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Welchol

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Welchol

Welchol

CLINICAL PHARMACOLOGY

Mechanism Of Action

Primary Hyperlipidemia

Colesevelam hydrochloride, the active pharmaceutical ingredient in WELCHOL, is a non-absorbed, lipid-lowering polymer that binds bile acids in the intestine, impeding their reabsorption. As the bile acid pool becomes depleted, the hepatic enzyme, cholesterol 7-α-hydroxylase, is upregulated, which increases the conversion of cholesterol to bile acids. This causes an increased demand for cholesterol in the liver cells, resulting in the dual effect of increasing transcription and activity of the cholesterol biosynthetic enzyme, HMG-CoA reductase, and increasing the number of hepatic LDL receptors. These compensatory effects result in increased clearance of LDL-C from the blood, resulting in decreased serum LDL-C levels. Serum TG levels may increase or remain unchanged.

Type 2 Diabetes Mellitus

The mechanism by which WELCHOL improves glycemic control is unknown.

Pharmacodynamics

A maximum therapeutic response to the lipid-lowering effects of WELCHOL was achieved within 2 weeks and was maintained during long-term therapy. In the diabetes clinical studies, a therapeutic response to WELCHOL, as reflected by a reduction in hemoglobin A1C (A1C), was initially noted following 4-6 weeks of treatment and reached maximal or near-maximal effect after 12-18 weeks of treatment.

Pharmacokinetics

Absorption

Colesevelam hydrochloride is a hydrophilic, water-insoluble polymer that is not hydrolyzed by digestive enzymes and is not absorbed.

Distribution

Colesevelam hydrochloride is not absorbed, and therefore, its distribution is limited to the gastrointestinal tract.

Metabolism

Colesevelam hydrochloride is not metabolized systemically and does not interfere with systemic drug-metabolizing enzymes such as cytochrome P-450.

Excretion

In 16 healthy volunteers, an average of 0.05% of administered radioactivity from a single 14C-labeled colesevelam hydrochloride dose was excreted in the urine.

Drug Interactions

Drug interactions between colesevelam and concomitantly administered drugs were screened through in vitro studies and confirmed in in vivo studies. In vitro studies demonstrated that cephalexin, metformin, and ciprofloxacin had negligible binding to colesevelam hydrochloride. Therefore, an in vivo pharmacokinetic interaction of WELCHOL with these drugs is unlikely. WELCHOL was found to have no significant effect on the bioavailability of aspirin, atenolol, digoxin, enalapril, fenofibrate, lovastatin, metoprolol, phenytoin, pioglitazone, quinidine, rosiglitazone, sitagliptin, valproic acid, and warfarin. The results of additional in vivo drug interactions of WELCHOL are presented in Table 5.

Table 5 : Mean Change in Drug Exposure (AUC0-∞ and Cmax) when Administered with WELCHOL (3.75 g)a

  Dose Co-administered 1 hr prior to WELCHOL 4 hr prior to WELCHOL
Drug AUC0-∞ Cmax AUC0-∞ Cmax AUC0-∞ Cmax
Cyclosporine 200 mg -34% -44% N/A N/A N/A N/A
Ethinyl Estradiol* b 0.035 mg -24% -24% -18% -1% -12% 0%
Glimepiride b 4 mg -18% -8% N/A N/A -6% 3%
Glipizide b 20 mg -12% -13% N/A N/A -4% 0%
Glyburide b 3 mg -32% -47% -20% -15% -7% 4%
Levothyroxine b 600 ?g -22% -33% 6% -2% 1% 8%
Metformin ER c 1500 mg 44% 8% N/A N/A N/A N/A
Norethindrone* b 1 mg -1% -20% 5% -3% 6% 7%
Olmesartan Medoxomilb 40 mg -39% -28% N/A N/A -15% -4%
Repaglinide 2 mg -7% -19% -6% -1% N/A N/A
Verapamil sustained-release 240 mg -31% -11% N/A N/A N/A N/A
aWith verapamil, the dose of WELCHOL was 4.5 g
bShould be administered at least 4 hours prior to WELCHOL [See DRUG INTERACTIONS].
cPatients receiving concomitant metformin ER and colesevelam should be monitored for clinical response as is usual for the use of anti-diabetes drugs [See DRUG INTERACTIONS].
dCyclosporine levels should be monitored and, based on theoretical grounds, cyclosporine should be administered at least 4 hours prior to WELCHOL [See DRUG INTERACTIONS].
* Oral contraceptive containing norethindrone and ethinyl estradiol. N/A – Not Available

Animal Toxicology And/Or Pharmacology

Reproductive Toxicology Studies

Reproduction studies have been performed in rats and rabbits at doses up to 3 g/kg/day and 1 g/kg/day, respectively (approximately 50 and 17 times the maximum human dose, based on body weight, mg/kg) and have revealed no evidence of harm to the fetus due to colesevelam hydrochloride.

