Moderate-dose Statin Research Articles

Diabetogenic effect of statins: a comprehensive review on the clinical relevance, underlying pathomechanisms and rationale for tailored statin therapy

Statins are potent hypolipidemic drugs effectively reducing low-density lipoprotein (LDL) cholesterol serum concentration, but also exerting a wide range of pleiotropic effects. In numerous clinical trials statins were proven to substantially decrease cardiovascular morbidity and mortality both in primary and secondary prevention. However, a growing body of evidence suggests that statins, although safe and generally well-tolerated, are associated with an increased occurrence of new-onset diabetes mellitus (DM). The aim of this review is to explore the relationship between statin therapy and new-onset DM, including its clinical relevance and underlying pathomechanisms, and to discuss the concept of tailored statin therapy. According to our recently published comprehensive network meta-analysis including 113,394 patients, the high-dose statin regimens were connected with an elevated risk of new-onset DM as compared with moderate-dose statin regimens and a gradient for the risk of new-onset DM across different types and doses of statins was demonstrated. There are multiple possible mechanisms explaining the diabetogenic effect of statins (e.g., decreased insulin secretion, induction of b-cell apoptosis, increased insulin resistance or compromised glucose transport into the cells). Statins are among the most widely used drugs worldwide and physicians should be aware of the fact that there is a risk of new-onset DM across different types and doses of statins. Selection of adequate statin that suits patient’s needs remains the challenge of hypolipidemic therapy. The identification of individuals who would benefit more from smaller doses and/or use of less diabetogenic compounds could help to optimize the treatment and reduce the number of patients developing DM. The non-pharmacological approach such as adequate physical activity, weight reduction and low fat diet should not be neglected either. These actions create a chance to decrease baseline LDL-cholesterol concentration and reduce the number of both cardiovascular and DM risk factors. All in all, statins with their exceptional cardiovascular benefits will undoubtedly defend their position of a cornerstone of cardiovascular prevention because profits derived from statin therapy far exceed the potential harms connected with statin-induced impairments of glucose metabolism.

The RADICAL-PC trial.

178 Background: Cardiovascular disease (CVD) occurs frequently in men with prostate cancer (PC), but the reasons are unclear. Specifically, the role of androgen deprivation therapy (ADT) in promoting CVD remains uncertain. There is a lack of evidence to inform preventive strategies against CVD in this high risk group. It is unknown if the evidence to support CVD preventive strategies in the general population can be validly extrapolated to men with PC. Methods: RADICAL-PC combines two prospective studies, one of which is embedded in the other. The Role of Androgen Deprivation Therapy in Cardiovascular Disease – A Longitudinal Prostate Cancer Study (RADICAL PC1) is a prospective cohort study of men within one year of their first diagnosis of PC, or who are within one month of commencing ADT for the first time. Its goal is to identify factors associated with the development of CVD among men with PC, with a particular focus on ADT. The Randomized Intervention for Cardiovascular and Lifestyle Risk Factors in Prostate Cancer Patients (RADICAL PC2) is a randomized, controlled trial embedded in RADICAL PC1. RADICAL PC2 will test a systematic approach to modifying CV and lifestyle risk factors. The intervention group will receive: 1) Standardized advice on healthy diet and exercise; 2) Low-dose antiplatelet agent; 3) Low- to moderate-dose statin; and 4) ACE-I for baseline systolic blood pressure ≥ 130mmHg. Results: The study has been recently funded by Movember clinical trial program of Prostate Cancer Canada, and is launched across Canada. The primary outcome is the occurrence of the composite of cardiovascular death, myocardial infarction, stroke, heart failure, or arterial revascularization. For RADICAL-PC1, 6000 participants will have 90% power to detect a hazard ratio 0.86 for a given exposure. For RADICAL-PC2, 4116 participants randomized, with 434 primary outcome events will have 85% power to detect a hazard ratio of 0.75 in the intervention group. Conclusions: RADICAL PC will be one of the largest prospective studies of CVD – the main competing risk – in men with PC. It will clarify the determinants of CVD in these men, the role of ADT in CVD, and will simultaneously test an intervention to lower the CVD risk in this high-risk population.

