The largest-ever study of niacin has failed to show a clinical benefit for niacin and even found a strong signal of harm. Merck announced today that the HPS2-THRIVE (Heart Protection Study 2-Treatment of HDL to Reduce the Incidence of Vascular Events) study did not meet its primary endpoint. In that study, the combination of a statin and Merck’s niacin compound, Tredaptive, a combination of extended-release niacin and laropiprant, an anti-flushing agent, was compared to statin therapy alone in 25,673 patients at high risk for cardiovascular events.

After a median followup of 3.9 years, the combination of niacin and laropiprant ”did not significantly further reduce the risk of the combination of coronary deaths, non-fatal heart attacks, strokes or revascularizations compared to statin therapy,” according to Merck. Even more troubling, the company reported that there was “a statistically significant increase in the incidence of some types of non-fatal serious adverse events in the group that received extended-release niacin/laropiprant.”

Merck said it was now no longer planning to seek approval of Tredaptive in the United States. The drug’s initial application for approval in the US was rejected in 2008. HPS2-THRIVE was designed to answer criticism from the FDA and other experts about the lack of any evidence demonstrating clinical benefit.

Tredaptive (also known as Cordaptive in some places) is approved in some countries outside the US. Merck said it is “recommending that providers not start new patients” on the drug. It is unclear whether the drug will remain on the market in these places.

Although niacin, a natural vitamin, has been used for decades to raise HDL, a clinical benefit has never been demonstrated. In 2011 the NIH’s  AIM-HIGH trial found no benefit for extended-release niacin. Critics said the trial was underpowered and otherwise flawed. HPS2-THRIVE, most agreed, would provide a more definitive test of the effect of niacin.

HPS2-THRIVE adds to the string of failures associated with trials of HDL-related therapies, although some hope remains for CETP inhibitors, despite the failure of two large clinical trials. It appears likely that the results of HPS2-THRIVE will also impact the use of existing niacin products. Bernstein analyst Timothy Anderson said it may “cause some collateral damage to AbbVie’s Niaspan.”

Responding to the breaking news, Steve Nissen said he had three initial thoughts about the trial:

What were the “non-fatal serious adverse events” that showed a statistically significant increase?

Did the study fail because of niacin or laropiprant?

We will need to decide whether to withdraw patients from niacin.

Update: Here’s a terrific comment posted below from cardiologist John Osborne:

Also don’t forget that this trial did not have a cut-off for HDL, so that patients could have any level of HDL and still get into this trial, not just patients with low HDL where presumptively the greatest benefit would be seen, according to the HDL-raising hypothesis. We will need to see how this sub-group responded, which was a pre-specified sub-group analysis. As far as the vague “excess of non-fatal serious adverse events”, it is no surprise given the known issues with the use of niacin, such as flushing (even occasionally to the point of causing vasodilation resulting in rare syncope), hyperuricemia, gout and gout flares, peptic ulcer disease, and hyperglycemia. If these non-fatal adverse events were higher int the niacin-laropriprant arm, I would not be at all surprised. If, however, we saw an excess of non-fatal strokes, as a tendency was seen in AIM-HIGH, that would be much more concerning. Obviously science and medical care cannot and should not be based on lay press reports and we need to see and digest all the data from this trial when it comes out. Stay by your radios (and Internet feeds), my friends!

Update #2: James Stein sent the following comment:

HPS did not THRIVE!  I am disappointed.  It suggests that in people on a statin with well controlled LDL and non-HDL cholesterol levels, adding niacin may not reduce CVD risk.  I still think niacin is a useful drug for those who can’t reach goals on statins or who can’t take them, and for selected patients with combined dyslipidemia.  However, this may be as much about laropiprant as it is about niacin. I am especially concerned about the increase in non-fatal serious adverse events in the group that received extended-release niacin/laropiprant. You may recall that the idea for using laropiprant was to improve the tolerability of niacin by blocking flushing. However a close look at the laropiprant data for its effectiveness as a flushing blocker showed that at the dose it was being used at, it was not significantly better than adult dose aspirin.

More worrisome, pre-clinical Merck research showed an off-target effect of laropiprant on platelet DP1 receptors. Bleeding times were not prolonged, so the meaning of this off-target effect is unclear, but this is evidence that the drug may affect more than just the DP1 receptor on dermal blood vessels.   We know DP1 receptors also are on neurons and lung tissue, among other places.  We in the lipid world need to be very humble about off target effects – even if we can’t explain them with our current knowledge base.

Click here to read the Merck press release…