, no more than three months prior to the interview; (2) systolic and diastolic blood pressures measured during the visit with a sphygmomanometer after the patient had been seated for at least 5 min; and (3) a comprehensive eye examination by an ophthalmologist no more than six months before.
Definitions A patient was defined as hypertensive if he/she used an antihypertensive treatment or had a blood pressure 140/90 mm Hg. Patients were classified as having CHD if they had: (1) a positive history for hospital admission for either an acute myocardial infarction (AMI) or an episode of angina; (2) a positive 12-lead ECG for prior acute myocardial infarction or angina coded using the Minnesota coding system (criteria I 1e3,
34
A. Avogaro et al.
IV 1e3, V 1e2, and VII 1); (3) a positive history for coronary artery bypass graft (CABG); or (4) a positive history for percutaneous transluminal coronary angioplasty (PTCA) [14]. Patients were classified as hyperlipidemic if they had a total cholesterol 200 mg/dl, HDL cholesterol < 40 mg/dl for men and <50 mg/dl for women, or if they were on lipid lowering therapy [15]. Patients were classified as having cerebrovascular disease if they had had an episode of neurological dysfunction caused by a cerebral vascular episode associated either with temporary or permanent brain injury [16]. Patients were classified as having peripheral artery disease if they had a ratio of arm/foot systolic pressure 0.7 or a previous history of lower limb revascularization or evidence or a significant arterial stenosis detected either by angiography or by Doppler ultrasound [17]. Patients were classified as having a chronic renal failure if glomerular filtration rate was less than 30 cc/min according to the Cockroft formula [18]. Definition of the components of metabolic syndrome was derived from the NCEP-ATP III [19].
Statistical analysis Continuous variables were expressed as mean standard deviation and were compared with
Table 1
Results A total of 9921 patients were included for the analysis. For all participants, the data listed in the methods were collected; patients were excluded from the analysis if data on sex, age, HbA1c, glycaemia, and lipids were missing or implausible. The main characteristics of the study population are presented in Table 1. Diabetic women showed a higher severity of risk factors for CVD, a worse metabolic control, and a substantially lower prevalence of previous acute myocardial infarction than men, but a similar prevalence of history of angina. The revascularization procedures were less frequently performed in women than men. The burden of atherosclerotic disease in peripheral arteries was also more frequent in men than women, who had, at variance, higher prevalence of diabetic microangiopathy. As shown in Table 2, women were receiving more blockers of the renineangiotensin system than men, who at variance, were receiving more antiplatelet drugs. Diuretics and antidiabetic agents were more employed in women. Only
Anthropometric and clinical characteristics of the study population
Sex (male %) Age (years) Type 1 diabetic patients (%) Hypertension (%) Hyperlipidemia (%) Previous acute myocardial infarction (%) History of angina (%) Revascularization (PTCA/CABG) (%) Cerebrovascular disease (%) Peripheral vascular disease (%) Diabetic retinopathy (%) Chronic renal failure (%) Systolic blood pressure (mm Hg) Diastolic blood pressure (mm Hg) Total cholesterol (mg/dl) HDL cholesterol (mg/dl) LDL cholesterol (mg/dl) Triglycerides (mg/dl) Fasting plasma glucose (mg/dl) HbA1c (%) Mean SD.
analysis of variance. Categorical variables were expressed as percent frequency and compared with Pearson c2 test. Differences were considered statistically significant when p-value was <0.05.
