Janelle F. Ruisinger

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.

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.

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.

Apple pectin for the reduction of niacin-induced flushing

BACKGROUND Niacin, or vitamin B3, when used in high doses can significantly improve the levels of all major lipoproteins. Despite these benefits, the use of niacin is greatly limited secondary to benign yet bothersome cutaneous flushing primarily involving the face and upper extremities. Pretreatment with aspirin or other prostaglandin inhibitors has demonstrated significant reductions in niacin-induced flushing (NIF), but other treatment options are needed. Clinical and anecdotal evidence suggests the ingestion of pectin-containing fruits (eg, apple) mitigates NIF; however, clinical trials evaluating this are nonexistent. OBJECTIVE That pretreatment with encapsulated apple pectin would limit the incidence, severity, time of initiation, and duration of NIF. METHODS We enrolled 100 niacin-naïve subjects (n = 25 per group) and preteated them in a double-blind manner with apple pectin, apple pectin + aspirin, aspirin, or placebo, followed by a one-time 1000 mg dose of niacin extended-release (niacin ER). Subjects then assessed major flushing parameters hourly for the next 6 hours with a validated visual analog scale. RESULTS Apple pectin and aspirin each significantly lowered the duration of NIF and produced nonsignificant but positive improvements in all other major flushing parameters compared with placebo. CONCLUSION Apple pectin may potentially be an alternative to aspirin for the prevention of NIF. Larger trials are needed to further evaluate the benefit of pectin on NIF.

Statin-associated muscle symptoms—Managing the highly intolerant

Musculoskeletal symptoms are the most commonly reported adverse effects associated with statin therapy. Yet, certain data indicate that these symptoms often present in populations with underlying musculoskeletal complaints and are not likely statin related. Switching statins or using lower doses resolves muscle complaints in most patients. However, there is a growing population of individuals who experience intolerable musculoskeletal symptoms with multiple statins, regardless of the individual agent or prescribed dose. Recent randomized, placebo-controlled trials enrolling highly intolerant subjects provide significant insight regarding statin-associated muscle symptoms (SAMS). Notable findings include the inconsistency with reproducing muscle complaints, as approximately 40% of subjects report SAMS when taking a statin but not while receiving placebo, but a substantial cohort reports intolerable muscle symptoms with placebo but none when on a statin. These data validate SAMS for those likely experiencing true intolerance, but for others, suggest a psychosomatic component or misattribution of the source of pain and highlights the importance of differentiating from the musculoskeletal symptoms caused by concomitant factors. Managing the highly intolerant requires candid patient counseling, shared decision-making, eliminating contributing factors, careful clinical assessment and the use of a myalgia index score, and isolating potential muscle-related adverse events by gradually reintroducing drug therapy with the utilization of intermittent dosing of lipid-altering agents. We provide a review of recent data and therapeutic guidance involving a focused step-by-step approach for managing SAMS among the highly intolerant. Such strategies usually allow for clinically meaningful reductions in low-density lipoprotein cholesterol and an overall lowering of cardiovascular risk.

Patient Satisfaction With Pharmacist-Led Chronic Disease State Management Programs:

Purpose: To assess patient satisfaction, perception of self-management, and perception of disease state knowledge with pharmacist-led diabetes and cardiovascular disease state management (DSM) programs. Methods: A self-insured chain of grocery store pharmacies in the Kansas City metropolitan area administers pharmacist-led diabetes and cardiovascular DSM programs for eligible employees and dependents. A modified version of the Diabetes Disease State Management Questionnaire was used to assess patient satisfaction with the DSM programs. Demographic information was also collected. Survey items were based on a 5-point Likert scale (1 = strongly disagree and 5 = strongly agree). Patients were eligible to complete the survey if he or she had been in at least 1 DSM program for 6 months. Data were assessed using descriptive statistics and analysis of variance. Results: Across 20 pharmacies, 281 eligible participants were identified, and 46% (n = 128) completed a survey. Means for summed items relating to overall satisfaction (8 items), self-management (5 items), and knowledge (4 items) were 36.6/40 (standard deviation [SD] = 3.9), 20.9/25 (SD = 3.4), and 17.6/20 (SD = 2.1), respectively. Participant comments further indicated that the program and pharmacists are helpful and increase motivation and accountability. Conclusions: Positive patient responses to the program support use of pharmacist-led DSM programs.

