Diabetogenic Action of Statins: Mechanisms.

PURPOSE OF REVIEW: Observational studies and meta-analyses of randomized clinical trials data have revealed a 10-12% increased risk of new-onset diabetes (NOD) associated with statin therapy; the risk is increased with intensive treatment regimens and in people with features of the metabolic syndrome or prediabetes. The purpose of this review is to provide an updated summary of what is known about the potential mechanisms for the diabetogenic effect of statins. RECENT FINDINGS: Hydroxyl methyl glutaryl coenzyme A reductase (HMGCoAR) is the target of statin therapy and the activity of this key enzyme in cholesterol synthesis is reduced by statins in a partial and reversible way. Mendelian randomization studies suggest that the effect of statins on glucose homeostasis reflect reduced activity of HMGCoAR. In vitro and in vivo data indicate that statins reduce synthesis of mevalonate pathway products and increase cholesterol loading, leading to impaired ß-cell function and decreased insulin sensitivity and insulin release. While this effect has been thought to be a drug class effect, recent insights suggest that pravastatin and pitavastatin could exhibit neutral effects on glycaemic parameters in patients with and without diabetes mellitus. The mechanisms by which statins might lead to the development of NOD are unclear. The inhibition of HMGCoAR activity by statins appears to be a key mechanism. It is difficult to offer a comprehensive view regarding the diabetogenic effect of statins because our understanding of the most widely recognized potential mechanisms, i.e. underlying statin-induced reduction of insulin sensitivity and/or insulin secretion, is still far from complete. The existence of this dual mechanism is supported by the results of a study in a large group of non-diabetic men, showing that a 46% higher risk of NOD in statin users compared to non-users was accompanied by a significant 12% reduction in insulin secretion and a 24.3% increase in insulin resistance. Although statin therapy is associated with a modest increase in the risk of NOD (about one per thousand patient-years), patients should be reassured that the benefits of statins in preventing cardiovascular disease (CVD) events far outweigh the potential risk from elevation in plasma glucose.

Apolipoprotein CIII and N-terminal prohormone b-type natriuretic peptide as independent predictors for cardiovascular disease in type 2 diabetes.

BACKGROUND AND AIMS: Developing sparse panels of biomarkers for cardiovascular disease in type 2 diabetes would enable risk stratification for clinical decision making and selection into clinical trials. We examined the individual and joint performance of five candidate biomarkers for incident cardiovascular disease (CVD) in type 2 diabetes that an earlier discovery study had yielded. METHODS: Apolipoprotein CIII (apoCIII), N-terminal prohormone B-type natriuretic peptide (NT-proBNP), high sensitivity Troponin T (hsTnT), Interleukin-6, and Interleukin-15 were measured in baseline serum samples from the Collaborative Atorvastatin Diabetes trial (CARDS) of atorvastatin versus placebo. Among 2105 persons with type 2 diabetes and median age of 62.9 years (range 39.2-77.3), there were 144 incident CVD (acute coronary heart disease or stroke) cases during the maximum 5-year follow up. We used Cox Proportional Hazards models to identify biomarkers associated with incident CVD and the area under the receiver operating characteristic curves (AUROC) to assess overall model prediction. RESULTS: Three of the biomarkers were singly associated with incident CVD independently of other risk factors; NT-proBNP (Hazard Ratio per standardised unit 2.02, 95% Confidence Interval [CI] 1.63, 2.50), apoCIII (1.34, 95% CI 1.12, 1.60) and hsTnT (1.40, 95% CI 1.16, 1.69). When combined in a single model, only NT-proBNP and apoCIII were independent predictors of CVD, together increasing the AUROC using Framingham risk variables from 0.661 to 0.745. CONCLUSIONS: The biomarkers NT-proBNP and apoCIII substantially increment the prediction of CVD in type 2 diabetes beyond that obtained with the variables used in the Framingham risk score.

Differing predictive relationships between baseline LDL-C, systolic blood pressure, and cardiovascular outcomes.