Total, n ¼ 9921
Females, n ¼ 4943
Males, n ¼ 4978
p
50 65 12 8.3 56.6 34.3 7.4 5.6 4.1 4.2 8.8 21.4 4.1 141 19 81 9 207 40 51 14 126 34 151 102 163 69 7.5 1.6
0 66 12 8.2 61.5 36.3 4.7 5.9 2.4 3.8 6.8 22.6 3.2 142 19 81 9 211 40 53 15 128 35 149 94 166 79 7.6 1.6
100 64 12 8.5 51.7 32.3 10.1 5.2 5.8 4.6 10.8 20.2 5.0 140 19 81 9 202 40 48 13 124 33 154 109 161 58 7.4 1.6
e <0.001 0.635 <0.001 <0.001 <0.001 0.088 <0.001 0.047 <0.001 0.005 <0.001 <0.001 0.693 <0.001 <0.001 <0.001 0.005 0.004 <0.001
Under-use of statin in type 2 diabetic patients attending diabetic clinics 20.4% of diabetic patients were receiving statins which were more commonly prescribed in women than in men. Table 3 shows the anthropometric and clinical characteristics of diabetic patients without CVD as a function of the number of principal risk factors co-segregating with diabetes: patients with more risk factors, including diabetes, were older, had a higher atherosclerotic burden, a higher prevalence of diabetic microvascular disease, and worse metabolic and pressure controls. Statin therapy was more progressively prescribed in those with other risk factors in addition to diabetes. Table 4 reported the same analysis for diabetic patients with CVD: comparable results for these patients were obtained as for those without CVD. However, patients with CVD had higher prevalence of retinopathy, chronic renal failure, and had higher HbA1c than those without. Statins were significantly more prescribed in those with CVD than in those without. Among those who were not treated with statins, higher cholesterol levels were less likely to be associated with type 1 diabetes, prior acute myocardial infarction, and cerebrovascular disease (Table 5). As shown in Table 6, the patients treated with statins were more likely to have CHD, CVD
Table 2 Drug treatment in the entire cohort according to sex Totals, Females, Males, p n ¼ 9921 n ¼ 4943 n ¼ 4978 ACE-inhibitors 30.8 (%) ATII inhibitors 12.0 (%) Beta-blockers 8.5 (%) Antiplatelets 19.7 (%) Anticoagulants 2.2 (%) Ca-channel 17.6 blockers (%) Digitalis (%) 2.6 Antiarrhythmics 0.9 (%) Diuretics (%) 17.0 Nitrates (%) 5.4 Antidiabetics 84.8 agentsa (%) Fibrates (%) 2.9 Omega 3 (%) 1.0 Statins (%) 20.4
32.2
29.4
0.003
13.6
10.5
<0.001
8.7
8.4
0.59
17.3
22.2
<0.001
1.9
2.5
0.062
18.8
16.5
0.002
2.9 0.9
2.2 1.0
0.023 0.863
19.6 5.6 85.8
14.4 5.2 83.8
<0.001 0.31 0.006
2.5 0.7 21.8
3.2 1.3 19.1
0.036 0.003 <0.001
a Antidiabetic agents include oral hypoglycemic agents plus insulin.
35
and worse major risk factors for CVD. However, as shown in Fig. 1, only 60% of diabetic patients with prior myocardial infarction and total cholesterol higher than 252 mg/dl were on statin treatment, 56% of those with angina, 66% those with a prior revascularization procedure, 54% of those with cerebrovascular disease, and 51% of those with peripheral artery disease.
Discussion This study shows that: (1) statins are not prescribed to the majority of diabetic patients; (2) treatment with statins is more frequent in patients with increasing severity of cardiovascular burden; however, a major proportion of diabetic patients, irrespective of the presence of CVD, is not receiving statin therapy despite a clinically manifest peripheral artery disease. This study shows that the prevalence of CHD is 11% in women and 16% in men. The prevalence in women is comparable to that reported in a previous Italian study [14]; in contrast we found a higher prevalence of CHD in men. This discrepancy is not readily apparent. Either a different randomization strategy between the two studies or a different reperfusion attitude between participating centres may explain such a difference [20]. Women had lower prevalent CVD than men despite worse risk factor profile: this incongruity may be due to the fact that women were more treated than men; moreover women, despite similar treatment, appear to gain more protection in terms of primary end points [6]. Another potential caveat which could partially explain the observed results is that the reported lipid data were obtained in different laboratories with different procedures. Unfortunately, there was no possibility to assay biomarkers in a single core laboratory. Another potential limitation of this study is that the data collected in this survey relate to diabetic patients referring to the outpatient diabetic units; unfortunately, in some Italian regions, up to 60% of type 2 diabetic patients are followed by their general practitioner. Undoubtedly this may affect the information gained in the study which may not be representative of the whole Italian diabetic population. ATP III set the goal for LDL cholesterol lowering in high-risk patients to be <100 mg/dl, the practical limit endorsed by available clinical trials. This limit is further reduced to <70 mg/dl in patients at very high risk. Diabetes is a high-risk condition, and diabetes plus CHD is a very high-risk condition [21]. The data presented in this study demonstrate
