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NDT Advance Access originally published online on September 23, 2006
Nephrology Dialysis Transplantation 2007 22(1):118-127; doi:10.1093/ndt/gfl538
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© The Author [2006]. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Effect of statin treatment on renal function and serum uric acid levels and their relation to vascular events in patients with coronary heart disease and metabolic syndrome

A subgroup analysis of the GREek Atorvastatin and Coronary heart disease Evaluation (GREACE) Study

Vasilios G. Athyros1, Dimitri P. Mikhailidis2, Evangelos N. Liberopoulos3, Anna I. Kakafika1, Asterios Karagiannis1, Athanasios A. Papageorgiou1, Konstantinos Tziomalos1, Emmanuel S. Ganotakis4 and Moses Elisaf3

1Atherosclerosis and Metabolic Syndrome Units, 2nd Propedeutic Department of Internal Medicine, Aristotelian University, Hippocration Hospital, Thessaloniki, Greece, 2Department of Clinical Biochemistry (Vascular Prevention clinics), Royal Free Hospital, Royal Free and University College Medical School, London, UK, 3Department of Internal Medicine, Medical School, University of Ioannina, Ioannina, Greece and 4Department of Internal Medicine, Medical School, University of Crete, Heraklion, Greece

Correspondence and offprint requests to: Moses S. Elisaf, MD, FASA, FRSH, Professor of Medicine, Department of Internal Medicine, Medical School, University of Ioannina, 451 10, Ioannina, Greece. Email: egepi{at}cc.uoi.gr; vaglimp{at}yahoo.com



   Abstract
Top
 Abstract
Introduction
 Study population: methods
 Results
 Discussion
 Conclusions
 References
 
Background. Metabolic syndrome (MetS) is associated with increased risk for both vascular and chronic kidney disease. Whether statins ameliorate these risks is not established.

Methods. This post hoc analysis of the GREek Atorvastatin and Coronary heart disease (CHD). Evaluation (GREACE) examines the effect of statins on estimated glomerular filtration rate (e-GFR) and serum uric acid (SUA) levels and their relation to vascular events in CHD patients with MetS. MetS patients were divided into two groups: Group A (n = 365) received lifestyle advice, target-driven treatment with statins (mainly atorvastatin) and treatment for hypertension and elevated glucose. Group B (n = 347) received the same except for statins. Patients without MetS were divided into those who received treatment similar to Group A and Group B [Groups C (n = 504) and D (n = 384), respectively]. All patients were followed for 3 years.

Results. A total of 12.1% of patients in Group A experienced a vascular event vs 28% in Group B; risk ratio (RR) 0.43, 95% confidence interval (CI) 0.20–0.64, P < 0.0001, while in those without MetS (Group C vs Group D), the respective RR was 0.59, 95% CI 0.41–0.79, P < 0.0001. In Group A, e-GFR increased by 13.7% and SUA levels fell by 8.9%, while in Group B e-GFR was reduced by 5.8% and SUA increased by 4.3% (P < 0.005). Stepwise regression analysis showed that these changes were independently related to vascular events.

Conclusion. Among CHD patients, those with MetS benefited more from statin treatment than those without MetS. This benefit could be partially attributed to favourable changes in e-GFR and SUA levels probably induced by statin treatment.

Keywords: atorvastatin; cardiovascular metabolic syndrome; chronic renal disease; coronary artery disease; glomerular filtration rate; kidney; serum uric acid; statins



   Introduction
Top
 Abstract
 Introduction
Study population: methods
 Results
 Discussion
 Conclusions
 References
 
Recent findings suggest that the metabolic syndrome (MetS) is closely associated with chronic kidney disease (CKD) [1]. It is estimated that more than 10 million Americans have CKD [2], and these patients are at high risk for the development of cardiovascular disease (CVD) [3,4].

Renal injury from hypertension and diabetes mellitus (DM) is well documented [5]. Dyslipidaemia also emerged as a risk factor for CKD [6]. DM, hypertension and dyslipidaemia (especially when combined) may therefore influence the long-term ‘renal future’ of patients with MetS. The current worldwide epidemic of MetS, with its potential for renal damage, mandates our commitment to renal protection at the earliest stages of MetS [5].

