Long-term Intervention With Pravastatin In Ischemic Disease Research Articles

Plasma Protein Biomarkers and Long-Term Cardiovascular Mortality Risk in Patients With Chronic Coronary Heart Disease.

Protein biomarkers that reflect different pathophysiological pathways have been associated with the risk of adverse cardiovascular events. However, it is uncertain whether these associations are sustained with increasing years after the biomarkers are measured. In this cohort study, 7745 patients with coronary heart disease who participated in the LIPID (Long-Term Intervention With Pravastatin in Ischemic Disease) trial, BNP (B-type natriuretic peptide), troponin I, cystatin-C, C-reactive protein, d-dimer and midregional proadrenomedullin were measured at baseline and after 1 year. Discrimination of plasma biomarker concentrations for cardiovascular death were evaluated in landmark analyses from 1 year for the next 5 years of the randomized trial, and for 10 additional years after trial completion. All 6 biomarkers were associated with risk of cardiovascular death (n=1903) both during and after the clinical trial (each P<0.001). C-statistics for BNP were 0.706 and 0.704; cystatin-C, 0.686 and 0.693; troponin I, 0.686 and 0.689; C-reactive protein, 0.655 and 0.684; d-dimer, 0.670 and 0.679, and midregional adrenomedullin, 0.686 and 0.688, respectively. In multivariable models, adding all 6 biomarkers to models with clinical risk factors increased the C-statistic for cardiovascular death from 0.709 to 0.775 during the clinical trial, and from 0.713 to 0.751 during 10-year follow-up after the randomized trial (P<0.001 for both). In patients with chronic coronary heart disease, biomarkers that reflect different pathophysiological pathways are associated with the risk of cardiovascular death for at least the next 15 years.

B‐Type Natriuretic Peptide and Long‐Term Cardiovascular Mortality in Patients With Coronary Heart Disease

BackgroundThe plasma concentration of B‐type natriuretic peptide (BNP) is a strong predictor of adverse cardiovascular events. The aim of this study was to determine whether the association between plasma BNP concentration and cardiovascular mortality is sustained or diminishes with increasing time after BNP is measured.Methods and ResultsSix thousand seven hundred forty patients with a history of myocardial infarction or unstable angina who participated in the LIPID (Long‐Term Intervention with Pravastatin in Ischemic Disease) trial had plasma BNP concentration measured at baseline and after 1 year. Associations with cardiovascular mortality were evaluated in landmark analyses 1 to <5, 5 to <10, and 10 to 16 years after randomization. There were 1640 cardiovascular deaths. The cardiovascular mortality rate increased progressively from 10.2 to 19.1 to 26.3/1000 patient‐years from 1 to <5, 5 to <10, and 10 to 16 years after baseline, respectively. The average of baseline and 1‐year BNP concentration was more strongly associated with cardiovascular mortality compared with baseline or 1‐year BNP only. The hazard ratio (HR) for cardiovascular death associated with each doubling of average BNP concentration was similar during years 1 to <5 (HR, 1.53 [95% CI, 1.44–1.63]), years 5 to <10 (HR, 1.52 [95% CI, 1.44–1.60]), and years 10–16 (HR, 1.43 [95% CI, 1.36–1.50]), P<0.0001 for all.ConclusionsBNP concentration remains an independent predictor of cardiovascular mortality more than a decade after it is measured. Because of random variation in plasma concentrations, the average of >1 BNP measurement improves long‐term risk prediction.

Circulating Cystatin C Is an Independent Risk Marker for Cardiovascular Outcomes, Development of Renal Impairment, and Long-Term Mortality in Patients With Stable Coronary Heart Disease: The LIPID Study.

