Combination therapy for global lipid improvement

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Harold E Bays
MD FACP
Medical Director/President
Louisville Metabolic and
Atherosclerosis Research Center
USA
E:[email protected]

Primary and secondary atherosclerotic coronary heart disease (CHD) prevention trials have demonstrated that monotherapy agents that lower low-density lipoprotein cholesterol (LDL-C) levels, such as statins, reduce the risk of CHD events by 20–40% relative to placebo.(1) If further CHD reduction is to occur with lipid-altering drugs, it will require more aggressive monotherapy with statin treatment, or the combined use of statins with other complementary lipid-altering drugs, yielding a more global improvement in lipid parameters.(2–7)

Statin monotherapy reduces LDL-C levels but is less effective in improving HDL-C and TG levels. Alternatively, niacin monotherapy predominantly improves HDL-C and TG levels (as well as other lipid parameters such as lipoprotein particle size and subclass distribution and lipoprotein (a),(5,8) but niacin is less effective in reducing LDL-C levels. Thus, statin plus niacin has become a mainstay in the treatment of patients with complex dyslipidaemias.(1) In 2001, Advicor(®) (niacin extended-release [ER]/lovastatin; Kos Pharmaceuticals) became the first FDA-approved lipid- altering combination product for the management of primary hypercholesterolaemia and mixed dyslipidaemias.(9)

Niacin
Niacin is available in three formulations: immediate-release (crystalline) (IR), sustained-release (SR), and intermediate or “extended-release” (ER).(10–12) Niacin ER (found in niacin ER/lovastatin) employs a unique hydrogel delivery system that provides a dissolution time of 8–12 hours, which is longer than that of the IR formulation but shorter than that of the SR formulation.(13) Niacin IR requires three-times-a-day dosing. Niacin ER (Niaspan) is approved for once-a-day administration. Another advantage of the ER preparation is improved tolerability and safety due to its metabolism – the intermediate-release rate compared with the other two formulations.(11,14,15)

Niacin inhibits the liver catabolism of apolipoprotein (apo) A-I, which is a major component of HDL particles, thus raising HDL-C levels.(16) With regard to triglycerides (TGs), niacin decreases secretion of very low-density lipoprotein (VLDL) and (subsequently) decreases circulating LDL particles.(17,18) Niacin administration may have additional potential benefits, such as increases in LDL particle size, increases in the larger, more cardioprotective HDL particles, as well as other potentially favourable effects upon lipoprotein particle size and subclass distribution.(5,8) Niacin has also been shown to have other possible antiatherosclerotic effects.(20) Perhaps most importantly, niacin administration as mono- or combination therapy has been shown to reduce CHD risk.(1,12,21–26) Adverse events and side-effects such as flushing, light-headedness, pruritis and increases in uric acid blood level have been described.(15)

Lovastatin
Lovastatin competitively inhibits HMG-CoA reductase, which catalyses the rate-limiting step in hepatic cholesterol biosynthesis.(9,13) Impaired intrahepatic cholesterol synthesis by lovastatin upregulates liver LDL receptor activity, resulting in enhanced clearance of LDL-C from the circulation. As with all statins, lovastatin may somewhat lower TG and modestly increase HDL-C levels.(27,28) Lovastatin may also enhance atherosclerotic plaque stability, decrease C-reactive peptide and fibrinogen levels and reduce endothelial dysfunction.(15,29) Lovastatin has been shown to reduce CHD events in both primary and secondary trials.(30–35) Adverse events and side-effects, such as myalgia, rhabdomyolysis and gastritis, have been described.(1)

Niacin ER/lovastatin

Efficacy
Advicor (niacin ER coated with lovastatin in a single pill) should be administered once a day at bedtime with a low-fat snack to minimise flushing. CHD outcome trials supported the CHD efficacy of a combination of niacin with statin. For example, the Familial Atherosclerosis Treatment Study (FATS) trial(34) demonstrated that combination therapy with colestipol/niacin, colestipol/lovastatin or conventional therapy not only improved lipid parameters but also resulted in a 73% reduction in clinical events relative to conventional therapy.(1,34) In addition, coronary artery stenosis regressed with colestipol/lovastatin and colestipol/niacin but progressed with conventional treatment.(1,34) The beneficial reduction in CHD events and death extended to a 10-year follow-up.(35) Similarly, the HDL-Atherosclerosis Treatment Study (HATS)(36) showed that niacin and simvastatin therapy resulted in a substantial improvement in various lipid parameters, accompanied by a reduction in mean percent coronary stenosis, compared with an increase in the placebo group. In patients who did not take antioxidants, clinical events were reduced by 90% relative to placebo.(1,36)

More recently, the one-year Arterial Biology for the Investigation of the Treatment Effects of Reducing Cholesterol (ARBITER)(2,37) study demonstrated that statin-treated patients with known CHD and low HDL-C levels (<45 mg/dl) who were administered niacin ER in addition to their statin had improvements in HDL-C and TG levels, and significantly less carotid intimal atherosclerotic progression as compared with statin plus placebo. Although the study was not powered to show differences in cardiovascular event endpoints, there was also a trend towards greater reduction in clinical cardiovascular events in the statin+niacin patients.