Clinical Studies

Primary Hyperlipidemia

WELCHOL reduces TC, LDL-C, apolipoprotein B (Apo B), and non-HDL-C when administered alone or in combination with a statin in patients with primary hyperlipidemia.

Approximately 1600 patients were studied in 9 clinical trials with treatment durations ranging from 4 to 50 weeks. With the exception of one open-label, uncontrolled, long-term extension study, all studies were multicenter, randomized, double-blind, and placebo-controlled. A maximum therapeutic response to WELCHOL was achieved within 2 weeks and was maintained during long-term therapy.

Monotherapy

In a study in patients with LDL-C between 130 mg/dL and 220 mg/dL (mean 158 mg/dL), WELCHOL was given for 24 weeks in divided doses with the morning and evening meals.

As shown in Table 6, the mean LDL-C reductions were 15% and 18% at the 3.8 g and 4.5 g doses. The respective mean TC reductions were 7% and 10%. The mean Apo B reductions were 12% in both treatment groups. WELCHOL at both doses increased HDL-C by 3%. Increases in TG of 9-10% were observed at both WELCHOL doses but the changes were not statistically different from placebo.

Table 6 : Response to WELCHOL Monotherapy in a 24-Week Trial -Percent Change in Lipid Parameters from Baseline

Grams/Day N TC LDL-C Apo B HDL-Ca Non-HDL-C TGa
Placebo 88 +1 +0 +0 –1 +1 +5
3.8 g (6 tablets) 95 –7* –15* –12* +3* –10* 10
4.5 g (7 tablets) 94 –10* –18* –12* 3 –13* 9
*p < 0.05 for lipid parameters compared to placebo, for Apo B compared to baseline.
aMedian % change from baseline.

In a study in 98 patients with LDL-C between 145 mg/dL and 250 mg/dL (mean 169 mg/dL), WELCHOL 3.8 g was given for 6 weeks as a single dose with breakfast, as a single dose with dinner, or as divided doses with breakfast and dinner. The mean LDL-C reductions were 18%, 15%, and 18% for the 3 dosing regimens, respectively. The reductions with these 3 regimens were not statistically different from one another.

Combination Therapy

Co-administration of WELCHOL and a statin (atorvastatin, lovastatin, or simvastatin) in 3 clinical studies demonstrated an additive reduction of LDL-C. The mean baseline LDL-C was 184 mg/dL in the atorvastatin study (range 156-236 mg/dL), 171 mg/dL in the lovastatin study (range 115-247 mg/dL), and 188 mg/dL in the simvastatin study (range 148-352 mg/dL). As demonstrated in Table 7, WELCHOL doses of 2.3 g to 3.8 g resulted in an additional 8% to 16% reduction in LDL-C above that seen with the statin alone.

Table 7 : Response to WELCHOL in Combination with Atorvastatin, Simvastatin, or Lovastatin -Percent Change in Lipid Parameters

Dose/Day N TC LDL-C Apo B HDL-Ca Non-HDL-C TGa
Atorvastatin Trial (4-week)
Placebo 19 +4 +3 -3 +4 +4 +10
Atorvastatin 10 mg 18 -27* -38* -32* +8 -35* -24*
WELCHOL 3.8 g/Atorvastatin 10 mg 18 -31* -48* -38* +11 -40* -1
Atorvastatin 80 mg 20 -39* -53* -46* +6 -50* -33*
Simvastatin Trial (6-week)
Placebo 33 -2 -4 4* -3 -2 +6*
Simvastatin 10 mg 35 -19* -26* -20* +3* -24* -17*
WELCHOL 3.8 g/Simvastatin 10 mg 34 -28* -42* -33* +10* -37* -12*
Simvastatin 20 mg 39 -23* -34* -26* +7* -30* -12*
WELCHOL 2.3 g/Simvastatin 20 mg 37 -29* -42* -32* +4* -37* -12*
Lovastatin Trial (4-week)
Placebo 26 +1 0 0 +1 +1 +1
Lovastatin 10 mg 26 -14* -22* -16* +5 -19* 0
WELCHOL 2.3 g/Lovastatin 10 mg Together 27 -21* -34* -24* +4 -27* -1
WELCHOL 2.3 g/Lovastatin 10 mg Apart 23 -21* -32* -24* +2 -28* -2
*p < 0.05 for lipid parameters compared to placebo, for Apo B compared to baseline.
aMedian % change from baseline.

