James M. Backes

Effectiveness and Tolerability of Every-other-Day Rosuvastatin Dosing in Patients with Prior Statin Intolerance

Background: Statins are generally well tolerated, but some patients discontinue therapy secondary to adverse effects. Dosing a statin (rosuvastatin) every other day (EOD) may provide significant lipoprotein changes while avoiding common adverse effects in this statin-intolerant population. Objective: To determine the effect and tolerance of EOD rosuvastatin in patients previously intolerant to statin therapy. Methods: We performed a retrospective analysis of patients treated with EOD rosuvastatin at 2 lipid specialty clinics: the University of Kansas Lipid, Atherosclerosis, and LDL-Apheresis Center and the Hartford Hospital Cholesterol Management Center. Approximately 2600 charts were reviewed to identify patients receiving rosuvastatin EOD who previously had experienced statin intolerance. Fifty-one patients were eligible for the analysis, which evaluated changes in the lipid profile, the number achieving their low-density lipoprotein cholesterol (LDL-C) goals, and the percent tolerating rosuvastatin EOD. Laboratory data were assessed immediately prior to rosuvastatin EOD therapy and at the first follow-up. Results: Myalgias (76.5%) and increased transaminase levels (19.5%) were the most common causes of prior statin intolerance, but 72.5% (37/51) of patients were able to tolerate the EOD therapy (mean dose 5.6 mg) regimen for 4 ± 2.9 (mean ± SD) months. Mean LDL-C decreased 34.5% (p < 0.001) in the patients who tolerated the regimen, enabling approximately 50% to achieve their LDL-C goal. All patients who were considered to be intolerant to rosuvastatin EOD therapy (27.5%; 14/51) reexperienced the symptoms of their prior statin intolerance. Conclusions: Treating patients intolerant to statins with rosuvastatin EOD was tolerated by the majority of patients and reduced LDL-C in our study. This dosing strategy may be useful in patients intolerant to once-daily statin dosing, although such an approach has not been documented to reduce cardiovascular events.

Role of C-Reactive Protein in Cardiovascular Disease

OBJECTIVE: To discuss the role of C-reactive protein (CRP) in cardiovascular disease as a predictor of vascular events and identify key factors that increase or decrease this inflammatory marker. DATA SOURCES: Articles were identified through searches of MEDLINE (1966–July 2003), International Pharmaceutical Abstracts (1970–June 2003), and bibliographies of selected articles. Search terms included C-reactive protein, HMG-CoA reductase inhibitors, fenofibrate, niacin, aspirin, estrogen, thiazolidinediones, and raloxifene. DATA SELECTION AND DATA EXTRACTION: All studies relevant to CRP and cardiovascular disease or the effects of pharmacologic and nonpharmacologic interventions on CRP levels were evaluated. All information deemed relevant to this review was included. DATA SYNTHESIS: Numerous studies have shown a strong association between CRP levels and future vascular events (i.e., coronary, cerebrovascular, peripheral vascular disease), with minimal correlation to low-density-lipoprotein cholesterol. Clinical guidelines have recently been published indicating that CRP levels of <1, 1–3, and >3 mg/L correspond to low, moderate, and high risk, respectively, for future vascular events. Drugs including statins, fibrates, niacin, thiazolidinediones, and antiplatelet agents, as well as weight loss and exercise, have demonstrated efficacy in lowering CRP levels. CONCLUSIONS: CRP appears to be a valuable tool for predicting future vascular events in patients striving for primary or secondary prevention of cardiovascular disease. While several pharmacologic and nonpharmacologic interventions have been shown to lower CRP levels, the impact on clinical outcomes requires further study.

Once-a-week rosuvastatin (2.5 to 20 mg) in patients with a previous statin intolerance.

The purpose of this study was to determine the efficacy of rosuvastatin dosed once a week in patients with a previous statin adverse event. Rosuvastatin once a week was tolerated by 37 (74%) of the 50 study participants, with doses ranging from 2.5 mg to 20 mg a week (mean 10 +/- 4 mg). Patients tolerating the once-a-week regimen experienced a 17% reduction in total cholesterol, 23% reduction in low-density lipoprotein cholesterol, 12% reduction in triglycerides, and a 5% increase in high-density lipoprotein cholesterol (all p <0.001), during a mean follow-up of 4 months +/- 2. Although this alternative dosing regimen has not been proven to reduce cardiovascular events, it may provide a therapeutic option for patients who may otherwise go without the proven benefits of statin therapy. In conclusion, this dosing strategy was well tolerated in patients with a history of an adverse event to 1 or more statins and led to significant lipoprotein changes.

Fibrates : What have we learned in the past 40 years?

