Physicians' Academy for Cardiovascular Education

CETP inhibition alters lipid profile in dyslipidaemic subjects and in CHD patients

Literature - J Clin Lipidol. 2015

Two studies in the Journal of Clinical Lipidology report on the effects of the cholesteryl ester transfer protein (CETP) inhibitor anacetrapib. CETP promotes the bidirectional transfer of cholesteryl esters and triglycerides (TG) between HDL and apolipoprotein (apo)-B-containing lipoprotein particles [1]. Inhibiting CETP with 2 weeks of treatment with anacetrapib 150 mg/day was shown to lower LDL-c levels by 26% and apoB by 29%, while HDL increased with 82% from baseline as compared to placebo, in healthy nondyslipidaemic subjects. Treatment with anacetrapib also modified plasma concentrations of other lipoprotein particles of different sizes, possibly suggesting increased catabolism of larger LDL particles, with an accumulation of very small LDL and larger HDL particles [2].
 

Changes in LDL particle concentrations after treatment with the cholesteryl ester transfer protein inhibitor anacetrapib alone or in combination with atorvastatin

Krauss RM, Pinto CA, Liu Y, et al.
J Clin Lipidol. 2015 Jan-Feb;9(1):93-102. doi: 10.1016/j.jacl.2014.09.013
 
Krauss et al., in a post-hoc analysis of a phase II randomised, double-blind, placebo-controlled study [3], now compared the effects of anacetrapib (150 or 300 mg/day)-atorvastatin combination therapy with atorvastatin monotherapy (20 mg/day) on particle concentrations of LDL, VLDL and intermediate-density lipoproteins (IDL) in patients with primary hypercholesterolemia or mixed hyperlipidemia.
 

Main results Krauss et al.

  • When comparing ana-ator combination therapy with atorvastatin alone, combination therapy resulted in incremental between-group reductions in LDL-c (25%), non-HDL-d (21%), apoB (14%) and Lp(a) (38%). Significant increases were seen for total cholesterol (TC) (9%), HDL-c (121%) and apoA1 (39%) with combination therapy). No significant between-group effect was seen for TG.
  • Combination therapy resulted in significant but modest between-group reductions in all VLDL and large IDL fractions (10-15%), as compared with atorvastatin monotherapy. Larger reductions were seen in large and medium LDL particles (34 to 39%).
    Concentration of LDL 3a significantly decreased by 7% with combination therapy vs. ator mono, while LDL3b increased by 40% and very small LDL 4a and 4b by increased by 84% and 76% respectively.
  • A similar general pattern of reductions in particle subtype concentrations were seen in patient subgroups defined by median baseline TG level (< and >154 mg/dL), with the exception that LDL 3b and 4a were increased in the low vs. high TG group for mono- and combination therapy.
 

Conclusion Krauss et al.

This study shows that, also in dyslipidaemic individuals, treatment with anacetrapib and atorvastatin results in discordant changes in concentrations of LDL particles with different particle sizes, in a different way than with atorvastatin monotherapy. Concentrations of large and medium-sized LDL particles decreased, while increases in levels of small LDL3b and very small 4a and 4b were seen. These changes were not much influenced by TG level at baseline.

 
Effects of anacetrapib on plasma lipids in specific patient subgroups in the DEFINE (Determining the Efficacy and Tolerability of CETP INhibition with AnacEtrapib) trial

Brinton EA, Kher U, Shah S, et al., DEFINE Investigators
J Clin Lipidol. 2015 Jan-Feb;9(1):65-71. doi: 10.1016/j.jacl.2014.10.005
 
Brinton et al. describe results of the Determining the Efficacy and Tolerability of cholesteryl ester transfer protein (CETP) INhibition with AnacEtrapib (DEFINE) trial, in which the effects of 24 weeks of treatment with anacetrapib on lipids and safety parameters was studied in 1623 patients with coronary heart disease (CHD) or CHD risk equivalents on background statin therapy [4]. Increases in HDL-c (138%) were seen, as well as lower LDL-c (estimated Friedewald calculation (Fc-LDL-c) : 40%), as compared with placebo. This report examines the effects of anacetrapib on key lipid endpoints in various subgroups of DEFINE patients, defined by age, gender, race, baseline HDL-c, baseline Fc-LDL-c, baseline TG, diabetes status, use of concomitant lipid-modifying therapy (LMT), type of concomitant statin or baseline TG.

 
Main results Brinton et al.

  • Anacetrapib treatment, as compared with placebo, yielded reductions in Fc-LDL-c in all subgroups examined.
  • Small differences (<7%, small as compared to overall LDL-c decrease of 40%) in percent reduction in Fc-LDL-c with anacetrapib were seen based on age, gender and type of LMT, and in patient with lower vs. higher baseline Fc-LDL-c, HDL-c or TG levels and diabetes status.
  • HDL-c increases with anacetrapib vs. placebo were also consistent across all subgroups, with modest differences (<30%, small relative to overall HDL-c increase of 138%) seen across demographic subgroups, or depending on type of LMT, and in patients with lower vs. higher lipid baseline levels.
  • Higher baseline TG levels (with cutoff of either >150 mg/dL or >200mg/dL) did not affect change in Fc-LDL-c and HDl-c with anacetrapib treatment.
  • Subgroups defined by background LMT and race had somewhat more effect on the Fc-LDL-c and HDL-c responses to anacetrapib than other subgroups.
  • Greater HDL-responses were seen in subjects taking less potent statins, as compared with simvastatin, atorvastatin or rosuvastatin, and in patients on background statin monotherapy as compared with nonstatin lipid therapies.
  • Smaller treatment effects were seen in black vs. white patients, but it should be noted that the number of black subjects was small.  
 

Conclusion

This analysis shows that the Fc-LDL-c lowering and HDL-increasing effect of anacetrapib in patients with CHD was generally independent of age, gender, diabetes status and lipid levels. Race and background lipid-modifying therapy may have an influence on the effect of treatment, although it is noted that these findings may be a play of chance as a consequence of the methodology.
 
Find Krauss et al. at J Clin Lipid.
Find Brinton et al. at J Clin Lipid.
 

References

1. Tall AR. Plasma cholesteryl ester transfer protein. J Lipid Res. 1993; 34:1255–1274.
2. Krauss RM, Wojnooski K, Orr J, et al. Changes in lipoprotein subfraction concentration and composition in healthy individuals treated with the CETP inhibitor anacetrapib. J Lipid Res. 2012; 53:540–547.
3. Bloomfield D, Carlson GL, Sapre A, et al. Efficacy and safety of the cholesteryl ester transfer protein inhibitor anacetrapib as monotherapy and coadministered with atorvastatin in dyslipidemic patients. Am Heart J. 2009;157:352–360.
4. Cannon CP, Shah S, Dansky HM, et al, for the DEFINE Investigators. Safety of anacetrapib in patients with or at high risk for coronary heart disease. N Engl J Med. 2010;363:2406–2415.

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