Statin Dose and the Risk of Intracerebral Hemorrhage: A Population-Based Longitudinal Study in Taiwan.

In the last 15 years, there has been considerable interest in statin use as a means to reduce the likelihood of vascular events. Several clinical trials have shown that high-dose statin (HDS) treatment could reduce vascular events. In high-risk populations, lipid treatment guidelines have generally suggested prescribing statin up to the highest recommended dosage. However, there remains concern about the risk of intracerebral hemorrhage (ICH) with HDS treatment. This was a national population-based cohort study from the National Health Insurance Research Database of Taiwan extending from July 2001 to December 2008. Patients with cerebrovascular or cardiovascular disease were enrolled. The HDS group was defined as those patients receiving more than 420 mg per year of atorvastatin or an equivalent potency statin. Moderate dose statin group (MDS) was defined as those patients receiving atorvastatin in amounts between 196-420 mg per year or an equivalent potency statin. Low dose statin (LDS) group was defined as those receiving less than 196 mg per year of atorvastatin or an equivalent statin. The primary endpoint is ICH. The secondary endpoints are myocardial infarction (MI), ischemic stroke (IS) and new-onset DM (NDM). A total of 5459 patients were enrolled in our study, with study participant ages ranging from 62.91 ± 11.85 years and a mean follow-up time of 2039 ± 6 days. After adjusting for age, gender, diabetes and hypertension, Cox regression analysis found ICH risk was lower in HDS and MDS groups compared with LDS (HR 0.49, 95% CI 0.26-0.91, p = 0.0246 and HR 0.45, 95% CI 0.24-0.86, p = 0.0157). The risk of IS is lower in patients with HDS treatment (HR 0.68, 95% CI 0.55-0.83, p < 0.01). However, the risk of MI and NDM incidence are not statistically significant between the different dose groups. In the real-world data provided by Taiwan's National Health Insurance research database, it was shown that patients who received a higher dose of statin had a reduced and not elevated risk of intracerebral hemorrhage. High-dose statin; Hyperlipidemia; Intracerebral hemorrhage; Ischemic stroke; New-onset DM.

Abstract 232: Cost-effectiveness Analysis of Lipoprotein Subfraction Testing in Patients at Intermediate Risk of Cardiovascular Events

Background: The 2013 ACC/AHA Guideline on the Treatment of Blood Cholesterol to Reduce Atherosclerotic Cardiovascular Disease (CVD) in Adults defined 4 patient groups who would benefit from statin therapy. For patients who are not classified into a statin benefit group, and have an estimated 10-year CVD risk between 5% and 7.5%, the guidelines suggest that additional risk factors may be considered to inform moderate-intensity statin treatment decisions. Low density lipoprotein concentration (LDL-P) has been shown to be associated with incident CVD events among patients with &lt;7.5% 10-year risk after adjusting for established risk factors. Objectives: To assess the cost-effectiveness of using LDL-P for risk assessment as an aid in making statin treatment decisions in patients with an estimated 10-year CVD risk of 5% to 7.5%. Methods: We conducted a cost-effectiveness analysis using a Markov model that assessed patient healthcare costs and outcomes from a payer perspective over a 5 year time horizon. A usual care strategy was compared with an LDL-P test-and-treat strategy in a hypothetical intermediate risk population_those with an estimated 10-year CVD risk of 5% to 7.5%. The test-and-treat strategy entailed testing LDL-P levels in 10,000 patients and treating only those in the top decile of LDL-P _those who would be reclassified above estimated 7.5% 10-year risk_with a moderate-dose statin therapy. Future cost and utilities were derived from published literature and were discounted at 3% annually. Single- and multi-variable sensitivity analyses were conducted to investigate the effect of the base-case assumptions on the difference in costs and quality-adjusted life years (QALYs) between the two strategies. Results: Compared with a usual care strategy, LDL-P testing of 10,000 patients followed by moderate-intensity statin therapy of patients in the top decile of LDL-P resulted in 17 fewer patients with CVD events, cost savings of more than $300,000, and about 13 additional QALYs over a 5 year horizon. Conclusions: CVD risk assessment by LDL-P testing of patients with estimated 10-year CVD risk of 5% to 7.5%, who were not classified into a statin benefit group, may be an event-reducing and a cost-saving strategy compared with usual care.