BackgroundElevated plasma cystatin C levels reflect reduced renal function and increased cardiovascular risk. Less is known about whether the increased risk persists long‐term or is independent of renal function and other important biomarkers.Methods and ResultsCystatin C and other biomarkers were measured at baseline (in 7863 patients) and 1 year later (in 6106 patients) in participants in the LIPID (Long‐Term Intervention with Pravastatin in Ischemic Disease) study, who had a previous acute coronary syndrome. Outcomes were ascertained during the study (median follow‐up, 6 years) and long‐term (median follow‐up, 16 years). Glomerular filtration rate (GFR) was estimated using Chronic Kidney Disease Epidemiology Collaboration equations (first GFR‐creatinine, then GFR‐creatinine‐cystatin C). Over 6 years, in fully adjusted multivariable time‐to‐event models, with respect to the primary end point of coronary heart disease mortality or nonfatal myocardial infarction, for comparison of Quartile 4 versus 1 of baseline cystatin C, the hazard ratio was 1.37 (95% CI, 1.07–1.74; P=0.01), and for major cardiovascular events was 1.47 (95% CI, 1.19–1.82; P<0.001). Over 16 years, the association of baseline cystatin C with coronary heart disease, cardiovascular, and all‐cause mortality persisted (each P<0.001) and remained significant after adjustment for estimated GFR‐creatinine‐cystatin C. Cystatin C also predicted the development of chronic kidney disease for 6 years (odds ratio, 6.61; 95% CI, 4.28–10.20) independently of estimated GFR‐creatinine and other risk factors. However, this association was no longer significant after adjustment for estimated GFR‐creatinine‐cystatin C.ConclusionsCystatin C independently predicted major cardiovascular events, development of chronic kidney disease, and cardiovascular and all‐cause mortality. Prediction of long‐term mortality was independent of improved estimation of GFR.RegistrationURL: https://anzctr.org.au; Unique identifier: ACTRN12616000535471.

Abstract 13022: Hemodynamic Parameters of Pulmonary Circulation in Acute Coronary Syndrome: Incremental Prognositic Value for Long-term Survival

Objectives: To identify right heart catheterization (RHC)-assessed hemodynamic parameters of pulmonary circulation that were prognostic predictive of long-term survival in acute coronary syndrome (ACS), and to explore the incremental value of those parameters to the established risk models of coronary heart disease. Methods: Consecutive patients with ACS who underwent coronary angiography together with RHC were retrospectively reviewed. The primary endpoint was all-cause mortality. To identify the association between hemodynamic parameters and survival, Cox proportional hazards models were conducted. The optimal parameter identified was included in three subsequent models, which contained the Global Registry of Acute Coronary Events (GRACE), the Long-Term Intervention with Pravastatin in Ischemic Disease (LIPID) and the Cardiovascular Disease Research Using Linked Bespoke Studies and Electronic Health Records (CALIBER) models respectively. Model performance was evaluated before and after the addition of hemodynamic parameters. Results: A total of 251 patients were enrolled, with a median follow-up time of 34.7 months. By Cox analyses, systolic pulmonary arterial pressure [hazard ratio (HR): 1.043, 95% confidence interval (CI): 1.013-1.074], diastolic pulmonary arterial pressure (HR: 1.086, 95% CI: 1.014-1.164), mean pulmonary arterial pressure (HR: 1.077, 95% CI: 1.024-1.132), right ventricular systolic pressure (HR: 1.039, 95% CI: 1.008-1.070) and diastolic pressure gradient (HR: 1.101, 95% CI: 1.015-1.193) were found to be independent predictors of long-term survival. Furthermore, the addition of mean pulmonary arterial pressure to the established risk models yielded an improvement in model performance (integrated discriminatory index for the GRACE, LIPID and CALIBER model: 4.3%, 4.4% and 4.7%, respectively; all had a P&lt;0.05). Conclusions: Hemodynamic parameters of pulmonary circulation can be predictive of long-term survival and provide incremental prognostic value to risk assessment in patients with ACS.

Development and validation of a ceramide- and phospholipid-based cardiovascular risk estimation score for coronary artery disease patients.

