Colesevelam added to combination therapy with a statin and ezetimibe in patients with familial hypercholesterolemia: a 12-week, multicenter, randomized, double-blind, controlled trial.
BACKGROUND
Familial hypercholesterolemia (FH) has been associated with increased cardiovascular risk when untreated or when normal LDL-C concentrations are not reached. Some patients with FH do not reach LDL-C goals despite intensive combination therapy.


OBJECTIVE
This study assessed the efficacy and tolerability of colesevelam added to maximally tolerated, stable-dose combination treatment with a statin + ezetimibe.


METHODS
This Phase IV, multicenter, randomized, double-blind, placebo-controlled trial enrolled patients aged 18 to 75 years with FH and an LDL-C concentration >2.5 mmol/L who were receiving a maximally tolerated and stable regimen of a statin + ezetimibe. Patients were randomly assigned to receive colesevelam 3.75 g/d or placebo added to the statin + ezetimibe for 12 weeks. The primary efficacy outcome was the difference in LDL-C between the colesevelam and placebo groups after 6 weeks. Secondary efficacy outcomes were between-group differences in LDL-C, total cholesterol (TC), HDL-C, triglyceride (Tg), apolipoprotein (apo) B, and apoA-I concentrations, as well as apoB/apoA-I ratio after 12 weeks. Tolerability was assessed based on the prevalences of adverse events by organ system class in each treatment group.


RESULTS
Eighty-six patients were randomized (45 colesevelam, 41 placebo), of whom 84 (44 colesevelam, 40 placebo) were included in the primary analysis. The mean (SD) age of the participants was 52.8 (10.8) years, and 51 (59%) were men. The difference (95% CI) in LDL-C between colesevelam and placebo after 6 weeks was -18.5% (-25.3 to -11.8). Between-group differences in LDL-C, TC, HDL-C, Tg, and apoB/apoA-I ratio after 12 weeks were -12.0% (-17.8 to -6.3), -7.3% (-12.0 to -2.6), +3.3% (-2.4 to +9.0), +2.8% (-10.4 to +15.9), and -12.2% (-20.2 to -4.2), respectively. Colesevelam was generally well tolerated, with gastrointestinal adverse events in 12 of 45 patients (27%) versus 7 of 40 (18%) in the placebo group (P = NS).


CONCLUSIONS
In these patients with FH, colesevelam added to a combination of a statin + ezetimibe was associated with significantly improved LDL-C concentrations compared with placebo during the 12-week study period and was generally well tolerated.
Huijgen
Roeland
R
Department of Vascular Medicine, Academic Medical Centre, Amsterdam, the Netherlands.
Abbink
Evertine J
EJ
Bruckert
Eric
E
Stalenhoef
Anton F H
AF
Imholz
Ben P M
BP
Durrington
Paul N
PN
Trip
M D
MD
Eriksson
Mats
M
Visseren
Frank L J
FL
Schaefer
Juergen R
JR
Kastelein
John J P
JJ
D000293:Adolescent; D000328:Adult; D000368:Aged; D000499:Allylamine / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000627:therapeutic use; D000924:Anticholesteremic Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D001053:Apolipoproteins / Q000097:blood; D001384:Azetidines / Q000008:administration & dosage / Q000627:therapeutic use*; D015992:Body Mass Index; D002784:Cholesterol / Q000097:blood; D000069472:Colesevelam Hydrochloride; D004311:Double-Blind Method; D004359:Drug Therapy, Combination; D000069438:Ezetimibe; D005260:Female; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000008:administration & dosage / Q000627:therapeutic use*; D006938:Hyperlipoproteinemia Type II / Q000188:drug therapy*; D008297:Male; D008875:Middle Aged; D012907:Smoking; D014280:Triglycerides / Q000097:blood; D055815:Young Adult
D000924:Anticholesteremic Agents; D001053:Apolipoproteins; D001384:Azetidines; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D014280:Triglycerides; D000499:Allylamine; D002784:Cholesterol; D000069438:Ezetimibe; D000069472:Colesevelam Hydrochloride