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© The European Society of Cardiology 2005. All rights reserved. For Permissions, please e-mail: journals.permissions{at}oupjournals.org

Under-treated high-risk patients: identifying patients in high-risk subgroups and treating them to LDL-C targets

H. Schuster{dagger}

Humboldt University, Berlin, Germany

{dagger} Present address: Prof. Dr Herbert Schuster, INFOGEN GmbH, Xantener Strasse 10, 10707 Berlin, Germany. Tel: +49 30 31018724; fax: +49 30 31018726. E-mail address: herbert.schuster{at}infogen.de


   Abstract
Top
 Abstract
Introduction
 Peripheral arterial disease
 Heterozygous FH
 Diabetes
 The metabolic syndrome
 Conclusion
 Discussion
 References
 
Many patients at high risk for coronary heart disease (CHD) are not readily identified by routine risk assessment in clinical practice and are consequently at risk for inadequate management. Peripheral arterial disease is a CHD risk equivalent, requiring intensive low-density lipoprotein cholesterol (LDL-C) lowering to the lowest recommended target levels; however, asymptomatic disease, although still associated with elevated risk, is not likely to be recognized in routine clinical practice. Heterozygous familial hypercholesterolaemia (FH) is associated with early and aggressive atherosclerotic disease, yet individuals with FH may go unrecognized in the absence of family screening. The metabolic syndrome is very common and is also associated with increased CHD risk, but affected individuals may not be identified if attention is not given to the relatively simple clinical criteria currently recommended for use in diagnosis. Although it is widely known that type 2 diabetes is associated with elevated CHD risk, the fact that statin treatment in diabetic patients is warranted even in those with relatively low LDL-C levels may not be widely appreciated. Recent modifications of the National Cholesterol Education Program Adult Treatment Panel III guidelines include optional reductions in both LDL-C goals and thresholds for initiating therapy in light of persuasive clinical trial evidence that patients at high risk and moderately high risk derive protective benefits from statin therapy even when treatment is started at LDL-C levels below prior goal or threshold levels. Increased vigilance for high-risk conditions that may elude routine risk assessment is necessary to ensure that all high-risk patients receive adequate treatment.

Key Words: Coronary heart disease • Peripheral arterial disease • Cholesterol lowering • Metabolic syndrome • Type 2 diabetes • Adult Treatment Panel III guidelines


   Introduction
Top
 Abstract
 Introduction
Peripheral arterial disease
 Heterozygous FH
 Diabetes
 The metabolic syndrome
 Conclusion
 Discussion
 References
 
As our experience with statins for the management of hypercholesterolaemia and our knowledge of their beneficial effects in reducing risk for coronary heart disease (CHD) have grown, it has been recognized that a wide range of patients can benefit from statin therapy. Among the high-risk patients whose degree of risk and need for intensive lipid-lowering therapy may frequently go unrecognized in the clinical practice setting are those without established CHD, including patients with peripheral arterial disease (PAD), those with heterozygous familial hypercholesterolaemia (FH), and those with diabetes or the metabolic syndrome. Heightened vigilance is needed in routine clinical practice to ensure that such patients receive optimum management.


   Peripheral arterial disease
Top
 Abstract
 Introduction
 Peripheral arterial disease
Heterozygous FH
 Diabetes
 The metabolic syndrome
 Conclusion
 Discussion
 References
 
PAD is associated with very high rates of myocardial infarction (MI) and sudden cardiac death. Under the National Cholesterol Education Program Adult Treatment Panel III (ATP III) guidelines, PAD is considered a CHD risk equivalent, warranting treatment to the lowest low-density lipoprotein cholesterol (LDL-C) target levels.1,2 An idea of the magnitude of cardiovascular risk associated with asymptomatic and symptomatic disease is provided by a 10-year prospective follow-up of individuals in whom large-vessel disease was diagnosed by non-invasive means. Criqui and colleagues3 assessed 565 men and women (average age, 66 years), who were initially studied under a Lipid Research Clinics protocol, for the presence of large-vessel PAD, using segmental blood pressure measurement and measurement of flow velocity via Doppler ultrasound. In total, 67 subjects (11.9%) were found to have large-vessel disease. Over follow-up, death occurred in 61.8% (21/34) of men and 33.3% (11/33) of women with large-vessel disease, compared with 16.9% (31/183) of men and 11.6% (26/225) of women without such disease. On multivariate analysis including adjustment for age, sex, and cardiovascular risk factors, the relative risks for death among subjects with large-vessel disease were 3.1 for all-cause mortality, 5.9 for cardiovascular mortality, and 6.6 for CHD death. After exclusion of subjects with a history of cardiovascular disease at baseline, the relative risk for CHD death remained significantly elevated at 4.3. Additional analyses showed that among patients with disease that might not normally come to clinical attention (for example, unilateral, moderately severe, or asymptomatic disease, or disease isolated to the posterior tibial artery), there was a three- to six-fold increase in risk of death due to cardiovascular disease and CHD; for patients with symptomatic or severe disease, there was a 10- to 15-fold increase in risk of death due to cardiovascular disease or CHD, with the relative risk of such mortality being increased 15-fold in those with symptomatic and severe disease compared with subjects without large-vessel disease (Figure 1).




