Tuesday, May 31, 2011
Treating lab tests or people? Chasing our good HDL cholesterol
Long term observational studies show that people with high levels of bad cholesterol have an increased risk of acute cardiovascular events (MACE) such as heart attacks, strokes and death. Peopole with high levels of good cholesterol have decreased rates of MACE.
Thus it is logical to assume that treatments to decrease bad cholesterol or increase good cholesterol, would lower risks of MACE.
To determine if this works in practice, not just in theory, there have been randomized trials of one class of cholesterol lowering agents (the statins, brands such as Lipitor) showing that taking a statin lowers the LDL-C and, and, here is the critical part, also lowers the rates of MACE including heart attacks, strokes and death.
It is logical to assume that these good patient outcomes (not just lowering the bad cholesterol but also improving survival and reducing rates of heart attack and stroke) would also ensue if we were able to increase the amount of ‘good’ cholesterol.
Indeed government regulatory agencies, informed by experts, decided that while a clinical trial to prove that raising good cholesterol would entail health benefits, the costs and delays in doing such a trial were thought unnecessary and fenofibrate was approved for treatment of adults that had low levels of good cholesterol (HDL-C).
On the 19th of May the US FDA Advisory Committee on fenobibrate/fenofibric acid [link] (Trilipix, Abbott Laboratories) received preliminary results of the the ACCORD trial and were asked to consider this evidence. Fenofibrate had been approved for the treatment of high triglycerides in 1993. The company sought approval for the treatment of low levels of good cholesterol.
The trial aimed to show that when Trilipix was administered with a statin (such as Lipitor, (simvastatin) to adult patients with mixed atherogenic dyslipidemia (Fredickson Type IIb) not only would their bad cholesterol (LDL-C) fall, as it does with statins, the good cholesterol (HDL-C) would rise AND, importantly, they would suffer fewer heart attacks and strokes.
The results of a planned interval analysis reveal that after a total of 2,765 patients with diabetes type II were randomized to simvastatin alone or simvastatin plus Trilipix major acute cardiovascular events (MACE) were not decreased in the group taking Trilipix: The addition of Trilipix did not change rates of MACE: 11.3% of patients in the simvastatin and 10.8% in the simvastatin plus fenofibrate group, a trivial and both clinically and statistically insignificant result. There was no benefit.
Furthermore there was evidence of harm in the group taking Trilipix and a suggestion that MACE events were slightly greater women randomly assigned to the Trilipex plus statin group as compared to men. Side effects were also found in patients taking Trilipex: These included increased elevations in serum creatinine (kidney function worse) and aminotransferases (liver effects). Two patients taking Trilipex developed a venous thromboembolic event (phlebitis) vs. none in the statin only group. There were no reports of massive muscle disease (rhabdomyolysis, thought to be associated with niacin/Triplix like drugs) and no reports of severe renal or liver failure. One patient taking Trilipex developed pancreatitis. These adverse events did not occur frequently and the findings may be due to chance.
The results have not been formally published. It is undoubtedly too early to change course and completely avoid Trilipex in combination with statins. Indeed the FDA panel assembled to study the results recommended, (on vote of 9 vs. 6) no change to current FDA approvals and that the drug maker must conduct another clinical trial.
Clinicians and patients however should take note. While therapy must always be individualized and guidelines (even from the FDA) are just guidelines it might be wise to avoid aggressively targeting therapy to increase HDL levels. The outcome events simply don’t support such an approach and there is a potential for harm.
All drugs have multiple effects when ingested or injected. It is unclear why statins reduce MACE event rates. The LDL-C is certainly a good marker to guide therapy but statins have multiple effects and the benefits probably derive from some non-cholesterol lowering effects of the drug.
Chasing laboratory test results without clinical trial results showing life-altering benefits will always be a judgement of faith or hope.
There is a good clip of Dr. Steven Nissen of the Cleveland Clinic discussing this issue on NPR news.