Comparison of the effects of different statins and doses on lipid levels in patients with diabetes: Results from VOYAGER

doi:10.1016/j.numecd.2012.03.003

Nutrition, Metabolism and Cardiovascular Diseases

Volume 22, Issue 9, September 2012, Pages 697-703

https://doi.org/10.1016/j.numecd.2012.03.003 Get rights and content

Abstract

Background and aims

Diabetes mellitus is a well-known risk factor for cardiovascular disease, and brings an increased risk of vascular events and a higher mortality rate. Treatment guidelines recommend statins in patients with diabetes, with low-density lipoprotein cholesterol (LDL-C) targets of 100 mg dl⁻¹ (∼2.5 mmol l⁻¹), and 80 (∼2.0 mmol l⁻¹) or 70 mg dl⁻¹ (∼1.8 mmol l⁻¹) in especially high-risk patients. The current study used the VOYAGER (an indiVidual patient data-meta-analysis Of statin therapY in At risk Groups: Effects of Rosuvastatin, atorvastatin, and simvastatin) database to characterise effects of rosuvastatin, atorvastatin and simvastatin in different doses on lipid levels in diabetes patients.

Methods and results

The VOYAGER database included individual patient data from 37 studies involving comparisons of rosuvastatin with either atorvastatin or simvastatin. Of the 32 258 patients included, 8859 (27.5%) had diabetes. Rosuvastatin appeared to be the most efficacious of the three statins, both for lowering LDL-C and for reaching a target level of <70 mg dl⁻¹ for LDL-C. It was also more effective than atorvastatin at raising high-density lipoprotein cholesterol in the diabetes population. These results are consistent with the overall VOYAGER results.

Conclusions

This meta-analysis of 8859 patients with diabetes mellitus shows favourable effects on lipids with the three statins studied, in line with results for the overall VOYAGER population. The importance of using an effective statin at an effective dose to reach treatment goals for such high-risk patients is evident.

Section snippets

Identification of studies

The VOYAGER database includes individual patient data from 37 studies involving fixed-dose comparisons of rosuvastatin with either atorvastatin or simvastatin and recorded baseline and on-therapy lipid parameters [20]. Studies of <4 weeks duration, that were open-label extension, observational or only evaluated pharmacokinetics, were not included. Studies for inclusion in the database were identified by a comprehensive search of the Cochrane Controlled Trials Registry, Medline (1999–2007),

Results

Table 1 shows baseline characteristics and the number of patient exposures to statin therapy for patients with diabetes, and the overall VOYAGER population. In total, there were 8859 diabetes patients in the VOYAGER database, receiving 11 042 exposures to individual doses of statin agents.

Discussion

These results on patients with diabetes are compatible with the results from the overall VOYAGER population [20], and those of the population without diabetes (Table 2). At approved doses, rosuvastatin appeared to be the most efficacious of the three statins investigated in the diabetes patients included in the VOYAGER database, both for lowering LDL-C and for reaching target LDL-C levels <70 mg dl⁻¹ (∼1.8 mmol l⁻¹). Rosuvastatin was also more effective than atorvastatin at raising HDL-C in the

Funding

The VOYAGER individual patient data meta-analysis was supported by AstraZeneca, which provided funding for the statistical analyses and was involved in the decision to submit the article.

Conflicts of interests

B.W. Karlson is an employee of AstraZeneca. P.J. Barter has served on Advisory Boards for AstraZeneca, Merck, Roche and Novartis and received honoraria for lectures and speaker bureaus from AstraZeneca, Merck, Pfizer and Roche. M.K. Palmer holds stock/stock options for AstraZeneca; his institution has received consultancy fees, as well as fees for statistical analyses for the current article from AstraZeneca, and honoraria for serving on Advisory Boards and speaker bureaus, and for lectures and

Acknowledgements

Editorial support during the later stages of manuscript development was provided by V. Moss, from Prime Medica Ltd, Knutsford, UK, and funded by AstraZeneca. Responsibility for opinions, conclusions and interpretation of data lies with the authors. Some of the data presented in this article were presented at the International Symposium on Atherosclerosis, Boston, June 14–18, 2009 and some were presented at the European Atherosclerosis Society meeting Gothenburg, Sweden, June 26–29, 2011.