BACKGROUND: Traditional cardiovascular risk factors, such as hypertension and dyslipidemia, predispose individuals to cardiovascular disease, particularly patients with diabetes. We investigated the predictive value of baseline systolic blood pressure (SBP) and low-density lipoprotein cholesterol (LDL-C) on the risk of vascular outcomes in a large population of patients at high risk of future cardiovascular events. METHODS: Data were pooled from the TNT (Treating to New Targets), CARDS (Collaborative Atorvastatin Diabetes Study), and IDEAL (Incremental Decrease in End-Points Through Aggressive Lipid Lowering) trials and included a total of 21,727 patients (TNT: 10,001; CARDS: 2838; IDEAL: 8888). The effect of baseline SBP and LDL-C on cardiovascular events, coronary events, and stroke was evaluated using a multivariate Cox proportional-hazards model. RESULTS: Overall, risk of cardiovascular events was significantly higher for patients with higher baseline SBP or LDL-C. Higher baseline SBP was significantly predictive of stroke but not coronary events. Conversely, higher baseline LDL-C was significantly predictive of coronary events but not stroke. Results from the subgroup with diabetes (5408 patients; TNT: 1501; CARDS: 2838; IDEAL: 1069) were broadly consistent with those of the total cohort: baseline SBP and LDL-C were significantly predictive of cardiovascular events overall, with the association to LDL-C predominantly related to an effect on coronary events. However, baseline SBP was not predictive of either coronary or stroke events in the pooled diabetic population. CONCLUSIONS: In this cohort of high-risk patients, baseline SBP and LDL-C were significantly predictive of cardiovascular outcomes, but this effect may differ between the cerebrovascular and coronary systems. TRIAL REGISTRATION NUMBER: NCT00327691 (TNT); NCT00327418 (CARDS); NCT00159835 (IDEAL).

Effect of atorvastatin on glycaemia progression in patients with diabetes: an analysis from the Collaborative Atorvastatin in Diabetes Trial (CARDS).

AIMS/HYPOTHESIS: In an individual-level analysis we examined the effect of atorvastatin on glycaemia progression in type 2 diabetes and whether glycaemia effects reduce the prevention of cardiovascular disease (CVD) with atorvastatin. METHODS: The study population comprised 2,739 people taking part in the Collaborative Atorvastatin Diabetes Study (CARDS) who were randomised to receive atorvastatin 10 mg or placebo and who had post-randomisation HbA1c data. This secondary analysis used Cox regression to estimate the effect of atorvastatin on glycaemia progression, defined as an increase in HbA1c of ≥ 0.5% (5.5 mmol/mol) or intensification of diabetes therapy. Mixed models were used to estimate the effect of atorvastatin on HbA1c as a continuous endpoint. RESULTS: Glycaemia progression occurred in 73.6% of participants allocated placebo and 78.1% of those allocated atorvastatin (HR 1.18 [95% CI 1.08, 1.29], p < 0.001) by the end of follow-up. The HR was 1.22 (95% CI 1.19, 1.35) in men and 1.11 (95% CI 0.95, 1.29) in women (p = 0.098 for the sex interaction). A similar effect was seen in on-treatment analyses: HR 1.20 (95% CI 1.07, 1.35), p = 0.001. The net mean treatment effect on HbA1c was 0.14% (95% CI 0.08, 0.21) (1.5 mmol/mol). The effect did not increase through time. Diabetes treatment intensification alone did not differ with statin allocation. Neither baseline nor 1-year-attained HbA1c predicted subsequent CVD, and the atorvastatin effect on CVD did not vary by HbA1c change (interaction p value 0.229). CONCLUSIONS/INTERPRETATION: The effect of atorvastatin 10 mg on glycaemia progression among those with diabetes is statistically significant but very small, is not significantly different between sexes, does not increase with duration of statin and does not have an impact on the magnitude of CVD risk reduction with atorvastatin.

The diabetogenic action of statins - mechanisms and clinical implications.

