HDL: who needs it?

One of the problems with writing editorials is the capacity for events to embarrass you. Recently, I reviewed the potential mechanisms of action and clinical evidence base behind niacin when commenting on the predictable identity of activity of one preparation in many different patient groups (1). To re-iterate, niacin raises HDL-C by more than other agent and has an evidence base in surrogate outcome studies when added to a statin and also in the original Coronary Drug Project (CDP) outcomes study with monotherapy (1,2). However, the capacity of events to mis-direct commentators was shown by the decision to abandon the AIM-HIGH trial on the grounds of futility a few weeks later (3). There was no observable benefit of niacin and indeed a suggestion of an increased rate of strokes. Surrogate outcome studies have a potential to mislead based on the performance or stability of the marker studied (4). Thus, regulators have tended to rely even more on outcome studies. This has been noticeable when surrogate markers such a glucose (or microvascular events) have misled clinicians in appraising classes of drugs such as thiazolidionediones when assessed on their overall outcomes of CVD events. Whether other new classes of hypoglycaemic drugs [e.g. Di-peptidyl peptidase (DPP)-IV inhibitors, novel insulins, glucagon-like peptide (GLP)-1 analogues] show similar effects is unclear, but under study. It is notable that these studies are not powered for non-inferiority, but for superiority over conventional treatments although this may be unlikely given the previous results of the UK Prospective Diabetes Study (UKPDS) (5). The Atherothrombosis Intervention in Metabolic syndrome with low HDL ⁄ high triglycerides: Impact on Global Health outcomes (AIM-HIGH) trial was designed to test the additive effects of niacin on HDL-C in a dyslipidaemic secondary prevention population that would be maintained at optimum target LDL-C in both groups (6). It actually recruited a dyslipidaemic population with a HDL-C of 0.90 mmol ⁄ l, an atherogenic index (TG:HDL-C ratio) of 2 and LDL-C 1.84 mmol ⁄ l (7). The study was powered for a 25% difference in CVD events (6) based on the outcomes of the Veterans Affairs HDL Intervention (VA-HIT) trial using gemfibrozil – a fibrate (8). This suggested that 3500 patients would be required and 3414 were recruited. However, a simple reading of the trial might well be misleading. The rate of events will be progressively reduced as LDL-C in parallel with absolute reductions in LDL-C. As trial designs are based on historical rates of CVD events, it has been increasingly common for trials [e.g. Study of the Effectiveness of Additional Reduction in Cholesterol and Homocysteine (SEARCH), Improved Reduction of Outcomes: VYTORIN Efficacy International Trial (IMPROVE-IT)] to be extended or have their numbers increased. Although the trial results have not been published, the event rate at 1% was low for this population. In addition, adjustment of LDL-C levels to < 70 mg ⁄ dl (< 1.75 mmol ⁄ l) was allowed using either statin or ezetimibe in both groups leaving this as an HDL-C adjustment trial. However, niacin has protean actions on all lipid fractions (1), and so this design would underestimate its likely effects. In addition, in all trials drop-out rates vary from 10% to 20% and might be higher with niacin given the continuing high rate of flushing with modifiedrelease preparations (e.g. Niaspan used in AIMHIGH). Although far less than those found with crystalline niacin in CDP, expectations of side-effects have changed dramatically over the last 40 years. In the active run-in to AIM-HIGH, more women (39%) discontinued than men (18%) mostly because of flushing. Thus, again the expectations of the trial were high if side-effects resulted in higher rates of discontinuation in the active treatment arm even though the ‘placebo’ group received a 50 mg flushing-induction dose to maintain blinding (6). The history of end-point trials with second-line agents is also a potential factor in explaining these results. The fibrate trials offer some potential analogies. The Fenofibrate Intervention in Endpoint Lowering in Diabetes (FIELD) study (9) although showing a small to moderate effect was confounded by statin drop-in that occurred more often in higher risk patients (10) and in those not receiving fenofibrate, which can reduce LDL-C by 6%. In AIMHIGH, the likeliest potential confounder will be found in differential prescribing of ezetimibe – in itself a controversial additional agent. Recently, the combination of simvastatin and ezetimibe has been shown to reduce CVD events by 23% in the Study of Heart and Renal Protection (SHARP) trial in patients with chronic renal failure (n = 9500) (11), whereas in the previous smaller Simvastatin-Ezetimibe in Aortic Stenosis (SEAS) trial (n = 1800) in patients with aortic stenosis (12), this combination only reduced CVD events by 17%, which was not EDITORIAL