Collaborative Atorvastatin Diabetes Study Research Articles

Atorvastatin

Atorvastatin

Utilization of Statins in Reducing Comorbidities of Diabetes Mellitus: A Systematic Review

Background: Medical care for the patients with diabetes, especially medication regimens, has become more complex over time, producing a barrier to achieving evidence-based goals of treatment. National and international clinical guidelines in the prevention of cardiovascular risk in diabetics advocate the utilization of statin therapy in appropriate patients. In this review, we will systematically review about utilization of Statins in reducing Comorbidities of Diabetes Mellitus. Methods: We searched the various electronic databases such as: PUBMED, BMJ, LANCET, WHO Website, Unicef Website and Google Scholar for studies related about utilization of Statins in reducing Comorbidities of Diabetes Mellitus. We also checked reference lists of reviews and retrieved articles for additional studies. By systemic searches, we reviewed each paper and retrieved potentially relevant references. Results: Many landmark studies across the world like the Heart Protection Study (HPS), the largest trial to date, confirmed the findings of earlier primary and secondary across a wide range of patients, including those with diabetes mellitus. In diabetic patients, statin therapy was associated with a significant 22% reduction in the risk of a first vascular event. The collaborative Atorvastatin diabetes study (CARDS) a study that involved over 2,800 men and women with type 2 diabetes (aged 40-75 years) and at least one other CHD risk factor, was stopped early when patients in the statin group showed significant reductions in myocardial infarction, stroke, angina and revascularization. Various Clinical trials such as MRC/BHF Heart Protections Study, Collaborative Atorvastatin Diabetes Study (CARDS) etc. showed evidence for the benefits of statins in diabetes. Conclusion: An overwhelming amount of data that confirm the morbidity and mortality benefit of statin therapy in diabetes mellitus have been reported, both in primary and secondary prevention settings. National and international clinical guidelines in the prevention of cardiovascular risk in diabetics advocate the utilization of statin therapy in appropriate patients. Key words: Diabetes Mellitus, Statins, Cardiovascular risk, Comorbidities.

Dyslipidemia.

Dyslipidemia.

Effectiveness of Lipid-Lowering Statin Therapy in Patients With and Without Psoriasis.

Psoriasis is associated with dyslipidemia and metabolic syndrome, and has been linked to an increased cardiovascular risk. The aim of this study was to compare baseline characteristics and effects of statin therapy on lipid levels and cardiovascular outcomes in patients with and without psoriasis. This post-hoc analysis assessed patients from one primary cardiovascular prevention statin trial (Collaborative AtoRvastatin Diabetes Study [CARDS]) and two secondary cardiovascular prevention statin trials (Treating to New Targets [TNT] and Incremental Decrease in End Points Through Aggressive Lipid Lowering [IDEAL]). Baseline characteristics, lipid changes from baseline, and cardiovascular event rates were analyzed. TNT and IDEAL data were pooled. Baseline characteristics and lipid profiles differed minimally in patients with and without psoriasis. In CARDS and TNT/IDEAL, similar apolipoprotein B, total cholesterol, and low-density lipoprotein cholesterol reductions occurred with statin therapy in patients with or without psoriasis. High-dose atorvastatin significantly reduced cardiovascular events vs. standard/low-dose statins in patients without psoriasis in TNT/IDEAL; similar numeric differences in event rates were observed in patients with psoriasis. In this post-hoc analysis, statins improved lipid levels and cardiovascular outcomes in patients with and without psoriasis, supporting statin use in patients with psoriasis. Trial registration (ClinicalTrials.gov) NCT00327418, registered 16 May, 2006; NCT00327691, registered 16 May, 2006; NCT00159835, registered 8 September, 2005.

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

BackgroundTraditional 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. MethodsData 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. ResultsOverall, 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. ConclusionsIn 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).

Development and Validation of a Model to Predict Absolute Vascular Risk Reduction by Moderate-Intensity Statin Therapy in Individual Patients With Type 2 Diabetes Mellitus: The Anglo Scandinavian Cardiac Outcomes Trial, Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial, and Collaborative Atorvastatin Diabetes Study.