Treatment with statins has transformed primary and secondary prevention of cardiovascular disease (CVD), including thrombotic stroke. Evidence-based data demonstrate the benefits and safety of statin therapy and help to guide clinicians in the management of populations at high risk of CVD. Nevertheless, clinical trials, meta-analyses and observational studies highlight a 10-12% increase in new-onset diabetes mellitus (NODM) among patients receiving statins. The risk further increases with intensive therapy and among individuals with known risk factors for NODM. Mechanisms underpinning this effect are not yet fully understood; however, Mendelian randomization studies suggest that they are related to lowered activity of HMG-CoA reductase, the target of statin therapy. In vitro research indicates that statins potentially impair ß-cell function and decrease insulin sensitivity but how these findings relate to patients is unknown. In the clinic, statins should be prescribed on the basis of CVD risk and individual patient characteristics. In addition, diet and lifestyle interventions should be emphasized to help mitigate the risk of NODM. Individuals who develop NODM while taking statins do not exhibit increased microvascular disease, which is reassuring. In diabetes mellitus of long duration, the effect of statins on glycaemic control is small and unlikely to be clinically important.

Serum Level of Soluble Receptor for Advanced Glycation End Products Is Associated with A Disintegrin And Metalloproteinase 10 in Type 1 Diabetes.

BACKGROUND: The receptor for advanced glycation end products (RAGE) is involved in the pathogenesis of diabetic complications, and soluble forms of the receptor (sRAGE) can counteract the detrimental action of the full-length receptor by acting as decoy. Soluble RAGE is produced by alternative splicing [endogenous secretory RAGE (esRAGE)] and/or by proteolytic cleavage of the membrane-bound receptor. We have investigated the role of A Disintegrin And Metalloproteinase 10 (ADAM10) in the ectodomain shedding of RAGE. METHODS: Constitutive and insulin-induced shedding of RAGE in THP-1 macrophages by ADAM10 was evaluated using an ADAM10-specific metalloproteinase inhibitor. Serum ADAM10 level was measured in type 1 diabetes and control subjects, and the association with serum soluble RAGE was determined. Serum total sRAGE and esRAGE were assayed by ELISA and the difference between total sRAGE and esRAGE gave an estimated measure of soluble RAGE formed by cleavage (cRAGE). RESULTS: RAGE shedding (constitutive and insulin-induced) was significantly reduced after inhibition of ADAM10 in macrophages, and insulin stimulated ADAM10 expression and activity. Diabetic subjects have higher serum total sRAGE and esRAGE (p<0.01) than controls, and serum ADAM10 was also increased (p<0.01). Serum ADAM10 correlated with serum cRAGE in type 1 diabetes (r = 0.40, p<0.01) and in controls (r = 0.31. p<0.01) but no correlations were seen with esRAGE. The association remained significant after adjusting for age, gender, BMI, smoking status and HbA1c. CONCLUSION: Our data suggested that ADAM10 contributed to the shedding of RAGE. Serum ADAM10 level was increased in type 1 diabetes and was a significant determinant of circulating cRAGE.

Effect of atorvastatin on C-reactive protein and benefits for cardiovascular disease in patients with type 2 diabetes: analyses from the Collaborative Atorvastatin Diabetes Trial.

AIMS/HYPOTHESIS: We investigated whether atorvastatin 10 mg daily lowered C-reactive protein (CRP) and whether the effects of atorvastatin on cardiovascular disease (CVD) varied by achieved levels of CRP and LDL-cholesterol. METHODS: CRP levels were measured at baseline and 1 year after randomisation to atorvastatin in 2,322 patients with type 2 diabetes (40-75 years, 69% males) in a secondary analysis of the Collaborative Atorvastatin Diabetes Study, a randomised placebo-controlled trial. We used Cox regression models to test the effects on subsequent CVD events (n = 147) of CRP and LDL-cholesterol lowering at 1 year. RESULTS: After 1 year, the atorvastatin arm showed a net CRP lowering of 32% (95% CI -40%, -22%) compared with placebo. The CRP response was highly variable, with 45% of those on atorvastatin having no decrease in CRP (median [interquartile range, IQR] per cent change -9.8% [-57%, 115%]). The LDL-cholesterol response was less variable, with a median (IQR) within-person per cent change of -41% (-51%, -31%). Baseline CRP did not predict CVD over 3.8 years of follow-up (HRper SD log 0.89 [95% CI 0.75, 1.06]), whereas baseline LDL-cholesterol predicted CVD (HRper SD 1.21 [95% CI 1.02, 1.44]), as did on-treatment LDL-cholesterol. There was no significant difference in the reduction in CVD by atorvastatin, with above median (HR 0.57) or below median (HR 0.52) change in CRP or change in LDL-cholesterol (HR 0.61 vs 0.50). CONCLUSIONS/INTERPRETATION: CRP was not a strong predictor of CVD. Statin efficacy did not vary with achieved CRP despite considerable variability in CRP response. The use of CRP as an indicator of efficacy of statin therapy on CVD risk in patients with type 2 diabetes is not supported by these data. Trial registration NCT00327418.