In all 3 studies, the LDL-C reduction achieved with the combination of WELCHOL and any given dose of statin therapy was statistically superior to that achieved with WELCHOL or that dose of the statin alone. The LDL-C reduction with atorvastatin 80 mg was not statistically significantly different from the combination of WELCHOL 3.8 g and atorvastatin 10 mg.

The effect of WELCHOL when added to fenofibrate was assessed in 122 patients with mixed hyperlipidemia (Fredrickson Type IIb). Inclusion in the study required LDL-C ≥ 115 mg/dL and TG 150 mg/dL to 749 mg/dL. Patients were treated with 160 mg of fenofibrate during an 8-week open-label run-in period and then randomly assigned to receive fenofibrate 160 mg plus either WELCHOL 3.8 g or placebo for 6 weeks of double-blind treatment. The overall mean LDL-C at the start of randomized treatment was 144 mg/dL. The results of the study are summarized in Table 8.

Table 8 : Response to WELCHOL Added to Fenofibrate in Patients with Mixed Hyperlipidemia (Mean % Change from Treated Baselineb at 6 Weeks)

Treatment N TC LDL-C Apo B HDL-C Non-HDL-C TGa
Placebo + Fenofibrate 160 mg 61 2 2 1 -1 2 -3
WELCHOL + Fenofibrate 160 mg 61 -6* -10* -7* 0 -8* 6
* p ≤ 0.0002 compared to placebo.
aFor triglycerides, median % change from baseline.
bTreated Baseline: following 8-week treatment with open-label fenofibrate 160 mg.

Pediatric Therapy

The safety and efficacy of WELCHOL in pediatric patients were evaluated in an 8-week, multi-center, randomized, double-blind, placebo-controlled, parallel-group study followed by an open-label phase, in 194 boys and postmenarchal girls 10-17 years of age (mean age 14.1 years) with heterozygous familial hypercholesterolemia (heFH), taking a stable dose of an FDA-approved statin (with LDL-C > 130 mg/dL) or na´ve to lipid-lowering therapy (with LDL-C > 160 mg/dL). This study had 3 periods: a single-blind, placebo stabilization period; an 8-week, randomized, double-blind, parallel-group, placebo-controlled treatment period; and an 18-week, open-label treatment period. Forty-seven (24%) patients were taking statins and 147 (76%) patients were statin-na´ve at screening. The mean baseline LDL-C at Day 1 was approximately 199 mg/dL.

During the double-blind treatment period, patients were assigned randomly to treatment: WELCHOL 3.8 g/day (n=64), WELCHOL 1.9 g/day (n=65), or placebo (n=65). In total, 186 patients completed the double-blind treatment period. After 8 weeks of treatment, WELCHOL 3.8 g/day significantly decreased plasma levels of LDL-C, non-HDL-C, TC, and Apo B and significantly increased HDL-C. A moderate, non-statistically significant increase in TG was observed versus placebo (Table 9).

Table 9 : Response to WELCHOL 3.8 g Compared to Placebo in Pediatric Patients 10-17 Years of Age – Mean Percent Change in Lipid Parameters from Baseline to Week 8

Treatment Difference TC
(N=128)
LDL-C
(N=128)
Apo B
(N=124)
HDL-C
(N=128)
Non-HDL- C
(N=128)
TGa
(N=128)
WELCHOL 3.8 g vs Placebo -7* -13* -8* +6* -11 * +5
*p ≤ 0.05 for lipid parameters compared to placebo
Values represent LS mean. Only patients with values at both study baseline and endpoint are included in this table. Study baseline was defined as the last value measured before or on Day 1 prior to the first dose of randomized study medication.
aFor triglycerides, median % change from baseline. Results were based on the ITT population with LOCF

During the open-label treatment period patients were treated with WELCHOL 3.8 g/day. In total, 173 (89%) patients completed 26 weeks of treatment. Results at Week 26 were consistent with those at Week 8.