In this study, we aimed to translate the average relative effect of statin therapy from trial data to the individual patient with type 2 diabetes mellitus by developing and validating a model to predict individualized absolute risk reductions (ARR) of cardiovascular events. Data of 2725 patients with type 2 diabetes mellitus from the Lipid Lowering Arm of the Anglo Scandinavian Cardiac Outcomes Trial (ASCOT-LLA) study (atorvastatin 10 mg versus placebo) were used for model derivation. The model was based on 8 clinical predictors including treatment allocation (statin/placebo). Ten-year individualized ARR on major cardiovascular events by statin therapy were calculated for each patient by subtracting the estimated on-treatment risk from the estimated off-treatment risk. Predicted 10-year ARR by statin therapy was <2% for 13% of the patients. About 30% had an ARR of >4% (median ARR, 3.2%; interquartile range, 2.5%-4.3%; 95% confidence interval for 3.2% ARR, -1.4% to 6.8%). Addition of treatment interactions did not improve model performance. Therefore, the wide distribution in ARR was a consequence of the underlying distribution in cardiovascular risk enrolled in these trials. External validation of the model was performed in data from the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT-LLT; pravastatin 40 mg versus usual care) and Collaborative Atorvastatin Diabetes Study (CARDS; atorvastatin 10 mg versus placebo) of 3878 and 2838 patients with type 2 diabetes mellitus, respectively. Model calibration was adequate in both external data sets, discrimination was moderate (ALLHAT-LLT: c-statistics, 0.64 [95% confidence interval, 0.61-0.67] and CARDS: 0.68 [95% confidence interval, 0.64-0.72]). ARRs of major cardiovascular events by statin therapy can be accurately estimated for individual patients with type 2 diabetes mellitus using a model based on routinely available patient characteristics. There is a wide distribution in ARR that may complement informed decision making. URL: http://www.clinicaltrials.gov. Unique identifier: NCT00327418 (CARDS) and NCT00000542 (ALLHAT).

Targeted Proteomics Identifies Paraoxonase/Arylesterase 1 (PON1) and Apolipoprotein Cs as Potential Risk Factors for Hypoalphalipoproteinemia in Diabetic Subjects Treated with Fenofibrate and Rosiglitazone

Low levels of high-density lipoprotein cholesterol (HDL-C) and high triglyceride levels contribute to the excess rate of cardiovascular events seen in subjects with type 2 diabetes. Fenofibrate treatment partially reverses dyslipidemia in these subjects. However, a paradoxical marked reduction in HDL-C and HDL's major protein, apolipoprotein A-I, is a complication of fenofibrate in combination with rosiglitazone, an insulin-sensitizing agent. Risk factors for this condition, termed hypoalphalipoproteinemia, have yet to be identified. Using a case-control study design with subjects enrolled in the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial, we tested the hypothesis that alterations in HDL's protein cargo predispose diabetic subjects to fenofibrate/rosiglitazone-induced hypoalphalipoproteinemia. HDL was isolated from blood obtained from controls (no decreases or increase in HDL-C while receiving fenofibrate/rosiglitazone therapy) and cases (developed hypoalphalipoproteinemia after fenofibrate/rosiglitazone treatment) participating in the ACCORD study before they began fenofibrate/rosiglitazone treatment. HDL proteins were quantified by targeted parallel reaction monitoring (PRM) and selected reaction monitoring (SRM) with isotope dilution. This approach demonstrated marked increases in the relative concentrations of paraoxonase/arylesterase 1 (PON1), apolipoprotein C-II (APOC2), apolipoprotein C-I, and apolipoprotein H in the HDL of subjects who developed hypoalphalipoproteinemia. The case and control subjects did not differ significantly in baseline HDL-C levels or other traditional lipid risk factors. We used orthogonal biochemical techniques to confirm increased levels of PON1 and APOC2. Our observations suggest that an imbalance in HDL proteins predisposes diabetic subjects to develop hypoalphalipoproteinemia on fenofibrate/rosiglitazone therapy.

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

Aims/hypothesisIn 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.MethodsThe 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.ResultsGlycaemia 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/interpretationThe 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.Electronic supplementary materialThe online version of this article (doi:10.1007/s00125-015-3802-6) contains peer-reviewed but unedited supplementary material, which is available to authorised users.

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/hypothesisWe 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.MethodsCRP 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.ResultsAfter 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/interpretationCRP 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 NCT00327418Electronic supplementary materialThe online version of this article (doi:10.1007/s00125-015-3586-8) contains peer-reviewed but unedited supplementary material, which is available to authorised users.