CKD [7], as established by low glomerular filtration rate (GFR), is considered a strong and independent predictor of CVD risk after a myocardial infarction (MI) [8].

It has also been shown that elevated serum uric acid (SUA) levels are a powerful and independent predictor of cardiac and overall mortality in both sexes in patients with coronary heart disease (CHD) [9] or arterial hypertension [10]. A relation between elevated SUA levels and stroke has also been demonstrated in patients with or without CHD [11], arterial hypertension [10] or DM [12]. Furthermore, elevated serum urate levels are associated with the presence of MetS [13].

We have shown that intensive atorvastatin treatment not only prevents the decline in renal function seen in CHD patients under ‘usual care’, but also significantly improves renal function and reduces SUA levels, potentially offsetting two additional factors associated with vascular risk [14–16]. However, the effect of statins on renal function and SUA levels as well as the association of this effect with vascular events in subjects with CHD with or without MetS has not yet been addressed by an end point clinical trial. In the present post hoc subgroup analysis of the GREek Atorvastatin and CHD Evaluation (GREACE) trial [17], we report the statin-related change in estimated GFR (e-GFR) and SUA concentration as well as their relation with vascular end points in CHD patients with or without MetS.



   Study population: methods
Top
 Abstract
 Introduction
 Study population: methods
Results
 Discussion
 Conclusions
 References
 
Study design, patients and methods
The design and main findings of the GREACE study have been previously described [14–17]. Briefly, GREACE included men (78%) and women (22%) of Caucasian origin with established CHD, aged <75 years (mean 58.3 years). Their serum low-density lipoprotein cholesterol (LDL-C) concentration was >100 mg/dl (2.6 mmol/l) and serum triglyceride (TG) levels <400 mg/dl (4.5 mmol/l). Patients with recent acute coronary syndromes were not excluded. All patients attended the Atherosclerosis or the Metabolic Syndrome Units of the University Hospital, Thessaloniki, and if eligible, were randomized either into the structured care group, followed up by the University Clinic, or into the usual care group followed up by heart specialists or general practitioners of the patient's choice outside the hospital. In the structured care group, the starting dose of atorvastatin was 10 mg/day. With evaluations every 6 weeks the dose of atorvastatin was titrated up to 80 mg/day for patients not reaching the National Cholesterol Education Program Adult Treatment Panel III (NCEP ATP III) LDL-C goal (<100 mg/dl; 2.6 mmol/l) with lower dosages. Patients in the usual care group were treated according to their physician's standard of care. Usual care consisted of similar lifestyle changes plus necessary drug treatment for other risk factors (e.g. DM, hypertension), including lipid-lowering agents. Atorvastatin was not excluded from the usual care group. Patients were followed for a mean 3-year period with visits every 6 months.

As mentioned earlier, in the initial intention to treat study, subjects were randomized either to structured care (n = 800, with up dose titration of atorvastatin to achieve the LDL-C target of <100 mg/dl; 2.6 mmol/l) and the usual care group (n = 800) that was followed by physicians of their choice. In this latter group, only 12% of subjects were on statin treatment and only 3% were at LDL-C target. In the present post hoc analysis, we divided subjects into those having or not having MetS and each group into those on statin and without statin treatment irrespective of their initial allocation to structured or usual care groups.

Serum creatinine (SCr) was measured using the Jaffé method (Olympus Diagnostica GmbH, Clare, Ireland); normal range 0.6–1.3 mg/dl (55–115 µmol/l). Here e-GFR was estimated using the Modification of Diet in Renal Disease (MDRD) study equation [18]. SUA concentration was assessed using an enzymatic colorimetric test [uricase; reference range, 2.5–7.0 mg/dl (150–415 µmol/l)]. The e-GFR in all patients and SUA levels only in patients not on diuretics (89% of the study population) were assessed at baseline, at the sixth treatment week and every 6 months thereafter. For patients who died during the study and for those who survived until the closeout of the study, the last e-GFR used was the last one before their death or the non-fatal vascular event, respectively, estimated during their follow-up.