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  		Figure 1 Kaplan–Meier survival curves showing (top) all-cause mortality among normal subjects and among subjects with asymptomatic, symptomatic, or severe symptomatic large-vessel PAD and (bottom) all-cause mortality among these groups after exclusion of subjects with cardiovascular disease at baseline. (Reproduced with permission from Criqui et al.3)

 

   Heterozygous FH
Top
 Abstract
 Introduction
 Peripheral arterial disease
 Heterozygous FH
Diabetes
 The metabolic syndrome
 Conclusion
 Discussion
 References
 
Heterozygous FH is an autosomal dominant disorder affecting about one in 500 people in the developed world. It is caused by a defect in the gene encoding the LDL receptor protein, resulting in reduced numbers of functional LDL receptors and elevated plasma LDL-C.4 Affected individuals are at increased risk for early atherosclerosis and CHD5; typically, affected men experience their first cardiovascular event at around 30–40 years of age and affected women at around 40–50 years of age.6 It is estimated that FH accounts for 5% of all MIs occurring in individuals aged less than 60 years.7 Treatment to lower LDL-C is the key to reducing CHD risk in these individuals. Statins both inhibit cholesterol synthesis and up-regulate LDL receptor function and are now considered to be first-line agents in the management of patients with FH.

Identification of individuals with FH does not hinge on molecular diagnostics. Individuals with the disorder can be reliably identified through family studies, since lipid levels are highly predictable within families. A history of early-onset cardiovascular disease in a relative should prompt assessment of cholesterol levels in the probands and close relatives, and the finding of high cholesterol levels in a child should also prompt suspicion of FH and initiation of family analysis (Figure 2). Within a pedigree, cholesterol levels show a clear bi-modal distribution between affected and unaffected individuals (Figure 3),8 rendering diagnosis fairly straightforward when such information is obtained. Identifying individuals with FH is critical to treatment decisions. Consider the case of a 49-year-old male with LDL-C of 187 mg/dL (4.8 mmol/L). This patient could have multi-factorial hyperlipidaemia with a calculated 10-year CHD risk of <10%; the LDL-C goal for this individual would be <160 mg/dL (4.1 mmol/L), requiring a 15% reduction in LDL-C that could be achieved via lifestyle intervention. On the other hand, the patient could have FH, with a 10-year CHD risk of >20%; the LDL-C goal in this case is <100 mg/dL (2.5 mmol/L), requiring statin therapy to produce the needed LDL-C reduction of at least 47%.



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  		Figure 2 Diagnosis of FH by segregation analysis. LDL-C levels (mg/dL) are untreated levels at initial presentation. Diagonal line through square (male) or circle (female) shows affected individuals in family.

 


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  		Figure 3 Intrafamilial cholesterol levels in FH. (Adapted from Williams et al.8)

 
Large reductions in LDL-C are achievable with the more effective LDL-C-lowering statins. In the largest lipid-lowering trial in FH patients conducted to date,9 623 patients with FH diagnosed on clinical and/or genetic criteria who had LDL-C of 220–500 mg/dL and triglycerides of ≤400 mg/dL were randomized to rosuvastatin (n=436) or atorvastatin (n=187), with doses starting at 20 mg and titrated at 6-week intervals to 40 mg. Mean LDL-C levels at baseline were 292 mg/dL in the rosuvastatin group and 288 mg/dL in the atorvastatin group. LDL-C was reduced by 47.1% with rosuvastatin and 38.0% with atorvastatin at 6 weeks (P<0.001) and by 53.9 vs. 46.0% at 12 weeks (P<0.001).

Another trial has shown evidence that statin treatment can beneficially affect atherosclerosis progression in children with FH.10 In this trial, 214 children aged 8–18 years received pravastatin 20–40 mg or placebo after initiation of a fat-restricted diet and encouragement of regular physical activity and were followed for changes in carotid intima media thickness (IMT) measured by B-mode ultrasound. Over 2 years, there was a trend towards IMT regression in the pravastatin group, with the mean change being –0.010 (0.048) mm (P=0.049), and a trend towards progression in the placebo group, with a mean change of +0.005 (0.044) mm (P=0.28); the difference between the two groups, 0.014 (0.046) mm, was statistically significant (P=0.02). These changes occurred in the context of a 24.1% reduction in LDL-C with pravastatin treatment and a 0.3% increase in the placebo group. No differences between groups were observed with regard to growth, muscle or liver enzymes, endocrine function parameters, Tanner staging scores, onset of menses, or testicular volume.


