Author + information
- Reynaria Pitts, MD,
- Elise Gunzburger, MS,
- Christie M. Ballantyne, MD,
- Philip J. Barter, MD, PhD,
- David Kallend, MBBS,
- Lawrence A. Leiter, MD,
- Eran Leitersdorf, MD,
- John J.V. McMurray, MBChB,
- Stephen J. Nicholls, MBBS, PhD,
- Eric J. Niesor, PhD,
- Anders G. Olsson, MD, PhD,
- Prediman K. Shah, MD,
- Jean-Claude Tardif, MD,
- John Kittelson, PhD and
- Gregory G. Schwartz, MD, PhD∗ ()
- ↵∗Cardiology Section, Denver VA Medical Center (111B), 1055 Clermont Street, Denver, Colorado 80220
Epidemiological data associate higher concentrations of high-density lipoprotein cholesterol (HDL-C) with lower cardiovascular risk. HDL-C isolated from healthy subjects exhibits potentially protective properties, including anti-inflammatory effects (1). However, some evidence suggests that cholesterol-overloaded HDL-C particles may lose protective properties (2), and drugs that raise HDL-C and particle size have thus far not reduced cardiovascular events in patients with established heart disease. Among these agents are inhibitors of cholesteryl ester transfer protein (CETP). These findings raise the question whether HDL-C formed under treatment with a CETP inhibitor loses some of its usual protective properties.
We hypothesized that the relationship between HDL-C and the inflammatory marker high-sensitivity C-reactive protein (hsCRP) is altered under treatment with the CETP inhibitor, dalcetrapib, compared with placebo. We tested this hypothesis by examining patient-level data from 13,783 participants in the dal-OUTCOMES (A Study of RO4607381 in Stable Coronary Heart Disease Patients With Recent Acute Coronary Syndrome; NCT00658515) trial. In that trial, randomized treatment with dalcetrapib or placebo began 4 to 12 weeks after an acute coronary syndrome and continued for a mean of 31 months (3). We used linear regression to relate the change in HDL-C between randomization and month 3 of assigned treatment to the concurrent change in log2 hsCRP. Adjusted models accounted for the following: age; sex; race; body mass index; history of hypertension, diabetes, stroke, peripheral arterial disease, previous myocardial infarction, or coronary revascularization procedure; baseline hsCRP, HDL-C, low-density lipoprotein cholesterol, triglycerides, and estimated glomerular filtration rate; treatment with aspirin, statin, beta-blocker, and angiotensin-converting enzyme inhibitor or angiotensin receptor blocker; and adherence to study medication.
At randomization, mean HDL-C was 42 mg/dl (standard deviation 12 mg/dl), and median hsCRP was 1.5 mg/l (interquartile range: 0.7 to 3.5 mg/l). Mean low-density lipoprotein cholesterol was 76 mg/dl. At 3 months of assigned treatment, the mean change from baseline in HDL-C was +13.7 mg/dl with dalcetrapib and +1.7 mg/dl with placebo (intergroup difference, p < 0.001). Concurrently, the mean change from baseline in hsCRP was +0.21 mg/l with dalcetrapib and −0.49 mg/l with placebo (intergroup difference, p < 0.001).
Figure 1 shows patient-level data and unadjusted linear regression relating the change in HDL-C to the corresponding percentage change in hsCRP by treatment group. The 2 regression lines differ (p < 0.001), with an upward shift and a decreased slope with dalcetrapib. Thus, for any given change in HDL-C, the associated change in hsCRP was less favorable (or unfavorable) in the dalcetrapib group compared with the placebo group. In covariate-adjusted analysis, a 10 mg/dl increase in HDL-C was associated with a decrease in log2 hsCRP of 0.23 units in the placebo group, compared with a decrease of 0.15 units in the dalcetrapib group (intergroup difference, p = 0.001). Using antilog transformation to place the findings in clinical context, increases in HDL-C of 5, 10, and 15 mg/dl were associated with relative decreases in hsCRP of 17%, 25%, and 31%, respectively, in the placebo group. In contrast, the same increases in HDL-C were associated with relative increases in hsCRP of 13%, 8%, and 3% in the dalcetrapib group (points indicated in Figure 1).
