Efficacy and safety of combination simvastatin and
colesevelam in patients with primary
hypercholesterolemia.
Knapp HH, Schrott H, Ma P, Knopp R, Chin B, Gaziano JM, Donovan JM, Burke SK,
Davidson MH.
Lipid Research Clinic, University of Iowa, Iowa City USA.
PURPOSE: To examine the efficacy and safety of colesevelam hydrochloride, a novel,
nonsystemic, lipid-lowering agent, when coadministered with starting doses of simvastatin
in a multicenter, randomized, double-blind, placebo-controlled trial. PATIENTS AND
METHODS: Subjects with hypercholesterolemia (plasma low density lipoprotein [LDL]
cholesterol level > 160 mg/dL and triglyceride level < or = 300 mg/dL) were randomly
assigned to receive daily doses of placebo (n = 33), colesevelam 3.8 g (recommended dose,
n = 37), simvastatin 10 mg (n = 35), colesevelam 3.8 g with simvastatin 10 mg (n = 34),
colesevelam 2.3 g (low dose, n = 36), simvastatin 20 mg (n = 39), or colesevelam 2.3 g with
simvastatin 20 mg (n = 37), for 6 weeks. RESULTS: Mean LDL cholesterol levels
decreased relative to baseline in the placebo group (P < 0.05) and in all active treatment
groups (P < 0.0001). For groups treated with combination therapy, the mean reduction in
LDL cholesterol level was 42% (-80 mg/dL; P < 0.0001 compared with baseline), which
exceeded the reductions for simvastatin 10 mg (-26%, -48 mg/dL) or 20 mg (-34%, -61
mg/dL) alone, or for colesevelam 2.3 g (-8%, -17 mg/dL) or 3.8 g (-16%, -31 mg/dL) alone
(P < 0.001). The effects of combination therapy on serum HDL cholesterol and triglyceride
levels were similar to those for simvastatin alone. Side effects were similar among treatment
groups, and there were no clinically important changes in laboratory parameters.
CONCLUSION: Coadministration of colesevelam and simvastatin was effective and well
tolerated, providing additive reductions in LDL cholesterol levels compared with either
agent alone.
PMID: 11286949 [PubMed - indexed for MEDLINE]
: Am J Med. 2001 Apr 1;110(5):352-60
1: Atherosclerosis. 2001 Oct;158(2):407-16.
Coadministration of colesevelam hydrochloride with
atorvastatin lowers LDL cholesterol additively.
Hunninghake D, Insull W Jr, Toth P, Davidson D, Donovan JM, Burke SK.
University of Minnesota Heart Disease Prevention Clinic, Minneapolis, MN 55455, USA.
Colesevelam hydrochloride is a novel, potent, non-absorbed lipid-lowering agent previously
shown to reduce low density lipoprotein (LDL) cholesterol. To examine the efficacy and
safety of coadministration of colesevelam and atorvastatin, administration of these agents
alone or in combination was examined in a double-blind study of 94 hypercholesterolemic
men and women (baseline LDL cholesterol > or =160 mg/dl). After 4 weeks on the
American Heart Association Step I diet, patients were randomized among five groups:
placebo; colesevelam 3.8 g/day; atorvastatin 10 mg/day; coadminstered colesevelam 3.8
g/day plus atorvastatin 10 mg/day; or atorvastatin 80 mg/day. Fasting lipids were measured
at screening, baseline and 2 and 4 weeks of treatment. LDL cholesterol decreased by 1253% in all active treatment groups (P<0.01). LDL cholesterol reductions with combination
therapy (48%) were statistically superior to colesevelam (12%) or low-dose atorvastatin
(38%) alone (P<0.01), but similar to those achieved with atorvastatin 80 mg/day (53%).
Total cholesterol decreased 6-39% in all active treatment groups (P<0.05). High density
lipoprotein cholesterol increased significantly for all groups including placebo (P<0.05).
Triglycerides decreased in patients taking atorvastatin alone (P<0.05), but were unaffected
by colesevelam alone or in combination. The frequency of side effects did not differ among
groups. At recommended starting doses of each agent, coadministration of colesevelam and
atorvastatin was well tolerated, efficacious and produced additive LDL cholesterol
reductions comparable to those observed with the maximum atorvastatin dose.
PMID: 11583720 [PubMed - indexed for MEDLINE]
Atherosclerosis. 2006 Apr;185(2):327-30. Epub 2005 Jul 11.
Colesevelam HCl reduces LDL particle number and
increases LDL size in hypercholesterolemia.
Rosenson RS.