   Diabetes
Top
 Abstract
 Introduction
 Peripheral arterial disease
 Heterozygous FH
 Diabetes
The metabolic syndrome
 Conclusion
 Discussion
 References
 
It is well known that patients with diabetes are at substantially elevated risk of cardiovascular disease,1,2,11,12 with the risk of MI in diabetic patients without a history of MI being as high as the risk of MI in non-diabetic patients with a history of CHD.13 The Heart Protection Study provided important information on optimizing management of cardiovascular risk in patients with diabetes. This trial14 enrolled 20 536 high-risk individuals, including those with prior MI or other CHD, occlusive disease of non-coronary arteries, treated hypertension, or diabetes, in whom statin treatment was neither contraindicated nor considered clinically necessary by their treating physicians. The trial found that treatment with simvastatin 40 mg was associated with a significant 24% reduction in risk for first occurrence of a major vascular event (19.8 vs. 25.2%, P<0.0001), with risk reduction in patients beginning treatment with LDL-C<100 mg/dL being the same as that among patients beginning treatment at higher LDL-C levels.14 Analysis of outcomes among the 5963 patients with diabetes in this trial15 showed that simvastatin treatment was associated with a significant 22% reduction in risk for first occurrence of a major vascular event (20.2 vs. 25.1%, P<0.0001), a 27% reduction in risk for first major coronary events (P<0.0001), a 33% reduction in risk for first major vascular events among the 2912 patients with no initial evidence of occlusive arterial disease (P=0.0003), and a 27% reduction in risk for first major vascular events among the 2426 patients with initial LDL-C<116 mg/dL (3.0 mmol/L).

The finding that diabetic patients benefit from LDL-C reduction with statin therapy no matter what their pre-treatment LDL-C has been confirmed in the Collaborative Atorvastatin Diabetes Study (CARDS). In this UK study, 2838 patients with diabetes and no pre-existing cardiovascular disease were randomized to treatment with atorvastatin 10 mg or placebo.16 The trial was stopped early because of the finding of a significant difference between groups with regard to risk for the composite primary endpoint of major coronary events, revascularization, stroke, unstable angina, or resuscitated cardiac arrest. Atorvastatin treatment was associated with a 37% reduction in the primary endpoint (P=0.001), as well as significant reductions in risk for acute coronary events (36% reduction) and stroke (48% reduction). A mean 41% reduction in LDL-C was achieved with atorvastatin treatment in a study population in which >50% of patients had initial LDL-C below the threshold for treatment initiation and one quarter had initial values below the European goal level of 100 mg/dL (2.6 mmol/L).

A number of studies have been undertaken to assess the effects of rosuvastatin and atorvastatin in reducing LDL-C levels and achieving target levels in diabetic patients. In the COmpare the effect of Rosuvastatin with Atorvastatin on apoB/apoA-1 ratio in patients with type 2 diabetes meLLitus and dyslipidaemia (CORALL) trial,17 263 patients with diabetes who had LDL-C≥130 mg/dL (3.4 mmol/L) and were statin-naïve, or who had LDL-C >115 and <190 mg/dL (3.0–4.9 mmol/L) and had received a statin within 4 weeks, and who had triglycerides ≤400 mg/dL (4.5 mmol/L) were randomized to rosuvastatin 10 mg (n=131) or atorvastatin 20 mg (n=132); doses were increased to rosuvastatin 20 mg vs. atorvastatin 40 mg and to rosuvastatin 40 mg vs. atorvastatin 80 mg at 6-week intervals. Baseline LDL-C levels were 4.23 mmol/L in the rosuvastatin group and 4.43 mmol/L in the atorvastatin group. Significantly greater LDL-C reductions were observed with rosuvastatin 10 mg vs. atorvastatin 20 mg at 6 weeks (45.9 vs. 41.3%), rosuvastatin 20 mg vs. atorvastatin 40 mg at 12 weeks (50.6 vs. 45.6%), and rosuvastatin 40 mg vs. atorvastatin 80 mg at 18 weeks (53.6 vs. 47.8%) (all P<0.05). The current European LDL-C goal of <2.5 mmol/L in diabetic patients was achieved by 78% of rosuvastatin patients vs. 70% of atorvastatin patients at week 6, 83 vs. 77% at week 12, and 90 vs. 78% at week 18 (P<0.05) (Figure 4, top).




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  		Figure 4 Comparisons of rosuvastatin and atorvastatin in patients with type 2 diabetes. Top: Proportions of patients reaching LDL-C goal of <2.5 mmol/L with rosuvastatin (RSV) 10, 20, or 40 mg vs. atorvastatin (ATV) 20, 40, or 80 mg after 18 weeks in the CORALL (COmpare the effect of Rosuvastatin with Atorvastatin on apoB/apoA-1 ratio in patients with type 2 diabetes meLLitus and dyslipidaemia) trial. Bottom: Proportions of patients reaching an LDL-C goal of <2.5 mmol/L with rosuvastatin vs. atorvastatin 10 mg (8 weeks) and rosuvastatin 20 mg vs. atorvastatin 20 mg (16 weeks) in the ANDROMEDA (A raNdomised, Double-blind, double-dummy, multicentre phase IIIb parallel group study to compare the efficacy and safety of Rosuvastatin [10 mg and 20 mg] and atOrvastatin [10 Mg and 20 mg] in subjEcts with type II DiAbetes mellitus) trial. Data are from Franken et al.17 (CORALL trial) and Betteridge et al.18 (ANDROMEDA trial).