B. W.

References (28)

P.J. Delahoy et al.
The relationship between reduction in low-density lipoprotein cholesterol by statins and reduction in risk of cardiovascular outcomes: an updated meta-analysis
Clin Ther
(2009)
H.M. Colhoun et al.
Primary prevention of cardiovascular disease with atorvastatin in type 2 diabetes in the Collaborative Atorvastatin Diabetes Study (CARDS): multicentre randomised placebo-controlled trial
Lancet
(2004)
Cholesterol Treatment Trialists' (CTT) Collaborators
Efficacy of cholesterol-lowering therapy in 18,686 people with diabetes in 14 randomised trials of statins: a meta-analysis
Lancet
(2008)
Cholesterol Treatment Trialists' (CTT) Collaboration
Efficacy and safety of more intensive lowering of LDL cholesterol: a meta-analysis of data from 170 000 participants in 26 randomised trials
Lancet
(2010)
L.H. Opie et al.
Controversies in stable coronary artery disease
Lancet
(2006)
S.J. Nicholls et al.
Meta-analysis of comparative efficacy of increasing dose of Atorvastatin versus Rosuvastatin versus Simvastatin on lowering levels of atherogenic lipids (from VOYAGER)
Am J Cardiol
(2010)
P.J. Barter et al.
Effect of statins on HDL-C: a complex process unrelated to changes in LDL-C: analysis of the VOYAGER Database
J Lipid Res
(2010)
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)
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)
S.M. Haffner 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)

American Diabetes Association

Standards of Medical Care in Diabetes–2006

Diabetes Care

(2006)

J.B. Buse et al.

Primary prevention of cardiovascular diseases in people with diabetes mellitus: a scientific statement from the American Heart Association and the American Diabetes Association

Circulation

(2007)

R.R. Holman et al.

Long-term follow-up after tight control of blood pressure in type 2 diabetes

N Engl J Med

(2008)

L. Rydén et al.

Task force on diabetes and cardiovascular diseases of the European Society of Cardiology (ESC); European Association for the study of diabetes (EASD). Guidelines on diabetes, pre-diabetes, and cardiovascular diseases: executive summary. The Task force on diabetes and cardiovascular diseases of the European Society of Cardiology (ESC) and of the European Association for the Study of Diabetes (EASD)

Eur Heart J

(2007)