Preventive Cardiology Center, Department of Medicine, Division of Cardiology,
Northwestern University, The Feinberg School of Medicine, Galter Pavilion, Suite 11-120,
201 East Huron Street, Chicago, IL 60611, USA. r-rosenson@norhwestern.edu
BACKGROUND: Although LDL-cholesterol (LDL-C) remains the target of cholesterollowering therapy, high levels of LDL particle numbers better differentiate cardiovascular
risk than LDL-C concentrations. Colesevelam HCl, a novel bile acid sequestrant, has also
been shown to reduce mean LDL-C by 18% with the maximum dose. The effect of
colesevelam HCl on LDL particle number and particle size has not been previously
published. LDL particle number and particle size were measured by NMR spectroscopy.
METHODS: In this multi-center, double-blind, placebo-controlled study, 149 patients with
moderate hypercholesterolemia (LDL-C > 160 mg/dL [4.14 mmol/L]; triglycerides < 300
mg/dL [3.39 mmol/L]) were randomized to colesevelam HCl (1.5-3.75 g/d) or placebo for 6
weeks. RESULTS: Colesevelam HCl reduced LDL particle number by 6.8% at a dosage of
3.0 g/d (P = 0.031), and 13.7% (P = 0.0002) at a dosage of 3.75 g/d. Baseline levels of
triglycerides or LDL size did not influence changes in LDL particle number. Further, mean
LDL particle size increased with colesevelam HCl 3.75 g/d (1.1% increase versus baseline,
P < 0.05). CONCLUSION: For patients with moderate hypercholesterolemia, treatment with
colesevelam HCl at the recommended starting dose of 3.75 g/d lowered LDL particle
number, and increased mean LDL particle size.
PMID: 16009365 [PubMed - indexed for MEDLINE]
Atherosclerosis. 2001 Oct;158(2):407-16.
Coadministration of colesevelam hydrochloride with
atorvastatin lowers LDL cholesterol additively.
Hunninghake D, Insull W Jr, Toth P, Davidson D, Donovan JM, Burke SK.
University of Minnesota Heart Disease Prevention Clinic, Minneapolis, MN 55455, USA.
Colesevelam hydrochloride is a novel, potent, non-absorbed lipid-lowering agent previously
shown to reduce low density lipoprotein (LDL) cholesterol. To examine the efficacy and
safety of coadministration of colesevelam and atorvastatin, administration of these agents
alone or in combination was examined in a double-blind study of 94 hypercholesterolemic
men and women (baseline LDL cholesterol > or =160 mg/dl). After 4 weeks on the
American Heart Association Step I diet, patients were randomized among five groups:
placebo; colesevelam 3.8 g/day; atorvastatin 10 mg/day; coadminstered colesevelam 3.8
g/day plus atorvastatin 10 mg/day; or atorvastatin 80 mg/day. Fasting lipids were measured
at screening, baseline and 2 and 4 weeks of treatment. LDL cholesterol decreased by 1253% in all active treatment groups (P<0.01). LDL cholesterol reductions with combination
therapy (48%) were statistically superior to colesevelam (12%) or low-dose atorvastatin
(38%) alone (P<0.01), but similar to those achieved with atorvastatin 80 mg/day (53%).
Total cholesterol decreased 6-39% in all active treatment groups (P<0.05). High density
lipoprotein cholesterol increased significantly for all groups including placebo (P<0.05).
Triglycerides decreased in patients taking atorvastatin alone (P<0.05), but were unaffected
by colesevelam alone or in combination. The frequency of side effects did not differ among
groups. At recommended starting doses of each agent, coadministration of colesevelam and
atorvastatin was well tolerated, efficacious and produced additive LDL cholesterol
reductions comparable to those observed with the maximum atorvastatin dose.
PMID: 11583720 [PubMed - indexed for MEDLINE]
Am J Med. 2001 Apr 1;110(5):352-60.
Links
Efficacy and safety of combination simvastatin and
colesevelam in patients with primary
hypercholesterolemia.
Knapp HH, Schrott H, Ma P, Knopp R, Chin B, Gaziano JM, Donovan JM, Burke SK,
Davidson MH.
Lipid Research Clinic, University of Iowa, Iowa City USA.