 
In the ANDROMEDA trial (A raNdomised, Double-blind, double-dummy, multicentre phase IIIb parallel group study to compare the efficacy and safety of Rosuvastatin [10 mg and 20 mg] and atOrvastatin [10 Mg and 20 mg] in subjEcts with type II DiAbetes mellitus),18 509 patients with diabetes and triglycerides ≤6.0 mmol/L were randomized to receive rosuvastatin or atorvastatin 10 mg for 8 weeks and 20 mg for an additional 8 weeks. Baseline LDL-C levels were 3.39 mmol/L in the rosuvastatin group and 3.39 mmol/L in the atorvastatin group. After 8 weeks of treatment with 10 mg, LDL-C was reduced by 51.3% with rosuvastatin vs. 39.0% with atorvastatin (P<0.001), with the reduction with rosuvastatin 10 mg at 8 weeks also being significantly greater than that with atorvastatin 20 mg at 16 weeks (P<0.001); at 16 weeks, reductions with 20-mg doses were 57.4% with rosuvastatin vs. 46.0% with atorvastatin (P<0.001). The proportion of patients achieving the European LDL-C goal of <2.5 mmol/L was 94% with rosuvastatin 10 mg, compared with 79% with atorvastatin 10 mg (P < 0.001), and 96% with rosuvastatin 20 mg, compared with 87% with atorvastatin 20 mg (P=0.02) (Figure 4, bottom). The inflammatory marker C-reactive protein (CRP), another indicator of cardiovascular risk (see Professor Faergeman's discussion in this supplement), was reduced by 34.1% with rosuvastatin 10 mg, by 39.8% with rosuvastatin 20 mg, by 21.2% with atorvastatin 10 mg, and by 33.8% with atorvastatin 20 mg. No comparison was significant.


   The metabolic syndrome
Top
 Abstract
 Introduction
 Peripheral arterial disease
 Heterozygous FH
 Diabetes
 The metabolic syndrome
Conclusion
 Discussion
 References
 
There is increasing attention to and concern over the augmented cardiovascular risk posed by the metabolic syndrome.1,2,12,19,20 This constellation of abnormalities, including abdominal obesity, increased blood pressure, elevated triglycerides and low high-density lipoprotein cholesterol (HDL-C), increased blood glucose, and elements of an increased inflammatory state, shares many metabolic characteristics of the diabetic state and is associated with increased risk of both diabetes and cardiovascular disease. Both ATP III1 and the Third Joint Task Force European guidelines12 recommend use of simple clinical criteria to diagnose the metabolic syndrome; diagnosis can be made on the basis of three or more of the following: abdominal obesity indicated by waist circumference of >102 cm in men and >88 cm in women, triglycerides ≥150 mg/dL, HDL-C<40 mg/dL in men and <50 mg/dL in women, blood pressure ≥130/≥85 mm Hg, and fasting glucose ≥110 mg/dL.

Although no clinical endpoint trial in an exclusive population of patients with the metabolic syndrome has yet been performed, retrospective analyses of available data sets from statin trials indicate that significant benefit is derived by these patients from lipid-lowering treatment. For example, a post hoc analysis of the Scandinavian Simvastatin Survival Study, which included patients with CHD and elevated LDL-C, compared characteristics and outcomes in patients with the highest quartile of triglyceride levels and the lowest quartile of HDL-C levels (lipid triad group, since all patients had elevated LDL-C) with those in patients with the lowest quartile of triglyceride levels and the highest quartile of HDL-C levels (isolated LDL-C elevation group).21 Patients in the lipid triad group who met the lipid criteria for the metabolic syndrome were significantly more likely than patients in the isolated LDL-C elevation group to have diabetes, impaired fasting glucose, and hypertension, and they had a significantly greater body mass index (BMI). The major coronary event rate was greatest in the placebo subgroup with the lipid triad, and the lipid triad patients receiving simvastatin treatment had the greatest relative reduction in risk (event rates of 19 vs. 35.9%, relative risk 0.48, P=0.00009). LDL-C was reduced by 37.5% in the lipid triad group and by 36.0% in the isolated LDL-C elevation group. A retrospective analysis of the West of Scotland Coronary Prevention Study (WOSCOPS), which was conducted in hypercholesterolaemic men without CHD, showed that 1691 (26.2%) of the 6447 patients met modified ATP III criteria for the metabolic syndrome (using BMI>28.8 kg/m2 instead of the waist circumference criterion for abdominal obesity).22 The hazard ratio for CHD events among pravastatin patients vs. placebo patients with the metabolic syndrome was 0.73; the ratio for pravastatin vs. placebo patients without the metabolic syndrome was 0.69. Event rates among patients with the metabolic syndrome were 7.7% in pravastatin patients vs. 10.4% in placebo patients; rates among patients without the metabolic syndrome were 4.4% in pravastatin patients vs. 6.2% in placebo patients. A recent analysis of data from the Third National Health and Nutrition Examination Survey (NHANES III)23 found that 18.5% of a sample of>8000 individuals aged 30–74 years without diabetes and CHD met ATP III criteria for the metabolic syndrome. It was estimated that approximately 20% of men and 5% of women with the metabolic syndrome would have CHD events within 10 years. Reduction of LDL-C to <130 mg/dL, a very modest reduction given the means of 137 mg/dL in men and 143 mg/dL in women in this sample, was estimated to prevent 9.3% of events in men and 9.8% of events in women; reduction of LDL-C to <100 mg/dL was projected to prevent 46.2% of events in men and 38.1% of events in women.