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Las estatinas son fármacos de alta eficacia para disminuir la concentración plasmática de lipoproteínas aterogénicas y prevenir las enfermedades cardiovasculares. Las guías de práctica clínica recomiendan el uso de estatinas de alta intensidad para disminuir el cLDL al menos un 50% en los pacientes con ECV y en los de alto RCV. Las recomendaciones para el tratamiento de la hipercolesterolemia del ACC/AHA han supuesto un cambio de paradigma en la prevención cardiovascular al abandonar los objetivos terapéuticos del cLDL y plantear el tratamiento con estatinas de alta o moderada intensidad en cuatro grupos poblacionales bien identificados de alto RCV. Dichas recomendaciones son distintas a las de las guías europeas de prevención cardiovascular en las que se mantienen dichos objetivos del cLDL. Este trabajo revisa dicha controversia desde distintos ángulos y desde la perspectiva del Comité Español Interdisciplinar para la Prevención Cardiovascular y también los estudios de intervención con estatinas de alta intensidad en prevención primaria, en pacientes con síndrome coronario agudo y con cardiopatía isquémica estable. Asimismo, se aborda el tratamiento con estatinas de alta intensidad en cuanto a su eficacia en prevención cardiovascular y a su seguridad, con particular atención a los efectos musculares, teniendo en cuenta las características farmacológicas de las distintas estatinas y la mayor seguridad de las que presentan un menor potencial de interacciones. Por último se describen nuevos agentes para el tratamiento de la hipercolesterolemia con especial énfasis en los anticuerpos monoclonales anti-PCSK9, un nuevo grupo terapéutico de alta eficacia hipocolesteremiante que supondrá un enorme progreso en la prevención de las enfermedades cardiovasculares.
Statins are highly effective drugs to decrease the plasma concentrations of atherogenic lipoproteins and prevent cardiovascular disease. The clinical practice guidelines recommend the use of high-intensity statins to lower LDL-cholesterol by at least 50% in patients with CVD and those at high cardiovascular risk. The recommendations for the treatment of hypercholesterolaemia by the ACC/AHA have led to a paradigm shift in cardiovascular prevention. These recommendations have abandoned the therapeutic goals of LDL-cholesterol, and recommend the treatment with statins of high or moderate intensity in four high cardiovascular risk groups. These recommendations are different from the European guidelines on cardiovascular disease prevention, in which their objectives are still towards LDL-cholesterol. This paper reviews this controversy from different angles and from the perspective of the Spanish Interdisciplinary Committee for Cardiovascular Disease Prevention. Intervention studies with high intensity statins in primary prevention, in patients with acute coronary syndrome, and with stable ischaemic heart disease are also described. Likewise, treatment with statins of high intensity is addressed in terms of their effectiveness in cardiovascular prevention and in terms of their safety, with particular attention to muscle effects, as well as taking into account the pharmacological characteristics of the different statins and the increased safety of those with less potential for interactions. Finally, new agents are described for the treatment of hypercholesterolaemia, with special emphasis on anti-PCSK9 monoclonal antibodies, a new therapeutic group for the treatment of hypercholesterolaemia that will offer a huge progress in the prevention of cardiovascular diseases.
To what extent do high-intensity statins reduce low-density lipoprotein cholesterol in each of the four statin benefit groups identified by the 2013 American College of Cardiology/American Heart Association guidelines? A VOYAGER meta-analysis
2015, Atherosclerosis
Citation Excerpt :
Another analysis of the VOYAGER database found that baseline LDL-C and choice of statin and dose are important for achieving LDL-C goals of <100 mg/dl and <70 mg/dl, with greater proportions of patients achieving the LDL-C goals with increasing statin dose across the spectrum of baseline LDL-C levels [7]. Finally, rosuvastatin appeared to be more efficacious when compared with atorvastatin and simvastatin for lowering LDL-C in patients with type-2 diabetes [8]. These results from the VOYAGER database confirm a previous analysis by Roberts, who observed that rosuvastatin 20 mg produced similar reductions in LDL-C as atorvastatin 80 mg [9].
The 2013 American College of Cardiology and American Heart Association (ACC/AHA) guidelines identify four patient groups who benefit from moderate- or high-intensity statin treatment; those with: 1) atherosclerotic cardiovascular disease (ASCVD); 2) low-density lipoprotein cholesterol (LDL-C) ≥190 mg/dl; 3) diabetes; or 4) a 10-year ASCVD risk ≥7.5%. High-intensity statins, anticipated to reduce LDL-C by ≥50%, were identified as rosuvastatin 20–40 mg and atorvastatin 40–80 mg.
Individual patient data (32,258) from the VOYAGER database of 37 studies were used to calculate least-squares mean (LSM) percentage change in LDL-C during 8496 patient exposures to rosuvastatin 20–40 mg, and atorvastatin 40–80 mg in the four patient benefit groups. LSM percentage reductions in LDL-C with rosuvastatin 20 and 40 mg were greater than with atorvastatin 40 mg, overall and in each statin benefit group, and with rosuvastatin 40 mg were greater than with atorvastatin 80 mg overall and in three of the four benefit groups (all p < 0.05). For example, in the ASCVD group, 40%, 59%, 57% and 71% of patients treated with atorvastatin 40 mg, atorvastatin 80 mg, rosuvastatin 20 mg and rosuvastatin 40 mg, respectively, had a ≥50% reduction in LDL-C.
The choice and dose of statin have an impact both on the percentage LDL-C reduction and achievement of ≥50% reduction in LDL-C, overall and within each of the four statin benefit groups outlined by the 2013 ACC/AHA guidelines. This may be of importance for clinicians in their choice of treatment for individual patients.
Expected impact of applying new 2013 AHA/ACC cholesterol guidelines criteria on the recommended lipid target achievement after acute coronary syndromes
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The Adult Treatment Panel (ATP III) recommended reaching a low-density lipoprotein cholesterol (LDL-C) target < 1.8 mmol/l (70 mg/dL) in very high-risk patients, such as patients with ACS [6,7]. The paradigm of targeting statin dose for a specific LDL-C goal means that an adequate dose of statin should be prescribed or adapted to reach recommended LDL-C [8]. Nevertheless, previous observational studies have shown that poorly controlled LDL-C levels after ACS are common and statin intensification sub-optimal [9–11].