Efficacy of statin monotherapy or in combination with coenzyme a capsule in patients with metabolic syndrome and mixed dyslipidemia.

BackgroundPatients with metabolic syndrome are at increased risk for cardiovascular disease. Combination lipid-lowering therapy is often needed in patients with metabolic syndrome and mixed dyslipidemia. The aim of this study was to compare the effect of statin combined with a new hypolipidemic agent, coenzyme A (CoA) with moderate-dose statin monotherapy in subjects with metabolic syndrome and mixed dyslipidemia by evaluating data from a subgroup of patients with metabolic syndrome and mixed dyslipidemia from a previously conducted randomized study.MethodsIn the present post hoc analysis, 212 patients were included, receiving statin monotherapy (n = 94) or statin combined with CoA 400 U/day (n = 118) for 8 weeks. The lipoprotein profile was determined at baseline and week 8 visits. Attainment of low-density lipoprotein-cholesterol (LDL-C) < 100 mg/dL, non-high-density lipoprotein-cholesterol (HDL-C) < 130 mg/dL, and the combined goal of these two parameters was also evaluated.ResultsThe mean percent change was more prominent with CoA plus statin compared with placebo plus statin in triglyceride (TG) (-32.5% vs. -8.7%, respectively; P = 0.0002), total cholesterol (-9.6% vs. -3.6%, P = 0.013), LDL-C (-7.5% vs. 2.1%, P = 0.033), and non-HDL-C (-14.3% vs. -6.4%, P = 0.011). Treatment with CoA plus statin resulted in larger percentages of participants attaining lipid goals for LDL-C (70.3% vs. 56.4%, P = 0.044), non-HDL-C (60.2% vs. 45.7%, P = 0.039), and the combined goal of LDL-C and non-HDL-C (57.6% vs. 42.6%, P = 0.038) than statin monotherapy.ConclusionThese results demonstrate that CoA plus statin therapy was more effective in improving lipoprotein parameters than statin alone in patients with metabolic syndrome and mixed hyperlipidemia.

Statins and type 2 diabetes: genetic studies on target

Statins and type 2 diabetes: genetic studies on target

Baseline very low-density lipoprotein cholesterol is associated with the magnitude of triglyceride lowering on statins, fenofibric acid, or their combination in patients with mixed dyslipidemia.

Fibric acid derivatives like fenofibric acid (FA) decrease hepatic production of very low-density lipoprotein (VLDL)-associated triglycerides (TG). Hepatic VLDL production can be estimated from VLDL-associated cholesterol (VLDL-C). We assessed if the degree of TG reduction observed with FA, statins, or their combination is associated with baseline VLDL-C. Overall, 2,715 patients with mixed dyslipidemia in three randomized, controlled studies were assigned to one of six treatment strategies: FA, low-dose statin (LDS), FA + LDS, moderate-dose statin (MDS), FA + MDS, and high-dose statin (HDS). Patients were dichotomized into low- or high-baseline VLDL-C groups. Pooled data were used to compare the degree of TG reduction in patients with low- vs. high-baseline VLDL-C for each treatment arm, using unpaired, two-sided t test. Additionally, the association between baseline VLDL-C level and percentage TG reduction from baseline was evaluated by linear regression. Diagnostic performance of baseline VLDL-C levels in predicting 5, 10, 15, and 20% TG reduction was assessed by receiver operating characteristics (ROC) analysis. In all treatment groups, following 12 weeks of therapy, a significantly greater percent change from baseline in TG was observed in the high-baseline VLDL-C group as compared with the low-baseline VLDL-C group. Linear regression analysis indicated that approximately 6 to 13% of the decrease in TG could be explained by baseline VLDL-C. ROC-derived cut points for baseline VLDL-C were obtained for 5, 10, 15, and 20% TG reduction. Baseline VLDL-C levels are associated with the degree of TG lowering using FA, statins, or their combination, thereof.