36
A. Avogaro et al.
Table 3 Anthropometric and clinical variables and statin therapy according to the number of risk factorsa in addition to diabetes in patients without cardiovascular disease Sex (male %) Age (years) Type 1 diabetic patients (%) Diabetic retinopathy (%) Chronic renal failure (%) Systolic blood pressure (mm Hg) Diastolic blood pressure (mm Hg) Total cholesterol (mg/dl) HDL cholesterol (mg/dl) LDL cholesterol (mg/dl) Triglycerides (mg/dl) HbA1c Statin therapy
Diabetes, n ¼ 829
þ1, n ¼ 3252
þ2, n ¼ 2414
þ3, n ¼ 1214
p
53 56 16 27.3
51 64 12 10.2
46 64 11 4.8
37 64 11 2.6
<0.001 <0.001 <0.001
15.6 1.9
19.5 2.7
16.9 3.3
21.6 3.8
<0.001 0.058
117 7
142 18
144 18
148 16
<0.001
73 7
81 9
82 9
84 9
<0.001
198 35 59 13 121 30 90 29 7.3 1.6 10.9
204 36 57 14 126 31 107 55 7.4 1.5 14.0
210 44 46 11 130 36 179 115 7.6 1.7 18.3
214 40 38 6 128 38 244 112 7.8 1.7 22.6
<0.001 <0.001 <0.001 <0.001 <0.001 <0.001
Mean SD. a Risk factors considered were: blood pressure 140/90, HDL cholesterol < 40 mg/dl for men and <50 mg/dl for women, triglycerides 150 mg/dl, and total cholesterol 200 mg/dl.
that, not only baseline LDL cholesterol in diabetic patients is much higher than this recommended level, but also that LDL cholesterol increases in patients with more than one component of the metabolic syndrome as defined by ATP III. Based on available outcomes, statin therapy should by initiated in all diabetic patients as outlined by the HPS
trial, and recently by the CARDS trial [8,22]. These studies also emphasize the finding that risk charts are not useful in establishing future cardiovascular risk in type 2 diabetic patients in order to initiate statin therapy. Our data are meagre in the sense that only 20.4% of diabetic patients periodically referring
Table 4 Anthropometric and clinical variables and statin therapy according to the number of risk factorsa in addition to diabetes in patients with cardiovascular disease Sex (male %) Age (years) Type 1 diabetic patients (%) Diabetic retinopathy (%) Chronic renal failure (%) Systolic blood pressure (mm Hg) Diastolic blood pressure (mm Hg) Total cholesterol (mg/dl) HDL cholesterol (mg/dl) LDL cholesterol (mg/dl) Triglycerides (mg/dl) HbA1c Statin therapy
Diabetes, n¼153
þ1, n¼901
þ2, n¼726
þ3, n¼432
p
70 69 9 9.2
66 70 9 7.1
57 69 9 3.9
42 69 9 4.4
<0.001 0.024 0.005
26.8 3.3
31.2 6.7
28.9 9.9
36.1 9.5
117 6
144 19
145 17
148 16
<0.001
73 8
80 10
80 9
82 10
<0.001
195 35 56 11 120 31 99 27 7.3 1.4 32.7
203 44 56 14 123 32 109 39 7.4 1.4 31.5
206 45 45 10 126 35 177 102 7.8 1.5 36.1
216 40 38 6 131 38 252 134 8.2 1.7 39.8
<0.001 <0.001 0.006 <0.001 <0.001 0.019
0.046 0.008
Mean SD. a Risk factors considered were: blood pressure 140/90, HDL cholesterol < 40 mg/dl for men and <50 mg/dl for women, triglycerides 150 mg/dl, and total cholesterol 200 mg/dl.