Very low levels of atherogenic lipoproteins and the risk for cardiovascular events: a meta-analysis of statin trials.

BACKGROUND: Levels of atherogenic lipoproteins achieved with statin therapy are highly variable, but the consequence of this variability for cardiovascular disease risk is not well-documented. OBJECTIVES: The aim of this meta-analysis was to evaluate: 1) the interindividual variability of reductions in low-density lipoprotein cholesterol (LDL-C), non-high-density lipoprotein cholesterol (non-HDL-C), or apolipoprotein B (apoB) levels achieved with statin therapy; 2) the proportion of patients not reaching guideline-recommended lipid levels on high-dose statin therapy; and 3) the association between very low levels of atherogenic lipoproteins achieved with statin therapy and cardiovascular disease risk. METHODS: This meta-analysis used individual patient data from 8 randomized controlled statin trials, in which conventional lipids and apolipoproteins were determined in all study participants at baseline and at 1-year follow-up. RESULTS: Among 38,153 patients allocated to statin therapy, a total of 6,286 major cardiovascular events occurred in 5,387 study participants during follow-up. There was large interindividual variability in the reductions of LDL-C, non-HDL-C, and apoB achieved with a fixed statin dose. More than 40% of trial participants assigned to high-dose statin therapy did not reach an LDL-C target <70 mg/dl. Compared with patients who achieved an LDL-C >175 mg/dl, those who reached an LDL-C 75 to <100 mg/dl, 50 to <75 mg/dl, and <50 mg/dl had adjusted hazard ratios for major cardiovascular events of 0.56 (95% confidence interval [CI]: 0.46 to 0.67), 0.51 (95% CI: 0.42 to 0.62), and 0.44 (95% CI: 0.35 to 0.55), respectively. Similar associations were observed for non-HDL-C and apoB. CONCLUSIONS: The reductions of LDL-C, non-HDL-C, and apoB levels achieved with statin therapy displayed large interindividual variation. Among trial participants treated with high-dose statin therapy, >40% did not reach an LDL-C target <70 mg/dl. Patients who achieve very low LDL-C levels have a lower risk for major cardiovascular events than do those achieving moderately low levels.

The use of statins in people at risk of developing diabetes mellitus: evidence and guidance for clinical practice.

Reducing low-density lipoprotein cholesterol (LDL-C) levels using statins is associated with significant reductions in cardiovascular (CV) events in a wide range of patient populations. Although statins are generally considered to be safe, recent studies suggest they are associated with an increased risk of developing Type 2 diabetes (T2D). This led the US Food and Drug Administration (FDA) to change their labelling requirements for statins to include a warning about the possibility of increased blood sugar and HbA1c levels and the European Medicines Agency (EMA) to issue guidance on a small increased risk of T2D with the statin class. This review examines the evidence leading to these claims and provides practical guidance for primary care physicians on the use of statins in people with or at risk of developing T2D. Overall, evidence suggests that the benefits of statins for the reduction of CV risk far outweigh the risk of developing T2D, especially in individuals with higher CV risk. To reduce the risk of developing T2D, physicians should assess all patients for T2D risk prior to starting statin therapy, educate patients about their risks, and encourage risk-reduction through lifestyle changes. Whether some statins are more diabetogenic than others requires further study. Statin-treated patients at high risk of developing T2D should regularly be monitored for changes in blood glucose or HbA1c levels, and the risk of conversion from pre-diabetes to T2D should be reduced by intensifying lifestyle changes. Should a patient develop T2D during statin treatment, physicians should continue with statin therapy and manage T2D in accordance with relevant national guidelines.