Impact of Female Sex on Lipid Lowering, Clinical Outcomes, and Adverse Effects in Atorvastatin Trials

The aim of this study was to evaluate the effect of atorvastatin on lipid lowering, cardiovascular (CV) events, and adverse events in women compared with men in 6 clinical trials. In the Incremental Decrease in End Points Through Aggressive Lipid Lowering (IDEAL) trial (atorvastatin 80 mg vs simvastatin 20 to 40 mg), the Treating to New Targets (TNT) trial (atorvastatin 80 vs 10 mg), the Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL) trial (atorvastatin 80 mg vs placebo), and the Collaborative Atorvastatin Diabetes Study (CARDS), the Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT), and the Atorvastatin Study for Prevention of Coronary Heart Disease Endpoints in Non-Insulin-Dependent Diabetes Mellitus (ASPEN) (atorvastatin 10 mg vs placebo), lipid changes on treatment were compared between genders with studies grouped by dose. The association of on-study low-density lipoprotein (LDL) cholesterol and CV events by gender was evaluated in the combined studies and the impact of gender on adverse events in each study separately. Major CV events occurred in 3,083 of 30,000 men (10.3%) and 823 of 9,173 women (9.0%). Changes in lipids were similar in women and men. Major CV events were associated with gender-specific quintiles of on-treatment LDL cholesterol for women and men. In women, LDL cholesterol was a significant predictor of stroke, but not in men. Discontinuation rates due to adverse events were higher in women in 4 of 6 trials, but in only 1 trial was a significant treatment-gender interaction seen. Myalgia rates were slightly higher in women in both statin and placebo groups. In conclusion, the response of women to atorvastatin was similar to that of men, with slightly more discontinuations due to adverse events. Higher on-treatment LDL cholesterol was significantly associated with more CV events in both genders, but the association was stronger for stroke in women and for coronary heart disease death in men.

Are statin trials in diabetes representative of real-world diabetes care: a population-based study on statin initiators in Finland

ObjectiveTo assess the representativeness of the Heart Protection Study (HPS) and the Collaborative Atorvastatin Diabetes Study (CARDS) for incident statin users.DesignA population-based analysis with linked register data.SettingFinland.Population56 963 patients with...

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

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. 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). 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. 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.

Optimal strategies for identifying kidney disease in diabetes: properties of screening tests, progression of renal dysfunction and impact of treatment - systematic review and modelling of progression and cost-effectiveness.

Annual screening for adults with type 2 diabetes to detect the early onset of kidney disease is widely recommended, but the recommendations are based on a limited methodological approach. In addition, there are continuing uncertainties about underlying rates of progression of the condition and the benefits of treatments with angiotensin-converting enzyme inhibitors and angiotensin receptor blockers. We aimed to estimate the clinical value and cost-effectiveness of different screening intervals to diagnose early diabetic kidney disease. We used the following databases for the literature review (searched January 2005 to August 2010): MEDLINE, EMBASE and the Cochrane Database of Systematic Reviews. Individual patient data were obtained from the Oxford Regional Prospective Diabetes Study and the Collaborative Atorvastatin Diabetes Study. Data from systematically identified randomised trials reporting the impact on renal outcomes of angiotensin-converting enzyme inhibitors and angiotensin 2 receptor blockers for type 1 and type 2 diabetes patients with normoalbuminuria and microalbuminuria were pooled to derive estimates of effect. Individual patient data for type 1 and type 2 diabetes patients were used to obtain parameters describing progression and variability of measurement over time for the albumin-to-creatinine ratio (ACR) and estimated glomerular filtration rate. Based on accepted diagnostic thresholds, we modelled whether these tests accurately identified patients who were developing early diabetic kidney disease and required intensification of treatment. Cost-effectiveness analyses were carried out using simulation outcome models to estimate the incremental costs per quality-adjusted life-year (QALY) for different screening intervals. In total, 49 trials (n = 34,082 patients) were eligible for inclusion in the systematic review. For type 1 diabetes, pooled estimates of urinary albumin excretion (UAE) for treated patients with microalbuminuria were on average 67% [95% confidence interval (CI) 54% to 77%] lower at the end of the trial than for untreated patients. There was no significant treatment effect for patients with normoalbuminuria (p interaction = 0.006). For treated patients with type 2 diabetes and normoalbuminuria or microalbuminuria, UAE was lower by, on average, 21% (95% CI 97% to 32%) or 27% (95% CI 15% to 38%), respectively. The proportion (95% CI) of men and women with type 1 diabetes screened annually for microalbuminuria over 6 years and inaccurately identified as having microalbuminuria would be 48% (43% to 53%) and 55% (48% to 61%), respectively. The corresponding proportions for type 2 diabetes are 36% (32% to 42%) and 48% (41% to 55%). Decreasing the screening interval to 3-yearly would reduce this for men with type 1 diabetes to 38% (33% to 44%), with an increase in those not identified over 6 years from 1.5% (95% CI 1% to 2%) to 4% (95% CI 3% to 5%). For type 1 diabetes, incremental cost per QALY [standard deviation (SD)] of a 5-yearly compared with a 4-yearly screening interval was £3612 (£6586), increasing to £9601 (£34,112) for annual compared with 2-yearly screening. The probability that the intervention is cost saving is around 25%, and it has around an 80% chance of being below a cost-effectiveness threshold of £30,000. For type 2 diabetes, incremental cost per QALY (SD) of a yearly compared with a 2-yearly screening interval was £606 (£1782). The intervention is almost certainly below a cost-effectiveness threshold of £5000. These results support current UK guidance, which recommends annual screening with ACR to identify early kidney disease in patients with diabetes, despite a high false-positive rate leading to, at worst, unnecessary or, at best, early therapeutic intervention. For type 1 diabetes, screening costs for annual compared with 2-yearly screening are well within the bounds of accepted cost-effectiveness. Annual screening is even more cost-effective in type 2 diabetes than in type 1 diabetes. Identification of alternative markers for developing diabetic nephropathy may improve targeting of treatment for those at high risk. The National Institute for Health Research Health Technology Assessment programme.