Under-use of statin in type 2 diabetic patients attending diabetic clinics to the diabetes unit are under statin treatment. Furthermore, a substantial proportion of diabetic patients with prevalent artery disease, i.e. very high-risk patients, do not receive appropriate statin therapy. Yet, among those who are receiving appropriate treatment, both total cholesterol and LDL cholesterol are still unacceptably high. These data not only emphasize the poor receptiveness of physicians to adhere to guideline recommendations but also support the findings of both EUROASPIRE I and II which demonstrated that most CHD patients are still not achieving the cholesterol goal, and that there is a considerable potential to raise the standards for preventive cardiology [13,23]. This analysis confirms the findings of another survey performed in Italy in which it was shown that in diabetic patients there is a substantial gap between therapeutic guidelines and actual treatment [24]. Since a positive correlation between the number of treatments taken and the assumption of statins was found using a multivariate model, physicians’ prescription attitudes were proposed as a possible reason for this behaviour. However, it must be kept in mind that our survey includes not the entire diabetic population but only a portion of it; there are indeed some Italian regions where more than
37
half of diabetic patients are seen by the general practitioners. Our data not only emphasize these concepts but also underpin another major negative aspect in treating the atherosclerotic burden in diabetic patients, i.e., statin therapy is only partially globally risk-driven; instead it appears to be organdamage driven. As shown in Fig. 1, it is indeed clear that there is a significant discrepancy in statin treatment between those who receive a coronary revascularization and those who show clinically evident peripheral or cerebrovascular artery disease. This is clinically unacceptable since it is evident that the presence of peripheral artery disease is not only itself a mirror of ongoing atherosclerotic vascular disease but coexists with atherosclerotic disease in other sections of the vascular tree [25]. As regards secondary prevention, until November 2004 in Italy, the National Health Service provided statins free of charge only to patients who experienced a coronary event. This may explain why patients with peripheral and cerebral artery diseases show such low rates of treatment. Statins have been shown to lower not only plasma LDL cholesterol and triglyceride levels in type 2 diabetic patients, but also small dense LDL
Table 5 Anthropometric and clinical variables of patients not treated with statins stratified according total cholesterol concentration
Sex (males %) Age (years) Tipe 1 diabetes (%) Hypertension (%) Hyperlipidemia (%) Prior acute myocardial infarction (%) Angina (%) Revascularization (%) Cerebrovascular disease (%) Peripheral artery disease (%) Chronic renal failure (%) Systolic blood pressure (mm Hg) Diastolic blood pressure (mm Hg) HDL cholesterol (mg/dl) LDL cholesterol (mg/dl) Triglycerides (mg/dl) Fasting plasma glucose (mg/dl) HbA1c (%) Mean SD.