Treatment of Hypercholesterolemia in Patients with Diabetes Mellitus

Numerous studies have shown that statins reduce cardiovascular events including stroke and mortality in diabetics. The American Diabetes Association 2013 guidelines recommend that diabetics at high risk for cardiovascular events should have their serum low-density lipopro- tein (LDL) cholesterol reduced to <70 mg/dL with statins. Lower-risk diabetics should have their serum LDL cholesterol reduced to < 100 mg/dL. The 2013 American College of Cardiology/American Heart Association lipid guidelines recommend giving high-dose statins to adult diabetics aged ≤75 years with atherosclerotic vascular disease (ASCVD) unless contraindicated with a class I indication and moderate-dose or high-dose statins to diabetics with ASCVD ≥75 years with a class IIa indication. Diabetics ≥ 21 years with a serum LDL cholesterol of ≥190 mg/dL should be treated with high-dose statins with a class I indication. For primary prevention in diabetics aged 40 to 75 years and serum LDL cholesterol between 70 to 189 mg/dL, moderate-dose statins should be given with a class I indica- tion. For primary prevention in diabetics aged 40 to 75 years, a serum LDL cholesterol between 70 to 189 mg/dL, and a 10-year risk of ASCVD of ≥7.5% calculated from the Pooled Heart Equation, high-dose statins should be given with a class IIa indication. For primary prevention in diabetics aged 21 to 39 years or older than 75 years and a serum LDL cholesterol between 70 to 189 mg/dL, moderate-dose statins or high-dose statins should be given with a class IIa indication. There is no additional ASCVD reduction from adding nonstatin therapy to further lower non-high-density lipoprotein (HDL) cholesterol once an LDL cholesterol goal has been reached. Clinical tri- als have found no lowering of cardiovascular events or mortality in diabetics treated with statins by addition of nicotinic acid, fibric acid derivatives, ezetemibe, or drugs that raise serum HDL cholesterol.

Putting the diabetes risk due to statins in perspective: A re-evaluation using the complementary outcome

AimsStatins are used extensively to treat dyslipidemia and have been associated with significant clinical benefit that increases with dose. However, recent studies have associated statins with an excess risk of developing diabetes mellitus, which may offset the clinical benefit to patients. Adverse events related to intensive-dose statin therapy were revisited in light of recent data regarding the use of relative risks. Data synthesisA meta-analysis was replicated with the event of interest redefined as the complementary outcome (no-onset of diabetes). Five randomised controlled trials that compared the risk of intense-dose with moderate-dose of statin therapy for the onset of diabetes with a follow-up greater than 12 months were included in the analysis. A reduction in the risk for no-onset of diabetes was found when intensive-dose statin therapy was compared with moderate-dose statin therapy, revealing a relative risk of 0.9908 (95%CI: 0.9849–0.99679). Over two years, one more patient was harmed by diabetes onset for every 237 patients exposed to intensive-dose statin therapy (95%CI: 123–3847) compared with standard dose statin therapy. ConclusionsStatins are associated with only a very small increase in risk of diabetes mellitus. Previous research selected the outcomes with the lower baseline risks and therefore the actual risk associated with statins has been largely over-estimated.

Is statin‐induced diabetes clinically relevant? A comprehensive review of the literature

In those predisposed to the development of diabetes (the insulin resistant, obese and older patients) statins may increase the risk of developing diabetes. Despite the fact that the conversion to diabetes is generated from post hoc analyses, it seems to be a class effect with a dose-response relationship. However, statins have not been clearly shown to increase diabetic microvascular complications (retinopathy, nephropathy and neuropathy). Thus, the clinical significance of increased glucose levels in patients treated on statins is uncertain. While the exact mechanism for how statins increase the risk of diabetes is unknown, a possible explanation is through a reduction in adiponectin levels. Despite the fact that higher statin doses are more likely to lead to new-onset diabetes, for every case of diabetes caused, there are approximately three cardiovascular events reduced with high dose versus moderate dose statin therapy. Overall, the small risk of developing type 2 diabetes with statin therapy is far outweighed by the potential of statins to decrease cardiac events.