The prominent use of fibric acid derivatives has lessened over the years because of unimpressive results in major clinical trials, safety concerns, and the emergence of 3‐hydroxy‐3‐methylglutaryl coenzyme A reductase inhibitors (statins). Clofibrate was widely used in the 1970s, but after publication of results from two major trials demonstrating only modest reductions in the rate of coronary heart disease (CHD) and concerns regarding an increase in the frequency of gallstones and overall mortality, its use subsided dramatically. With the introduction of gemfibrozil in the 1980s came a renewed interest in the class, which was also supported by the published results of the Helsinki Heart Study; however, despite a significant reduction in CHD events and a sound safety profile, overall mortality was comparable to that with placebo. Again, in the 1990s, awareness of the fibrates was heightened with the availability of fenofibrate and the findings of another major trial using gemfibrozil, the Veterans Affairs High‐Density Lipoprotein Cholesterol Intervention Trial (VA‐HIT), which demonstrated impressive results in reducing cardiovascular events. To further strengthen the VA‐HIT results, numerous post hoc analyses were performed on the data of major trials of fibrate therapy among patients with mixed dyslipidemia, with similar findings. Recently, however, data from the Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) study were published, indicating mixed results. Nearly 40 years after the introduction of the fibrates, practitioners are still contemplating the role of these agents in the treatment of CHD.

Quality of diabetes care for adults with developmental disabilities

BACKGROUND Given that individuals with developmental disabilities have a history of difficulty accessing appropriate health care, possess numerous risk factors for diabetes, and frequently have unique needs within the health care setting, it is important to conduct surveillance research to determine the quality of their diabetes care. OBJECTIVE/HYPOTHESIS We assessed the quality of diabetes care for adults with developmental disabilities enrolled in Kansas Medicaid. Developmental disability was defined in accordance with Kansas Medicaid program eligibility and included individuals with intellectual disability, cerebral palsy, autism, and/or seizure disorder. METHODS We identified a retrospective cohort of persons with developmental disabilities who were also diabetic and continuously enrolled in Kansas Medicaid. We tracked their quality of care measures (Hb(A1c)/glucose testing, cholesterol testing, eye examinations, microalbuminaria screening, and primary care visits) across the subsequent 12 months. Quality care measures were evaluated in relation to basic demographic variables and comorbid hypertension using unconditional logistic regression. RESULTS Among 5,960 adults with developmental disability, 666 had diabetes (11.2%). Annual testing rates were Hb(A1c)/glucose testing, 51.7%; cholesterol, 44.3%; eye examinations, 29.3%; and microalbuminaria, 18.5%. Nearly all (93.5%) had contact with a primary care provider during the period. Comorbid hypertension was associated with higher rates of Hb(A1c), cholesterol testing, and primary care visits. Dual eligibility was associated with lower Hb(A1c)/glucose testing and cholesterol testing rates but comparable rates for other measures. Caucasians were more likely to have had an eye examination but less likely to have had their microalbumin checked. CONCLUSIONS Adults with developmental disabilities and diabetes who were enrolled in the Kansas Medicaid Program were screened at lower frequency than published national figures for key quality indicators of diabetes care. These results call for action to find approaches to improve their quality of care. Further work is needed to understand the barriers to appropriate care and incentives that will remedy these gaps. In addition, research is needed to determine the accuracy of diabetes identification, treatment, and monitoring of adults with developmental disabilities.

Does Simvastatin Cause More Myotoxicity Compared with Other Statins

Objective: To review the literature regarding statins and myotoxicity and evaluate these data to determine whether incidence rates are higher with simvastatin. Data Sources: Literature was identified from a search of MEDLINE (1966–August 2009) and International Pharmaceutical Abstracts (1970–August 2009), as well as references of selected articles. Key search terms included the names of individual statins, rhabdomyolysis, myopathy, myalgia, myotoxicity, statins, and drug interactions. Study Selection and Data Extraction: All English-language articles discussing statin-related myotoxicity and relevant drug interactions that involved human subjects were examined. Data Synthesis: Simvastatin is a commonly prescribed, moderately potent statin. Recent evidence suggests that the risk of severe muscle toxicity with simvastatin may be higher than that with other statins, particularly when used in combination with cytochrome P450 isoenzyme inhibitors. However, the lack of direct comparative clinical trials assessing the risk of myotoxicity among the statins in equivalent doses precludes definitive conclusions. Data sources examining low-to-mode rate doses of simvastatin suggest that myotoxicity with this agent is infrequent, with rates similar to those seen with other statins. Conversely, findings from clinical trials using the maximum daily dose (80 mg) and a clinical trials database of varying doses of simvastatin suggest a possible increase in rates of myotoxicity with the 80-mg dose compared with lower doses and a higher incidence rate when compared with maximum doses of other statins. Conclusions: Overall, the rates of severe myotoxicity with all statins are low, especially with low-to-moderate doses. However, recent trials for those using simvastatin 80 mg daily suggest a higher incidence of myotoxicity compared with maximum approved doses of other statins. Practitioners should be aware of these possible risks and individualize therapy to limit myotoxicity.