Type 2 Diabetes Mellitus

WELCHOL has been studied as monotherapy and in combination with metformin, pioglitazone, sulfonylureas, and insulin. In these studies, WELCHOL and placebo were administered either as 3 tablets twice daily with lunch and dinner or as 6 tablets with dinner alone.

Monotherapy

The efficacy of WELCHOL 3.8 g/day as anti-diabetes monotherapy was evaluated in a randomized double-blind, placebo-controlled trial involving 357 patients (176 WELCHOL and 181 placebo) with T2DM who were treatment-na´ve or had not received antihyperglycemic medication within 3 months prior to the start of the study. Statin use at baseline was reported in 13% of the WELCHOL-treated patients and 16% of the placebo-treated patients.

WELCHOL resulted in a statistically significant reduction in A1C of 0.27% compared to placebo (Table 10).

The mean baseline LDL-C was 121 mg/dL in the monotherapy trial. WELCHOL treatment resulted in a placebo-corrected 11% reduction in LDL-C. WELCHOL treatment also reduced serum TC, ApoB, and non-HDL-C (Table 11). The mean change in body weight was 0.6 kg for WELCHOL and -0.7 kg for placebo treatment groups.

Table 10 : Glycemic Parameters in a 24-Week Placebo-Controlled Study of WELCHOL Monotherapy in Patients with Type 2 Diabetes

  WELCHOL 3.8 g/day Placebo
A1C (%), Mean
N 175 169
Baseline 8.25 8.17
Change from baselinea -0.26 0.01
Treatment difference (p-value) -0.27 (p=0.013)
FPG (mg/dL), Mean
N 172 166
Baseline 172 168
Change from baselinea -4.6 5.7
Treatment difference (p-value) -10.3 (p=0.037b)
a Least-squares mean change calculated from an Analysis of Covariance model
bNominal p=value, not controlled for multiplicity testing.
A1C = hemoglobin A1C, FPG = fasting plasma glucose

Table 11 :Percent Change in Lipid Parameters in a 24-Week Placebo-Controlled Study of WELCHOL Monotherapy in Patients with Type 2 Diabetes

Dose/Day N† TC LDL-C Apo B HDL-C Non-HDL-C TGa
WELCHOL 3.8 g 162 -3.3* -10.0* -5.6* 1.7 -4.4* 15.5
Placebo 160 1.8 1.2 0.9 -0.1 3.0 5.8
*p < 0.001 for lipid parameters compared to placebo (this more stringent criterion for statistical significance accounts for multiplicity testing of the lipid parameters, which were secondary endpoints in the diabetes trials)
aMedian % change from baseline.
†The number of patients with analyzable data, i.e., a baseline and post-treatment value (last-observation carried forward), varied slightly among different parameters. The N given represents the smallest number of patients included in the analysis for any parameter.

Add-on combination Therapy

The efficacy of WELCHOL 3.8 g/day in patients with type 2 diabetes mellitus was evaluated in 5 double-blind, placebo-controlled add-on therapy trials involving a total of 1691 patients with baseline A1C 7.5-9.5%. Patients were enrolled and maintained on their pre-existing, stable, background anti-diabetic regimen. Statin use at baseline was reported in 41% of the WELCHOL-treated patients and 48% of the placebo-treated patients.

In 3 add-on combination therapy trials (metformin, sulfonylurea and insulin), treatment with WELCHOL resulted in a statistically significant reduction in A1C of 0.5% compared to placebo. Similar placebo-corrected reductions in A1C occurred in patients who received WELCHOL in combination with metformin, sulfonylurea, or insulin monotherapy or combinations of these therapies with other anti-diabetic agents. In the pioglitazone trial, treatment with WELCHOL resulted in a statistically significant reduction in A1C of 0.32% compared to placebo. In the metformin, pioglitazone, and sulfonylurea trials, treatment with WELCHOL also resulted in statistically significant reductions in fasting plasma glucose (FPG) of at least 14 mg/dL compared to placebo.

WELCHOL had consistent effects on A1C across subgroups of age, gender, race, body mass index, and baseline A1C. WELCHOL's effects on A1C were also similar for the two dosing regimens (3 tablets with lunch and with dinner or 6 tablets with dinner alone).