2013 AHA/ACC guidelines on the treatment of cholesterol advised to tailor high-intensity statin after ACS, while previous ATP-III recommended titration of statin to reach low-density lipoprotein cholesterol (LDL-C) targets. We simulated the impact of this change of paradigm on the achievement of recommended targets.
Among a prospective cohort study of consecutive patients hospitalized for ACS from 2009 to 2012 at four Swiss university hospitals, we analyzed 1602 patients who survived one year after recruitment. Targets based on the previous guidelines approach was defined as (1) achievement of LDL-C target < 1.8 mmol/l, (2) reduction of LDL-C ≥ 50% or (3) intensification of statin in patients who did not reach LDL-C targets. Targets based on the 2013 AHA/ACC guidelines approach was defined as the maximization of statin therapy at high-intensity in patients aged ≤75 years and moderate- or high-intensity statin in patients >75 years.
1578 (99%) patients were prescribed statin at discharge, with 1120 (70%) at high-intensity. 1507 patients (94%) reported taking statin at one year, with 909 (57%) at high-intensity. Among 482 patients discharged with sub-maximal statin, intensification of statin was only observed in 109 patients (23%). 773 (47%) patients reached the previous LDL-C targets, while 1014 (63%) reached the 2013 AHA/ACC guidelines targetsone year after ACS (p value < 0.001).
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Changes in high-density-lipoprotein cholesterol upon statin treatment in type 2 diabetic patients: A meta-analysis
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Citation Excerpt :
Based on the above, our findings may result from the constellation of a diminished HDL-C increase in diabetic patients, the pharmacogenetic atorvastatin response in Asian populations, and the pharmacokinetic characteristics of atorvastatin in HDL-C metabolism. Although Karlson et al. [23] recently discussed the change in serum HDL-C after statin treatment in diabetic patients according to analysis of the VOYAGER database, our study may still provide additional information for current practice. It should be noted that the included studies of the VOYAGER database were all of a randomized design and were conducted in 4∼12 weeks.
To investigate the diversity of change in high-density-lipoprote in cholesterol (HDL-C) after statin treatment in patients with type 2 diabetes mellitus (T2DM).
A systemic review searched for trials that reported a serum change in HDL-C in patients with T2DM after statin treatment, and extracted data for meta-analysis. Of 6709 articles surveyed, 160 articles were identified as eligible articles. In the analysis of simvastatin, serum HDL-C was increased in Non-Asian and Asian patients with T2DM by 2.17 mg/dl (95% CI 1.43 ∼ 2.90 mg/dl, p < 0.001) and 2.31 mg/dl (95% CI 1.37 ∼ 3.25 mg/dl, p < 0.001), respectively. In the analysis of atorvastatin, although significant, serum HDL-C was subtly increased in Non-Asian patients with T2DM by 1.14 mg/dl (95% CI 0.28 ∼ 2.01 mg/dl, p = 0.010) mg/dl; however, atorvastatin treatment did not significantly change the serum HDL-C by 0.12 mg/dl (95% CI −1.04 ∼ 1.27 mg/dl, p = 0.839) mg/dl in Asian patients with T2DM. According to meta-regression analysis, the baseline HDL-C did not affect the change in serum HDL-C in Asian patients with T2DM after either simvastatin or atorvastatin treatment. However, contrary to simvastatin, the coefficient of regression (r) showed a significant negative association (r = −0.18; 95% CI −0.32 to −0.04; p = 0.01) between baseline HDL-C and the change of HDL-C in non-Asian patients with T2DM after atorvastatin treatment.
We have demonstrated for the first time that there may be a discrepancy in the change of serum HDL-C in Asian patients with T2DM after atorvastatin treatment.
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This cluster randomized trial evaluated the efficacy of a disease and care management (D&CM) model in cardiovascular (CVD) prevention in primary care.
Eligible subjects had ≥1 among: blood pressure ≥ 140/90 mmHg; glycated hemoglobin ≥ 7%; LDL-cholesterol ≥ 160 or ≥100 mg/dL (primary or secondary prevention, respectively); BMI ≥ 30; current smoking. The D&CM intervention included a teamwork including nurses as care managers for the implementation of tailored care plans. Control group was allocated to usual-care. The main outcome was the proportion of subjects achieving recommended clinical targets for ≥1 of uncontrolled CVD risk factors at 12-month. During 2008–2009 we enrolled 920 subjects in the Abruzzo/Marche regions, Italy. Following the exclusion of L'Aquila due to 2009 earthquake, final analyses included 762 subjects. The primary outcome was achieved by 39.1% (95%CI: 34.2–44.2) and 25.2% (95%CI: 20.9–29.9) of subjects in the intervention and usual-care group, respectively (p < 0.001). The D&CM intervention significantly increased the proportion of subjects who achieved clinical targets for both diabetes and hypertension, with no differences in hypercholesterolemia, smoking status and obesity.
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Meta-AnalysisComparison of the effects of different statins and doses on lipid levels in patients with diabetes: Results from VOYAGER

Abstract

Background and aims

Methods and results

Conclusions

Section snippets

Identification of studies

Results

Discussion

Funding

Conflicts of interests

Acknowledgements

Clin Ther

Lancet

Lancet

Lancet

Lancet

Am J Cardiol

J Lipid Res

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

MRC/BHF Heart Protection Study of cholesterol lowering with simvastatin in 20,536 high-risk individuals: a randomised placebo-controlled trial

Lancet

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

Standards of Medical Care in Diabetes–2006

Diabetes Care

Primary prevention of cardiovascular diseases in people with diabetes mellitus: a scientific statement from the American Heart Association and the American Diabetes Association

Circulation

Long-term follow-up after tight control of blood pressure in type 2 diabetes

N Engl J Med

Eur Heart J

Meta-Analysis
Comparison of the effects of different statins and doses on lipid levels in patients with diabetes: Results from VOYAGER