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NIACIN IS "A FIRST CHOICE DRUG" FOR PREVENTION OF CORONARY HEART DISEASE , NIH PANEL SAYS; OBSERVATIONS LINK ORAL ESTROGEN FOR WOMEN TO 50% CHD REDUCTION

Executive Summary

Niacin is "a first choice drug" for prevention of coronary heart disease (CHD) "because of its low cost and efficacy in altering multiple lipid fractions," according to the concluding statement of a Feb. 26-28 National Institutes of Health Consensus Development Conference on Triglyceride, High Density Lipoprotein and Coronary Heart Disease. Noting that "nicotinic acid decreases triglycerides in proportion to their elevations and is very effective in increasing low HDL," the consensus panel mentioned the vitamin therapy first in its discussion of general drug therapies. In combination use, "diet, bile acid sequestrants and niacin reduced the progression of atherosclerosis and the appearance of new lesions in patients with and without coronary bypass grafts." The consensus statement notes, however, that niacin is contraindicated for use "in non- insulin dependent diabetes." Oral estrogen for women is the first drug therapy discussed in the consensus statement. "From extensive observational studies in postmenopausal women," the consensus statement notes, estrogen treatment appears "to reduce CHD by approximately 50%." On the general topic of treatment of triglyceride and/or HDL levels, the panel found "considerable support for a causal relationship" between HDL and CHD through the data for triglyceride "are mixed." Despite insufficient data from clinical trials concerning the "specific benefits of perturbing triglyceride and/or HDL levels," the consensus statement holds that "lipid-lowering therapy is an effective strategy in CHD prevention." "The primary therapy for the treatment of elevated triglyceride and low HDL cholesterol levels is diet and weight control, exercise and smoking cessation," the NIH group asserts. The statement emphasizes that "hygienic measures always should be used first," delegating drug therapy to a "secondary role." The statement recommends that drug use be "restricted to patients considered at high risk" due to adverse lipid profiles, as well as "multiple other risk factors" including family history for CHD, diabetes mellitus, hypertension, cigarette smoking, male gender and obesity. Drug therapy also is suggested following the failure of hygienic measures for the treatment of hypertriglyceridemia to "reduce the risk of pancreatitis." The panel revised the original statement to include a general comment concerning the "side effects and potential risks" associated with "all medications." These risks "must be balanced with potential for benefit before their use can be justified," the statement says. The risk/benefit caution was added to the consensus statement after a short discussion concerning the fibric acid derivative, gemfibrozil (Lopid). The Warner-Lambert lipid- lowering drug precipated the most discussion of drug therapy throughout the conference. The debate was sparked by a review of the Helsinki Heart Study and the relevance of follow-up data from Helsinki II. In unscheduled remarks to the consensus panel, FDA medical officer Ross Pierce, MD, raised the issue of the unpublished secondary study, Helsinki II. He maintained that data from the second study indicated that the outcome of gemfibrozil treatment pointed to "adverse trends in total mortality." Ross noted that the significance of the follow-up Helsinki data had been addressed last year by FDA during the March 7 Endicrinologic and Metabolic Drugs Advisory Committee ("The Pink Sheet," March 11, 1991, p. 6). Pierce's comments followed a prepared presentation to the conference on the Helsinki Heart Report by Jussi Huttunen, MD, National Public Health Institute, Helsinki. Reporting on the main part of the trial (Helsinki I), Huttunen maintained that "averaged over the five-year trial, the gemfibrozil group showed a statistically significant...reduction of 3% in the incidence of definite coronary heart disease events." He added that "the increase in HDL cholesterol and the decrease in LDL [low density lipoprotein] cholesterol during treatment were both associated with a low risk of coronary events in the gemfibrozil group." In a written letter to the panel, Pierce reported that the divergence between the results of Helsinki I and Helsinki II led the Division of Metabolism & Endocrine Drug Products to question if gemfibrozil "is not effective for CHD event reduction in patients with established CHD or the true efficacy of gemfibrozil is much less than" is suggested "by the primary Helsinki Study." The FDAer's letter also links gemfibrozil to increased gallbladder toxicity and appendectomies and notes issues with the whole class of fibrate class of drugs. The letter states the "the hepatotoxicity of certain fibrates, such as fenofibrate, may preclude their consideration for use in CHD risk reduction." Lopid's labeling indicates a 1.2% frequency of acute appendicitis among the Lopid group as compared to .6% in the placebo group. Also, gallbladder surgery was performed in .9% of Lopid and .5% of placebo subjects, "a 64% excess, which is not statistically different from the excess of gallbladder surgery observed in the clofibrate compared to the placebo group of the World Health Organization Study." Huttunen responded that the Helsinki II results were "not statistically significant." Huttunen commented that Helsinki II was performed "to improve PR" and was "not a very good study." The patient population consisted of individuals who had been excluded from the original study. Claiming that there is "no mechanism to explain" the negative impact of gemfibrozil on cardiovascular mortality in the Helsinki II data, Huttunen concluded that the outcome of the test was most likely "a chance finding." The questions raised by Pierce at the NIH conference indicate a level of continuing concern within the FDA review division about gemfibrozil's appropriate role in lipid treatment. The product has been before advisory committees twice in the last four years and faced tough relabeling discussions. By coincidence, FDA's concerns with gemfibrozil treatment were further discussed in a Feb. 27 statement from Warner-Lambert that FDA is scrutinizing its application for the Lopid follow-up compound, Lopid SR. The company said that FDA has requested that the company "respond to a number of points" regarding the NDA and says that it is "responding quickly to these points." The company notes, however, that the request for further information makes it questionable whether W-L will be able to obtain a "timely approval" for the sustained-release product. W-L is in a race to get the new patent-protected form of the drug on the market before Lopid's exclusivity expires next January. The company issued the statement on the FDA review following a report about the FDA letter in the Feb. 27 San Francisco Chronicle. Despite the debate at the NIH conference, the consensus statement specifically recognizes gemfibrozil as a drug that "has been associated with reduced risk of CHD in patients with mixed hyperlipidemia and low HDL." On the final day of the NIH meeting, during the final preparation of the consensus statement, one of the scheduled speakers from the previous days, Stephen Hully, MD/MPH, University of California at San Francisco, requested that the consensus statement be changed to address the question of "cost- effectiveness and toxicity, especially with fibric acids." Panel Chairman Elliot Rapaport, MD, UCSF, answered that issues of cost- effectiveness were "beyond the scope" of the consensus. Hully then contended that to "not even mention the increased mortality... is a mistake." Another speaker at the conference, William Castelli, MD, director, Framingham Heart Study, countered: "There is no increased mortality." Following the exchange between Hully and Castelli, Rapaport read a letter sent to the panel by the Chairman of FDA's Endocrinologic & Metabolic Drugs Advisory Committee, Douglas Green, MD. The letter stated that the March 7 advisory committee last year decided that Helsinki II was "scientifically flawed." The committee concluded that Helsinki II "should not be interpreted to indicate" that gemfibrozil may increase primary cardiac events or that the results of Helsinki I were invalid. "The available data," Green wrote, "still indicate that benefits outweigh risks for gemfibrozil in patients with the triad of increased LDL cholesterol, low HDL cholesterol and elevated triglycerides." Other lipid-lowering drug therapies included in the statement are bile acid sequestrants, such as cholestyramine, and HMG-CoA reductase inhibitors such as Merck's lovastatin (Mevacor) or Bristol-Myers Squibb's pravastatin (Pravachol). Omega-3 fatty acids at high doses were shown to lower triglycerides.
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