The mean baseline LDL-C was 104 mg/dL in the metformin study (range 32-214 mg/dL), 107 mg/dL in the pioglitazone study (range 48-263 mg/dL), 106 mg/dL in the sulfonylurea study (range 41-264 mg/dL), 102 mg/dL in the insulin study (range 35-204 mg/dL). In these trials, WELCHOL treatment was associated with a 12% to 16% reduction in LDL-C levels. The percentage decreases in LDL-C were of similar magnitude to those observed in patients with primary hyperlipidemia. WELCHOL treatment was associated with statistically significant increases in TG levels in the studies of patients on insulin, patients on a sulfonylurea, and patients on pioglitazone but not in the study of patients on metformin. The clinical significance of these increases is unknown. WELCHOL is contraindicated in patients with TG levels > 500 mg/dL [See CONTRAINDICATIONS] and periodic monitoring of lipid parameters including TG and non-HDL-C levels is recommended [See WARNINGS AND PRECAUTIONS and ADVERSE REACTIONS].

Body weight did not significantly increase from baseline with WELCHOL therapy, compared with placebo, in any of the add-on combination diabetes studies.

Add-on Combination Therapy with Metformin

WELCHOL 3.8 g/day or placebo was added to background anti-diabetic therapy in a 26-week trial of 316 patients already receiving treatment with metformin alone (N=159) or metformin in combination with other oral agents (N=157). A total of 60% of these patients were receiving ≥ 1,500 mg/day of metformin. In combination with metformin, WELCHOL resulted in statistically significant placebo-corrected reductions in A1C and FPG (Table 12). WELCHOL also reduced TC, LDL-C, Apo B, and non-HDL-C (Table 13). The mean percent change in serum LDL-C levels with WELCHOL compared to placebo was -16% among statin users and statin non-users; the median percent change in serum TG levels with WELCHOL compared to placebo was -2% among statin users and 10% among statin non-users. The mean change in body weight was -0.5 kg for WELCHOL and -0.3 kg for placebo.

Table 12 : Glycemic Parameters in a 26-Week Placebo-Controlled Study of WELCHOL in Combination with Metformin in Patients with Type 2 Diabetes

  Total Patient Population Metformin Alone Metformin in Combination with Other Oral
WELCHOL 3.8 g/day Placebo WELCHOL 3.8 g/day Placebo Anti-Diabeti WELCHOL 3.8 g/day c Agents Placebo
A1C (%), Mean
N 148 152 79 76 69 76
Baseline 8.1 8.1 8.2 8.2 8.1 8.0
Change from baselinea -0.4 0.2 -0.4 0.0 -0.4 0.3
Treatment difference (p-value) -0.5 (p < 0.001) -0.5 (p=0.002) -0.6 (p < 0.001)
FPG (mg/dL), Mean
N 149 152 79 76 70 76
Baseline 178 174 184 180 171 168
Change from baselinea -3 11 -7 8 0 13
Treatment difference (p-value) -14 (p==0.01) -14 (p==0.07) -14 (p=0.10)
aLeast-squares mean change calculated from an Analysis of Covariance model.
A1C = hemoglobin A1C, FPG = fasting plasma glucose

Table 13 : Percent Change in Lipid Parameters in a 26-Week Placebo-Controlled Study of WELCHOL in Combination with Metformin in Patients with Type 2 Diabetes

Dose/Day N† TC LDL-C Apo B HDL-C Non-HDL- C TGa
Total Patient Population
WELCHOL 3.8 g 125 -4* -12* -4* 1 -6* 12
Placebo 126 3 4 4 0 5 7
Metformin Alone
WELCHOL 3.8 g 66 -3 -9 -2 1 -4 15
Placebo 61 2 0 1 -2 4 8
Metformin in Combination with Other Oral Anti-diabetic Agents
WELCHOL 3.8 g 59 -6* -15* -6* 1 -7* 8
Placebo 65 4 7 7 2 6 5
*p < 0.001 for lipid parameters compared to placebo (this more stringent criterion for statistical significance accounts for multiplicity testing of the lipid parameters, which were secondary endpoints in the diabetes trials)
aMedian % change from baseline.
†The number of patients with analyzable data, i.e., a baseline and post-treatment value (last-observation carried forward), varied slightly among different parameters. The N given represents the smallest number of patients included in the analysis for any parameter.

