Safety and Tolerability of Prolonged-Release Nicotinic Acid Combined With a Statin in NAUTILUS

Anja Vogt; Ursula Kassner; Ulrike Hostalek; Elisabeth Steinhagen-Thiessen; on behalf of the NAUTILUS Study Group


Br J Cardiol. 2006;13(4):273-277. 

In This Article

Abstract and Introduction

NAUTILUS (The multiceNtre, open, uncontrolled sAfety and tolerability stUdy of a modified-release nicoTinic acId formuLation in sUbjects with dySlipidaemia and low HDL cholesterol) was an open label, uncontrolled, phase IIIb study. The study population included a total of 566 patients with dyslipidaemia and low high-density lipoprotein (HDL) cholesterol (< 1.0 mmol/L [< 40 mg/dL] in men and < 1.2 mmol/L [< 46 mg/dL] in women) who were inadequately controlled by diet alone. Patients received once-daily treatment with prolonged release nicotinic acid (Niaspan®; target dose 2,000 mg/day), added to existing regimens for 15 weeks. At baseline, 40.5% of patients were receiving an HMG-CoA reductase inhibitor (statin), mostly simvastatin or atorvastatin.

Patients taking and not taking concomitant statin therapy reported a similar incidence of all-cause adverse events (AE) of 64.6% vs. 57.9%, respectively, treatment- related AE (54.6% vs. 47.2%), all-cause serious AE (3.9% vs. 3.6%), treatment-related serious AE (0.9% vs. 0.3%), and withdrawals for AE (17.5% in each group). The incidence of flushing was similar in patients with and without statin treatment (45.0% vs. 40.1%), as was the proportion of patients withdrawing because of flushing (8.7% vs. 10.4%). Only about one quarter of patients flushed more than five times. There was no sign of serious hepatic or muscle toxicity. The addition of prolonged-release nicotinic acid markedly raised HDL cholesterol levels irrespective of statin treatment; it was well tolerated and effective when combined with a statin in patients with dyslipidaemia.

Numerous randomised trials performed with HMG CoA reductase inhibitors (statins) in patients at increased cardiovascular risk show that these agents reduce the risk of an adverse cardiovascular outcome by 20–50%, irrespective of the precise nature of patient population studied.[1,2] The results of these trials have placed control of low-density lipoprotein (LDL) cholesterol with statins firmly at the centre of management strategies to improve cardiovascular outcomes through control of the lipid profile.[3,4] Further strategies are required, however, to address the substantial burden of cardiovascular risk that is apparently unaddressed by statin therapy. Patients with insulin resistance, especially those with the metabolic syndrome or type 2 diabetes mellitus, often present with an atherogenic lipid profile that is not dominated by hypercholesterolaemia, but rather by low levels of high-density lipoprotein (HDL) chol-esterol, elevated triglycerides and a lipoprotein sub-profile characterised by small, dense LDL.[5]

HDL cholesterol exerts a range of anti-atherosclerotic effects in the arterial wall,[6] and large observational studies conducted over several decades have established a low level of HDL cholesterol beyond doubt as an independent risk factor for cardiovascular disease.[7,8,9] Correcting low HDL cholesterol may therefore contribute to the management of overall cardiovascular risk. Nicotinic acid is the most powerful pharmacological agent currently available for increasing circulating levels of HDL cholesterol.[4] Intervention trials with this agent in populations with low HDL cholesterol levels, reviewed by Brown,[10] have demonstrated marked and significant improvements in cardiovascular outcomes, including a reduction in cardiovascular event rates of up to 90% vs. control in statin-treated patients in the HDL Atherosclerosis Treatment Study (HATS).[11]

The use of a fibrate, particularly gemfibrozil, in combination with a statin has led to concerns relating to an increased risk of rhabdomyolysis, a rare but potentially life-threatening manifestation of muscle toxicity.[12,13,14] There are no data suggesting that such concerns apply to nicotinic acid, nonetheless it is prudent to evaluate carefully the safety and tolerability profiles of this treatment when co-prescribed with a statin. Niaspan® is a once-daily, prolonged-release formulation of nicotinic acid with identical efficacy, superior tolerability and comparable anti-atherogenic benefits compared with the immediate-release formulation.[15,16] A clinical evaluation of prolonged-release nicotinic acid in patients with dyslipidaemia and low HDL cholesterol, NAUTILUS, (the multiceNtre, open, uncontrolled sAfety and tolerability stUdy of a modified-release nicoTinic acId formuLation in sUbjects with dySlipidaemia and low HDL cholesterol), included a substantial subgroup of patients who also received a statin. This report describes the safety and tolerability profiles of prolonged release nicotinic acid in patients who did and did not receive concomitant treatment with a statin.


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