The effect of moderate-dose versus double-dose statins on patients with acute coronary syndrome in China: Results of the CHILLAS trial

BackgroundCurrent guidelines recommend intensive low-density lipoprotein (LDL) cholesterol lowering with statins, with a target of 70mg/dL (1.81mmol/L) LDL cholesterol for those with a very high risk of coronary artery events. However, there is no multicenter study assessing the effect of intensive lipid-lowering therapy with statins on acute coronary syndrome (ACS) in a Chinese population with low baseline LDL cholesterol levels. Methods and resultsPatients (n=1355) with ACS were treated with a moderate dose of statin (atorvastatin 10 mg/d, or equivalent dose of other statins, n=675) or with an intensive dose of statin (atorvastatin, 20 or 40mg/d, or equivalent dose of other statins, n=680) for 2 years. The primary end points were cardiac death, non-fatal acute myocardial infarction (MI), revascularization, ischemic stroke and documented unstable angina or severe heart failure requiring emergency hospitalization. Baseline lipid levels were nearly identical in both groups with a mean LDL cholesterol level of 2.7mmol/L (103mg/dL). At 3 months, LDL cholesterol levels declined 20.2% in the moderate dose statin group and 26.6% in the intensive statin group, respectively (P<0.001). In a 2-year follow-up, a primary end point event occurred in 20 patients in the moderate dose statin group and in 28 patients in the intensive statin group. There was no significant between-group difference in the primary outcome (hazard ratio, 1.39; 95% confidence interval [CI], 0.78–2.46; P=0.245). ConclusionsFor ACS patients with a relatively low baseline LDL cholesterol level who received optimized current medication and interventional therapy, the incremental LDL cholesterol reduction of 6.4% achieved by double-dose statin did not bring significant clinical effectiveness.

High coronary plaque load: a heavy burden

This editorial refers to ‘Coronary atheroma volume and cardiovascular events during maximally intensive statin therapy’[†][1], by R. Puri et al ., on page 3182 Hydroxymethylglutaryl (HMG) CoA-reductase inhibitors, or statins, play an important role in the primary and secondary prevention of coronary heart disease. By inhibiting the enzyme HMG-CoA reductase, statins lower the production of cholesterol in the liver, resulting in lower LDL cholesterol levels. Besides lowering cholesterol levels, statin therapy slows down plaque progression and in some patients even causes plaque regression. In the beginning of the 1990s, the first trials were initiated to assess the effect of statin therapy on plaque dynamics. Randomized trials, such as MARS and REGRESS, used (quantitative) invasive coronary angiography (ICA) to assess luminal stenosis characteristics. Since ICA only allows assessment of the coronary lumen, differences in minimal lumen diameters (MLDs) and mean segment diameters (MSDs) between baseline and follow-up were assessed as a measurement of coronary plaque change.1,2 These early studies demonstrated that moderate dose statin therapy on average reduces plaque progression. Importantly, this was associated with a reduction of major adverse cardiovascular events (MACEs). Of note, it was shown that the beneficial effect of statin therapy is more pronounced in more severe lesions.1 A relative shortcoming of these studies was the inability of ICA to visualize true coronary atherosclerotic burden. Around the same time as the first angiographic studies with statin therapy were executed, a novel method for the assessment of coronary plaque burden was designed; intracoronary ultrasound (ICUS), nowadays known as intravascular ultrasound (IVUS). This invasive method uses ultrasound to create two-dimensional tomographic images of the coronary lumen and vessel wall morphology.3 Since then IVUS is frequently used for coronary plaque assessment and has been widely … [1]: #fn-2

Diabetes Mellitus and Cardiovascular Events in Older Patients With Myocardial Infarction Prescribed Intensive-Dose and Moderate-Dose Statins