LADA and CARDS: a prospective study of clinical outcome in established adult-onset autoimmune diabetes.

OBJECTIVE: Diabetes-associated autoantibodies can be detected in adult-onset diabetes, even when initially non-insulin requiring, i.e., with latent autoimmune diabetes. We aimed to identify adult-onset autoimmune diabetes in patients with established "type 2 diabetes" participating in the Collaborative Atorvastatin Diabetes Study (CARDS) to characterize their phenotype and clinical outcome. RESEARCH DESIGN AND METHODS: We prospectively studied 2,425 European patients with presumed type 2 diabetes (mean age 62 years, diabetes duration 7.9 years) for outcomes at 3.9 years after randomization to either atorvastatin or placebo. Subjects were screened for autoantibodies to GAD (GADA), insulinoma-associated antigen-2 (IA-2A), and zinc-transporter 8 (ZnT8A). RESULTS: A total of 173 patients (7.1%) had GADA, of whom 11 (0.5%) and 5 (0.2%) were also positive for IA-2A and ZnT8A, respectively. At baseline, 44% of GADA-positive patients were not on insulin. Fewer autoantibody-positive than autoantibody-negative patients had metabolic syndrome (64 vs. 80%), and more were on insulin (56 vs. 17%) (P < 0.0001 for each) without lower HbA1c (69 mmol/mol [8.5%] vs. 62 mmol/mol [7.8%]). The frequency of microvascular and macrovascular events was similar in both cohorts, independent of atorvastatin. CONCLUSIONS: Adult-onset autoimmune diabetes was prevalent, even in patients with established diabetes presumed to have type 2 diabetes. After 11.8 years' diabetes duration, nearly half the patients with autoimmune diabetes were not on insulin treatment and almost two-thirds had metabolic syndrome. The type of diabetes, whether autoimmune diabetes or type 2 diabetes, did not impact the risk of microvascular disease.

CDKN2B expression in adipose tissue of familial combined hyperlipidemia patients.

The purpose of this study was to determine the core biological processes perturbed in the subcutaneous adipose tissue of familial combined hyperlipidemia (FCHL) patients. Annotation of FCHL and control microarray datasets revealed a distinctive FCHL transcriptome, characterized by gene expression changes regulating five overlapping systems: the cytoskeleton, cell adhesion and extracellular matrix; vesicular trafficking; lipid homeostasis; and cell cycle and apoptosis. Expression values for the cell-cycle inhibitor CDKN2B were increased, replicating data from an independent FCHL cohort. In 3T3-L1 cells, CDKN2B knockdown induced C/EBPα expression and lipid accumulation. The minor allele at SNP site rs1063192 (C) was predicted to create a perfect seed for the human miRNA-323b-5p. A miR-323b-5p mimic significantly reduced endogenous CDKN2B protein levels and the activity of a CDKN2B 3'UTR luciferase reporter carrying the rs1063192 C allele. Although the allele displayed suggestive evidence of association with reduced CDKN2B mRNA in the MuTHER adipose tissue dataset, family studies suggest the association between increased CDKN2B expression and FCHL-lipid abnormalities is driven by factors external to this gene locus. In conclusion, from a comparative annotation analysis of two separate FCHL adipose tissue transcriptomes and a subsequent focus on CDKN2B, we propose that dysfunctional adipogenesis forms an integral part of FCHL pathogenesis.

Levels and changes of HDL cholesterol and apolipoprotein A-I in relation to risk of cardiovascular events among statin-treated patients: a meta-analysis.

