Patients with chronic kidney disease (CKD) have a high rate of cardiovascular morbidity and mortality1–3; therefore in different clinical guidelines this disease is considered a powerful and common predictor of cardiovascular events and mortality,4 which involves stratifying these patients as being at a high or very high risk of cardiovascular disease, and a tight control of different risk factors, including dyslipidaemia. Dyslipidaemia may contribute not only to the development of cardiovascular disease, but also to the onset and progression of CKD.5,6

HMG-CoA reductase inhibitors, or statins, are the most widely used lipid-lowering drugs for the management of dyslipidaemia. This is because the clear clinical evidence of their cardiovascular benefits, even in patients with CKD.7–9 In a recent systematic review and meta-analysis on the effects of statins in CKD patients, including 31 clinical trials with 48.429 patients, statin therapy achieved a 23% reduction in the risk of severe cardiovascular events, a reduction of 18% in the risk of coronary events and a 9% decreased risk of cardiovascular or total mortality.10 In addition, statins may delay the progression of CKD by reducing proteinuria, inflammation and fibrosis,11 although the evidence on this beneficial effect is limited and contradictory.10,12,13 However, one recent cohort study points to an increased risk of renal events with the use of statins.14 One recent consensus document by a panel of lipid experts on intolerance to statins recognises that statins may be associated with an increased risk of acute kidney failure and proteinuria.15

Not all statins are cleared uniformly by kidneys; some have a higher rate of renal excretion and require dose adjustments in CKD (e.g., pravastatin or rosuvastatin), while others have a significant risk of drug-related interactions16 this is a relevant fact for renal patients, who are usually polymedicated. Also, some evidence indicates that different statins may have different effects on urinary albumin excretion and the progression of kidney disease.17–21

The DIANA study was recently carried out to assess the knowledge and attitudes in relation to the diabetogenicity of the different statins, such as the differences that may exist amongst them, with a view to a more rational use in patients with type 2 diabetes mellitus or those predisposed to developing it.22 To determine the opinion of prescribing doctors about the screening and management of dyslipidaemia in patients with CKD, we performed a post hoc analysis of the DIANA study.

Of the 497 experts participating in the study, 58% were GPs and 42% specialist doctors (14% endocrinologists, 14% internists, 7% cardiologists and 7% nephrologists). Of the total number of experts participating, 62% had more than 20 years of professional practice and 80% cared on average for more than 50 dyslipidaemic patients a month. In addition, more than 60% of the participants reported that more than 50% of the patients treated in their offices were over 65 years of age, were polymedicated or had hypertension.

Table 1 shows the results obtained. There was a consensus (agreement of >80% of panellists) on the need for screening for dyslipidaemia in patients with CKD in the entire group (89.7%), with no statistically significant difference between GPs and specialists (87.9% vs. 92.4%, respectively; p=NS), nor any differences between nephrologists (91.4%) and non-nephrologists (92.4%; p=NS).

Agreement was also reached on when to screen for dyslipidaemia in patients with CKD in clinical practice, because 81.3% of the doctors surveyed stated that they performed this always/almost always, with no statistically significant differences between GPs and specialists (80.0% vs. 83.1%, respectively; p=NS). Although the differences were not significant, nephrologists responded more often that they screened always/almost always (91.4%) than non-nephrologist specialists (81.4%).

Regarding which parameters influence the choice of statin, there was agreement in which, amongst other aspects, patient profile influences the choice of statin (86.9%), as well as possible interaction with other drugs (84.9%), with no statistically significant differences between GPs and specialists (85.9 vs. 83.6%). When the data were analysed by differentiating between nephrologists and non-nephrologists, the former showed no consensus (77.1%), whereas the latter did show consensus (89.0%), with a similar figure for GPs (86.9%; p=0.0635). There was no difference between subgroups, and there was agreement amongst all of them when considering the patients’ polymedicated status on choosing a statin.

However, regarding the parameters to be considered when deciding on a statin, there was no consensus in the entire sample when considering estimated glomerular filtration rate (eGFR) (78.7%; GPs 82.4% vs. specialists 73.4%; p=NS). When analysing this parameter by considering a given expert's specialty, as with the GPs, the nephrologists deemed it necessary to consider eGFR when deciding on a statin (85.7%), but the non-nephrologists did not (70.9%; p=0.0458). Nor was a consensus reached with regard to albuminuria in the entire sample analysed (63.2%), though the nephrologists seemed to take it into account more often (74.3% nephrologists vs. 56.4% non-nephrologists vs. 65.9% GPs; p=0.0513).