Statin for the Primary Prevention of Cardiovascular Disease in Patients with Diabetes Mellitus

Stain is commonly used in subjects with diabetes for both primary and secondary prevention of cardiovascular diseases (CVDs) [1,2]. It is even recommended by the American Diabetes Association to be added to lifestyle therapy regardless of the baseline lipid levels for diabetic patients aged ≥40 years, even if they have no overt CVD [3], and recent guidelines from the American College of Cardiology and the American Heart Association states that statin therapy should be initiated and maintained for the primary prevention for CVD in adults 40 to 75 years of age with diabetes mellitus, regardless of their CVD risk if their low density lipoprotein cholesterol (LDL-C) level is ≥70 mg/dL [4]. The possibility of primary prevention of CVD with statin therapy for diabetic subjects with a high CVD risk has been well elucidated [1,5,6]. Collaborative Atorvastatin Diabetes Study (CARDS) [1] was a large randomized controlled trial aimed to show the efficacy of statin for the primary prevention of CVD in subjects with type 2 diabetes who had at least one or more of CVD risk factors, but the study terminated 2 years earlier than expected. This was because the statin group showed a superior risk reduction than expected: CVD event reduction of 37% (95% confidence interval [CI], -52 to -17) in statin group [1]. However, there are still insufficient evidence to show the effect of statin for the primary prevention of CVD in diabetic patients with a low risk. There have been claims that statins should be used with caution for the primary prevention in subjects with low CVD risk [7,8]. Furthermore, statin therapy has been reported to be associated with myopathy, elevated liver enzyme concentration, and incident diabetes mellitus [9,10]. However, recent meta-analysis of Cholesterol Treatment Trialists' (CTT) collaborators showed an overall relative risk reduction of major vascular events of 21% (relative risk, 0.79; 95% CI, 0.77 to 0.81) per 1 mmol/L reduction of LDL-C with statin; these benefits were similar in people with a lower CVD risk [11]. Subjects with less than 5% of CVD risk also showed a significant risk reduction of about 40% per 1 mmol/L reduction of LDL-C with statin [11]. In addition, Justification for Use of statins in Prevention: an Intervention Trial Evaluating Rosuvastatin (JUPITER) [12] showed that statin decreased the rate of CVD in healthy men and women with LDL-C level ≤130 mg/dL. Although CTT and JUPITER was not performed exclusively in diabetic patients, their results might be implicated with diabetic subjects with a low CVD risk. Moreover, diabetes is an important risk factor for CVD and is considered as an equivalent to coronary artery disease [13]. Reductions in CVD outcomes were greatest in people with high baseline CVD risk [10]. Nonetheless, subgroup analysis from the meta-analysis of CTT reported that statin could reduce CVD events in subjects with diabetes regardless of their baseline CVD risk or baseline LDL-C [6]. Lee et al. [14] reported that statin discontinuation could be considered based on the pretreatment lipid profiles, especially for subjects with baseline LDL-C less than 123 mg/dL. However, considering that statin therapy is not for reducing LDL-C itself but for reducing CVD risk, their results should be interpreted carefully to make the decision whether statin should be continued or not. As the authors mentioned, the effect of stopping statin on future CVD risk in diabetic patients with a low CVD risk remains to be elucidated. There have been obvious concerns on the cost-effectiveness of primary prevention of CVD with statin in diabetic subjects with a low CVD risk. CARDS applied the United Kingdom Prospective Diabetes Study risk engine for their study population to predict the probability of a CVD event for each CARDS patient and showed that the incremental cost-effectiveness ratio was £5,983 per event-free year for subjects with a low CVD risk and £2,077 per event-free year for subjects with a high CVD risk [15]. In addition, other issues such as feasibility and desirability should be considered to treat the majority of diabetic patients aged ≥40 years and the role of alternative public health strategies to lower blood cholesterol. In conclusion, the use of statins for the primary prevention in diabetic subjects with a low CVD risk remains suspensive in its cost-effectiveness. Considering the high risk of CVD in diabetic patients compared to non-diabetic individuals, further studies to elucidate whether statin therapy should be started and maintained for diabetic subjects with a low CVD risk should be performed.