Distinct ceramide lipids have been shown to predict the risk for cardiovascular disease (CVD) events, especially cardiovascular death. As phospholipids have also been linked with CVD risk, we investigated whether the combination of ceramides with phosphatidylcholines (PCs) would be synergistic in the prediction of CVD events in patients with atherosclerotic coronary heart disease in three independent cohort studies. Ceramides and PCs were analysed using liquid chromatography-mass spectrometry (LC-MS) in three studies: WECAC (The Western Norway Coronary Angiography Cohort) (N = 3789), LIPID (Long-Term Intervention with Pravastatin in Ischaemic Disease) trial (N = 5991), and KAROLA (Langzeiterfolge der KARdiOLogischen Anschlussheilbehandlung) (N = 1023). A simple risk score, based on the ceramides and PCs showing the best prognostic features, was developed in the WECAC study and validated in the two other cohorts. This score was highly significant in predicting CVD mortality [multiadjusted hazard ratios (HRs; 95% confidence interval) per standard deviation were 1.44 (1.28-1.63) in WECAC, 1.47 (1.34-1.61) in the LIPID trial, and 1.69 (1.31-2.17) in KAROLA]. In addition, a combination of the risk score with high-sensitivity troponin T increased the HRs to 1.63 (1.44-1.85) and 2.04 (1.57-2.64) in WECAC and KAROLA cohorts, respectively. The C-statistics in WECAC for the risk score combined with sex and age was 0.76 for CVD death. The ceramide-phospholipid risk score showed comparable and synergistic predictive performance with previously published CVD risk models for secondary prevention. A simple ceramide- and phospholipid-based risk score can efficiently predict residual CVD event risk in patients with coronary artery disease.

Dyslipidemia.

Dyslipidemia.

Persistent psychological distress and mortality in patients with stable coronary artery disease

BackgroundA single assessment of psychological distress, which includes depression and anxiety, has been associated with increased mortality in patients with coronary heart disease, but the prognostic importance of persistence of...

Long-Term Effectiveness and Safety of Pravastatin in Patients With Coronary Heart Disease: Sixteen Years of Follow-Up of the LIPID Study.

We aimed to assess the long-term effects of treatment with statin therapy on all-cause mortality, cause-specific mortality, and cancer incidence from extended follow-up of the Long-term Intervention with Pravastatin in Ischemic Disease (LIPID) trial. LIPID initially compared pravastatin and placebo over 6 years in 9014 patients with previous coronary heart disease. After the double-blind period, all patients were offered open-label statin therapy. Data were obtained over a further 10 years from 7721 patients, by direct contact for 2 years, by questionnaires thereafter, and from mortality and cancer registries. During extended follow-up, 85% assigned pravastatin and 84% assigned placebo took statin therapy. Patients assigned pravastatin maintained a significantly lower risk of death from coronary heart disease (relative risk [RR] 0.89; 95% confidence interval [CI], 0.81-0.97; P=0.009), from cardiovascular disease (RR, 0.88; 95% CI, 0.81-0.95; P=0.002), and from any cause (RR, 0.91; 95% CI, 0.85-0.97; absolute risk reduction, 2.6%; P=0.003).Cancer incidence was similar by original treatment group during the double-blind period (RR, 0.94; 95% CI, 0.82-1.08; P=0.41), later follow-up (RR, 1.02; 95% CI, 0.91-1.14; P=0.74), and overall (RR, 0.99; 95% CI, 0.91-1.08; P=0.83). There were no significant differences in cancer mortality, or in the incidence of organ-specific cancers. Cancer findings were confirmed in a meta-analysis with other large statin trials with extended follow-up. In LIPID, the absolute survival benefit from 6 years of pravastatin treatment appeared to be maintained for the next 10 years, with a similar risk of death among survivors in both groups after the initial period. Treatment with statins does not influence cancer or death from noncardiovascular causes during long-term follow-up.