BACKGROUND: It is unclear whether levels of high-density lipoprotein cholesterol (HDL-C) or apolipoprotein A-I (apoA-I) remain inversely associated with cardiovascular risk among patients who achieve very low levels of low-density lipoprotein cholesterol on statin therapy. It is also unknown whether a rise in HDL-C or apoA-I after initiation of statin therapy is associated with a reduced cardiovascular risk. METHODS AND RESULTS: We performed a meta-analysis of 8 statin trials in which lipids and apolipoproteins were determined in all study participants at baseline and at 1-year follow-up. Individual patient data were obtained for 38,153 trial participants allocated to statin therapy, of whom 5387 suffered a major cardiovascular event. HDL-C levels were associated with a reduced risk of major cardiovascular events (adjusted hazard ratio [HR], 0.83; 95% confidence interval [CI], 0.81-0.86 per 1 standard deviation increment), as were apoA-I levels (HR, 0.79; 95% CI, 0.72-0.82). This association was also observed among patients achieving on-statin low-density lipoprotein cholesterol levels <50 mg/dL. An increase of HDL-C was not associated with reduced cardiovascular risk (HR, 0.98; 95% CI, 0.94-1.01 per 1 standard deviation increment), whereas a rise in apoA-I was (HR, 0.93; 95% CI, 0.90-0.97). CONCLUSIONS: Among patients treated with statin therapy, HDL-C and apoA-I levels were strongly associated with a reduced cardiovascular risk, even among those achieving very low low-density lipoprotein cholesterol. An apoA-I increase was associated with a reduced risk of major cardiovascular events, whereas for HDL-C this was not the case. These findings suggest that therapies that increase apoA-I concentration require further exploration with regard to cardiovascular risk reduction.

Cardiovascular endocrinology in 2012: PCSK9-an exciting target for reducing LDL-cholesterol levels.

Systemic administration of anti-PCSK9 antibodies induces dramatic reductions in LDL-cholesterol levels, and the effect of this therapy on LDL-receptor activity seems to be additive to that of statin therapy. Inhibition of PCSK9 is potentially very important to the clinician, and should enable more patients to achieve their LDL-cholesterol-level goal.

Genome-wide association study of genetic determinants of LDL-c response to atorvastatin therapy: importance of Lp(a).

We carried out a genome-wide association study (GWAS) of LDL-c response to statin using data from participants in the Collaborative Atorvastatin Diabetes Study (CARDS; n = 1,156), the Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT; n = 895), and the observational phase of ASCOT (n = 651), all of whom were prescribed atorvastatin 10 mg. Following genome-wide imputation, we combined data from the three studies in a meta-analysis. We found associations of LDL-c response to atorvastatin that reached genome-wide significance at rs10455872 (P = 6.13 × 10(-9)) within the LPA gene and at two single nucleotide polymorphisms (SNP) within the APOE region (rs445925; P = 2.22 × 10(-16) and rs4420638; P = 1.01 × 10(-11)) that are proxies for the ε2 and ε4 variants, respectively, in APOE. The novel association with the LPA SNP was replicated in the PROspective Study of Pravastatin in the Elderly at Risk (PROSPER) trial (P = 0.009). Using CARDS data, we further showed that atorvastatin therapy did not alter lipoprotein(a) [Lp(a)] and that Lp(a) levels accounted for all of the associations of SNPs in the LPA gene and the apparent LDL-c response levels. However, statin therapy had a similar effect in reducing cardiovascular disease (CVD) in patients in the top quartile for serum Lp(a) levels (HR = 0.60) compared with those in the lower three quartiles (HR = 0.66; P = 0.8 for interaction). The data emphasize that high Lp(a) levels affect the measurement of LDL-c and the clinical estimation of LDL-c response. Therefore, an apparently lower LDL-c response to statin therapy may indicate a need for measurement of Lp(a). However, statin therapy seems beneficial even in those with high Lp(a).

Normal levels of inflammatory markers in treated patients with familial hypercholesterolaemia: a cross-sectional study.