n ¼ 7893
173, n ¼ 1612
174e212, n ¼ 3360
213e251, n ¼ 2207
252, n ¼ 714
p
51 65 12 9.4 53.6 21.6 5.4
58 64 14 13.0 49.3 10.5 5.2
53 64 12 9.6 53.0 13.1 6.3
47 66 12 6.8 56.5 30.4 4.5
39 64 11 8.3 57.3 58.8 4.5
<0.001 <0.001 <0.001 <0.001 <0.001 0.022
4.3 2.5 3.5 7.8 3.8 141 19
4.5 2.8 4.3 7.4 4.2 138 19
4.4 2.8 3.8 7.1 3.5 140 18
3.9 2.0 2.7 9.1 3.5 143 19
4.2 1.8 3.4 8.0 4.9 145 20
0.713 0.167 0.041 0.055 0.242 <0.001
81 9
79 9
81 9
82 9
83 10
<0.001
51 15 124 19 146 102 164 85
46 12 88 17 114 63 158 60
50 13 117 17 137 79 160 57
54 15 144 19 162 102 168 85
56 17 175 29 214 175 182 93
<0.001 <0.001 <0.001 <0.001
7.5 1.6
7.4 1.7
7.4 1.5
7.6 1.6
8.0 2.0
<0.001
38
A. Avogaro et al.
Table 6 Anthropometric and clinical variables of patients treated with statins stratified according total cholesterol concentration
Sex (males %) Age (years) Type 1 diabetes (%) Hypertension (%) Hyperlipidemia (%) Prior acute myocardial infarction (%) Angina (%) Revascularization (%) Cerebrovascular disease (%) Peripheral artery disease (%) Chronic renal failure (%) Systolic blood pressure (mm Hg) Diastolic blood pressure (mm Hg) HDL cholesterol (mg/dl) LDL cholesterol (mg/dl) Triglycerides (mg/dl) Fasting plasma glucose (mg/dl) HbA1c (%)
n ¼ 2028
173, n ¼ 305
174e212, n ¼ 602
213e251, n ¼ 636
252, n ¼ 485
p
47 66 12 4.3 68.1 83.7 15.2
58 66 9 4.6 72.5 77.7 27.2
50 66 9 4.5 70.6 82.1 16.8
45 66 9 4.1 64.6 83.5 11.9
39 65 10 4.3 66.8 89.9 9.9
<0.001 0.080 0.982 0.040 <0.001 <0.001
10.6 10.4 6.7
12.8 17 5.2
13 12.8 8.6
9.4 9 6.1
7.8 5.2 5.8
0.019 <0.001 0.129
12.8
13.1
14.3
11.6
12.4
0.559
5.3
8.5
4.7
4.4
5.2
0.048
142 19
140 17
142 18
141 18
145 19
<0.001
81 9
80 9
81 10
81 9
82 10
0.008
50 15
46 12
50 12
50 14
52 15
<0.001
135 19 171 102 162 85
85 19 137 75 153 48
114 19 153 80 156 51
147 21 173 95 164 85
183 29 212 155 171 57
<0.001 <0.001 <0.001
7.6 1.6
7.4 1.4
7.4 1.4
7.5 1.5
8.0 1.8
<0.001
Mean SD.
Patients treated with statins (%)
70
Revasc AMI
60
Angina
Revasc
CVD
Revasc
50
PVD
AMI Revasc
AMI
Angina
CVD
40 Angina
Angina
AMI CVD
30
PVD
PVD
PVD CVD
20
10
0 <173
174-212
213-251
>252
Total Cholesterol (mg/dl)
Figure 1 The percentage of diabetic patients treated with statins according to total cholesterol levels and to atherosclerotic disease. Black bars represent those with a history of acute myocardial infarction (AMI), the dark grey bars those with angina, the light bars those who had revascularization procedure (Revasc), the light squared bars (blue in web version) those with cerebrovascular disease (CVD), and the white bars those with peripheral vascular disease (PVD).
Under-use of statin in type 2 diabetic patients attending diabetic clinics levels [26]. It was shown that atorvastatin can positively modify LDL particle density in type 2 diabetic patients [27]. Similarly, fluvastatin reduces small dense LDL subfractions more effectively than more buoyant fractions in type 2 diabetic patients [28]. In contrast, simvastatin decreased cholesterol concentrations uniformly across all LDL subfractions in these patients [29]. In this study we do not report either the type of statin prescribed or the dose prescribed: this may explain why, even in those receiving statin therapy, adequate LDL cholesterol level is not achieved. However, as recently emphasized, most diabetic patients benefit from moderate doses of these drugs [30]. We also found that patients receiving statin treatment have a similar metabolic control to those who are not receiving the treatment: neither the CARDS nor the HPS assessed the impact of statin treatment of glycemic control, although some studies in nondiabetic patients showed that statins are able to decrease the onset of new diabetes and delay the start of insulin therapy [31e33]. The use of statin therapy has also been proposed for nonmacrovascular disease such as diabetic retinopathy and nephropathy. In this study 13.4% of patients had diabetic retinopathy among those without CVD vs. 30.7% among those with CVD: these data emphasize the tight association between micro- and macrovascular complication in type 2 diabetic patients [34]. We also show that 20.8% of those not treated with statin had evidence of diabetic retinopathy and 3.8% of chronic renal failure. Observational studies of patients with diabetes have shown an association between diabetic retinopathy and plasma cholesterol levels [35e37]. The presence of retinopathy was associated with higher cholesterol levels. In another study the severity of visual loss correlated with the severity of retinopathy [38]: by inference, reduction in cholesterol may favourably affect retinopathy. In conclusion we show that statins are not prescribed for the majority of diabetic patients and that a substantial proportion of patients not treated with statins present significant macro- and microvascular complications. Although optimal LDL-C levels have been set at <100 mg/dl for high-risk patients, this nationwide Italian study in ambulatory diabetic patients, as other recent studies, shows that only about 20% of such patients are under appropriate treatment. Thus, a large treatment gap remains which needs to be overcome if we are to continue to make significant inroads into preventing further morbidity and mortality in high-risk diabetic subjects.
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