Impacto de los niveles plasmáticos de pro-péptido natriurético tipo B aminoterminal, proteína quimiotáctica de monocitos-1 y galectina 3 en la capacidad predictiva de eventos de la escala clínica LIPID en la enfermedad coronaria estable

IntroductionAt present, there is no tool validated by scientific societies for risk stratification of patients with stable coronary artery disease (SCAD). It has been shown that plasma levels of monocyte chemoattractant protein-1 (MCP-1), galectin-3 and pro-B-type natriuretic peptide amino-terminal (NT-proBNP) have prognostic value in this population. ObjetiveTo analyze the prognostic value of a clinical risk scale published in Long-term Intervention with Pravastatin in Ischemic Disease (LIPID) study and determining its predictive capacity when combined with plasma levels of MCP-1, galectin-3 and NT-proBNP in patients with SCAD. Methods and resultsA total of 706 patients with SCAD and a history of acute coronary syndrome (ACS) were analyzed over a follow up period of 2.2±0.99 years. The primary endpoint was the occurrence of an ischemic event (any SCA, stroke or transient ischemic attack), heart failure, or death.A clinical risk scale derived from the LIPID study significantly predicted the development of the primary endpoint, with an area under the ROC curve (Receiver Operating Characteristic) of 0.642 (0.579 to 0.705); P<0.001. A composite score was developed by adding the scores of the LIPID and scale decile levels of MCP -1, galectin -3 and NT-proBNP. The predictive value improved with an area under the curve of 0.744 (0.684 to 0.805); P<0.001 (P=0.022 for comparison). A score greater than 21.5 had a sensitivity of 74% and a specificity of 61% for the development of the primary endpoint (P<0.001, log -rank test). ConclusionPlasma levels of MCP-1, galectin -3 and NT-proBNP improve the ability of the LIPID clinical scale to predict the prognosis of patients with SCAD.

Which lipid measurement should we monitor? An analysis of the LIPID study

ObjectivesTo evaluate the optimal lipid to measure in monitoring patients, we assessed three factors that influence the choice of monitoring tests: (1) clinical validity; (2) responsiveness to therapy changes and...

Association of Contemporary Sensitive Troponin I Levels at Baseline and Change at 1 Year With Long-Term Coronary Events Following Myocardial Infarction or Unstable Angina: Results From the LIPID Study (Long-Term Intervention With Pravastatin in Ischaemic Disease)

This study sought to assess whether baseline and change in contemporary sensitive troponin I (TnI) levels predicts coronary heart disease (CHD) death and myocardial infarction (MI), and to determine the effects of pravastatin on TnI levels. The role of troponins in predicting long-term outcomes in patients with stable CHD is not clearly defined. The LIPID (Long-Term Intervention With Pravastatin in Ischaemic Disease) study randomized patients with cholesterol levels of 155 to 271 mg/dl 3 to 36 months after MI or unstable angina to placebo or pravastatin 40 mg per day. TnI levels were measured at baseline and after 1 year in 7,863 patients. Median follow-up was 6 years. Change in TnI was defined as moving up or down 1 tertile or ≥50% change. Baseline TnI tertiles were<0.006 ng/ml,0.006 to <0.018 ng/ml, and≥0.018 ng/ml. TnI levels were related to CHD death and MI after adjustment for 23 risk factors and treatment (≥0.018 ng/ml vs.<0.006 ng/ml hazard ratio [HR]: 1.64; 95% CI: 1.41 to 1.90; p< 0.001). TnI levels increased in 23.0%, were unchanged in 51.3%, and decreased in 25.7% of patients. Pravastatin decreased TnI levels by 0.003 ng/ml versus placebo (p= 0.002). In landmark analyses, increases in TnI levels were associated with increased numbers of CHD death and MI (HR: 1.31; 95% CI: 1.06 to 1.62) and decreases with decreased risk (HR: 0.90; 95% CI: 0.74 to 1.09; overall p= 0.01). Data were similar with 50% change criteria. Net reclassification improvement by adding TnI to the baseline model for CHD death and MI was 4.8% (p= 0.01). Baseline TnI levels and change at 1 year are independent predictors of CHD death and MI. TnI levels are strong predictors of risk, and change modifies risk.