Practice guidelines recommend intensive-dose statins for patients with acute coronary syndrome, but recent data about the risk of new-onset diabetes mellitus have raised concerns about its use. Our main objective was to evaluate the association between intensive statin therapy and new-onset diabetes mellitus in patients with myocardial infarction and to evaluate the association of intensive statin therapy with long-term adverse clinical outcomes. A propensity score-matched cohort was created consisting of 17 080 patients with myocardial infarction aged >65 years old, hospitalized in Ontario, Canada, from 2004 to 2010. Clinical outcomes were compared in patients prescribed intensive-dose versus moderate-dose statins at hospital discharge. At 5 years, 13.6% of patients receiving intensive-dose statins and 13.0% of patients receiving moderate-dose statins had new-onset diabetes, which was not significantly different (P=0.19). By contrast, the 5-year rate of death or acute coronary syndrome was significantly lower at 44.8% in the intensive-dose statin group compared with 46.5% in the moderate-dose group (P=0.044). The reduction in combined clinical outcome was driven mainly by a significantly lower rate of acute coronary syndrome (P=0.039) associated with intensive-dose statins. No significant difference in mortality rates (34.8% in both groups) was observed between the treatment groups during the study period (P=0.89). In older patients with myocardial infarction, we found intensive-dose statin therapy to be effective in reducing repeat hospitalization for acute coronary syndrome. The rate of new-onset diabetes mellitus at long term was not significantly different between intensive-dose and moderate-dose statins.

Adverse events of statin–fenofibric acid versus statin monotherapy: a meta-analysis of randomized controlled trials

Background:Patients with mixed dyslipidemia can benefit from the combination of fenofibric acid (FA) with statins, but concerns about adverse events make physicians reluctant to prescribe the combination therapy.Objective:In the present study, we performed a meta-analysis of randomized controlled trials (RCTs) to assess the efficacy and adverse events in patients taking statins and FA.Methods:Medline, Embase and the Cochrane Library were searched to identify studies that reported adverse events. Finally, five trials covering 2704 patients were selected in this study.Results:There were significant decreases in TG and increases in HDL-C in patients receiving combination therapy compared with statin monotherapy. The incidence of hepatic toxicity (OR, 3.57; 95% CI, 1.17–10.83; P < 0.05) and increased creatinine (OR, 3.22; 95% CI, 1.28–8.11; P < 0.05) was significantly higher in the FA + low-dose statin group than in the corresponding statin monotherapy. The incidence of CK elevations and muscle-associated AEs was not statistically different between the two groups. The adverse events in the FA + moderate-dose statin group were almost identical to those in the FA + low-dose statin group.Conclusions:In conclusion, combination therapy could improve the blood lipid profile. Addition of FA to statins therapy is more frequently associated with hepatic and renal toxicity than muscle-associated AEs. Therefore patients taking the combination of FA with statins should have liver enzyme and renal function monitored. However, we still need large-scale and long follow-up period RCTs to definitively confirm the adverse events of FA–statin therapy.

Meta-Analysis of Impact of Different Types and Doses of Statins on New-Onset Diabetes Mellitus

Recent reports indicate that statins are associated with an increased risk for new-onset diabetes mellitus (DM) compared with placebo and that this relation is dose dependent. The aim of this study was to perform a comprehensive network meta-analysis of randomized controlled trials (RCTs) investigating the impact of different types and doses of statins on new-onset DM. RCTs comparing different types and doses of statins with placebo were searched for using the MEDLINE, Embase, and Cochrane databases. A search of RCTs pertinent to this meta-analysis covering the period from November 1994 to October 2012 was conducted by 2 independent investigators using the MEDLINE, Cochrane, Google Scholar, and Embase databases as well as abstracts and presentations from major cardiovascular meetings. Seventeen RCTs reporting the incidence of new-onset DM during statin treatment and including a total of 113,394 patients were identified. The RCTs compared either a statin versus placebo or high-dose versus moderate-dose statin therapy. Among different statins, pravastatin 40 mg/day was associated with the lowest risk for new-onset DM compared with placebo (odds ratio 1.07, 95% credible interval 0.86 to 1.30). Conversely, rosuvastatin 20 mg/day was numerically associated with 25% increased risk for DM compared with placebo (odds ratio 1.25, 95% credible interval 0.82 to 1.90). The impact on DM appeared to be intermediate with atorvastatin 80 mg/day compared with placebo (odds ratio 1.15, 95% credible interval 0.90 to 1.50). These findings were replicated at moderate doses. In conclusion, different types and doses of statins show different potential to increase the incidence of DM.