Although niacin ER has not yet been shown to result specifically in reductions in CHD events, the formulation has been shown to result in significant and widespread improvement in lipid parameters.(38,39) In the “head-to-head” comparative ADvicor Versus Other Cholesterol-modulating Agents Trial Evaluation (ADVOCATE) trial,(40) niacin ER/lovastatin produced greater global improvements in standard lipid parameters than atorvastatin or simvastatin monotherapies; niacin ER/lovastatin also demonstrated greater benefit in effects upon lipoprotein particle size and subclass distribution without increasing liver enzymes (see Table 1).(5)

[[HPE20_table1_69]]

Safety and tolerability
The combination of niacin with statins has shown long-term safety.(38–41) The main side-effect of niacin ER/lovastatin is flushing, which is due to the niacin component and, in most cases, can be adequately managed by preventive measures.(1,38–45)

Hepatotoxicity is a known potential adverse effect of niacin that has most been described in patients who are administered more than 1,000–1,500mg of niacin SR per day.(46) With regard to the combined use of niacin and statins, liver transaminase elevation has been reported with statin monotherapy alone.(47–49) Thus, some degree of liver enzyme elevation is to be expected when niacin and statin are used together.

In the past, it was thought that niacin in combination with statin increased the risk of myopathy. However, this belief was based upon older, isolated case reports that have not been supported by findings in subsequent controlled clinical trials.(41) Little objective evidence from clinical trials supports that the use of niacin ER plus statins increases the risk of myopathy.(1) However, all statins have the potential to cause myalgias, myopathy and the very rare serious adverse effect of rhabdomyolysis. This potential for muscle toxicity includes lovastatin therapy.(28) The potential for muscle toxicity due to statin may occur whether the statin is used alone, or in combination with niacin.(50)

Niacin may increase the risk of hyperglycaemia in susceptible patients, mainly those who experience a sufficient increase in insulin resistance.(41,51,52 )

An important consideration in the use of niacin in patients with diabetes mellitus is to note the kind of dyslipidaemia often described with type 2 diabetes mellitus and metabolic syndrome. This typically includes decreased HDL-C levels, elevated TG levels, and abnormalities in lipoprotein particle size and subclass distribution,(1,5,53) which has been shown to improve with niacin therapy in patient with diabetes mellitus. These lipid abnormalities are often the same lipid abnormalities most improved by niacin, which may help to explain why niacin monotherapy administration has resulted in an observed trend toward providing the greatest CHD outcome benefits among patients with the metabolic syndrome or among patients with fasting baseline glucose levels of Ž126mg/dl.(56) Similarly, niacin in combination with simvastatin has also been shown to reduce CHD events significantly compared with placebo in subjects with diabetes or impaired fasting glucose.(57) In recognition of the lipid and potential CHD outcomes benefits of niacin, the American Diabetes Association guidelines have recommended niacin (at doses of </=2 g/day) as an acceptable treatment option for type 2 diabetes patients who have low HDL-C levels. Appropriate glucose monitoring should be performed and, if needed, adjustment should be made in antidiabetic therapies.(3) In clinical trials of niacin ER/lovastatin that included patients with diabetes mellitus, hyperglycaemia in niacin ER/lovastatin-administered subjects did not demonstrate a statistical increase compared with those who received niacin ER, lovastatin, atorvastatin or simvastatin alone.(1,38–40) Nonetheless, whether it be niacin monotherapy or niacin ER/lovastatin,(41) hyperglycaemia may occur. In patients with pre-existing diabetes mellitus, worsening blood sugars may be observed. Therefore, glucose levels should be monitored in niacin-administered patients, and blood sugar levels managed appropriately.

Clinical use
Niacin ER/lovastatin may be considered for the treatment of primary hypercholesterolaemia and mixed dyslipidaemia.(9) If further TG lowering or HDL-C level raising is considered a favourable treatment goal despite existing statin therapy, then niacin ER/lovastatin may be indicated in such patients. Similarly, for patients who are thought to benefit from further LDL-C level lowering despite niacin therapy, niacin ER/lovastatin is again an indicated treatment option. When niacin ER/lovastatin is substituted for niacin ER alone, it is recommended to start at the equivalent dose of niacin.

In patients treated with other niacin preparations, niacin ER should start at 500mg, and switched to niacin ER/lovastatin if further lipid-altering efficacy is thought to be in the best interest of the patient. Niacin ER/lovastatin doses of >2,000mg/40mg per day are not recommended. If discontinued for more than seven days, niacin ER/lovastatin should be restarted at the lowest dose (500mg/20mg), and then subsequently titrated.

Laboratory monitoring
Liver enzyme levels should be measured before niacin ER/lovastatin therapy, and then every six to 12 weeks during the first six months, and every six months thereafter.(9) Patients with pretreatment muscle symptoms or conditions associated with muscle enzyme elevations should have creatine kinase levels drawn before therapy (“baseline”). Afterwards, just as with treatment with statins in monotherapy, combination statin and niacin treated patients should be monitored for muscle pain or weakness, particularly during any period in which the lovastatin dose is escalated.

Niacin ER/lovastatin should be avoided in combination with fibrates, and because lovastatin is metabolised by the cytochrome P450 3A4 enzyme system, niacin ER/lovastatin should be also avoided in combination with other drugs that may affect this enzyme system, as lovastatin blood levels may increase, thus increasing the risk of muscle toxicity.

Conclusion
Niacin ER/lovastatin is a lipid-altering drug that offers a therapeutic treatment option that provides widespread and global improvement in multiple atherogenic lipid parameters.