Add-on Combination Therapy with pioglitazone

WELCHOL 3.8 g/day or placebo was added to background anti-diabetic therapy in a 24-week trial of 562 patients already receiving treatment with pioglitazone alone (N=51) or pioglitazone in combination with other oral agents (N=511). Of these, most were on dual therapy with metformin (N=298) or triple therapy with metformin and a sulfonylurea (N=139). In combination with pioglitazone-based therapy, WELCHOL resulted in statistically significant reductions in A1C and FPG compared to placebo (Table 14). WELCHOL also reduced TC, LDL-C, Apo B, and non-HDL-C but increased serum TG (Table 15). The mean change in body weight was 0.8 kg for WELCHOL and 0.4 kg for placebo.

Table 14 : Glycemic Parameters in a 24-Week Placebo-Controlled Study of WELCHOL in Combination with Pioglitazone Based Therapy in Patients with Type 2 Diabetes

  WELCHOL 3.8 g/day Placebo
A1C (%), Mean
N 271 276
Baseline 8.2 8.1
Change from baselinea -0.34 -0.02
Treatment difference (p-value) -0.32 (0.0001)
FPG (mg/dL), Mean
N 268 270
Baseline 155 157
Change from baselinea -4.8 +9.9
Treatment difference (p-value) -14.7 ( < 0.0001)
aLeast-squares mean change calculated from an Analysis of Covariance model.
A1C = hemoglobin A1C, FPG = fasting plasma glucose

Table 15 : Percent Change in Lipid Parameters in a 24-Week Placebo-Controlled Study of WELCHOL in Combination with Pioglitazone Based Therapy in Patients with Type 2 Diabetes

Dose/Day N† TC LDL-C Apo B HDL-C Non-HDL- C TGa
Total Patient Cohort
WELCHOL 3.8 g 262 -3* -9* -5* +3 -5* +14*
Placebo 262 +3 +7 +4 +1 +5 +2
*p < 0.001 for lipid parameters compared to placebo
aMedian % change from baseline.
† The N given represents the smallest number of patients included in the analysis for any parameter.

Add-on Combination Therapy with Sulfonylurea

WELCHOL 3.8 g/day or placebo was added to background anti-diabetic therapy in a 26-week trial of 460 patients already treated with sulfonylurea alone (N=156) or sulfonylurea in combination with other oral agents (N=304). A total of 72% of these patients were receiving at least half-maximal doses of sulfonylurea therapy. In combination with a sulfonylurea, WELCHOL resulted in statistically significant placebo-corrected reductions in A1C and FPG (Table 16). WELCHOL also reduced TC, LDL-C, Apo B, and non-HDL-C, but increased serum TG (Table 17). The mean percent change in serum LDL-C levels with WELCHOL compared to placebo was -18% among statin users and -15% among statin non-users; the median percent increase in serum TG with WELCHOL compared to placebo was 29% among statin users and 9% among statin non-users. The mean change in body weight was 0.0 kg for WELCHOL and -0.4 kg for placebo.

Table 16 : Glycemic Parameters in a 26-Week Placebo-Controlled Study of WELCHOL in Combination with Sulfonylurea in Patients with Type 2 Diabetes

  Total Patient Population Sulfonylurea Alone Sulfonylurea in Combination with Other Oral Anti-diabetic Agents
WELCHOL 3.8 g/day Placebo WELCHOL 3.8 g/day Placebo WELCHOL 3.8 g/day Placebo
A1C (%), Mean
n 218 218 69 80 149 138
Baseline 8.2 8.3 8.2 8.4 8.2 8.3
Change from baselinea -0.3 0.2 -0.3 0.5 -0.4 0.0
Treatment difference (p-value) -0.5 (p < 0.001) -0.8 (p < 0.001) -0.4 (p < 0.001)
FPG (mg/dL), Mean
n 218 217 70 80 148 137
Baseline 177 181 181 186 175 178
Change from baselinea -4 10 3 15 -11 4
Treatment difference (p-value) -14 (p=0.009) -12 (p=0.18) -14 (p=0.03)
aLeast-squares mean change calculated from an Analysis of Covariance model.
A1C = hemoglobin A1C, FPG = fasting plasma glucose

Table 17 : Percent Change in Lipid Parameters in a 26-Week Placebo-Controlled Study of WELCHOL in Combination With Sulfonylurea in Patients with Type 2 Diabetes

