Physicians' Academy for Cardiovascular Education

New add-on lipid-lowering therapy well tolerated in hypercholesterolemia patients

Stein et al., J Clin Lipidol 2016

Efficacy and Safety of Gemcabene as Add-on to Stable Statin Therapy in Hypercholesterolemic Patients

 
Stein E, Bays H, Koren M, et al.
Journal of Clinical Lipidology 2016; published online ahead of print
 

Background

Data support that each 1.0 mmol/L (38.7 mg/dL) lowering in LDL-C reduces the incidence of major coronary events, coronary revascularisations, and ischemic stroke by approximately 20% [1]. Based on this well-established relationship, most guidelines recommend [2,3]:
  • lowering of LDL-C to < 100 mg/dL (< 2.59 mmol/L) for patients at high CV risk
  • lowering of LDL-C to < 70 mg/dL (< 1.81 mmol/L) in patients with established CV disease.
The first line therapy for LDL-C lowering are statins, however, there are patients intolerant to statins and patients who cannot achieve LDL-C targets with statins alone. Existing add-on therapies for additional LDL-C reduction include bile acid sequestrants, fibrates, nicotinic acid and ezetimibe, but their use is restricted by tolerability issues, side effects or limited efficacy, while PCSK9 monoclonal antibody inhibitors are expensive and require parenteral administration.
 
Gemcabene enhances the clearance of VLDL through the reduction of hepatic apolipoprotein C-III (apoC-III) messenger RNA (mRNA) [4-6]. In Phase 2 studies, gemcabene was well tolerated and resulted in significant lowering of LDL-C, apolipoprotein B (apoB), and C-reactive protein (CRP) in hypercholesterolaemia patients, and in significant lowering of triglycerides (TGs) and increase in HDL-C in hypertriglyceridaemia patients.
In this phase 2 8-week, double-blind, placebo-controlled study the efficacy and safety of gemcabene was evaluated when added to stable statin-therapy, in patients with LDL-C ≥ 130 mg/dL (3.4 mmol/L) despite statin therapy.
 

Main results

  • Mean LDL-c (+SE) at baseline was 157.4 (5.7) in those randomised to placebo, and 149.6 (6.8) and 149.0 (6.1) in those randomised to gemcabene 300 and 900 mg respectively.
  • The mean (±SE) percent LDL-C changes were: for gemcabene 300 mg (n=20): –23.4 ± 4.7% (P=0.009), for gemcabene 900 mg (n=22): –27.7 ± 4.37% (P< 0.001), for placebo (n=24): -6.2 ± 4.3%.
  • The mean (±SE) percent non-HDL-C changes were: for gemcabene 300 mg: -19.8 ± 4.3% (P=0.032), for gemcabene 900mg: -23.9 ± 4.0% (P=0.004), for placebo: -6.9 ± 3.9%.
  • The mean (±SE) percent apoB changes were: for gemcabene 300 mg: -11.9 ± 6.6% (P=0.301), for gemcabene 900 mg: -17.2 ± 6.0% (P=0.086), for placebo: -2.80 ± 5.7%.
  • The median percent changes in CRP were: for gemcabene 300 mg: -26.1% (P=0.196), for gemcabene 900 mg: -53.9% (P<0.001), for placebo -11.1%.
  • The mean (±SE) percent TG changes were: for gemcabene 300 mg: -15.6 ± 3.5% (P=0.026), for gemcabene 900 mg: -19.9 ± 3.1% (P=0.001), for placebo: -4.8 ± 3.1%.
  • There was no change in HDL-C with gemcabene vs. placebo.
  • Gemcabene was well tolerated. Changes in clinical laboratory assessments were small, non-significant and similar across treatment groups. There were no clinically meaningful changes in physical exams or vital signs during the study.

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Conclusion

The investigational lipid-lowering agent gemcabene was well tolerated in hypercholesterolemia patients on statin therapy and 300 mg and 900 mg produced significant reductions of LDL-C, non-HDL-c and CRP levels. These data support the further development of gemcabene as an add-on therapy to reduce LDL-C in patients unable to reach LDL-C goal despite statin therapy.
 
Find this article online at J Clin Lipidology
 

References

1. Baigent, C., Keech, A., Kearney, et al. 2005. Efficacy and safety of cholesterol-lowering treatment: prospective meta-analysis of data from 90,056 participants in 14 randomised trials of statins. Lancet 366:1267-1278.
2. Grundy, S.M., Cleeman, J.I., Merz, C.N., et al and Coordinating Committee of the National Cholesterol Education, P. 2004. Implications of recent clinical trials for the National Cholesterol Education Program Adult Treatment Panel III Guidelines. J Am Coll Cardiol 44:720-732.
3. Smith, S.C., Jr., Allen, J., Blair, S.N., et al. 2006. AHA/ACC guidelines for secondary prevention for patients with coronary and other atherosclerotic vascular disease: 2006 update: endorsed by the National Heart, Lung, and Blood Institute. Circulation 113:2363-2372.
4. Bisgaier, C.L., Creger, P.L., Saltiel, A.R., et al. 1998. US Patent 5,756,544 Carboxyalkylethers, formulations, and treatment of vascular diseases. United States: Warner-Lambert Company (Morris Plains, NJ).
5. Bisgaier, C.L., Newton, Roger Schofield 2013. US Patent 8,557,835 Statincarboxyalkylether combinations. United States: Warner-Lambert Company, LLC (New York, NY, US).
6. Bisgaier, C.L., Essenburg, A.D., Barnett, B.C., et al. 1998. A novel compound that elevates high density lipoprotein and activates the peroxisome proliferator activated receptor. J Lipid Res 39:17-30.