Vascular events included all-cause and coronary mortality, coronary morbidity (non-fatal MI, revascularization, unstable angina and congestive heart failure) and stroke.

Definition of MetS
Participants having three or more of the following criteria (according to the American Heart Association/National Heart, Lung, and Blood Institute statement (AHA/NHLBI) [19]), were defined as having MetS:

  1. Abdominal obesity: waist circumference ≥102 cm in men and ≥88 cm in women.
  2. Hypertriglyceridaemia: fasting triglycerides (TGs) ≥150 mg/dl (1.7 mmol/l).
  3. Low high-density lipoprotein cholesterol (HDL-C) <40 mg/dl (1.0 mmol/l) in men and <50 mg/dl (1.3 mmol/l) in women.
  4. Raised blood pressure: ≥130/≥85 mm Hg or use of antihypertensive medication.
  5. Raised fasting plasma venous glucose: ≥100 mg/dl (5.6 mmol/l) or treatment for DM.

Cost-effectiveness
The Marcov model was used [20]. Patients incur incremental costs according to their current health state. For example, patients undergoing lipid-lowering therapy incur annual costs of medication, periodic physician visits and related diagnostic tests (lipid profiles, safety measurements). Patients with vascular events incur costs associated with the occurrence of acute events as well as annual maintenance costs. Using the Markov process, the total costs of therapy (including treatment of CHD) and effectiveness (life expectancy) were estimated over time. Incremental differences in cost and effectiveness between the two treatment groups were then estimated and the cost-effectiveness ratio was calculated. Indirect costs such as loss of productivity, sick leave, change of profession and pensions due to death or disability were not taken into consideration.

Statistical analyses
Treatment-based analyses of all patients according to the presence or absence of MetS with or without statin treatment were performed. Analysis of variance (ANOVA) was used to assess percent change in CVD risk in all four groups: Group A: MetS (+) statin (+), Group B: MetS (+) statin (–), Group C: MetS (–) statin (+), Group D: MetS (–) statin (–). In the study e-GFR values were compared with those at baseline using ANOVA to assess differences over time within and between treatment groups. A univariate analysis was initially performed, including 25 predictors of vascular events. Then, after removal of six predictors with a P > 0.10, 19 predictors were included in a Multivariate Cox Predictive Model, involving backward stepwise logistic regression, for all events. All predictors were recorded as categorical factors (0–1), except for e-GFR and SUA levels, which were analysed as continuous parameters. All univariate or multivariate analyses were performed with an e-GFR at 5% and an SUA concentration at 5% stepwise increase or reduction from baseline. The incremental cost-effectiveness for statin relative to no statin treatment was calculated as the ratio of differences in total treatment cost and quality-adjusted life expectancy. All data are expressed as mean values ± SD. The SPSS 11.01 software package (SPSS, Inc., Chicago, IL) program was used for all statistical analyses. A two-tailed P < 0.05 was considered significant. The number needed to treat (NNT) is the number of patients you need to treat to prevent one additional adverse outcome (death, myocardial infarction, stroke, etc.). The NNT is the inverse of the absolute risk reduction (ARR): NNT = 1/ARR. NNTs are rounded up to the nearest whole number.



   Results
Top
 Abstract
 Introduction
 Study population: methods
 Results
Discussion
 Conclusions
 References
 
Treatment groups
This was an intention-to-treat analysis that included 1600 CHD patients. Of those, Group A consisted of 365 CHD patients with MetS who were on statins (mainly atorvastatin, n = 323), Group B included 347 patients with CHD and MetS not on statin treatment, Group C had 504 CHD patients without MetS but on statins (mainly atorvastatin, n = 457), and Group D included 384 CHD patients without MetS and not on statins. Of the 365 patients included in Group A, 322 were initially randomized to intensive care and 43 to usual care, while of the 504 patients included in Group C 478 were initially randomized to intensive care and 26 to usual care. All patients in Groups B and D were initially randomized to usual care. The baseline and end of study patient characteristics are shown in Tables 1 and 2.


