One drug, so many off-target beneficial effects?

The background required for assessing

this paper by Hanefeld and Forst

is derived from clinical studies using statin and peroxisome proliferator-activated receptors (PPAR)γ agonists. Although in vitro studies suggest that acute reduction of cholesterol, especially under conditions in which cell growth is limited by the ambient cholesterol, can alter macrophage function, it is unclear whether such conditions ever exist in statin-treated humans. Moreover, although statins have been a breakthrough therapy for prevention and treatment of atherosclerosis, by and large their effects parallel cholesterol reduction; there are no clinical data showing that statin-mediated reduction of cholesterol is more beneficial than cholesterol reduction by any other means. Lowering plasma cholesterol is likely to affect the biology of many cells and processes in vivo. If the pleiotrophic effects on inflammation occur in humans, their benefits remain to be proven.

A similar argument has been made in assessing the actions of PPARγ agonists. PPARγ agonists dramatically reduce atherosclerosis in some mouse models¹ and affect the inflammatory status of macrophages.² Pioglitazone reduces triglyceride, modestly raises high density lipoprotein, reduces blood pressure and, of course, improves blood glucose and insulin sensitivity. Shouldn’t the improvement in these factors account for the reduction in coronary disease events seen in the PROACTIVE trial?³ This trial and others are reviewed elsewhere⁴ and have led others to conclude that clear-cut benefits of this class of agents in cardiovascular disease require further analysis. The recently completed CHICAGO Trial⁵ randomly assigned subjects to pioglitazone versus glimepiride; curiously, rather than preventing disease, the pioglitazone group showed a reduction in carotid intimal media ratio at 24 weeks and this reduction continued for the 72-week trial. High density lipoprotein levels were improved by pioglitazone, the glucose control was similar at 24 weeks but better in the pioglitazone group at the conclusion of the trial. So, there is some clinical data suggesting vascular benefit for PPARγ agonists. Whether these benefits exceed what would be expected from alteration in conventional cardiac risk factors is unclear; whether there are additional pleiotrophic actions of these drugs is also not established.

What happens, not to disease, but to several surrogates when subjects are given either a statin (40 mg simvastatin), pioglitazone (45 mg), or both? Diabetes was an excluding factor among subjects in the Hanefeld study; inclusion criteria were metabolic syndrome and elevated C-reactive protein (CRP). So this was a group that reflects many of the high-risk patients seen in practice. With more than 40 subjects in each group, the reductions in CRP, increases in adiponectin and homeostasis model assessment (HOMA), and reduction in triglyceride suggest that adding pioglitazone to statin in this nondiabetic group appears to be beneficial. The downside of this approach was weight gain, edema in >20% of the subjects, and the cost and unknown long-term side-effects of the therapy.

There are often times when it is necessary to treat patients using the best available judgment. Other options for reducing cardiovascular risk are available including more potent cholesterol lowering and, of course, the most efficacious but difficult and time-consuming approach of lifestyle modification. I am sure that some physicians will be anxious to add another drug and it may well be that a combination of a statin and PPARγ agonist will be conventional treatment in the future. Other physicians will await outcome data and the knowledge that they will be doing no harm.