PURPOSE: To examine the efficacy and safety of colesevelam hydrochloride, a novel,
nonsystemic, lipid-lowering agent, when coadministered with starting doses of simvastatin
in a multicenter, randomized, double-blind, placebo-controlled trial. PATIENTS AND
METHODS: Subjects with hypercholesterolemia (plasma low density lipoprotein [LDL]
cholesterol level > 160 mg/dL and triglyceride level < or = 300 mg/dL) were randomly
assigned to receive daily doses of placebo (n = 33), colesevelam 3.8 g (recommended dose,
n = 37), simvastatin 10 mg (n = 35), colesevelam 3.8 g with simvastatin 10 mg (n = 34),
colesevelam 2.3 g (low dose, n = 36), simvastatin 20 mg (n = 39), or colesevelam 2.3 g with
simvastatin 20 mg (n = 37), for 6 weeks. RESULTS: Mean LDL cholesterol levels
decreased relative to baseline in the placebo group (P < 0.05) and in all active treatment
groups (P < 0.0001). For groups treated with combination therapy, the mean reduction in
LDL cholesterol level was 42% (-80 mg/dL; P < 0.0001 compared with baseline), which
exceeded the reductions for simvastatin 10 mg (-26%, -48 mg/dL) or 20 mg (-34%, -61
mg/dL) alone, or for colesevelam 2.3 g (-8%, -17 mg/dL) or 3.8 g (-16%, -31 mg/dL) alone
(P < 0.001). The effects of combination therapy on serum HDL cholesterol and triglyceride
levels were similar to those for simvastatin alone. Side effects were similar among treatment
groups, and there were no clinically important changes in laboratory parameters.
CONCLUSION: Coadministration of colesevelam and simvastatin was effective and well
tolerated, providing additive reductions in LDL cholesterol levels compared with either
agent alone.
PMID: 11286949 [PubMed - indexed for MEDLINE]
Clin Cardiol. 2001 Jun;24(6):467-74. Links
Low-dose combination therapy with colesevelam
hydrochloride and lovastatin effectively decreases lowdensity lipoprotein cholesterol in patients with primary
hypercholesterolemia.
Davidson MH, Toth P, Weiss S, McKenney J, Hunninghake D, Isaacsohn J, Donovan
JM, Burke SK.
The Chicago Center for Clinical Research, Chicago, Illinois, USA.
BACKGROUND: Colesevelam hydrochloride is a novel, lipid-lowering agent that binds
bile acids with high affinity. A multicenter, randomized, double-blind, placebo-controlled,
parallel-design study was conducted to assess the efficacy and tolerability of combination
low-dose colesevelam and lovastatin treatment in patients with primary
hypercholesterolemia. HYPOTHESIS: Combination therapy with low doses of colesevelam
and lovastatin decreases low density (LDL) cholesterol with minimal adverse events.
METHODS: Following a 4- to 6-week dietary lead in, 135 patients were randomized into
five groups for a 4-week treatment period: placebo, colesevelam 2.3 g at dinner, lovastatin
10 mg at dinner, the combination of colesevelam and lovastatin given at dinner (dosed
together), and combination treatment with colesevelam given at dinner and lovastatin
administered at bedtime (dosed apart). RESULTS: Combination colesevelam and lovastatin
treatment decreased LDL cholesterol by 34% (60 mg/dl, p < 0.0001) and 32% (53 mg/dl, p
< 0.0001) when colesevelam and lovastatin were dosed together or dosed apart, respectively.
Both combination therapies were superior to either agent alone (p < 0.05). Decreases in
LDL cholesterol exceeded the combined decreases observed for colesevelam alone (13
mg/dl, 7%) and lovastatin alone (39 mg/dl, 22%). Both combination treatments reduced total
cholesterol by 21% (p < 0.0001) and apolipoprotein B by 24% (p < 0.0001). Neither
combination treatment significantly altered high-density lipoprotein cholesterol or
triglycerides. Adverse side effects were not significantly different among randomized
groups. CONCLUSIONS: Combination colesevelam and lovastatin was efficacious and well
tolerated, resulting in additive decreases in LDL cholesterol levels whether or not both
agents were administered simultaneously.
PMID: 11403509 [PubMed - indexed for MEDLINE]
Mayo Clin Proc. 2001 Oct;76(10):971-82. Links
Effectiveness of colesevelam hydrochloride in decreasing
LDL cholesterol in patients with primary
hypercholesterolemia: a 24-week randomized controlled
trial.
Insull W Jr, Toth P, Mullican W, Hunninghake D, Burke S, Donovan JM, Davidson
MH.
Baylor College of Medicine, Lipid Research Clinic, Houston, Tex, USA.
