COMMENTARIES

The Safety of Statin-Niacin Combination Therapy

Alawi A. Alsheikh-Ali, M.D. and Richard H. Karas, M.D., Ph.D.,
Molecular Cardiology Research Institute and Division of Cardiology, Department of Medicine, Tufts-New
England Medical Center and Tufts University School of Medicine,
Boston,
Massachusetts, USA

Current national guidelines advocate aggressive lipid goals for the prevention of cardiovascular disease [1,2]. In addition to setting low-density lipoprotein cholesterol (LDL-C) as the primary target, they recognize high-density lipoprotein cholesterol (HDL-C) as an independent risk factor, and encourage the use of HDL-C raising therapies in high-risk patients [1,2]. Nonetheless, there remains gross under-treatment of HDL-C in high-risk patients. While several factors may contribute to the underutilization of HDL-C raising therapies in appropriate patients, concerns about the safety of combining a statin with niacin may be partly responsible. These concerns are reflected in current drug labeling as approved by the United States Food and Drug Administration (US FDA), which warns against an increased risk of adverse events with the combination of statin and niacin derivatives. However, the perception of an increased risk of adverse events with combination statin-niacin therapy compared to either agent alone is based on a small number of case reports and has not been systematically evaluated [3].

          In a recently published analysis, we examined the safety of statin-niacin combination therapy utilizing the US FDA adverse event reporting system [4]. This methodology takes advantage of a single systematic source of post-marketing adverse event reports covering the entire U.S. population, hence providing a large exposure base required to detect differences in relatively rare adverse events. Using a computerized search engine, we analyzed rates of reported adverse events filed with the US FDA from 1999 to March 2005 to identify any signals of a potential interaction between extended-release niacin and the commonly used statins: atorvastatin, simvastatin, pravastatin, and lovastatin. Of the available niacin formulations, we chose to focus on extended-release niacin since it is the most widely used prescription niacin formulation, and given its superior safety profile compared to other niacin preparations [5]. The following types of reported adverse events per million prescriptions were considered: serious adverse events, defined as fatal, considered life-threatening by the reporter, or resulted in hospitalization, hepatotoxicity, and rhabdomyolysis. In the primary analysis, we compared rates of reported adverse events associated with Advicor, a combination drug of extended-release niacin and lovastatin, to rates of adverse events associated with lovastatin or the statins alone, as well as to extended-release niacin alone. The rationale for this approach is that were there to be an increased risk of adverse events with the combination therapy, this would be reflected in a significantly higher rate of Advicor-associated adverse events compared to each agent alone (lovastatin alone or extended-release niacin alone). All rates were corrected for number of prescriptions dispensed over the time frame of the analysis. Prescription data for the drugs of interest were obtained from IMS-Healthô (Fairfield, Connecticut). In a secondary analysis, we calculated the prevalence of concomitant extended-release niacin therapy in statin-associated adverse events. To correct for multiple comparisons, a p < 0.01 was considered statistically significant.

          We observed that the rate of reported serious adverse events associated with the combination drug Advicor is similar to the rates associated with lovastatin, extended-release niacin, or pravastatin, alone (11 versus 8, 12 and 15 per million prescriptions, respectively, p = NS) and significantly less than the commonly used statins atorvastatin and simvastatin (20 and 23 per million prescriptions, respectively, p < 0.01). Likewise, the rates of reported hepatotoxicity or rhabdomyolysis associated with the combination drug Advicor were similar to those of monotherapy with the statins or extended-release niacin (except for a higher rate of simvastatin-associated reports of rhabdomyolysis compared to Advicor, 9 versus 3 per million prescriptions, respectively, p < 0.01). Additionally, concomitant use of extended-release niacin in statin-associated adverse events was rare (range 0-1 % of reports) for the various types of adverse events considered, and did not differ among the statins.

          Taken together, these findings do not support a clinically significant adverse drug interaction between extended-release niacin and commonly used statins. They demonstrate that the safety of statin-niacin combination is comparable to the safety of each of the drugs alone. There are several potential barriers to the optimal utilization of HDL-C raising therapies in high-risk patients. Such barriers may include physician lack of awareness, familiarity, or agreement with updated guidelines, patient-related barriers such as medical non-compliance, and other external barriers (e.g. medication intolerance, physician time limitations, or lack of insurance coverage). One additional barrier is the preception of an increased risk of adverse drug-drug interaction with combination statin-niacin therapy. This perception is evident in current FDA drug labeling which states: “Physicians contemplating combined therapy with HMG-CoA reductase inhibitors and NIASPAN ® should carefully weigh the potential benefits and risks and should carefully monitor patients for any signs and symptoms of muscle pain, tenderness, or weakness, particularly during the initial months of therapy and during any periods of upward dosage titration of either drug” [6]. Furthermore, while our understanding of the potential adverse interaction with statin-fibrate therapy is well described, our perception of the risk of adverse events with concomitant statin-niacin therapy is based solely on a small number of case reports. Nonetheless, it is often assumed that the potential for drug-drug interaction is similar for the two combinations. This assumption is also evident in current FDA drug labeling for simvastatin which reads: “The benefit of further alterations in lipid levels by the combined use of simvastatin with other fibrates or niacin should be carefully weighed against the potential risks of these combinations” [7]. The present findings do not support these assumptions and hence should encourage the safe use of this combination in appropriate high-risk patients, as recommended by national guidelines.