Dyslipidemia

Dyslipidemia

Editorial on Treatment of Dyslipidemia in Patients with Diabetes Mellitus

Lifestyle measures are important in the treatment of diabetics with dyslipidemia. The diabetic should achieve and maintain a desirable weight. The diet should be low in cholesterol (less than 200 mg daily). Less than 30% of total caloric intake should be fatty acids. Saturated fatty acids should comprise less than 7% of total calories, polyunsaturated acids up to 10% of total calories, and monounsaturated fatty acids 10% to 15% of total calories. The diet should also be high in fiber and high in fruits and vegetables. There is no strong evidence to support any dietary supplements. A more liberalized diet is warranted in elderly persons prone to malnutrition. Moderate intensity exercise is recommended for 30 to 60 minutes daily. Smoking should be stopped, hypertension treated, and the hemoglobin A1C level controlled. Numerous studies have documented that statins reduce cardiovascular events including stroke and mortality in patients with diabetes mellitus [1-4]. In the Collaborative Atorvastatin Diabetes Study, 2,838 patients (62% older than 60 years) with diabetes mellitus, no cardiovascular disease, and a serum low-density lipoprotein cholesterol level less than 160 mg/dL were randomized to atorvastatin 10 mg daily or to placebo [1]. At 3.9-year median follow-up, compared with placebo, atorvastatin significantly reduced time to first occurrence of acute coronary events, coronary revascularization, or stroke by 37%, acute coronary events by 36%, and stroke by 48% [1]. In the Heart Protection Study, 5,963 United Kingdom adults aged 40 to 80 years with diabetes mellitus were randomized to simvastatin 40 mg daily or to double-blind placebo [2]. First major vascular event (major coronary event, stroke, or revascularization) was reduced by simvastatin 22% by simvastatin in diabetics (p<0.001), 33% in diabetics without occlusive arterial disease (p = 0.0003), and 27% in diabetics with a serum low-density lipoprotein cholesterol level below 116 mg/ dL [2]. Statin treatment for 5 years prevented 45 diabetics per 1,000 treated from having at least one major vascular event and among these 45 persons, to prevent 70 first or subsequent events. This study showed that statin therapy reduced major vascular events in diabetics, regardless of age, gender, and serum lipid levels. In an observational prospective study of 171 men and 358 women, mean age 79 years, with prior myocardial infarction, diabetes mellitus, and a serum low-density lipoprotein cholesterol level of 125 mg/dL or higher, 53% of persons were treated with statins [3]. At 29-month followup, compared with no treatment with statins, use of statins significantly decreased in diabetics coronary death or nonfatal myocardial infarction by 37% and stroke by 47% [3].

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).