Time to first occurrence of death resulting from coronary heart disease, nonfatal acute myocardial infarction, hospitalization for unstable angina, ischemic stroke, or cardiac arrest with resuscitation was not associated either with the change in HDL-C from randomization to month 3 (hazard ratio [HR]: 0.998/1 mg/dl increase; 95% confidence interval [CI]: 0.991 to 1.01; p = 0.63) or with treatment with dalcetrapib versus placebo (HR: 1.02; 95% CI: 0.87 to 1.20; p = 0.81), but it was associated with the change in hsCRP from randomization to month 3 (HR: 1.13 for a doubling of hsCRP; 95% CI: 1.05 to 1.21; p < 0.001). There was no interaction of treatment assignment on this relationship. Thus, increasing hsCRP was associated with worse prognosis in both treatment groups, but it was more likely to occur in the dalcetrapib group.
In summary, patient-level data reveal an adverse shift in the relationship between HDL-C and hsCRP in patients treated with dalcetrapib. These findings are associative and do not reveal a mechanism. However, one possibility is that HDL formed under CETP inhibition loses some of its normal anti-inflammatory properties. If so, the observations may help to explain the absence of clinical benefit observed thus far with dalcetrapib and other CETP inhibitors.
Please note: The dal-OUTCOMES (A Study of RO4607381 in Stable Coronary Heart Disease Patients With Recent Acute Coronary Syndrome) trial was funded by F. Hoffmann-La Roche. Dr. Ballantyne has received research support from Abbott Diagnostic, Amarin, Amgen, Eli Lilly, Esperion, Novartis, Pfizer, Otsuka, Regeneron, Roche Diagnostic, Sanofi-Synthelabo, Takeda, the National Institutes of Health, the American Heart Association, and the American Diabetes Association (ADA); and is also a consultant for Roche. Dr. Barter has received research support from Merck, Pfizer, and the National Health and Medical Research Council of Australia; has ownership interest in Nil; has served on the advisory board of Merck, Pfizer, Amgen, Sanofi-Regeneron, Novartis, Kowa, Roche, and Eli Lilly; and has received honoraria from Amgen, AstraZeneca, CSL-Behring, Eli Lilly, Merck, Novartis, Pfizer, and Sanofi-Regeneron. Dr. Kallend was an employee of F. Hoffmann-LaRoche at the time the dal-OUTCOMES trial was performed; and is currently an employee of The Medicines Company, Zurich, Switzerland. Dr. Leiter has received research funding from Aegerion, Amgen, The Medicines Company, Merck, Pfizer, Regeneron, and Sanofi; has served on the advisory board of Aegerion, Amgen, Merck, and Sanofi-Regeneron; and has provided continuing medical education on behalf of Amgen, Merck, and Sanofi-Regeneron. Dr. Leitersdorf is a consultant for Novartis, AstraZeneca, Sanofi, and Amgen; serves on advisory boards for Novartis and Cerenis; and has received research grants from Amgen, Merck, and Pfizer. Dr. Niesor was a former employee of F. Hoffman-La Roche; and is currently consulting for AstraZeneca, Cerenis, and Nestlé. Dr. McMurray, through his institution, has received funding from AbbVie, Amgen, Cardiorentis, GlaxoSmithKline, Novartis, Pfizer, Roche, and Sanofi. Dr. Nicholls has received research support from Amgen, Anthera, Eli Lilly, Cerenis, AstraZeneca, Novartis, Resverlogix, and Sanofi-Regeneron; he is also a consultant for Amgen, AstraZeneca, Boehringer Ingelheim, CSL Behring, Eli Lilly, Kowa, Novartis, Merck, Takeda, Roche, Pfizer, and Sanofi-Regeneron. Dr. Olsson has received research grants from Amgen, AstraZeneca, Karobio, Merck, Pfizer, Roche, and Sanofi; and has consulted for AstraZeneca, Merck Sharp and Dohme, Merck, Pfizer, and Roche. Dr. Tardif has received research support from Amarin, AstraZeneca, DalCor, Eli Lilly, Hoffmann-LaRoche, Merck, Pfizer, Sanofi, Cymabay, Novartis, and Servier; has received honoraria from Hoffmann-LaRoche, Pfizer, Servier, AstraZeneca, DalCor, and Valeant; is a shareholder of DalCor; and is an author of a patent that has the findings of genotype-dependent results of dalcetrapib on clinical outcomes as its basis. Dr. Kittelson has received consulting fees from Bayer Healthcare, Cystic Fibrosis Foundation Therapeutics, Novo Nordisk, Genentech, and BioMarin; and has received honoraria for steering committee participation from CPC Clinical Research. Dr. Schwartz, through his institution, has received research grants from Cerenis, The Medicines Company, Resverlogix, Roche, and Sanofi. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose. Dr. Pitts and Ms. Gunzburger contributed equally to this work.