Plasma Lipoprotein(a) Concentration Predicts Future Coronary and Cardiovascular Events in Patients With Stable Coronary Heart Disease

Association between lipoprotein(a) (Lp(a)) level and a first-ever coronary (CHD) event is recognized. Less is evident in patients with overt CHD and stable symptoms in whom we investigated associations between Lp(a) and future events. Relationships between Lp(a) concentration and CHD and cardiovascular disease outcomes during 6 years' median follow-up were evaluated in the Long-Term Intervention with Pravastatin in Ischaemic Disease (LIPID) study. Lp(a) concentrations were measured in plasma from 7863 patients who had sustained a previous coronary event and been randomized to pravastatin or placebo. Lp(a) levels were categorized by lowest half, third quartile, 75th to 90th percentile, and highest decile. The prognostic value of Lp(a) on outcomes was assessed by fitting a Cox proportional-hazards model after adjustment for other risk factors and baseline cardiovascular disorders. The prognostic value of a change in Lp(a) at year 1 categorized by quartiles was assessed using Cox regression in a landmark model incorporating the above factors and baseline levels. Baseline Lp(a) concentration was associated with total CHD events (P<0.001), total cardiovascular disease events (P=0.002), and coronary events (P=0.03). Greatest risk occurred at >73 mg/dL, upper decile. For events after year 1, an increase in Lp(a) at 1 year was associated with adverse outcomes for total CHD events and total cardiovascular disease events (P=0.002 each). In the LIPID study, baseline Lp(a) was associated with future cardiovascular disease and CHD events. Increased Lp(a) concentrations after 1 year were also associated with future events, supporting measurement of Lp(a) for risk assessment of patients with known CHD.

Changes in Lipoprotein‐Associated Phospholipase A2 Activity Predict Coronary Events and Partly Account for the Treatment Effect of Pravastatin: Results From the Long‐term Intervention with Pravastatin in Ischemic Disease Study

BackgroundLipoprotein‐associated phospholipase A2 (Lp‐PLA2) levels are associated with coronary heart disease (CHD) in healthy individuals and in patients who have had ischemic events.Methods and ResultsThe Long‐term Intervention with Pravastatin in Ischemic Disease (LIPID) study randomized 9014 patients with cholesterol levels of 4.0 to 7.0 mmol/L to placebo or pravastatin 3 to 36 months after myocardial infarction or unstable angina and showed a reduction in CHD and total mortality. We assessed the value of baseline and change in Lp‐PLA2 activity to predict outcomes over a 6‐year follow‐up, the effect of pravastatin on Lp‐PLA2 levels, and whether pravastatin treatment effect was related to Lp‐PLA2 activity change. Lp‐PLA2 was measured at randomization and 1 year, and levels were grouped as quartiles. The prespecified end point was CHD death or nonfatal myocardial infarction. Baseline Lp‐PLA2 activity was positively associated with CHD events (P<0.001) but not after adjustment for 23 baseline factors (P=0.66). In 6518 patients who were event free at 1 year, change in Lp‐PLA2 was a significant independent predictor of subsequent CHD events after adjustment for these risk factors, including LDL cholesterol and LDL cholesterol changes (P<0.001). Pravastatin reduced Lp‐PLA2 by 16% compared with placebo (P<0.001). After adjustment for Lp‐PLA2 change, the pravastatin treatment effect was reduced from 23% to 10% (P=0.26), with 59% of the treatment effect accounted for by changes in Lp‐PLA2. Similar reductions in treatment effect were seen after adjustment for LDL cholesterol change.ConclusionReduction in Lp‐PLA2 activity during the first year was a highly significant predictor of CHD events, independent of change in LDL cholesterol, and may account for over half of the benefits of pravastatin in the LIPID study.

Dyslipidemia

Dyslipidemia

Abstract 3289: Novel Biomarkers Add Prognostic Value over Traditional Risk Factors for Nonhemorrhagic Stroke in Patients with Known Coronary Heart Disease: the Long-Term Intervention with Pravastatin in Ischaemic Disease (LIPID) Trial