The effect of atorvastatin therapy on tumour necrosis factor-α and vascular adhesion molecules in patients with type 2 diabetes mellitus with no prior history of coronary heart disease

We examined the effect of atorvastatin (and placebo) on tumour necrosis factor (TNF)α, soluble vascular cell adhesion molecule-1 (sVCAM-1) and soluble intercellular cell adhesion molecule-1 (sICAM-1) in patients with type 2 diabetes without prior cardiovascular disease (CVD) and investigated whether adhesion molecules were associated with incident CVD. Baseline and follow-up concentrations of TNFα, sVCAM-1 and sICAM-1 were measured in patients from the Collaborative AtoRvastatin Diabetes Study (CARDS). Patients had a mean age of 61 years (standard deviation = 8) and 70% were men. TNFα 2.20 pg/mL (1.82–2.86), sVCAM-1 865 ng/mL (729–1059) and sICAM-1 619 ng/mL (533–753) concentrations (median, interquartile range 25, 75%) were similar at baseline in atorvastatin (given values) and placebo groups and not significantly different at 2 years. The multivariable hazard ratios for the associations between sVCAM-1 and sICAM-1 (doubling the concentration) and CVD were, 0.82 (95% confidence interval (CI) 0.66–1.0) and 0.59 (95% CI 0.50–0.71), respectively. In conclusion atorvastatin had no significant effect on TNFα, sVCAM-1 or sICAM-1 levels in type 2 diabetic patients without a prior history of CVD compared with placebo. In addition, both sVCAM-1 and sICAM-1 concentrations were associated with a decreased risk of CVD.

Persistent lipid abnormalities in diabetes; are we approaching the treatment optimally?

There is overwhelming evidence that reducing LDL cholesterol with the use of statins leads to reductions in cardiovascular disease in diabetes. This has resulted in international and country-specific guidelines of the treatment of dyslipidaemia in diabetes, with recommendations of target LDL cholesterol to be achieved. Consequently, in many countries the majority of people with Type 2 diabetes are now being treated with a statin. Nonetheless, there is a growing body of evidence that, in clinical practice, target LDL cholesterol levels are not achieved and therapy is not targeted at the dyslipidaemia associated with diabetes, namely low HDL cholesterol and high triglycerides. In this edition of Diabetic Medicine, Leiter and colleagues on behalf of the Dyslipidaemia International Study (DYSIS) investigators (page 1349) have performed a cross-sectional study of 22 063 statin-treated outpatients consecutively recruited by clinicians in Canada and 11 European countries. Forty-one per cent of outpatients had diabetes and, in those patients, only 48% were at cholesterol target and many had persistent lipid abnormalities. Simvastatin was the most common statin, being prescribed at a dose of 20–40 mg per day; 14% patients were taking ezetimibe alone or in combination with a statin. The possible barriers to effective lipid interventions are manyfold and need tackling at all levels. In some parts of the world this is related to finance and limits set by insurance companies or health providers. Whilst it is reasonable to always prescribe the cheapest statin in the majority of people with diabetes in the first instance, if the targets are not achieved or there is evidence of dyslipidaemia it is important to consider the use of a more potent or appropriate statin. Physician attitudes are another important contributor to the problem and aggressive marketing of some of the non-statin lipid-lowering drugs can influence prescribing patterns. It is likely that the other most important contributor to less effective lipid lowering is at the level of the person with diabetes themselves. We place many demands on the person with diabetes, who has to take many medications, several of which have side effects. It is well documented that even in the setting of clinical trials not all patients take their tablets; indeed, in the Collaborative Atorvastatin Diabetes Study (CARDS) trial, on average 20% of patients on statin were not taking their medication over the course of the 4-year study. In clinical practice, it seems likely that the most common reason not to achieve target cholesterol is therefore going to relate to the underuse of medication by people with diabetes. It is therefore of the highest importance that the person with diabetes has the locus of control compared with health professional-focused approaches. It seems highly likely that in addition to LDL cholesterol we should be considering optimizing HDL cholesterol and triglycerides. Currently, the evidence base for second-line therapy to treat diabetic dyslipdaemia is not strong, but nonetheless suggests that further benefits may be achieved using either fibrate- and nicotinic acid-containing medications. Despite their relatively high uptake, the current evidence for the use of ezetimibe to reduce cardiovascular disease in diabetes remains comparatively weak. We therefore eagerly await the results of several ongoing trials addressing these issues, including AIM-HIGH, HPS2-THRIVE, dal-OUTCOME, IMPROVE-IT and others. In the meanwhile, it is important that the majority of people with diabetes have the opportunity to be treated with the best statin and at the most appropriate dose to prevent cardiovascular disease, whilst at the same time attention is paid to all other reversible cardiovascular risk factors.

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

OBJECTIVECirculating 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 METHODSWe 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.RESULTSsRAGE 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.CONCLUSIONSHigher levels of sRAGE and esRAGE are associated with incident CHD but not stroke in type 2 diabetes.