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  		Table 1. Baseline characteristics of patients with and without the metabolic syndrome (MetS) receiving or not receiving statin treatment

 

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  		Table 2. Characteristics of patients with and without the metabolic syndrome (MetS) receiving or not receving statin treatment at the end of the study

 
Effect of statins on lipid profile
All patients in groups A (CHD and MetS) and C (CHD without MetS) were on statins. Of them, 90% were on atorvastatin (mean dose 23 mg/day), and the rest on various statins at various doses. Statin-treated patients experienced a reduction in LDL-C levels by 43% (P < 0.0001). They had lower LDL-C levels than patients not receiving statin treatment in Groups B (CHD and MetS) and D (CHD without MetS) (P < 0.0001) (Table 2), and most of them (92%) were at the NCEP ATP III LDL-C target (<100 mg/dl; 2.6 mmol/l). In Groups A and C the mean reduction in TGs was about 29% and in non-HDL-C, 44% (P < 0.0001 vs baseline and Groups B and D, for both comparisons). The mean increase in HDL-C levels in Groups A and C was 8% (P = 0.001 vs baseline and P = 0.003 vs Groups B and D). Time course of changes in total cholesterol and TGs in Groups A and B are presented in Figure 1.


Figure 1
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  		Fig. 1. Time course of changes in total cholesterol and triglycerides in Group A [MetS (+) on statins] and Group B [MetS (+) not on statins] during the study (MetS = metabolic syndrome).

 
Vascular events
During the (mean) 3-year follow-up, 63 patients died (10 patients in Group A, 23 in Group B, 11 in Group C and 19 in Group D). Moreover, there were 292 overall vascular events (including fatal ones). Of those, 44 (12.1%) events were reported in 365 patients with CHD and MetS on statins (Group A) and 97 (28%) in 347 patients with CHD and MetS but not on statin treatment (Group B); risk ratio (RR) 0.43, 95% confidence interval (CI) 0.20–0.64, P < 0.0001. In subjects with CHD but without MetS, 66 vascular events were recorded (13.1%) in those on statins (Group C) (n = 504), while in those not on statin treatment (n = 384) (Group D) 85 events (22.1%) occurred; RR 0.59, 95% CI 0.40–0.79, P < 0.0001. The difference in vascular event rate between Groups A and C was not significant (12.1% vs 13.1%, P = 0.063), whereas the difference between Groups B and D was (28% vs 22.1%, P = 0.003). The difference in RR reduction (RRR) between the two groups on statins (with and without MetS, Groups A and C) in comparison with the respective groups not on statin treatment (Groups B and D) was 16%, P < 0.0001 (Figure 2A). The time course of vascular events is shown in Figure 2A.


Figure 2
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  		Fig. 2. Relative risk reduction (RRR) of vascular events (Panel A) and percentage change in estimated glomerular filtration rate (e-GFR) (Panel B) and serum uric acid (SUA) concentration (Panel C) in the treatment groups (treatment-based analysis) (CHD = coronary heart disease, MetS = metabolic syndrome).

 
Numbers needed to treat—cost-effectiveness
A statin needed to be added to other treatments in seven patients with CHD and MetS and in 11 patients with CHD but no MetS for a 3-year period to avoid one fatal or nonfatal vascular event. In that setting the costs per quality-adjusted life-year gained with statin treatment was estimated at $6750.

Renal function at baseline
At baseline, e-GFR (as estimated by the MDRD equation) in both MetS groups (with or without statin treatment, n = 712) was 69 ml/min/1.73 m2 (Table 1). This was significantly (P = 0.002) lower compared with the e-GFR (82 ml/min/1.73 m2) of patients without MetS (n = 888) (Table 1).