Dose/Day N† TC LDL-C Apo B HDL-C Non-HDL- C TGa
Total Patient Population
WELCHOL 3.8 g 186 -5* -16* -6* 1 -6* 20*
Placebo 193 0 1 1 0 1 1
Sulfonylurea Alone
WELCHOL 3.8 g 57 -5 -14* -5 -1 -6 17
Placebo 68 0 1 1 1 0 -1
Sulfonylurea in Combination with Other Oral Anti-diabetic Agents
WELCHOL 3.8 g 129 -5 -18* -7* 1 -6 21*
Placebo 125 0 0 1 0 1 2
*p < 0.001 for lipid parameters compared to placebo (this more stringent criterion for statistical significance accounts for multiplicity testing of the lipid parameters, which were secondary endpoints in the diabetes trials)
aMedian % change from baseline.
† The number of patients with analyzable data, i.e., a baseline and post-treatment value (last-observation carried forward), varied slightly among different parameters. The N given represents the smallest number of patients included in the analysis for any parameter.

Add-on Combination Therapy with Insulin

WELCHOL 3.8 g/day or placebo was added to background anti-diabetic therapy in a 16-week trial of 287 patients already treated with insulin alone (N=116) or insulin in combination with oral agents (N=171). At baseline, the median daily insulin dose was 70 units in the WELCHOL group and 65 units in the placebo group. In combination with insulin, WELCHOL resulted in a statistically significant placebo-corrected reduction in A1C (Table 18). WELCHOL also reduced LDL-C and Apo B, but increased serum TG (Table 19). The mean percent change in serum LDL-C levels with WELCHOL compared to placebo was -13% among statin users and statin non-users; the median percent increase in serum TG levels with WELCHOL compared to placebo was 24% among statin users and 17% among statin non-users. The mean change in body weight was 0.6 kg for WELCHOL and 0.2 kg for placebo.

Table 18 : Glycemic Parameters in a 16-Week Placebo-Controlled Study of WELCHOL in Combination with Insulin in Patients with Type 2 Diabetes

  Total Patient Population Insulin Alone Insulin in Combination with Oral Anti-diabetic Agents
WELCHOL 3.8 g/day Placebo WELCHOL 3.8 g/day Placebo WELCHOL 3.8 g/day Placebo
A1C (%), Mean
n 144 136 54 55 90 81
Baseline 8.3 8.2 8.2 8.3 8.3 8.2
Change from baselinea -0.4 0.1 -0.4 0.2 -0.4 0.0
Treatment difference (p-value) -0.5 (p < 0.001) -0.6 (p < 0.001) -0.4 (p < 0.001)
FPG (mg/dL), Mean
n 144 136 54 55 90 81
Baseline 165 151 165 163 165 143
Change from baselinea 2 16 8 17 -4 14
Treatment difference (p-value) -15 (p=0.08) -9 (p=0.51) -18 (p=0.09)
aLeast-squares mean change calculated from an Analysis of Covariance model.
A1C = hemoglobin A1C, FPG = fasting plasma glucose

Table 19 : Percent Change in Lipid Parameters in a 16-Week Placebo-Controlled Study of WELCHOL in Combination with Insulin in Patients with Type 2 Diabetes

Dose/Day N† TC LDL-C Apo B HDL-C Non-HDL- C TGa
Total Patient Cohort
WELCHOL 3.8 g 129 -3 -12* -4 -1 -3 23*
Placebo 121 1 1 1 0 1 0
Insulin Alone
WELCHOL 3.8 g 46 -3 -12 -5 0 -3 19
Placebo 48 2 4 2 3 2 -2
Insulin in Combination with Oral Anti-diabetic Agents
WELCHOL 3.8 g 83 -4 -13 -4 -1 -3 25*
Placebo 73 -1 -3 0 -1 -1 2
*p < 0.001 for lipid parameters compared to placebo (this more stringent criterion for statistical significance accounts for multiplicity testing of the lipid parameters, which were secondary endpoints in the diabetes trials)
aMedian % change from baseline.
† The number of patients with analyzable data, i.e., a baseline and post-treatment value (last-observation carried forward), varied slightly among different parameters. The N given represents the smallest number of patients included in the analysis for any parameter.

Last reviewed on RxList: 2/3/2014
This monograph has been modified to include the generic and brand name in many instances.

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