Analysis of data from large-scale comparative statin lipid-lowering trials indicates that statin treatment produces beneficial alterations in lipid profiles of patients with the metabolic syndrome and suggests that LDL-C-lowering effects are similar in patients with the metabolic syndrome and those without the metabolic syndrome.24 In the Atorvastatin Comparative Cholesterol Efficacy and Safety Study (ACCESS), 3916 hypercholesterolaemic patients received atorvastatin, simvastatin, pravastatin, lovastatin, and fluvastatin, beginning at starting doses, with the doses titrated to the highest approved dose over 54 weeks and the aim of reaching ATP II LDL-C goals. In a retrospective analysis,25 1342 patients were found to satisfy modified ATP III criteria (BMI≥30 kg/m2 instead of the waist circumference criterion) for the metabolic syndrome. Among these patients, LDL-C was reduced by 43% with atorvastatin, 37% with simvastatin, 36% with lovastatin, 32% with fluvastatin, and 30% with pravastatin. A retrospective analysis of the Measuring Effective Reductions in Cholesterol Using Rosuvastatin therapY (MERCURY) I trial, which compared rosuvastatin 10 mg, atorvastatin 10 or 20 mg, simvastatin 20 mg, and pravastatin 40 mg in 3140 high-risk patients (coronary or other atherosclerotic disease or diabetes) with LDL-C ≥2.99 mmol/L and triglycerides <4.52 mmol/L, found that 1342 patients met modified ATP III criteria (BMI>30 kg/m2 instead of the waist circumference criterion).26 After 8 weeks, reductions in LDL-C in patients with the metabolic syndrome vs. those without the metabolic syndrome were very similar: rosuvastatin 10 mg, 46.7 vs. 47.1%; atorvastatin 10 mg, 36.5 vs. 37.7%; atorvastatin 20 mg, 44.5 vs. 42.9%; simvastatin 20 mg, 35.1 vs. 35.6%; and pravastatin 40 mg, 29.9 vs. 31.7%. The LDL-C reduction with rosuvastatin 10 mg in patients with the metabolic syndrome was significantly greater than reductions with atorvastatin 10 mg, simvastatin 20 mg, and pravastatin 40 mg (P<0.0001 for all). As shown in Figure 5, rates of achievement of ATP III LDL-C goals were similar in patients with and without the metabolic syndrome according to treatment, with the possible exception of the pravastatin group. Among patients with the metabolic syndrome, the LDL-C goals were reached by significantly more patients with rosuvastatin 10 mg than with atorvastatin 10 mg, simvastatin 20 mg, or pravastatin 40 mg (P<0.0001).



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  		Figure 5 Proportions of high-risk patients in the MERCURY I (Measuring Effective Reductions in Cholesterol Using Rosuvastatin therapY) trial with metabolic syndrome and without metabolic syndrome who reached ATP III low-density lipoprotein cholesterol (LDL-C) goals after 8 weeks of treatment with rosuvastatin (RSV) 10 mg, atorvastatin (ATV) 10 or 20 mg, simvastatin (SIM) 20 mg, or pravastatin (PRA) 40 mg. (Reproduced with permission from Stender et al.26)

 

   Conclusion
Top
 Abstract
 Introduction
 Peripheral arterial disease
 Heterozygous FH
 Diabetes
 The metabolic syndrome
 Conclusion
Discussion
 References
 