Effect of statin treatment on e-GFR and SUA levels (treatment-based analysis)

  1. Without statin treatment. During the (mean) 3-year follow-up in group B (CHD and MetS not on statins), there was a mean reduction in e-GFR by 5.8%, P = 0.0003 vs baseline, and an increase in SUA levels by 4.3%, P = 0.001 vs baseline (Table 2, Figure 2B and C). During the same time period in Group D (CHD without MetS not on statins), there was a mean reduction in e-GFR of 4.1%, P = 0.004 vs baseline, and an increase in SUA levels of 3.2%, P = 0.008 vs baseline (Table 2, Figure 2B and C).
  2. On statin treatment. During the (mean) 3-year follow-up in group A (CHD and MetS on statins) there was a mean increase in e-GFR of 13.7%, P < 0.0001 vs baseline, and a reduction in SUA levels of 8.9%, P < 0.0001 vs baseline (Table 2, Figure 2B and C). In Group C (CHD without MetS on statins), there was a mean increase in e-GFR of 8.4%, P < 0.0001 vs baseline, and a reduction in SUA levels of 6.2%, P < 0.0001 vs baseline (Table 2, Figure 2B and C). In Group A the increase in e-GFR was significantly higher in comparison to Group C (P = 0.02). Higher doses of atorvastatin were related with a greater increase in e-GFR (r = 0.578, P = 0.001) and a greater reduction in SUA levels (r = 0.458, P = 0.003). The time course of changes in e-GFR and SUA levels in the two MetS groups is reported in Figure 3B and C.


Figure 3
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  		Fig. 3. Change over time (up to 48 months) in vascular event rate (Panel A), estimated glomerular filtration rate (e-GFR) (Panel B), and serum uric acid (SUA) concentration (Panel C), in the treatment groups (treatment-based analysis) [CHD = coronary heart disease, MetS = metabolic syndrome; asterisk indicates the time at which change became statistically significant (P < 0.05) vs baseline; square indicates the time at which change became statistically significant vs the other group (P < 0.05)].

 
Relation between e-GFR and SUA concentration changes and clinical outcome
In MetS patients, multivariate analysis of vascular events showed a hazard ratio (HR) of 1.16 (95% CI 1.07–1.28, P = 0.0003) for each 5% reduction in e-GFR (Table 3) and a HR of 1.23 (95% CI 1.14–1.39, P < 0.0001) for each reduction of 10% in e-GFR. In contrast, multivariate analysis of vascular events revealed an HR of 0.82 (95% CI 0.70–0.93, P = 0.001) for each 5% increase in e-GFR (Table 2) and an HR 0.72 (95% CI 0.64–0.82, P < 0.0001) for each 10% increase in e-GFR. For SUA concentration changes and vascular events there was an HR of 0.85 (95% CI 0.74–0.95, P = 0.002) for each 5% reduction in SUA levels (Table 3) and an HR of 1.09 (95% CI 1.03–1.18, P = 0.008) for each 5% increase in SUA levels (Table 3). This relationship between SUA levels and vascular events was calculated without considering the changes in e-GFR. If e-GFR is included in the regression model, the changes in SUA levels are no longer significantly related to vascular risk. Changes in e-GFR and SUA levels became significant by the sixth treatment week and there was a further improvement during the following months (Figure 3B and C). Relative reduction of events was recorded by the sixth treatment month and became statistically significant at the end of the study (Figure 3A). Thus, changes in e-GFR and SUA concentration preceded the RRR in vascular events. This fact combined with the multiple regression analysis results (Table 3) does not exclude the possibility that the changes in e-GFR and SUA concentration are causally related to the RRR in vascular events.


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  		Table 3. Multivariate Cox predictive model for all vascular related events involving backward stepwise logistic regression (variables with P > 0.10 in univariate analysis were removeda) in subjects with CHD and metabolic syndrome (MetS) on statin and CHD and MetS not on statin treatment

 
Other factors that may have influenced renal function and vascular events
There were no significant differences between Groups A and B in demographic characteristics and CHD risk factors at baseline or in concomitant drug treatment (especially in angiotensin converting enzyme inhibitors or angiotensin II receptor blockers that might influence renal blood flow, Table 2), and level of glycaemic control or blood pressure during the study. Treatment rate with losartan that might affect SUA levels [13] was low (<2%) in each group and similarly distributed among them. Both at entry and during the study, smokers (4.1 and 3.9%, respectively) were similarly distributed in the two treatment groups. Moreover, results were fully adjusted for 25 predictors of vascular events (Table 3).