OBJECTIVE: To evaluate the efficacy, tolerability, and safety of colesevelam
hydrochloride, a new nonsystemic lipid-lowering agent. PATIENTS AND METHODS: In
this double-blind, placebo-controlled trial performed in 1998, 494 patients with primary
hypercholesterolemia (low-density lipoprotein [LDL] cholesterol level > or = 130 mg/dL
and < or = 220 mg/dL) were randomized to receive placebo or colesevelam (2.3 g/d, 3.0 g/d,
3.8 g/d, or 4.5 g/d) for 24 weeks. Fasting serum lipid profiles were measured to assess
efficacy. Adverse events were monitored, and discontinuation rates and compliance rates
were analyzed. The primary outcome measure was the mean absolute change of LDL
cholesterol from baseline to the end of the 24-week treatment period. RESULTS:
Colesevelam lowered mean LDL cholesterol levels 9% to 18% in a dose-dependent manner
(P<.001), with a median LDL cholesterol reduction of 20% at 4.5 g/d. The reduction in LDL
cholesterol levels was maximal after 2 weeks and sustained throughout the study. Mean total
cholesterol levels decreased 4% to 10% (P<.001), while median high-density lipoprotein
cholesterol levels increased 3% to 4% (P<.001). Median triglyceride levels increased by 5%
to 10% in placebo and colesevelam treatment groups relative to baseline (P<.05), but none
of these differences were significantly different from placebo. Mean apolipoprotein B levels
decreased 6% to 12% in an apparent dose-dependent manner (P<.001). No significant
differences occurred in adverse events or discontinuation rates between groups, and
compliance rates were between 88% and 92% for all groups. CONCLUSIONS:
Colesevelam was efficacious, decreasing mean LDL cholesterol levels by up to 18%, and
well tolerated without serious adverse events.
PMID: 11605698 [PubMed - indexed for MEDLINE]
Am J Cardiol. 2006 Apr 15;97(8):1198-205. Epub 2006 Mar 3.
Erratum in:
Am J Cardiol. 2006 Aug 1;98(3):428.
Links
Effects of colesevelam hydrochloride on low-density
lipoprotein cholesterol and high-sensitivity C-reactive
protein when added to statins in patients with
hypercholesterolemia.
Bays HE, Davidson M, Jones MR, Abby SL.
Louisville Metabolic and Atherosclerosis Research Center Incorporated, Louisville,
Kentucky, USA. hbaysmd@aol.com
Elevated high-sensitivity C-reactive protein (hs-CRP) levels are associated with an increased
risk of atherosclerotic coronary heart disease (CHD). The addition of the bile acid
sequestrants, such as colesevelam hydrochloride (HCl), to statins further reduces lowdensity lipoprotein (LDL) cholesterol levels. However, the effects of approved cholesterollowering bile acid sequestrants on hs-CRP have not previously been reported. Three
randomized, double-blind, placebo-controlled, parallel, 6-week clinical trials of similar
design investigated the efficacy of adding colesevelam HCl to stable simvastatin,
atorvastatin, or pravastatin treatment in 204 patients with primary hypercholesterolemia. The
primary end point was the mean percent change in the LDL cholesterol levels. Secondary
end points included the effects on other lipid parameters and hs-CRP levels. A pooled
analysis showed that adding colesevelam HCl to statin therapy significantly lowered LDL
cholesterol levels (21 mg/dl or 16% mean reduction from baseline, p = 0.0013, and 11 mg/dl
or 9% mean reduction compared with placebo, p = 0.0003). Four times as many patients
receiving colesevelam HCl plus a statin achieved a LDL cholesterol target of <100 mg/dl
compared with patients receiving a statin plus placebo (39% vs 10%, respectively, p
<0.0001). The incidence of mild gastrointestinal adverse effects was slightly higher in the
colesevelam HCl plus statin group than in the placebo plus statin group. Finally, the
differences in the change in hs-CRP levels with colesevelam HCl plus statin therapy were
significant compared with the changes with placebo plus statin (median change -23%, p =
0.0069). In conclusion, this is the first report suggesting that an approved cholesterollowering bile acid sequestrant, specifically colesevelam HCl, decreases hs-CRP levels when
added to statin therapy.
PMID: 16616026 [PubMed - indexed for MEDLINE]
Endocr Pract. 2007 Jan-Feb;13(1):11-6.
Colesevelam hydrochloride-ezetimibe combination lipidlowering therapy in patients with diabetes or metabolic
syndrome and a history of statin intolerance.
Rivers SM, Kane MP, Busch RS, Bakst G, Hamilton RA.
Department of Pharmacy Practice, Albany College of Pharmacy, Albany, NY 12208, USA.