Also, no agreement was reached on measuring eGFR (78.1%: GPs 78.3% vs. specialists 77.8%; p=NS) or urinary albumin excretion (65.2%: GPs 67.6% vs. specialists 61.8%; p=NS) during follow-up after starting statin therapy. When the specialty was subdivided between nephrologists and non-nephrologists, the nephrologists considered evaluating eGFR (88.6%), whereas the non-nephrologists, as well as the GPs, did not reach a consensus (75.6%; p=0.1704). Something similar happened with albuminuria, but in this parameter there were statistically significant differences amongst the groups of experts (GPs 67.6%; 82.9% vs. nephrologists vs. 57.6% non-nephrologists; p=0.0112).

Regarding which parameters should be considered when prescribing a statin, it was considered that a patient's renal function/albuminuria should be accounted for (85.7%: GPs 90.0% vs. specialists 81.6%; p=0.0175), with no differences between specialist types (nephrologists 82.9 vs. 81.4% non-nephrologists).

In this post hoc analysis of the DIANA study, there was agreement that dyslipidaemia should be studied in patients with CKD and that it is routine practice to screen for it in this population. This means that the participating doctors recognised the high cardiovascular risk associated with CKD, as indicated in the guidelines and consensus documents.4,31 The Kidney Disease | Improving Global Outcomes (KDIGO) guide on managing dyslipidaemia in CKD recommends measuring the lipid profile in this specific population to establish a diagnosis of dyslipidaemia,32 which amongst nephrologists is an almost-universal practice. In addition, the study confirmed that renal function/albuminuria should be considered amongst the parameters for the choice of statin, as it would classify the patient as having a high or very high cardiovascular risk.

There was also agreement that patient profile, as well as possible interaction with other drugs, should be considered when choosing a statin. However, the nephrologists did not reach a consensus on whether patient profile influenced the choice of statin (77.1%). This may be due to the fact that, in general, renal patients seen by nephrologists are in more advanced stages of the disease, and these patients have a very high cardiovascular risk. Therefore, statin therapy is almost mandatory.32 In a word, prescribing doctors are aware that, in addition to considering the efficacy of a statin in meeting an LDL-C goal, they should consider other aspects related to patients and polymedication.

However, there was no consensus in considering eGFR or urinary albumin excretion as factors to be taken into account in the choice of statin. However, according to the subgroups of doctors surveyed, both GPs and nephrologists did reach a consensus in considering eGFR as an element to account for in the choice of statin, but this was not achieved in non-nephrologist specialists (70.9%), with a significant difference. This discrepancy may be due to different drug-prescription patterns amongst different specialists. It seems then that whereas GPs integrate the different prescribed treatments and clinical conditions and perform long-term patient monitoring, specialists often follow a fire-and-forget strategy, which is advocated by the latest US guidelines, which recommend starting statin therapy with fixed doses with no LDL-C goal.33 The KDIGO guidelines32 also recommend the use of a statin or statin/ezetimibe in patients with CKD who are older than 50 years with an eGFR<60ml/min/1.73m2. By contrast, the 2012 European guidelines on cardiovascular disease prevention in clinical practice34 consider patients with stage 4–5 CKD (eGFR<30ml/min/1.73m2) to have a very high cardiovascular risk, and they establish the same goal for monitoring such patients (LDL-C below 70mg/dl, or at least a 50% reduction compared with the baseline) as for patients with a history of atherosclerotic vascular disease (secondary prevention). Further, patients with stage 3 CKD (eGFR between 30 and 60ml/min/1.73m2) are classified as having a high cardiovascular risk and they are assigned an LDL-C goal of <100mg/dl. Alternatively, it could be inferred that amongst non-nephrologist specialists there is less knowledge that some statins show greater renal clearance and therefore require dose adjustments.