We used the recent AHA/NHLBI update of the NCEP ATP III definition to diagnose MetS [19]. This update sets a lower threshold for fasting glucose [i.e. 100 mg/dl (5.6 mmol/l) instead of 110 mg/dl (6.1 mmol/l)]. Because of this lower threshold, 11 patients (five in Group A and six in Group B) were classified as having MetS according to the AHA/NHLBI but not the NCEP ATP III definition. Results did not change when these 11 patients were excluded form the analyses.



   Discussion
Top
 Abstract
 Introduction
 Study population: methods
 Results
 Discussion
Conclusions
 References
 
Our study identified a positive and significant relationship between MetS and risk for CKD. Both at baseline (for all patients) and at the end of the study (only for those not receiving statin treatment) patients with CHD and MetS had a lower e-GFR than those without MetS (Tables 1 and 2). Therefore, statin treatment may reverse the deteriorating effect of MetS on kidney function. This is not surprising as several studies documented that DM [21], impaired fasting glucose [1], hypertension [4], and dyslipidaemia [22,23] are risk factors for the development and progression of CKD. Most of our MetS patients had a combination of these factors.

We previously reported that in the GREACE study renal function declines, as shown by the significant decrease in e-GFR levels over a period of 3 years in dyslipidaemic CHD patients with normal or near normal renal function at baseline who were not treated with a statin [14]. Moreover, atorvastatin treatment not only inhibited this deterioration, but it significantly increased e-GFR in these patients [14], and reduced SUA levels [15]. In the present analysis, the greatest benefit in renal function and SUA levels was seen in those with renal dysfunction at baseline (Table 2). An e-GFR decline by 4.1% per 3 years may simply reflect the ageing process in Group D [i.e. MetS(–)/statin(–)]. However, this decline reached 5.8% per 3 years in Group B [i.e. MetS(+)/statin(–)], which may be greater than what is expected only due to ageing. The presence of MetS might have played a role in this further decline. Furthermore, we noticed a 13% rise in e-GFR in Group A [i.e. MetS(+)/statin(+)] and an 8.4% rise in Group C [i.e. MetS(–)/statin(+)]. This probably means that statin treatment not only offsets the age-related decline, but also resulted in a significant improvement of e-GFR (Figure 2).

CKD is usually accompanied by anaemia [24]. Of note, changes in haematocrit values nearly paralleled those of e-GFR in our study (Table 2). This finding provides further support that the observed alterations in e-GFR are clinically meaningful.

The changes in e-GFR and SUA levels were independently related to vascular events in CHD patients with MetS on statins (Table 3). When comparing time courses, the beneficial changes in e-GFR and SUA levels preceded the benefit in subsequent vascular events (Figure 3A, B and C). Thus, it is highly plausible that the increase in e-GFR and the reduction in SUA levels induced by statin treatment might have significantly contributed to the reduction in clinical events since the benefit [as multivariate regression analysis showed (Table 3)] was over and above that seen with lipid values or other CVD risk factor improvement. These results suggest that e-GFR and SUA levels could represent possible targets of treatment, at least in patients with MetS, within the context of secondary CHD prevention.

In the present analysis of GREACE, both patient groups treated with a statin and those untreated received similar lifestyle advice and drug treatment for other CVD risk factors (e.g. DM, hypertension) (Table 2). Thus, the differences in e-GFR and SUA levels should mainly be attributed to statin treatment.