Introduction: The potential for novel biomarkers to identify risk of future nonhemorrhagic stroke in patients with coronary heart disease (CHD) has not been determined. We examined the potential of 8 novel biomarkers, measured at baseline, to predict future nonhemorrhagic stroke in 7863 patients (17% women, median age 62 years) enrolled in the LIPID study, a double-blind, placebo-controlled trial of pravastatin in patients with prior CHD. Methods and Results: Over 6 years’ median follow-up, 310 patients had a nonhemorrhagic stroke. In Cox regression analysis for each novel biomarker, BNP, CRP, cystatin-C, D-dimer (each P &lt;0.004) and troponin I ( P &lt;0.02) were significant, but LP(a), midregional pro-adrenomedullin, and Lp-PLA2 activity were not. Treatment with pravastatin was an independent predictor of nonhemorrhagic stroke in each of the models (all P ≤0.05). There was no evidence that this effect was modified by the baseline level of any of the novel biomarkers. In the multivariable model, BNP, CRP and cystatin-C remained independent predictors for nonhemorrhagic stroke ( Table 1 ). The effect of pravastatin also remained significant, as were the traditional risk factors: age, prior stroke, prior hypertension, diabetes mellitus, atrial fibrillation, and systolic blood pressure. This multivariable model was used to create risk groups based on the upper and lower quartiles of the score ( Table 2 ). Conclusion: BNP, CRP, and cystatin-C levels significantly improve the identification of future nonhemorrhagic stroke in patients with known CHD. Relative treatment effects of pravastatin were similar across all risk levels.

Abstract 16968: Troponin I Is an Independent Predictor of Long-Term Coronary Events Following Myocardial Infarction or Unstable Angina: Results from the Long-term Intervention with Pravastatin in Ischaemic Disease (LIPID) Trial

Background The role of higher-sensitivity troponins in predicting long-term outcomes in patients with stable CHD is not clearly defined. Objective: To assess the value of a higher sensitivity troponin I (TnI) assay to predict outcomes during median follow-up of 6 years and to assess the effect of pravastatin on TnI levels and outcomes. Methods Among 9014 patients in LIPID with cholesterol levels 4.0-7.0 mmol/L randomized to placebo or pravastatin after MI or unstable angina 3-36 months previously, TnI levels (Siemens ultra, level of detection 0.006 ng/mL, 99th percentile with CV 10% 0.04 ng/mL) were measured at randomization and at 1 year. Baseline TnI levels (ng/ml) were assessed in 3 groups: not detectable (38%), 0.006-0.018 (31%), and ≥0.018 (31%), and change over 1 year defined as a change in group. Results Patients with the highest TnI levels were older, more likely to have previous MI, and to be on ACE inhibitors but less likely to be on beta-blockers. Levels of TnI at 1 year had decreased in 25%, were unchanged (51%) or increased (23%), but pravastatin had no effect on TnI levels. In a multivariable Cox regression for CHD death or nonfatal MI, HR was 2.02 (95% CI 1.66-2.45), P &lt;0.001, for levels of TnI above the reference 99th percentile (0.04 ng/mL), vs undetectable levels, adjusted for baseline risk factors. In multivariable landmark analysis of 6544 patients event-free at 12 months, baseline TnI levels and changes in TnI were both independent predictors of subsequent CHD events ( P &lt;0.001), even after adjustment for 23 traditional risk factors, including treatment. The effect of pravastatin in reducing CHD events remained highly significant in each model ( P &lt;0.02) and was independent of TnI levels. Conclusions Baseline and change to 1 year in TnI levels, additional to traditional risk factors, were independent predictors of CHD death and MI. TnI was more powerful for predicting fatal than nonfatal events (table), and the benefits of pravastatin were independent of TnI levels.

Monitoring adherence to drug treatment by using change in cholesterol concentration: secondary analysis of trial data

Objective To estimate the accuracy of monitoring cholesterol concentration for detecting non-adherence to lipid lowering treatment.Design Secondary analysis of data on cholesterol concentration in the LIPID (long term intervention with...