          The present analysis is relevant given the renewed focus on HDL-C in cardiovascular prevention. The emphasis on targeting HDL-C in high-risk patients is based on a large body of evidence linking low HDL-C to cardiovascular disease even in patients with “controlled” LDL-C levels, and the appreciation that a significant number of major adverse cardiac events are not prevented with statin monotherapy and intensive LDL-C lowering alone [8]. Given the independent contribution of these two lipoproteins to cardiovascular risk, the targeting of HDL-C in addition to LDL-C represents an added opportunity for further cardiovascular prevention. This is especially critical given the gross under-treatment of HDL-C in high-risk patients. In men presenting with premature coronary artery disease, 36% have low HDL-C (defined as less than 35 mg/dL) [9]. Interestingly, among those with premature coronary disease and apparently controlled total cholesterol (< 200 mg/dL), about three quarters of patients have low HDL-C [9]. Similarly, among high-risk women in a managed care setting, more than half have suboptimal HDL-C levels defined as < 50 mg/dL [10]. In addition, medications with a predominant effect on HDL-C and triglycerides, such as niacin or fibrate therapy, were prescribed to 11% of women with an HDL-C < 50 mg/dL and/or a non–HDL-C > 130 mg/dL [10]. More recently, in an ambulatory high-risk population with coronary disease risk equivalents, two thirds of patients had low HDL-C and less than 5% were on combination statin-niacin therapy [11]. Furthermore, the prevalence of low HDL-C appears to be independent of statin use and is seen in the vast majority of patients despite well-controlled LDL-C levels. In a recent analysis, we found that 79% of high-risk patients with well-controlled LDL-C levels had low HDL-C [12]. In the same population, there was a poor correlation between HDL-C and LDL-C levels with less than 1% of the variability in HDL-C explained by variability in LDL-C [12]. This poor correlation between the two markers was apparent in both genders and whether or not patients were treated with statins.

          In conclusion, the safety of statin-niacin combination is comparable to the safety of each of the drugs alone. Given the prevalence of low HDL-C in high-risk patients, and the independent nature of this risk factor, the present findings should encourage the use of statin-niacin combination in high-risk patients per current national guidelines.

References

1.    Grundy SM, Cleeman JI, Merz CN, et al. Implications of recent clinical trials for the National Cholesterol Education Program Adult Treatment Panel III guidelines. Circulation Jul 13 2004;110(2):227-39.
2.    Mosca L, Appel LJ, Benjamin EJ, et al. Evidence-based guidelines for cardiovascular disease prevention in women. Circulation Feb 10 2004;109(5):672-93.
3.    McKenney J. New perspectives on the use of niacin in the treatment of lipid disorders. Arch Intern Med Apr 12 2004;164(7):697-705.
4.    Alsheikh-Ali AA, Karas RH. Safety of lovastatin/extended release niacin compared with lovastatin alone, atorvastatin alone, pravastatin alone, and simvastatin alone (from the United States Food and Drug Administration adverse event reporting system). Am J Cardiol Feb 1 2007;99(3):379-81.
5.    Alsheikh-Ali A, Abourjaily HM, Karas RH. Relative safety of extended-release niacin versus other niacin formulations [Abstract 3754]. Circulation 2004;110(17):III-813.
6.    Niaspan [package insert], Kos Pharmaceuticals, Inc., Cranbury, NJ (2005).
7.    Zocor [package insert], Merck & Co, Whitehouse Station, NJ (2005).
8.    Alsheikh-Ali AA, Kuvin JT, Karas RH. High-density lipoprotein cholesterol in the cardiovascular equation: does the "good" still count? Atherosclerosis Jun 2005;180(2):217-23.
9.    Genest J, Jr., McNamara JR, Ordovas JM, et al. Lipoprotein cholesterol, apolipoprotein A-I and B and lipoprotein (a) abnormalities in men with premature coronary artery disease. J Am Coll Cardiol Mar 15 1992;19(4):792-802.
10.    Mosca L, Merz NB, Blumenthal RS, et al. Opportunity for intervention to achieve American Heart Association guidelines for optimal lipid levels in high-risk women in a managed care setting. Circulation Feb 1 2005;111(4):488-93.
11.    Alsheikh-Ali AA, Lin JL, Abourjaily P, et al. Extent to which accepted serum lipid goals are achieved in a contemporary general medical population with coronary heart disease risk equivalents. Am J Cardiol Nov 1 2006;98(9):1231-33.
12.    Alsheikh-Ali AA, Lin JL, Abourjaily P, et al. Prevalence of low high-density lipoprotein cholesterol in ambulatory patients with coronary heart disease (CHD) or CHD risk equivalents. J Am Coll Cardiol 2007;49(9):Supplement 389-A.