It is also surprising that there is no consensus in considering baseline albuminuria amongst any of the groups of doctors, although there are studies that indicate that statins are not homogeneous in this regard.20,21

All of this indicates the need for a better understanding of the implications of CKD in prescribing statins amongst specialists in order to reduce cardiovascular risk and minimise the risk of renal adverse effects in this population.15

Nor was it considered necessary to monitor renal function or urinary albumin excretion during follow-up after prescribing a statin, nor amongst GPs or specialists, although when analysed by subgroup, the nephrologists reached a consensus in evaluating eGFR and albuminuria during follow-up of their patients. In this regard, some observational studies have shown an increased risk of renal events (acute kidney failure) with the use of statins,14,35,36 but this has not been observed in other clinical trials, prospective studies or meta-analyses.10,12,13,37

Although it may seem that the effects of statins on renal function are minor, many of the positive studies stem from the analysis of clinical trials designed to evaluate cardiovascular events in which the measure of renal function was limited to the eGFR. With respect to specific statins, some evidence indicates a beneficial effect on renal function in some,17,19 and a neutral effect in others.12 In comparative clinical trials of statins, differences have been observed amongst them in terms of progression of CKD21 or of reduction of albuminuria.20 This seems to be known in particular amongst nephrologists, and to a lesser extent amongst GPs and non-nephrologists. Finally, a recent meta-analysis indicates that high-efficacy statins might have a beneficial effect on decreased renal function (but not those of medium-low efficacy) in patients with CKD.38

As mentioned above, patients with CKD have a higher risk of developing adverse effects when treated with statins15; therefore it is important to choose a statin with sufficient hypocholesterolaemic efficacy, with no risk of accumulation in the presence of CKD, and with a low risk of drug interactions that, if possible, have shown a beneficial effect on the progression of CKD. In this regard the European guidelines for the treatment of dyslipidaemia recommend the use of statins that show a lower renal excretion, such as fluvastatin, atorvastatin and pitavastatin, in patients with CKD,39 although they do not refer to dose adjustments in the presence of CKD. The Spanish consensus document on CKD is similar in this sense.31 Also in this vein, the KDIGO guidelines include dose adjustments for each statin in patients with CKD.32 It should also be noted that statins metabolised by cytochrome P450 3A4 (lovastatin, simvastatin and atorvastatin) may cause adverse reactions due to their interaction with other drugs commonly used for these patients. The lack of consensus in the recommendations on the type and maximum dose of statin in CKD, especially in advanced CKD, and on the relationship between statins and proteinuria/albuminuria is therefore evident. Therefore a consensus document/guide to advise specialists in the choice of statin in CKD would be useful.

This study's main limitation is that the questionnaire was not specifically designed to show whether the presence of CKD had any effect on screening for dyslipidaemia or on selecting a hypolipidaemic treatment. Nor did it specifically ask whether there are differences between statins regarding renal function or albuminuria, or regarding possible differences between high- and low-medium-efficacy statins; this should be addressed in a future study. However, the answers contained in this analysis are novel, based on clinical practice, and allow us to detect training-related deficiencies of prescribing doctors in terms of the appropriate choice of a statin in patients with CKD. By contrast, the number of nephrologists included is small, and therefore the results of the study may not be extrapolated to all nephrologists. The statistical power of the study is limited when analysing the data by nephrologist and non-nephrologist: a “false negative” may be obtained, i.e., maintaining that there are no differences amongst groups, when in fact differences exist.

In summary, the data from this study show that there is a consensus on the need to detect dyslipidaemia in CKD, thus indicating that doctors recognise that the condition involves stratifying patients as being at a high or very high cardiovascular risk, and therefore, the need to prescribe statins in this population. However, there does not appear to be adequate knowledge about the clinically relevant differences that exist amongst different statins in relation to CKD. Improving this situation, by developing a guide/consensus document and conducting training on the subject for different specialties, might allow doctors to choose the most suitable statin for each patient and to minimise the risk of adverse effects in this population.

This study was funded by Laboratorios Esteve, which did not, however, participate in the preparation of the survey, statistical analysis, discussion of results or the writing of the article, which were the responsibility of the committee of experts who signed as authors of the article.

All the authors actively contributed to developing the study and drafting the manuscript, approving the final version and its submission for publication in Nefrología.

All authors state that there are no conflicts of interest in the writing of the manuscript, and any type of financial or personal relationship that might interfere with the study has been specified.