For a great many high-risk individuals, including those with PAD, heterozygous FH, and the metabolic syndrome, barriers to successful management include inadequate identification of the conditions posing increased risk. Many of the patients with these conditions remain asymptomatic until late-stage atherosclerotic disease is present, and screening for the CHD risk factors currently used in routine risk assessment does not dependably identify these individuals. CHD risk is thus likely to be under-estimated in many of these patients, with the result that lipid-lowering therapy is likely to be inadequate. Vigilance must be maintained in the clinical practice setting for conditions such as PAD, FH, and the metabolic syndrome, with additional steps beyond routine risk assessment being taken to ensure that patients with such conditions are appropriately diagnosed and effectively treated. Increased awareness of the benefits of LDL-C reduction in diabetic patients irrespective of their pre-treatment LDL-C level is also needed. It should be noted that recent modifications to the ATP III guidelines provide for optional LDL-C goal levels of <70 mg/dL in patients with very high risk and <100 mg/dL in those with moderately high risk, with LDL-C thresholds for initiating lipid-lowering treatment also being lowered.27 The modifications also include the recommendation that lipid-lowering therapy in patients with high or moderately high risk be initiated at an intensity sufficient to achieve at least a 30–40% reduction in LDL-C. Increased awareness and efforts are needed to ensure that such optimal treatment is extended to all high-risk patients. Rosuvastatin may be an optimal choice because of its ability to produce large reductions in LDL-C compared with other statins.


   Discussion
Top
 Abstract
 Introduction
 Peripheral arterial disease
 Heterozygous FH
 Diabetes
 The metabolic syndrome
 Conclusion
 Discussion
References
 
Audience Question: It really seems that the issue now is not so much which patients we should treat but which patients we should not treat. In Sweden, the cost of simvastatin has gone down by about 70–80% since Zocor came off patent, and this certainly makes it easier to make treatment more widely available. In line with what Professor Færgeman was discussing, it may make sense to move towards medicalization—I think we should be treating a lot more, and not only ‘patients’ but a lot more ‘people’, particularly, for example, those over the age of 55.

Professor Cobbe: Would it be correct to say that we no longer need to stipulate that it is patients with type 2 diabetes and dyslipidaemia who need to receive statin therapy to normalize their lipid profile, saying, instead, simply that all patients with type 2 diabetes should receive statin therapy?

Professor Schuster: Absolutely, yes. I cannot recall many patients with diabetes who have LDL-C of 70 mg/dL, triglycerides below 150 mg, and HDL-C above 60 mg/dL without treatment too. In that regard, I believe it is correct to shorten the message and say that patients with diabetes should be treated with a statin.

Professor Cobbe: That corresponds with the beautiful simplicity of the Heart Protection Study concept—that if you have any manifestation of atherosclerotic disease, more or less regardless of your LDL-C, you can benefit from statin treatment. I think we have reached the same situation with type 2 diabetes.

Professor Schuster: I fully agree with this concept. We combine absolute reduction and relative reduction. This is reflected in the modified ATP III guidelines too. We set absolute goals in terms of LDL-C levels, but once we start treating, we want to lower LDL-C at least 30–40%. I think that makes a lot of sense.

Audience Question: I am from Poland. I have a general question about rosuvastatin: it looks more effective, but how about its side effects in comparison with other statins?

Professor Schuster: I am the principal investigator for the MERCURY I trial. In that trial comparing various statins in more than 3500 individuals, there were no significant differences among the various statins with regard to adverse effects, tolerability, and safety. I also believe that in general, we should consider statins to be very safe, particularly in comparison with other drugs.

Dr Ballantyne: This is an important question, because there has been a lot of confusion about rosuvastatin safety data; this has particularly been the case in the USA, where it seems that people have been confusing data with 80 mg rosuvastatin, for which there never was an application for approval, with the data on the approved doses of 5–40 mg. When the rosuvastatin data went to the Food and Drug Administration, there were more than 10 000 patients in the database. The data were carefully reviewed by the US authorities, and now the drug has been approved in over 60 countries. The database now includes, I believe, some 42 000 individuals in controlled clinical trials. If one takes a look across the board at all currently approved statins, the rates of myopathy and rhabdomyolysis with rosuvastatin at the approved doses fall within the ranges of all the other statins. This is not to say that the safety profiles of statins may be somewhat different outside of their approved dose ranges, and this is not to say that there are not patients in whom statins should be used with caution. Of course, we have to be mindful of drug interactions, renal insufficiency and other factors that may affect safety in our patients.

Professor Kastelein: I also think that this is a very important point—all this negative publicity about rosuvastatin actually distracts us from the real issues we have to face in treatment and is beginning to worry the public as well. I am co-author of a publication that will appear in the American Journal of Cardiology in October, and I think everyone should read it very carefully [Shepherd J et al. Safety of rosuvastatin. Am J Cardiol 2004;94:882–888]. It shows that there is absolutely no difference in terms of safety among the different statins, with the exception of Baycol (cerivastatin), in terms of safety data from randomized trials. The clinical trial data set for rosuvastatin does indeed now amount to over 40 000 patients, which is way bigger than that for any other statin at a similar stage of development, and there is no difference between rosuvastatin and the other statins with regard to safety in randomized trials. That is the first point. The second point, as I have mentioned, is that in post-marketing surveillance there has not been a single case of fatal rhabdomyolysis with rosuvastatin in the context of 9 or 10 million prescriptions. At a similar stage, there had already been 30 cases with Baycol.