2013 American College of Cardiology/American Heart Association Guidelines on Treatment of Hypercholesterolemia

High-dose statins reduce serum low-density lipoprotein (LDL) cholesterol ≥ 50% and include atorvastatin 40 mg to 80 mg daily and rosuvastatin 20 mg to 40 mg daily [1]. Moderate-dose statins reduce serum LDL cholesterol 30% to 49% and include atorvastatin 10 mg to 20 mg daily, rosuvastatin 5 mg to 10 mg daily, simvastatin 20 mg to 40 mg daily, pravastatin 40 mg to 80 mg daily, lovastatin 40 mg daily, fluvastatin XL 80 mg daily, fluvastatin 40 mg twice daily, and pitavastatin 2mg to 4 mg daily [1]. Low-dose statins reduce serum LDL cholesterol less than 30% and include simvastatin 10 mg daily, pravastatin 10 mg to 20 mg daily, lovastatin 20 mg daily, fluvastatin 20 mg to 40 mg daily, and pitavastatin 1 mg daily [1].

Assessing appropriateness of lipid management among patients with diabetes mellitus: moving from target to treatment.

Performance measures that emphasize only a treat-to-target approach may motivate overtreatment with high-dose statins, potentially leading to adverse events and unnecessary costs. We developed a clinical action performance measure for lipid management in patients with diabetes mellitus that is designed to encourage appropriate treatment with moderate-dose statins while minimizing overtreatment. We examined data from July 2010 to June 2011 for 964 818 active Veterans Affairs primary care patients ≥18 years of age with diabetes mellitus. We defined 3 conditions as successfully meeting the clinical action measure for patients 50 to 75 years old: (1) having a low-density lipoprotein (LDL) <100 mg/dL, (2) taking a moderate-dose statin regardless of LDL level or measurement, or (3) receiving appropriate clinical action (starting, switching, or intensifying statin therapy) if LDL is ≥100 mg/dL. We examined possible overtreatment for patients ≥18 years of age by examining the proportion of patients without ischemic heart disease who were on a high-dose statin. We then examined variability in measure attainment across 881 facilities using 2-level hierarchical multivariable logistic models. Of 668 209 patients with diabetes mellitus who were 50 to 75 years of age, 84.6% passed the clinical action measure: 67.2% with LDL <100 mg/dL, 13.0% with LDL ≥100 mg/dL and either on a moderate-dose statin (7.5%) or with appropriate clinical action (5.5%), and 4.4% with no index LDL on at least a moderate-dose statin. Of the entire cohort ≥18 years of age, 13.7% were potentially overtreated. Facilities with higher rates of meeting the current threshold measure (LDL <100 mg/dL) had higher rates of potential overtreatment (P<0.001). Use of a performance measure that credits appropriate clinical action indicates that almost 85% of diabetic veterans 50 to 75 years of age are receiving appropriate dyslipidemia management. However, many patients are potentially overtreated with high-dose statins.

Effects of AMG 145 on Low-Density Lipoprotein Cholesterol Levels: Results From 2 Randomized, Double-Blind, Placebo-Controlled, Ascending-Dose Phase 1 Studies in Healthy Volunteers and Hypercholesterolemic Subjects on Statins