Impact of a community-based diabetes self-management program on key metabolic parameters

Objective: Characterize the impact of a pharmacist-led diabetes self-management program on three key metabolic parameters: glycosylated hemoglobin (HbA1c), low-density lipoprotein cholesterol (LDL-C), and mean arterial blood pressure (MAP) among employee health program participants. Methods: A self-insured company in the Kansas City metropolitan area began offering a pharmacist-led diabetes self-management program to eligible company employees and their dependents in 2008. A retrospective pre-post analysis was conducted to determine if the program affected key metabolic parameters in participants by determining mean change after one year of participation. Results: Among 183 program participants, 65 participants met inclusion criteria. All three key metabolic parameters were significantly reduced from baseline to one year of program participation: HbA1c decreased from 8.1 % to 7.3% (p=0.007); LDL-C decreased from 108.3 mg/dL to 96.4 mg/dL (p=0.009); and MAP decreased from 96.1 to 92.3 mm Hg (p=0.005). Conclusions: The pharmacist-led diabetes self-management program demonstrated significant reductions in HbA1c, LDL-C, and MAP from baseline to one year of program participation. Improvements were statistically significant and clinically relevant for each parameter. Previous studies indicate these reductions may cause reduced overall healthcare costs.

Statin intolerance and vitamin D supplementation: Sunny, but a few clouds remain...

Dear Editor, We read with interest the article by Khayznikov et al., regarding the resolution of statin intolerance with vitamin D repletion.[1] We too have tried this strategy among a similarly statin intolerant population (median – three previous statins) and believe vitamin D supplementation plays a role in treating certain individuals. Our results demonstrated that vitamin D repletion to >30 ng/ml, allowed 53% (18/34) of the intolerant patients to utilize some form of alternative or daily statin dosing or a higher dose among those receiving a statin but experiencing tolerable symptoms, for at least four months (mean follow up 8.5 + 4.4 months). Our findings are encouraging but well below the 88-95% statin tolerability rates reported in the present study. Directly comparing study populations and results is not feasible; however, one potential explanation for response differences may be the vitamin D level achieved. For instance, the vitamin D levels among those tolerating the statin rechallenge in our group was 44 ng/ml compared to 53-55 ng/ml in the current report, suggesting that perhaps our vitamin D repletion was incomplete, despite each group falling within the range suggested by the Endocrine Society.[2] Another factor that we believe played a prominent role in the resolution of myalgic symptoms in the current study was the predominant utilization of rosuvastatin. The authors recognize that rosuvastatin is less frequently associated with myotoxicity; however, this should not be minimized. In fact, the same research center performed a similar study, and determined that the vast majority of previously statin intolerant subjects reported no adverse effects when rechallenged with rosuvastatin 5-10 mg daily.[3] Lastly, we agree with the authors that an optimal study evaluating statin intolerance would be blinded and placebo-controlled, given the subjective nature of most myotoxicity. In fact, this design was recently utilized to assess various lipid-altering agents, including the investigational proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors, among subjects unable to tolerate two or more different statins because of unexplained muscle-related symptoms.[4] After successful completion of a four-week single-blind placebo run-in period, subjects were randomized in a double-blind manner to a PCSK9 injection Q two weeks + oral placebo daily, ezetimibe 10 mg daily + placebo injection Q two weeks, or atorvastatin 20 mg daily + placebo injection Q two weeks, for 24 weeks. Such a study design provided novel, insightful, and revealing findings with regard to statin intolerance. For example, the trial demonstrated that 6.9% of subjects were excluded from randomization due to muscle-related adverse events during the placebo run-in period. Further, 75% of the previously intolerant patients tolerated the atorvastatin 20 mg daily for the duration of the 24-week study period. Such results strongly highlight the subjectivity of statin intolerance and the major influence of a placebo effect in many patients. Statin intolerance, especially among patients with previous sensitivity to multiple agents, is a complex and poorly understood issue that remains a clinical challenge. In the present study, vitamin D repletion likely improved muscle function and resolved symptoms in some patients. However, the vitamin D supplementation may have also provided a placebo effect, while the utilization of rosuvastatin further enhanced response. Financial support and sponsorship Nil. Conflicts of interest There are no conflicts of interest.

Variability in Potency Among Commercial Preparations of Berberine

ABSTRACT Berberine is an isoquinoline alkaloid plant extract that is widely available as a dietary supplement in the United States and has demonstrated efficacy in the treatment of type 2 diabetes mellitus and dyslipidemia. Because of its increased use and purported pharmacological properties, potential variations in product quality could pose a barrier to berberines safety and effectiveness in clinical practice. Thus, this study evaluated the potency of dietary supplements containing berberine available in the U.S. commercial market. Fifteen unique dietary supplements containing berberine were purchased through U.S. dietary supplement vendors. For each product, berberine was extracted from 3 unique capsules and analyzed by ultra-high-performance liquid chromatography tandem mass spectrometry. Percentage content based on the product label claim was determined for each product. The average berberine content across the products was found to be 75% ± 25% of the product label claim, with product potency ranging from 33% to 100%. Nine of the 15 tested products (60%) failed to meet the potency standards of 90% to 110% of labeled content claim, as commonly required of pharmaceutical preparations by the U.S. Pharmacopeial Convention. Evaluation of the relationship between product cost and the measured potency failed to demonstrate an association between quality and cost. Variability in product quality may significantly contribute to inconsistencies in the safety and effectiveness of berberine. In addition, the quality of the berberine product cannot be inferred from its cost.