OBJECTIVE: To assess the relationship of levels of inflammatory risk markers to presence of clinical coronary artery disease (CAD) in patients with treated heterozygous familial hypercholesterolaemia. DESIGN: A cross-sectional study of patients on the Simon Broome Familial Hyperlipidaemia Register. SETTING: Six hospital outpatient clinics in the UK. PARTICIPANTS: A total of 211 men and 199 women with heterozygous familial hypercholesterolaemia. MAIN OUTCOME MEASURES: Analysis of conventional risk factors and concentrations of high-sensitivity C-reactive protein (hsCRP), lipoprotein(a), serum intercellular adhesion molecule (sICAM), interleukin-6 (IL-6) and lipoprotein-associated phospholipase A2 (LpPLA2) mass. RESULTS: CAD was present in 104 men and in 55 women; the mean ages of onset were 43.1 and 46.5 years, respectively. On univariate analysis there was a positive relationship of CAD with age, male sex, smoking, IL-6 and sICAM, and an inverse relationship with low-density lipoprotein (LDL) and LpPLA2. On multivariate analysis, age, smoking, low LDL and low LpPLA2 were associated with CAD. When LpPLA2 values were adjusted for apoB and aspirin usage, there was no significant difference between those with and without CAD. Only age and smoking were independently associated with CAD in men, and IL-6 and lipoprotein(a) in women. CONCLUSIONS: Although on univariate analysis inflammatory marker levels were associated with CAD in these patients, the majority of the associations, including that for hsCRP, disappeared when corrected for smoking and apoB. This may be because atherosclerotic plaques in these statin-treated patients were quiescent or an effect of aspirin usage. In this observational study newer risk markers were not usefully associated with the presence or absence of symptomatic CAD.

Total soluble and endogenous secretory receptor for advanced glycation end products as predictive biomarkers of coronary heart disease risk in patients with type 2 diabetes: an analysis from the CARDS trial.

OBJECTIVE: Circulating levels of soluble receptor for advanced glycation end products (sRAGE) likely comprise both a secreted isoform (esRAGE) and wild-type RAGE cleaved from the cell membrane. Both sRAGE and esRAGE have been proposed as biomarkers of cardiovascular disease (CVD), but prospective data are limited. We examined the relationship of sRAGE and esRAGE to incident coronary heart disease (CHD) and stroke in type 2 diabetic patients followed for 3.9 years in a trial of atorvastatin: the Collaborative Atorvastatin Diabetes Study (CARDS). RESEARCH DESIGN AND METHODS: We used a nested case-control design sampling all incident cases of CVD with available plasma and randomly selecting three control subjects, who were free of CVD throughout follow-up, per case. Analysis was by Cox regression with adjustment for treatment allocation and relevant covariates. RESULTS: sRAGE and esRAGE were strongly correlated (ρ = 0.88) and were both higher in those with lower BMI (P < 0.001), higher adiponectin (P < 0.001), lower estimated glomerular filtration rate (P = 0.009), and white ethnicity (P < 0.001). Both sRAGE and esRAGE were associated with incident CHD events, independently of treatment allocation and the above factors; hazard ratio (HR) = 1.74 (95% CI 1.25-2.41; P = 0.002) for a doubling of the sRAGE level; HR = 1.45 (1.11-1.89; P = 0.006) for a doubling of the esRAGE level. There was no significant association with stroke; HR for sRAGE = 0.66 (0.38-1.14). Atorvastatin, 10 mg daily, did not alter sRAGE. CONCLUSIONS: Higher levels of sRAGE and esRAGE are associated with incident CHD but not stroke in type 2 diabetes.

Achievement of recommended lipid and lipoprotein levels with combined ezetimibe/statin therapy versus statin alone in patients with and without diabetes.