The aim of this study was to evaluate the safety, tolerability, and effects of AMG 145 on low-density lipoprotein cholesterol (LDL-C) in healthy and hypercholesterolemic subjects on statin therapy. Proprotein convertase subtilisin/kexin type 9 (PCSK9) down-regulates surface expression of the low-density lipoprotein receptor (LDL-R), increasing serum LDL-C. AMG 145, a fully human monoclonal antibody to PCSK9, prevents PCSK9/LDL-R interaction, restoring LDL-R recycling. Healthy adults (phase 1a) were randomized to 1 dose of AMG 145: 7, 21, 70, 210, or 420 mg SC; 21 or 420 mg IV; or matching placebo. Hypercholesterolemic adults (phase 1b) receiving low- to moderate-dose statins were randomized to multiple SC doses of AMG 145: 14 or 35 mg once weekly (QW) ×6, 140 or 280 mg every 2 weeks (Q2W) ×3, 420 mg every 4 weeks ×2, or matching placebo. Eleven subjects receiving high-dose statins and 6 subjects with heterozygous familial hypercholesterolemia were randomized to SC AMG 145 140 mg or placebo Q2W ×3. In the trials (AMG 145 n = 85, placebo n = 28), AMG 145 reduced LDL-C up to 64% (p < 0.0001) versus placebo after 1 dose ≥21 mg and up to 81% (p < 0.001) with repeated doses ≥35 mg QW. No serious adverse events (AEs) occurred. Overall incidence of treatment-emergent AEs was similar in AMG 145 versus placebo groups: 69% versus 71% (phase 1a); 65% versus 64% (phase 1b). In phase 1 studies, AMG 145 significantly reduced serum LDL-C in healthy and hypercholesterolemic statin-treated subjects, including those with heterozygous familial hypercholesterolemia or taking the highest doses of atorvastatin or rosuvastatin, with an overall AE profile similar to placebo.

Effects of Statins on Energy and Fatigue With Exertion: Results From a Randomized Controlled Trial

No drug is without adverse effect potential, and fatigue and exertional intolerance are adverse effects reported by patients receiving statins.1,2 Little direct information is available regarding the typical or average impact of statins on energy or exertional fatigue. Although many observational reports have cited fatigue and exertional fatigue with statin use, to our knowledge, no randomized trials have addressed this issue to date. Energy and exertional fatigue were measured as tertiary and/or exploratory outcomes in the University of California, San Diego (UCSD) Statin Study, which aimed to examine a range of noncardiac outcomes.3 We capitalized on these data to evaluate whether moderate-dose statins affected energy and exertional fatigue in a broadly sampled primary prevention population.

Balancing the cardiometabolic benefits and risks of statins

Although the cardiovascular benefits of statins are unquestionable, concern has been raised about the potential diabetogenic effect of these drugs. 1 Rajpathak SN Kumbhani DJ Crandall J Barzilai N Alderman M Ridker PM Statin therapy and risk of developing type 2 diabetes: a meta-analysis. Diabetes Care. 2009; 32: 1924-1929 Crossref PubMed Scopus (346) Google Scholar , 2 Preiss D Seshasai SR Welsh P et al. Risk of incident diabetes with intensive-dose compared with moderate-dose statin therapy: a meta-analysis. JAMA. 2011; 305: 2556-2564 Crossref PubMed Scopus (1078) Google Scholar This risk is most pertinent to the prescription of statins for people at low risk of cardiovascular disease—so-called primary prevention. In this setting, the absolute cardiovascular benefits of statins are less than in individuals at higher risk of cardiovascular disease and might be offset by drug side-effects, particularly new-onset diabetes. Cardiovascular benefits and diabetes risks of statin therapy in primary prevention: an analysis from the JUPITER trialIn the JUPITER primary prevention trial, the cardiovascular and mortality benefits of statin therapy exceed the diabetes hazard, including in participants at high risk of developing diabetes. Full-Text PDF The effects of lowering LDL cholesterol with statin therapy in people at low risk of vascular disease: meta-analysis of individual data from 27 randomised trialsIn individuals with 5-year risk of major vascular events lower than 10%, each 1 mmol/L reduction in LDL cholesterol produced an absolute reduction in major vascular events of about 11 per 1000 over 5 years. This benefit greatly exceeds any known hazards of statin therapy. Under present guidelines, such individuals would not typically be regarded as suitable for LDL-lowering statin therapy. The present report suggests, therefore, that these guidelines might need to be reconsidered. Full-Text PDF Open Access