Statins

Coronary heart disease (CHD) is the leading cause of death in India resulting in loss of young Indians. Statins have proved to reduce the CHD mortality in various clinical trials. The aim of the study is to find the cost-effectiveness ratio (CER) for each major coronary event averted and a coronary death avoided by use of statins in different clinical settings based on the data from the major clinical trials on statins. Using electronic database and as per our inclusion and exclusion criteria we selected the West of Scotland Coronary Prevention Study (WOSCOPS), the Air Force Coronary Atherosclerosis Prevention Study (AFCAPS) and the Anglo-Scandinavian Cardiac Outcomes Trial--Lipid Lowering Arm (ASCOT-LLA) study for primary prevention; the Cholesterol and Recurrent Events Trial (CARE), the Long-term Intervention with Pravastatin in Ischemic Disease (LIPID) Study and the Scandinavian Simvastatin Survival Study (4S) for secondary prevention and two studies, the Heart Protection Study (HPS) and the Pravastatin in elderly individuals at risk of vascular disease (PROSPER) study for high-risk patients. The results of these studies were used for cost-effectiveness analysis of statins in different patient groups. Absolute risk reduction, Number Needed to Benefit (NNTB), NNTB/year for total sample and in subgroups of males, females and age >65 was derived. CER for branded and generic versions was calculated by using the prices of statins listed in Indian Drug Review Triple i. Cost-effectiveness ratio (CER) in primary prevention studies i.e., the WOSCOPS, the AFCAPS and the ASCOT-LLA was Rs. 25.8 lacs, Rs. 23.8 lacs and Rs. 7.9 lacs per major coronary event averted respectively. CER in secondary prevention studies i.e., the CARE and the LIPID was approximately Rs. 20 lacs per major coronary event averted while it was Rs. 52.4 lacs and Rs. 37 lacs per coronary heart disease (CHD) death avoided. CER from the 4S was Rs. 6.9 lacs per major coronary event and Rs. 16.9 lacs per CHD death averted. CER in the HPS and the PROSPER study was Rs. 17.9 lacs and Rs. 27.1 lacs per major coronary event avoided in high-risk patients. Cost associated with the use of statins is higher in primary prevention as compared to secondary prevention. More studies are needed to confirm the cost-effectiveness of statins to make any decision for health policy.

Statin use in patients with chronic kidney disease stages 2–4: targeting beyond improved mortality rates

The well-designed study by Neves et al. [1] showed that statin and/or vitamin D non-use were independent risk factors of mortality (p = 0.005) in their cohort of patients (n = 95) with chronic kidney disease (CKD) stages 4 and 5 (mean estimated glomerular filtration rate [eGFR] = 16.1 ml/min/1.73 m). After a mean follow-up of 24.1 ± 9.8 months, all patients receiving both statins and vitamin D were alive (18 of 18 patients; 100%). In contrast, only 24 of the 43 patients (56.4%) receiving neither a statin nor vitamin D were alive at the end of the study [1]. Statin use in patients with CKD offers several advantages besides improving mortality rates. Cardiovascular disease (CVD) is the leading cause of death in patients with stages 4 and 5 CKD [2, 3]. Mortality from CVD in this population is approximately 10 to 20 times higher than in the general population [4]. In an analysis of the Pravastatin Pooling Project [5], a subject-level database combining the results from 3 randomized trials of the effects of pravastatin 40 mg/day vs. placebo, the benefit induced by statin use on CVD risk in 19,700 participants with mild/moderate CKD was determined. The 3 randomized studies included in this analysis were the following: the Cholesterol and Recurrent Events (CARE) trial [6], the Long-term Intervention with Pravastatin in Ischemic Disease (LIPID) study [7] and the West of Scotland Coronary Prevention Study (WOSCOPS) [8]. Of the 19,700 total participants in these studies, 12,333 (62.6%) had mild CKD, as defined by an estimated glomerular filtration rate (eGFR) of 60 to 89.9 ml/min/1.73 m and 4,491 (22.8%) had moderate CKD as defined by an eGFR of 30 to 59.9 ml/min/1.73 m. Pravastatin significantly reduced the adjusted incidence of the primary outcome of coronary mortality, non-fatal myocardial infarction and coronary revascularization (hazard ratio [HR], 0.77; 95% confidence interval [CI] 0.68–0.86) and the expanded outcome (cardiovascular mortality, non-fatal myocardial infarction, coronary revascularization or stroke; HR, 0.79; 95% CI 0.71–0.88) in people with moderate CKD [5]. Thus, the effects of statin use in patients with CKD not only include reduction of mortality rates, but also a decrease in CVD events (non-fatal myocardial infarction, stroke and revascularization episodes). K. I. Paraskevas (&) Department of Vascular Surgery, Red Cross Hospital, Athens, Greece e-mail: paraskevask@hotmail.com

Does intensive cholesterol lowering increase the risk of diabetes?

