AIM-HIGH is the first large randomized trial to evaluate the effect of niacin on cardiovascular events among statin-treated patients with established atherosclerotic cardiovascular disease who are at goal for LDL-C but who have residual abnormalities in HDL-C and triglycerides (ie, so-called atherogenic dyslipidemia). Previous studies with niacin as secondary prevention have several limitations. The Coronary Drug Project,19
the only large placebo-controlled trial of niacin monotherapy, enrolled 1,119 patients on niacin (niacin was one of 5 active treatments) and 2,789 on placebo. Participants were followed for approximately 5 years. Although the results show a decrease in fatal and nonfatal cardiovascular events, including stroke,19
and a late benefit on total mortality 10 years after the trial ended,15
the study was conducted over 40 years ago, long before the advent of statins. Clinical studies with primarily coronary angiographic end points using niacin, such as the Familial Atherosclerosis Treatment study13
and the HDL Atherosclerosis Treatment study,20
or noninvasive imaging studies using B-mode carotid ultrasound (eg, ARBITER 2, 3, and 616,21,22
) have all been limited in size (generally in the range of 150-300 randomized subjects who were likewise followed for limited periods [1-2.5 years]) and were not primarily powered statistically to detect the effects of treatment on clinical outcome.
Thus, AIM-HIGH will provide much needed clinical and scientific information on the potential impact of HDL-C raising among patients who have achieved their target LDL-C primarily on a statin to more fully test the so-called HDL hypothesis that there is incremental risk reduction with combination dyslipidemic therapy. It should be noted that although the mean LDL-C at baseline in the study among participants on a statin was 71 mg/dL, there were participants with an LDL-C as low as 19 mg/dL, while 25% of the patients had LDL-C <59 mg/dL.
The baseline demographic characteristics of AIM-HIGH further show a study population with atherogenic dyslipidemia, a high prevalence of hypertension (71%) and metabolic syndrome (81%), enriched in diabetes (34%), and with a large number of current or former smokers (20% and 55%, respectively). This pattern of risk factors is typical of patients with coronary heart disease, among whom 80% to 90% have one or more of the conventional risk factors of smoking, hypertension, hyperlipidemia, or diabetes.23
Furthermore, residual low HDL-C, with or without high triglycerides, is quite commonly seen in clinical practice, in up to 50% of such individuals currently receiving statin therapy in a general medical environment.24
Thus, the results of AIM-HIGH should be broadly applicable to the typical coronary patient population commonly seen in clinical practice today.
It is noteworthy that the study participants had well-controlled levels of apoB-containing lipoproteins, as indicated by the low baseline LDL-C, apoB, very low density lipoprotein cholesterol (VLDL-C), and lipoprotein (a), with only moderately elevated triglycerides (). Also of interest is that ApoCIII, a VLDL apolipoprotein that inhibits lipolysis and hepatic VLDL uptake,25
was at the upper limit of normal; however, total HDL-C was low, and most HDL is in the HDL3 subclass, with depressed HDL2 levels.
Thus, in addition to having multiple major coronary risk factors such as hypertension and diabetes, participants in this study have a pro–atherogenic lipoprotein profile. Although LDL-C was well controlled, there is likely to be a preponderance of small dense LDL particles, as suggested by the low total HDL-C, depressed HDL2, and reduced LDL-C/apoB ratio of 0.88, a ratio <1.3 being a good indicator of the atherogenic LDL phenotype B.26
Actual LDL and HDL particle size and distribution are being assessed in a prospective substudy. Nonetheless, this is a study population whose principal lipid abnormality is in the HDL number and fractions. These patients are precisely the ones who are likely to respond to niacin therapy, which principally impacts the number of HDL particles and fractions.
AIM-HIGH was designed with an active lead-in, during which tolerability to the combination of extended-release niacin and simvastatin was assessed, randomizing only those who tolerated a dose of extended-release niacin of ≥1,500 mg/d. Results show that the combination of extended-release niacin with simvastatin was well tolerated, despite the rapid uptitration of the dose from 500 mg/d to 2,000 mg/d during a 4-week period (up to 8 weeks was permitted). Ultimately, 19% were not subsequently randomized to double-blind therapy, largely accounted for by intolerance of the ≥1,500-mg dose. The predominant reason for inability to tolerate this dose was cutaneous side effects, especially among women. Participant refusal was cited as the reason for another 17% (women) and 19% (men) not continuing to be randomized. None had elevated liver enzymes that prevented subsequent entry into the double-blind portion of the study.
In summary, AIM-HIGH is a secondary prevention trial that provides a robust test of the HDL hypothesis in patients with optimally treated LDL-C levels on a statin and residually low levels of HDL-C at baseline, using a well-tolerated combination dyslipidemic therapy regimen. The results of this trial should significantly inform clinical practice as to the incremental benefit of niacin in reducing cardiovascular events in patients with atherosclerotic cardiovascular disease and optimally controlled LDL-C levels.