I think that for me this issue is becoming a bit silly, and we should probably move on once these data are out there and really start concentrating on what we need to do in terms of lowering LDL-C in our patients.

Professor Færgeman: The 10-year follow-up of the 4S trial was just published in Lancet; it showed that there was no increase in cancers in the statin population, providing additional evidence that statins seem to be very safe [Strandberg TE et al. Mortality and incidence of cancer during 10-year follow-up of the Scandinavian Simvastatin Survival Study (4S). Lancet 2004;364:771–777].

Professor Cobbe: Indeed, there has been a very extensive analysis of all the statin trials with regard to cancer, and that analysis supports that conclusion for all of the statins thus far [Bjerre LM, LeLorier J. Do statins cause cancer? A meta-analysis of large randomized clinical trials. Am J Med 2001;110:716–723].

Audience Question: What is the threshold LDL-C level that you would use to start treatment in a diabetic patient?

Dr Ballantyne: My personal opinion is that anyone who has CHD or a CHD risk equivalent should be put on a statin. Of course, there is clinical judgment involved in the treatment decision; if you have a patient who is dying of cancer and has congestive heart failure, you may not want to add a statin to all the other treatments. But, in general, it now appears that patients with CHD have benefit from statin therapy regardless of their initial LDL-C level, and the same is true for diabetes. The CARDS study was quite impressive in terms of making this point. So, I would put my patients with diabetes on a statin, if clinical judgment does not dictate otherwise.

Professor Cobbe: A question from the audience: Should a combination of a statin with ezetimibe be considered only after failure of the highest doses of such statins as rosuvastatin and atorvastatin to bring a patient to goal LDL-C levels, or should an initial strategy involve moderate doses of a statin in combination with ezetimibe?

Professor Schuster: I am a strong believer in the pleiotropic effects of statins, so I actually up-titrate the statin first and then add another drug if I cannot reach the target with statin monotherapy. This is also a more cost-effective approach.

Professor Færgeman: I am not a strong believer in the pleiotropic effects of statins, but I am mindful that ezetimibe has not yet been shown to have preventive effects against disease in clinical trials; we just do not have the same documentation for protective benefit that we have for the statins. Having said that, I must also say that I like the concept of lower-dose statins plus ezetimibe.

Professor Kastelein: To summarize, Professor Færgeman has told us that the coronary artery disease epidemic is well understood and that basically we know what to do about it. We need societal change. I think there is actually a very good example of this from Poland; Poland removed the subsidies for butter, and this action was promptly followed by a decrease in incidence of coronary artery disease. At the same time, we should realize that now, with the widespread use of statins serving as an example, the medicalization of society is something that we are likely to see in the years to come.

Professor Ballantyne shared with us some of the changes in lipid-lowering guidelines. Although definitive proof still awaits some of the ongoing large-scale endpoint trials, there is certainly persuasive evidence from the last five or so trials that we need to go lower than LDL-C of 100 mg/dL in some groups of patients. We also learned that we have the powerful statins necessary to reduce LDL-C to these levels, and that these reductions can be achieved without compromising safety.

Professor Schuster has told us that although we know what to do with individuals at high risk and actually have the tools to do it, there are still important patient groups out there in which we fail to do what we should. He also gave us some clues on how to achieve better management and treatment results in these high-risk patient groups.

It is to be hoped that all of us here take some of this information back to our respective countries and try to translate it into clinical practice. Thank you.


   References
Top
 Abstract
 Introduction
 Peripheral arterial disease
 Heterozygous FH
 Diabetes
 The metabolic syndrome
 Conclusion
 Discussion
 References
 