Treatment guidelines identify low-density lipoprotein cholesterol (LDL-C) as the primary target of therapy with secondary targets of non-high-density lipoprotein cholesterol (non-HDL-C) and apolipoprotein B (apoB). Data were pooled from 27 randomised, double-blind, active or placebo-controlled trials in 21,794 adult hypercholesterolaemic patients (LDL-C 1.81-6.48 mmol/L) receiving ezetimibe/statin or statin for 4-24 weeks. Percentages of patients achieving various targets were calculated among diabetes (n = 6541) and non-diabetes (n = 15,253) subgroups. Significantly more patients with and without diabetes achieved specified levels of LDL-C (< 2.59, < 1.99, < 1.81 mmol/L), non-HDL-C (< 3.37, < 2.59 mmol/L) and apoB (< 0.9, < 0.8 g/L) with ezetimibe/statin versus statin. Patients with diabetes had larger mean per cent reductions in LDL-C and non-HDL-C than non-diabetes patients. A greater percentage of patients achieved both the LDL-C and apoB targets and all three LDL-C, apoB, and non-HDL-C targets with ezetimibe/statin versus statin in both subgroups. Patients with diabetes benefitted at least as much as, and sometimes more than, non-diabetes patients following treatment with ezetimibe/statin.

Lipid control in patients with diabetes mellitus.

Patients with diabetes mellitus are at increased risk of cardiovascular disease (CVD). Dyslipidemia, an important component of the insulin resistance syndrome and type 2 diabetes, is strongly related to CVD risk and is open to therapeutic intervention. Statins have proved to be safe, very-well tolerated, and highly effective in reducing the levels of LDL cholesterol and apolipoprotein B. Primary and secondary CVD prevention trials have shown that use of statins leads to highly significant reductions in the incidence of major CVD events. A wealth of data on the outcomes of statin therapy is now available to guide clinical practice in the population of patients with type 2 diabetes. Statin therapy in patients with type 1 diabetes seems to have a similar benefit to that seen in patients with type 2 diabetes. However, despite statin therapy, high CVD risk persists in these populations. More-intensive statin therapy produces greater reduction in the incidence of CVD events, but a more-global approach to lipid management is likely to result in further risk reduction. After reductions in the levels of LDL cholesterol and apolipoprotein B, the next target of lipid-lowering therapy is to increase HDL-cholesterol levels, which tend to be low in patients with type 2 diabetes. The most effective HDL-cholesterol-raising agent currently available for use in clinical practice is niacin. Trials with surrogate end points have pointed to the cardiovascular benefit of adding niacin to statin therapy. Large CVD end point trials, which include many patients with diabetes, are underway to test the combination of a statin and niacin versus a statin alone.

Enhanced expression of receptor for advanced glycation end-products is associated with low circulating soluble isoforms of the receptor in Type 2 diabetes.

The sRAGE [soluble RAGE (receptor for advanced glycation end-products)] lack the transmembrane and cytoplasmic domain of the full-length receptor and can function as a decoy for RAGE ligands. Recent evidence suggests that sRAGE may be a potential biomarker of RAGE-mediated pathology. The present study aimed to examine the relationship between RAGE expression in peripheral blood monocytes and circulating sRAGE and esRAGE (endogenous sRAGE, a splice variant of sRAGE) in Type 2 diabetes. Protein expression of RAGE and esRAGE in monocyte cell lysate was determined by Western blot in 53 diabetic patients and 52 controls. Monocyte cell-surface-bound full-length RAGE expression was measured using flow cytometry. Serum sRAGE, esRAGE and AGE (advanced glycation end products) were assayed by ELISA. The mean HbA1c (glycated haemoglobin) of the diabetic patients was 9.74% and serum AGEs was increased. Monocyte full-length RAGE expression was significantly higher in diabetic patients whereas esRAGE expression was reduced, and serum AGEs concentration was an independent determinant of monocyte cell surface full-length RAGE expression. Serum levels of sRAGE [573.3 (375.7-754.3) compared with 608.1 (405.3-940.8) pg/ml, P<0.05] and esRAGE [241.8 (154.6-356.6) compared with 286.5 (202.6-390.0) pg/ml, P<0.05; values are medians (interquartile range)] were decreased. There was an inverse association between monocyte RAGE expression and log(serum sRAGE) (r=-0.34, P=0.01) but not with esRAGE. In conclusion, despite an increase in full-length RAGE expression, esRAGE expression was down-regulated in the diabetic patients, and serum sRAGE and esRAGE was also reduced. Hence increased full-length RAGE levels are not associated with a similar increase in sRAGE isoforms levels.