The effect of statins on renal function has been addressed in post hoc analyses of secondary prevention statin trials with vascular end points, regardless of the presence of MetS. The Cholesterol and Recurrent Events trial (CARE) [25] showed that only the participants with an e-GFR of less than 40 ml/min/1.73 m2 (only 32 patients out of the 4159 included in the study) experienced a slower reduction in the rate of decline in e-GFR during long-term follow-up when compared with patients receiving a placebo. In the Heart Protection Study (HPS) the allocation to simvastatin significantly attenuated the rise in SCr levels in diabetic and nondiabetic subjects in comparison with placebo [26]. Simvastatin was also associated with beneficial effects on SCr and SUA levels in patients with peripheral arterial disease [27]. Recently, a post hoc analysis of the Treating to New Targets (TNT) trial became available [J. Shepherd and N. Wenger for the TNT Steering Committee and Investigators. Intensive lipid lowering with atorvastatin is associated with a significant improvement in renal function: The Treating to New Targets (TNT) Study. American College of Cardiology 2006 Scientific Sessions; 13 March 2006; Atlanta, GA. Abstract 808-3]. The analysis included data from 7965 of the overall population of about 10 000 patients with stable CHD, for whom SCr levels at baseline and at the final study visit were available. Results showed that instead of the expected decline of about 1 ml/min/year (or 5 ml/min over the 5-year study period) there was a significant increase in e-GFR with both the 10 mg/day (by 5.6%) and the 80 mg/day dose of atorvastatin (by 8.4%). Our data are in agreement with those of the TNT subgoup analysis. Nevertheless, CARE, HPS and TNT trials did not investigate the effect of statin treatment on SUA levels and, most important, the relation of these changes in renal function or SUA levels with clinical outcome. Moreover, these effects in patients with CHD and MetS have not been investigated at all.

The mechanisms mediating the benefit of statin treatment on renal function are not clear. In our study, blood pressure or glucose levels did not differ between MetS groups (i.e. between those with and without statin treatment). We speculate that the benefit probably relates to improved endothelial function and renal blood flow with treatment as well as from LDL-C lowering. The e-GFR levels gradually increased after the sixth treatment week. There are three possible explanations for that. First, this effect of atorvastatin may be dose-dependent [see TNT trial in the preceding text]. Our results suggest that higher doses of atorvastatin increase e-GFR more than lower doses. By the sixth treatment week, all atorvastatin treated patients were on a 10 mg/day dose, while after titration the majority of patients received higher doses. Second, a gradual improvement of the lipid profile during the titration period, as atorvastatin doses increased, might be due to another possible explanation (e.g. duration of treatment). Third, patients on statin treatment experienced fewer recurrent CHD events during the study, thus possibly preserving cardiac performance and renal blood flow.

The early increase of e-GFR in the statin-treated groups is probably related to an effect on endothelial-related vasodilatation. It is well known that statins reduce peripheral resistance, raise cardiac output and improve endothelial function [28]. Therefore, better renal blood flow is a possibility. On the other hand, in a recent study, atorvastatin improved renal function without any change in renal blood flow in patients with peripheral arterial disease [29]. However, this negative finding may reflect a lack of sensitivity in the ultrasound technique used to measure renal blood flow [29]. Regression of atheromatous renal artery stenosis, or regression of intimal hyperplasia in arcuate arteries, or reversal of hyaline arteriosclerosis in afferent arterioles could not be achieved as early as the sixth treatment week but might be involved in the further gradual increase of e-GFR during the 3-year period. It has also been suggested that dyslipidaemia per se represents a significant aggravating factor for renal dysfunction in subjects with DM [30] and arterial hypertension [31] (several of our patients had both these risk factors). High serum cholesterol seems to have a similar action on glomerular mesangial cells and endothelial cells. This appears to be analogous to the process of atherosclerosis, as mesangial cells possess binding sites for LDL and oxidized LDL, help recruit macrophages and secrete proliferative factors. Clinical and experimental studies have demonstrated the role of lipids and lipoproteins in the decline of renal function with emphasis on glomerulosclerosis [32]. Statins have been shown to have a protective effect on renal function, by reducing the contribution of lipids to glomerulosclerosis [33], reducing neutrophil and macrophage infiltration [33], and up-regulating endothelial nitric oxide synthase [34].