Comparison of gemfibrozil and Fenofibrate in patients with dyslipidemic coronary heart disease

Study Objective. To compare the lipid‐lowering effects of gemfibrozil and fenofibrate in patients with dyslipidemic coronary heart disease.

Effect of Lipid-Lowering Drug Therapy on Small-Dense Low-Density Lipoprotein

OBJECTIVE: To review the effects of lipid-lowering therapy on small-dense low-density lipoprotein cholesterol (sdLDL-C). DATA SOURCES: Literature was obtained from MEDLINE (1989–September 2004) and references of selected articles. Key search terms included small-dense LDL-C and lipid-lowering drug therapy. DATA SYNTHESIS: Statins, fibrates, and niacin have demonstrated favorable effects on sdLDL-C, especially among patients with mixed dyslipidemia or hypertriglyceridemia. These effects include a reduction of sdLDL-C and/or a shift to the larger, less atherogenic LDL-C. CONCLUSIONS: Data suggest that statins, fibrates, and niacin are effective at reducing concentrations of sdLDL-C and possibly normalizing LDL-C subclasses.

Effect of low-density lipoprotein apheresis on plasma levels of apolipoprotein e4.

Apolipoprotein E4 (apoE4) is a positively charged proinflammatory apolipoprotein bound to high-density lipoprotein (HDL) cholesterol and remnant lipoproteins. ApoE4 is associated with an increased risk of cardiovascular and cerebrovascular disease. Low-density lipoprotein (LDL) apheresis, a therapy for patients with familial hypercholesterolemia, removes apolipoprotein B and other positively charged plasma proteins but negatively charged proteins such as HDL cholesterol are generally spared. Despite their negative charge, LDL apheresis still removes 10% to 15% of HDL cholesterol, in particular, inflammatory HDL cholesterol. Patients with familial hypercholesterolemia have increased plasma levels of apoE4 and apoE4-bound HDL cholesterol. We tested the hypothesis that LDL apheresis would reduce the plasma levels of apoE4. We analyzed the plasma apoE4 levels using enzyme-linked immunosorbent assay immediately before and after LDL apheresis in 10 patients with familial hypercholesterolemia who had tested positive for the apoE4 isoform. After one treatment, the mean plasma apoE4 levels had been reduced by 39%, LDL cholesterol by 75%, triglycerides by 38%, and HDL cholesterol by 18%. The change in HDL cholesterol was significantly related to the apoE4 baseline values (r = -0.83, p = 0.001) and apoE4 levels after apheresis (r = 0.816, p = 0.004). In conclusion, LDL apheresis acutely reduced the plasma levels of apoE4. The mechanism of apoE4 reduction by LDL apheresis might be related to the selective reduction of a particular HDL cholesterol.

Important considerations for treatment with dietary supplement versus prescription niacin products.

Abstract Niacin is a water-soluble B vitamin (B3) known to have favorable effects on multiple lipid parameters, including raising high-density lipoprotein cholesterol (HDL-C) levels and lowering triglycerides (TGs), lipoprotein(a), and low-density lipoprotein cholesterol (LDL-C). Although LDL-C remains the primary target of lipid-altering therapy, current guidelines emphasize HDL-C and other modifiable lipid factors as key secondary targets. Thus, niacin is considered an important therapeutic option to help reduce the risk of cardiovascular disease in patients with mixed dyslipidemia who, in addition to high LDL-C, have elevated TGs and low HDL-C. Although available prescription niacin products, including immediate-release niacin (IR; Niacor) and an extended-release niacin formulation (Niaspan), have demonstrated safety and efficacy in randomized clinical trials, confusion remains among health care providers and their patients regarding the various commercially available nonprescription dietary supplement niacin products. These dietary supplements, which include IR, sustained-release (SR), and “no-flush” or “flush-free” niacin products, are not subject to the same stringent US Food and Drug Administration regulations as prescription drugs. In fact, both the American Heart Association and the American Pharmacists Association recommend against the use of dietary supplement niacin as a substitute for prescription niacin. Although some dietary supplement IR and SR niacin products have demonstrated a lipid response in clinical trials, products labeled as “no-flush” or “flush-free” that are intended to avoid the common niacin-associated adverse effect of flushing generally contain minimal or no free, pharmacologically active niacin and therefore lack beneficial lipid-modifying effects. To clarify important differences between available prescription and dietary supplement niacin products, this article contrasts current regulatory standards for dietary supplements and prescription drugs and provides an overview of available clinical data from key trials of niacin.