In 1944, President Franklin Roosevelt developed marked worsening of his chronic hypertension. There were no antihypertensive medications at the time, and Roosevelt soon died of a hypertensive stroke. Thirty years later, antihypertensive medications were available, but a substantial number of patients were noncompliant because of side effects [1]. In 2013, antihypertensive medications are cheap, effective, and well-tolerated.
At one time, conventional wisdom held that there never would be a successful antiviral medication because viruses utilized the same cellular machinery as their human host. Now, because of the drug regimen called the “triple cocktail,” AIDS is a chronic, treatable illness instead of a death sentence. This is a tremendous accomplishment for which, in my opinion, the medical community does not receive enough credit.
In the 1950’s, antipsychotic medications emptied long term residential facilities for schizophrenics, allowing them to be treated as outpatients. Prior to that, antibiotics revolutionized medicine. Effective drugs have played a major role in medical successes ever since.
Life expectancy in the United States increased from 69.7 years in 1960 to 77.8 years in 2008. I doubt whether anyone will ever be able to parse out how much of this increase is due to nutrition, lifestyle, vaccination, public health initiatives, medicines, absence of world war, or some other factor, but I suspect medications have played an important role.
Clinical Trials of Inhibitors of Cholesteryl Ester Transfer Protein: Motivated by Profit, Drug Companies Perform Good Science
Patients with genetic deficiency of cholesteryl ester transfer protein (CETP) have markedly increased serum HDL-cholesterol levels, a fact that has spurred interest in the creation of pharmacologic inhibitors for CETP. Mainstream thinking holds that HDL protects against atherosclerosis by removing cholesterol from the periphery, i.e., reverse cholesterol transport [2]. To date, trials of two inhibitors of CETP, torcetrapib and dalcetrapib, have been terminated early despite producing marked increase in serum HDL levels. Torcetrapib therapy resulted in excess deaths, heart failure, angina, and revascularization procedures. Trials of dalcetrapib were halted when they showed a lack of clinically meaningful efficacy. Why?
Lipoproteins affect blood viscosity at low shear rates by modulating erythrocyte aggregation. Erythrocytes can approach each other to within a distance of approximately 7.9 nm, due to the repulsive force of their strong electronegative surface charge [3]. Molecules such as fibrinogen which are large enough to span this distance can simultaneously bind two erythrocytes and cause erythrocyte aggregation. This is the basis for the laboratory test known as sedimentation rate. LDL particles are also large enough to span this minimum distance and simultaneously bind two erythrocytes, causing aggregation and increasing blood viscosity. Normal HDL is too small to simultaneously bind two erythrocytes and antagonizes erythrocyte aggregation by competing with LDL for erythrocyte binding sites, decreasing blood viscosity [4].
Inhibitors of CETP increase HDL particle size so that they foster erythrocyte aggregation and increase blood viscosity. Torcetrapib, 120 mg per day, resulted in an increase in HDL particle size from 8.4 to 9.1 nm, and the same medication 120 mg twice daily increased HDL particle size from 8.4 to 9.7 nm. Post-hoc analysis of data from the EPIC-Norfolk study show that the odds for a major coronary event progressively increase with HDL particle sizes of 8.6 nm and greater, being 8 times higher for HDL particle sizes of more than 10.07 nm [5]. Thus, it is reasonable to suggest that normal HDL particles already approach the maximum size which will not increase the risk of cardiovascular disease, and it is difficult to improve on what evolution has wrought.
Although it is doubtful he was aware of the above analysis, in assessing the failure in clinical trials of two CETP antagonists, University of Michigan, Ross School of Business professor Erik Gordon, an academician who specializes in the biomedical industry, said, “all the possible drugs in development that are based on the mechanism will similarly fail. The failure is for lack of efficacy and that is less fixable than failing due to side effects.” This was in stark contrast with the stubborn impartiality of nationally recognized cardiologist Steven Nissen, who said at the time the trial was halted, “People are starting to say HDL isn’t going to work. We don’t know that yet. It’s too early to bury the HDL hypothesis.” [6]
Lessons from the Failure of CETP Inhibitors
Everyone is aware of the risky nature of the pharmaceutical business. One lesson that I have taken away from the CETP inhibitor episode is that drug companies, motivated by profit, are willing to undertake truly high impact research. In contrast, some major funding agencies have been criticized for supporting only conventional, incremental research [7]. I suggest that the drug company Roche’s study tested the reverse transport theory of cholesterol more definitively than any NIH-funded study ever would whether because of lack of resources or vision on the part of government agencies. In my opinion, the failure of simply raising serum HDL-cholesterol to prevent cardiovascular disease refutes the theory that reverse cholesterol transport is atheroprotective. Only normal HDL will decrease blood viscosity and protect against atherosclerosis. More research on lipoprotein-erythrocyte binding is necessary and will probably be therapeutically relevant.
The failed dalcetrapib study cost Roche hundreds of millions of dollars, and Roche stock fell 3.5% when the study was halted last year. For me, this shows how the profit motive can actually promote adherence to the scientific method. I admire Roche for investing in the science that produced such insights—for following the evidence and acting decisively to cut their loss by terminating the clinical trial.
References:
1. Freis ED. Historical Development of Antihypertensive Treatment. In: Laragh JH, Brenner BM, eds. Hypertension: Pathophysiology, Diagnosis, and Management. 2nd ed. New York: Raven Press; 1995: 2741-51. Link to full text http://profiles.nlm.nih.gov/ps/access/XFBBGL.pdf.
6. Kresge N, Bennett S. Roche Drops after Halting Cholesterol Drug Development. Bloomberg News. May 7, 2012. Available at: http://www.bloomberg.com/news/2012-05-07/roche-halts-testing-on-dalcetrapib-cholesterol-treatment-1-.html. Accessed May 2, 2013.
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