  1. Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. Executive summary of the 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). JAMA 2001;285:2486–2497.[Free Full Text]
  2. 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;106:3143–3421.[Free Full Text]
  3. Criqui MH, Langer RD, Fronek A et al. Mortality over a period of 10 years in patients with peripheral arterial disease. N Engl J Med 1992;326:381–386.[Abstract]
  4. Goldstein JL, Brown MS. The LDL receptor locus and the genetics of familial hypercholesterolemia. Annu Rev Genet 1979;13:259–289.[CrossRef][ISI][Medline]
  5. Rifkind BM, Schucker B, Gordon DJ. When should patients with heterozygous familial hypercholesterolemia be treated? JAMA 1999;281:180–181.[Free Full Text]
  6. Goldstein JL, Brown MS. The LDL receptor defect in familial hypercholesterolemia. implications for pathogenesis and therapy. Med Clin North Am 1982;66:335–362.[ISI][Medline]
  7. Genest JJ Jr, Martin-Munley SS, McNamara JR et al. Familial lipoprotein disorders in patients with premature coronary artery disease. Circulation 1992;85:2025–2033.[Abstract/Free Full Text]
  8. Williams RR, Hunt, SC, Schumacher MC et al. Diagnosing heterozygous familial hypercholesterolemia using new practical criteria validated by molecular genetics. Am J Cardiol 1993;72:171–176.[CrossRef][ISI][Medline]
  9. Stein EA, Strutt K, Southworth H et al. Comparison of rosuvastatin vs. atorvastatin in patients with heterozygous familial hypercholesterolemia. Am J Cardiol 2003;92:1287–1293.[CrossRef][ISI][Medline]
  10. Wiegman A, Hutten BA, de Groot E et al. Efficacy and safety of statin therapy in children with familial hypercholesterolemia: a randomized controlled trial. JAMA 2004;292:331–337.[Abstract/Free Full Text]
  11. Kannel W, McGee D. Diabetes and glucose tolerance as risk factors for cardiovascular disease: the Framingham study. Diabetes Care 1979;2:120–126.[Abstract]
  12. Third Joint Task Force of European and other Societies on Cardiovascular Disease Prevention in Clinical Practice. Executive summary. European guidelines on cardiovascular disease prevention in clinical practice. Eur Heart J 2003;24:1601–1610.[Free Full Text]
  13. Haffner SM, Lehto S, Ronnemaa T et al. Mortality from coronary heart disease in subjects with type 2 diabetes and in nondiabetic subjects with and without prior myocardial infarction. N Engl J Med 1998;339:229–234.[Abstract/Free Full Text]
  14. Heart Protection Study Collaborative Group. MRC/BHF Heart Protection Study of cholesterol lowering with simvastatin in 20,536 high-risk individuals: a randomised placebo-controlled trial. Lancet 2002;360:7–22.[CrossRef][ISI][Medline]
  15. Heart Protection Study Collaborative Group. MRC/BHF Heart Protection Study of cholesterol-lowering with simvastatin in 5963 people with diabetes: a randomized placebo-controlled trial. Lancet 2003;361:2005–2016.[CrossRef][ISI][Medline]
  16. Colhoun C, Betteridge J, Durrington P et al, on behalf of the CARDS investigators. Collaborative Atorvastatin Diabetes Study. Latest news: CARDS results presentation. Available at: http://www.cardstrial.com. Accessed December 2, 2004.
  17. Franken A, Wolffenbuttel B, Vincent H. Cholesterol-lowering effects of rosuvastatin compared with atorvastatin in patients with type 2 diabetes. Atheroscler Suppl(Abstract M513) 2004;5:118.
  18. Betteridge J, Gibson M, on behalf of the ANDROMEDA study investigators. Effect of rosuvastatin and atorvastatin on LDL-C and CRP levels in patients with type 2 diabetes: results of the ANDROMEDA study. Poster presentation at: the 74th European Atherosclerosis Society Congress; April 17–21, 2004; Seville, Spain.
  19. Lakka HM, Laaksonen DE, Lakka TA et al. The metabolic syndrome and total and cardiovascular disease mortality in middle-aged men. JAMA 2002;288:2709–2716.[Abstract/Free Full Text]
  20. Norhammer A, Tenerz A, Nilsson G et al. Glucose metabolism in patients with acute myocardial infarction and no previous diagnosis of diabetes mellitus: a prospective study. Lancet 2002;359:2140–2144.[CrossRef][ISI][Medline]
  21. Ballantyne CM, Olsson AG, Cook TJ et al. Influence of low high-density lipoprotein cholesterol and elevated triglyceride on coronary heart disease events and response to simvastatin therapy in 4S. Circulation 2001;104:3046–3051.[Abstract/Free Full Text]
  22. Sattar N, Gaw A, Scherbakova O et al. Metabolic syndrome with and without C-reactive protein as a predictor of coronary heart disease and diabetes in the West of Scotland Coronary Prevention Study. Circulation 2003;108:414–419.[Abstract/Free Full Text]
  23. Wong ND, Pio JR, Franklin SS et al. Preventing coronary events by optimal control of blood pressure and lipids in patients with the metabolic syndrome. Am J Cardiol 2003;91:1421–1426.[CrossRef][ISI][Medline]
  24. Deedwania PC, Hunninghake DB, Bays H. Effects of lipid-altering treatment in diabetes mellitus and the metabolic syndrome. Am J Cardiol 2004;93(Suppl.):18C–26C.[ISI][Medline]
  25. Newman C, Hopkinson C, Messig M et al. Efficacy of atorvastatin in dyslipidemic patients with metabolic syndrome in the ACCESS study. Diabetes(Abstract 2141-PO) 2003;52(Suppl. 1):A494.
  26. Stender S, Schuster H, Barter P et al. Comparison of rosuvastatin with atorvastatin, simvastatin, and pravastatin in achieving cholesterol goals and improving plasma lipids in hypercholestrolaemic patients with or without the metabolic syndrome (MERCURY I trial). Diabetes Obes Metab, in press.
  27. Grundy SM, Cleeman JI, Merz CN et al. Implications of recent clinical trials for the National Cholesterol Education Program Adult Treatment Panel III guidelines. Circulation 2004;110:227–239.[Abstract/Free Full Text]

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