Epidemiological studies confirmed a positive association between raised SUA levels and risk of CHD or CVD in the general population, among hypertensive patients and those with established CHD, stroke, DM and heart failure [9–12]. A study [35] examined the 20-year experience of 7978 mild-to-moderate hypertensive participants in a systematic worksite treatment program. Despite blood pressure control, SUA levels increased during treatment and were significantly and directly associated with CVD events independently of diuretic use and other CVD risk factors. It has also been calculated that higher SUA levels have a greater effect on vascular event rates in the presence of DM independently of other prognostic factors [36]. Though the role of SUA in stroke pathophysiology remains uncertain, interventions to lower urate may be worth considering [36].

MetS is usually associated with increased SUA levels [13], while atorvastatin has been shown to decrease SUA levels [15]. In this analysis of GREACE, there was a significant reduction in urate in statin (mainly atorvastatin)-treated patients not receiving diuretics, which was inversely correlated with the increase of e-GFR (r = 0.87, P < 0.0001). Improvement of renal function is the most probable factor for the fall in SUA levels. It is plausible that the beneficial effect of renal function improvement on subsequent vascular events might be in part mediated through SUA level reduction. However, SUA levels were not independently predictive of vascular risk if e-GFR was considered (Table 3).

A post hoc analysis of the 4S study [37] suggested that nondiabetic CHD patients with or without MetS derived a similar relative risk reduction in vascular events after simvastatin treatment. However, the absolute benefit was greater in MetS patients because they were at a higher absolute risk. The 4S analysis did not assess the effect of simvastatin on renal function and SUA levels. In our study, the vascular event rate was greater in MetS(+) (Groups A and B) compared with MetS(–) patients (Groups C and D) whether statins were administered or not. As expected, the risk was highest in the untreated MetS(+) Group [vascular events: 28% vs 22.1% in the untreated MetS(–) Group, P = 0.003]. However, the difference was small between the two statin-treated groups [vascular events: 12.1% in MetS(+) vs 13.1% in MetS(–) statin-treated patients, P = 0.063]. In addition, there was a higher relative risk reduction associated with statin use (–57% vs –41%, P < 0.0001) in MetS patients compared with those without MetS. In other words, the increased risk of a vascular event associated with MetS was abolished by statin treatment.

Study limitations
We used the MDRD study equation to estimate renal function. However, this equation has been reported to be less accurate in populations without CKD [38]. On average, GFR estimates of less than 90 ml/min/1.73 m2 are lower compared with the directly measured values [38]. Therefore, the potential effect of statins on renal function will need to be more extensively investigated by more specific tests (e.g. urine collections for microalbuminuria and proteinuria and the use of markers or isotopes such as inulin or 51Cr-EDTA).

The GREACE study [17] was not double-blinded and placebo-controlled, because of ethical and practical issues. This study adopted this design because its main goal was to assess the clinical benefit from NCEP ATP III guideline implementation in comparison with that seen with ‘usual care’ treatment patterns. Only a few patients on statins other than atorvastatin were evaluated.

We only considered overall vascular events since the absolute numbers were too small to evaluate each event category separately. Furthermore, it was not possible to test for an effect of DM because the patient numbers were not large enough to be analysed.



   Conclusions
Top
 Abstract
 Introduction
 Study population: methods
 Results
 Discussion
 Conclusions
References
 
In CHD patients with MetS not treated with statins there was a further decline in e-GFR over time, which was associated with an increase in SUA levels. Both these factors seemed to increase the risk for vascular events. In contrast, CHD patients with MetS on long-term target-driven statin treatment (mainly atorvastatin) experienced a significant increase in e-GFR and a reduction in SUA levels, which may have contributed to the reduction in risk for vascular events. Prevention of an additional CVD risk factor, such as renal impairment might prove to be beneficial for patients with established CHD and MetS, who are already at very high risk [39]. Renal impairment and CVD may progress in parallel. Statins may be beneficial in preventing both subsequent vascular events and CKD in MetS patients with CHD.

Conflict of interest statement. This study was conducted independently; no company or institution supported it financially. Some of the authors have attended conferences, given lectures and participated in advisory boards or other trials sponsored by various pharmaceutical companies.



   References
Top
 Abstract
 Introduction
 Study population: methods
 Results
 Discussion
 Conclusions
 References
 

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Received for publication: 7. 6.06
Accepted in revised form: 11. 8.06


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