OBJECTIVE: To determine the effectiveness and safety of colesevelam hydrochloride
(HCl) and ezetimibe combination therapy in statin-intolerant patients with dyslipidemia and
diabetes mellitus (DM) or metabolic syndrome (MS). METHODS: We identified potential
study subjects through a computerized text search of patient electronic medical records
using the terms colesevelam, WelChol, ezetimibe, and Zetia. Medical records were
subsequently reviewed to identify all patients with DM or MS. Baseline total cholesterol
(TC), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol
(HDL-C), non-HDL-C, and triglyceride levels immediately before the initiation of therapy
with colesevelam HCl (1.875 g twice a day) or ezetimibe (10 mg daily) were compared with
those after a minimum of 3 months of single drug therapy and after a minimum of 3 months
of combination therapy. Drug safety was evaluated by review of transaminase levels and
reports of side effects or drug discontinuation. RESULTS: The computerized search initially
identified 91 electronic medical records; 16 patients fulfilled all study criteria. Baseline
patient demographics included a mean age of 62.5 (+/-11.8) years and a mean body mass
index of 31.4 (+/-5.2) kg/m2; 50% of patients were female, 75% had type 2 DM, and 25%
had MS. In comparison with baseline, colesevelam HCl-ezetimibe combination therapy was
associated with significant reductions in mean levels of total cholesterol (27.5%), LDL-C
(42.2%), and non-HDL-C (37.1%). In addition, 50% of patients achieved the National
Cholesterol Education Program Adult Treatment Panel III LDL-C target of less than 100
mg/dL. Therapy was well tolerated, with no significant changes in mean transaminase
levels, no reports of myalgia, and no discontinuation of therapy. CONCLUSION:
Colesevelam HCl-ezetimibe combination therapy was associated with improved TC, LDLC, and non-HDL-C lipid profiles and was well tolerated. Such therapy may be a reasonable
consideration for statin-intolerant patients with DM or MS who have elevated cholesterol
levels.
PMID: 17360295 [PubMed - indexed for MEDLINE]
Curr Med Res Opin. 2006 Nov;22(11):2191-200.
Links
Lipid-lowering effects of colesevelam HCl in combination
with ezetimibe.
Bays H, Rhyne J, Abby S, Lai YL, Jones M.
Louisville Metabolic and Atherosclerosis Research Center Inc., Louisville, KY 40213, USA.
hbaysmd@aol.com
OBJECTIVE: The primary aim of this study was to compare the effect of colesevelam HCl
in combination with ezetimibe to ezetimibe monotherapy on low-density lipoprotein
cholesterol (LDL-C) levels in subjects with primary hypercholesterolemia. METHODS:
Subjects with primary hypercholesterolemia (N = 86) were enrolled in a multicenter,
randomized, double-blind, placebo-controlled, parallel-group study. After a 4- to 8-week
washout period, subjects received colesevelam HCl 3.8 g/day plus ezetimibe 10 mg/day or
colesevelam HCl placebo plus ezetimibe 10 mg/day for 6 weeks. The primary efficacy
endpoint was the mean percent change in LDL-C during randomized treatment. Secondary
endpoints included mean absolute change in LDL-C, mean absolute and mean percent
change in levels of high-density lipoprotein cholesterol (HDL-C), non-HDL-C, total
cholesterol (TC), apolipoprotein (apo) A-I and apo B, and median absolute and percent
changes in triglycerides (TG) and high-sensitivity C-reactive protein from baseline to end of
treatment. Of the 86 subjects randomized to treatment, 85 were included in the intent-totreat analysis. RESULTS: After 6 weeks of treatment, colesevelam HCl plus ezetimibe
produced a mean percent change in LDL-C of -32.3% versus -21.4% with ezetimibe
monotherapy (p < 0.0001). Colesevelam HCl plus ezetimibe was significantly more
effective than ezetimibe alone at producing mean percent reductions in TC, non-HDL-C,
and apo B and increases in apo A-I (p < 0.005 for all). Neither treatment regimen resulted in
significant changes in median TG levels compared with baseline (p = NS). Both treatments
were safe and generally well tolerated. CONCLUSIONS: Colesevelam HCl plus ezetimibe
combination therapy significantly reduced mean LDL-C, TC, non-HDL-C, and apo B levels
and increased apo A-I levels (p < 0.005 for all) without significantly increasing median TG
levels in hypercholesterolemic subjects compared with ezetimibe alone. Although limited in
that atherosclerotic coronary heart disease outcomes were not evaluated, this study
demonstrated that combining colesevelam HCl with ezetimibe is a therapeutic option in
hypercholesterolemic patients, such as those in whom statins are contraindicated and/or who
may have intolerances to statin therapy.
PMID: 17076980 [PubMed - indexed for MEDLINE]