Drug Topics - November 5, 2007 - (Page 33)

33 2. Mature HDL-C can interact with SR-B1 receptors found on arterial macrophages to cause an efflux of free cholesterol. 3. Mature HDL-C can accept more free cholesterol into its structure through interaction with ATP-binding cassette transporter G1 (ABCG1) found on arterial macrophages. Despite these plausible benefits of CETP inhibition, a recent trial, ILLUMINATE, which was testing the effects of torcetrapib (a CETP inhibitor) in combination with atorvastatin (Lipitor), was stopped early as a result of preliminary reports indicating increased cardiovascular events and all-cause mortality. The failure is thought to be attributed to torcetrapib-induced hypertension. Other CETP inhibitors are currently under investigation. There is limited clinical literature regarding these agents. Preliminary data from one drug company suggest that a CETP inhibitor being investigated by them has not been associated with adverse cardiovascular changes or increases in blood pressure when given as monotherapy or in combination with statins. At this time, it remains to be seen whether this mode of HDL-C elevation will prove more effective at reducing poor cardiovascular outcomes than standard therapy. PPAR agonists. The family of peroxisome proliferatoractivated receptors contains many subtypes. Increased interest in this class of agents is a result of other PPAR agonists such as fibric acid derivatives’ and thiazolidinediones’ abilities to increase levels of HDL-C. The goal is to develop a new PPAR agent that can selectively increase HDL-C while avoiding the downfalls seen with others in this class, most notably the increased cardiovascular warnings associated with thiazolidinediones. These agents under investigation are still in early development but offer a potentially new and exciting treatment modality for the management of low HDL-C levels. ApoA-I therapies: There are many agents in the investigation pipeline that attempt to use, mimic, or enhance apoA-I. A promising investigation regarding this class conducted by Nissen et al. was released in JAMA in November 2003. Of the 57 subjects entering the study, 47 completed the trial, 11 received placebo, 21 received low-dose therapy, and 15 received highdose therapy. The agent under investigation was a combination of recombinant apoA-I Milano/phospholipid complex. The combination is designed to serve as recombinant HDL, or socalled rHDL. This study did not measure HDL-C levels or any HDL-C subtypes. Instead, the investigators measured the change in percent of coronary atheroma volume using intravascular ultrasound (IVUS). The drug was given via intravascular infusions once weekly for a total of five infusions. The active groups had a combined median reduction of atheroma volume by 0.81% (95% CI -1.53%, -0.34%, p = 0.2), while the placebo group experienced a median increase of 0.3% (95% CI -1.11%, 1.43%, p = 0.97). Whether or not this percentage of atheroma reduction will prove clinically significant remains to be seen. The investigators concluded that larger clinical trials measuring safety, morbidity, and mortality are warranted. Novel nicotinic acid formulations: A newer combination agent containing extended-release niacin and laropiprant could soon hit the pharmacy shelves. Laropiprant is a potent antagonist of the prostaglandin D2 receptor 1. Blockade of this prostaglandin receptor is theorized to greatly reduce the common side effect of flushing that is experienced by patients using niacin products. Data from an unpublished phase III clinical trial were recently announced. This trial compared placebo, ER niacin, and ER niacin/laropiprant in 1,613 patients with primary hypercholesterolemia or mixed dyslipidemia. The primary outcomes assessed were lipid efficacy and flushing profile for ER niacin/laropiprant, both as monotherapy and when combined with statin therapy. Therapy for ER niacin and ER niacin/laropiprant started at 1 gm for four weeks, then was increased to 2 gm for an additional 20 weeks. The lipid alterations were as expected and similar to the use of ER niacin. The common side effect of flushing was measured by the Global Flushing Severity Score (GFSS). Though not published, the announcement suggested that all of the efficacy of the comparative lipid parameters and flushing effects presented from this study were statistically significant (p<0.001). The reported incidence of flushing for ER niacin/laropiprant cohort was reduced. In the first week, 69% on the combination therapy versus 44% on the monotherapy had either no flushing symptoms or only mild flushing symptoms. While this may sound like an improvement, it still means that nearly 31% of patients receiving ER niacin/laropiprant scored more than “mild flushing symptoms” per the GFSS. At week 24, the frequency of moderate to severe flushing was 0.7 days/week versus 0.2 days/week for ER niacin and ER niacin/laropiprant, respectively. Put in a different perspective, this means that, on average, patients experienced one less episode of moderate to severe flushing every two weeks. The question remains, Is this decrease in frequency of moderate to severe flushing clinically significant? Another outcome measured was therapy. Twenty-two percent of patients receiving ER niacin experienced flushing that led to discontinuation, versus 10% with ER niacin/laropiprant. The publication of this trial is anticipated for further analysis of the results. Back to J.K. Concerns about a patient’s health often heighten following a traumatic health-related event, whether it occurs directly to them or a close, loved one. J.K.’s younger brother recently suffered an MI and now she feels the need to get her health conditions under control. She should be commended for taking this difficult step. Many components of her case will need to be addressed in order to reduce her risk for heart disease. However, gradually introducing these changes may increase compliance and the likelihood of achieving targeted goals. J.K. mentions that she recently began taking her medications consistently, and again, encouragement is warranted. Offering strategies such as pillboxes, stopwatches, and other refill reminders may be beneficial to help her continue with medication adherence and timely refills. When looking at her blood pressure, J.K. is not currently at her goal of <130/80 mmHg. Thus, increasing the dose of lisinopril may be warranted to avoid the addition of another medication that may be, yet, another pill burden for her. Her renal function and potassium were both within normal limits. The addition of a thiazide diuretic such as hydrochlorothiazide may also be considered based on current hypertension guidelines. Her fasting blood sugar is elevated and ideally should be between 90 and 130 mg/dl. It would be prudent to ensure that

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Drug Topics - November 5, 2007 Contents Latebreakers Latebreakers in Depth Letters Rx Care Community Practice 150 Years of American Pharmacy Hospital Practice Pharmacists at Risk Government and Law High-Density Lipoprotein New Products Advertisers Index Classified Viewpoint

Drug Topics - November 5, 2007

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