To the Editor: Dr Kostapanos and colleagues reported that in hyperlipidaemic patients with impaired fasting glucose, rosuvastatin treatment was associated with a dose-dependent increase in insulin resistance (1). In the accompanying editorial, Dr Wierzbicki highlighted the puzzling effects of cholesterol-lowering drugs on diabetes risk (2). We suggest that the effect of statin therapy on the subsequent risk of diabetes might be influenced by the amount of drug-induced cholesterol reduction. Increasing evidence indicates that statins, beyond their cholesterol-lowering action, may exert a variety of inhibitory effects on inflammatory processes; this anti-inflammatory potential seems to be mediated to a considerable part independent of cholesterol lowering (3). On the other hand, it is well known that the development of type 2 diabetes may be preceded by subclinical systemic inflammation, which is believed to be pathogenic in diabetogenesis by way of an increase in insulin resistance or even a decrease in insulin secretion (4). However, mounting evidence suggests also a critical role for endogenous cholesterol in the normal function of pancreatic beta-cells. It has recently been demonstrated that the inhibition of cholesterol biosynthesis impairs insulin secretion (5). Moreover, an observational study performed in a very large number of Veteran patients found that statin therapy was associated with a rise of fasting plasma glucose levels over a mean duration of 2 years in patients with and without diabetes (6). Retrospective analysis of the West of Scotland Coronary Prevention Study (WOSCOPS) revealed that 5 years of treatment with pravastatin reduced diabetes incidence by 30% (7). It was suggested that although lowering of triglyceride levels could have influenced diabetes incidence, other mechanisms such as anti-inflammatory action might have been involved. In the multivariate Cox model, baseline total cholesterol did not predict the development of diabetes (7). Of note, the median low density lipoprotein (LDL) cholesterol level in individuals assigned to pravastatin at the end of follow-up was roughly 140 mg/dl (8). Furthermore, pravastatin did not decrease diabetes incidence in the Long-Term Intervention with Pravastatin in Ischemic Disease (LIPID) trial, which included glucose-intolerant patients (median LDL cholesterol level in the pravastatin group at the end of the trial was roughly 110 mg/dl) (9). On the other hand, in the Justification for the Use of Statins in Prevention: an Intervention Trial Evaluating Rosuvastatin (JUPITER) trial, which studied apparently healthy persons without hyperlipidaemia but with elevated high-sensitivity C-reactive protein levels (10), the risk of diabetes was significantly increased by a factor of 1.25 among individuals receiving rosuvastatin 20 mg daily compared with placebo. Strikingly, among persons assigned to rosuvastatin, the median LDL cholesterol level at 12 months was 55 mg/dl. Estimates of global diabetes prevalence (11) indicate that the number of people with diabetes, a pathology closely related to unhealthy lifestyles, is projected to increase from 246 million to up to 380 million by 2025. On the basis of these projections, it is therefore imperative that a serious battle against this pandaemia should mainly rely on lifestyle modifications. In this setting, it should be noted that salutary lifestyle measures, which might exert their beneficial actions through an anti-inflammatory mechanism without a strong cholesterol-lowering effect, beyond reducing cardiovascular events and total mortality, might also reduce the risk of diabetes and other chronic degenerative diseases. Therefore, it is plausible that, at high statin doses, the drug-induced cholesterol depletion is limiting, overwhelming any anti-inflammatory beneficial effect on diabetogenesis. Lowering cholesterol at the expense of increasing diabetes might be counterproductive over the long-term. Most importantly, this needs our attention, given the widespread use of statins at high doses even in the primary prevention of cardiovascular disease. None.