Welchol (colesevelam hydrochloride 625 mg) Dailymed

8.1 Pregnancy

Pregnancy Category B. There are no adequate and well-controlled studies of colesevelam use in pregnant women. Animal reproduction studies in rats and rabbits revealed no evidence of fetal harm. Requirements for vitamins and other nutrients are increased in pregnancy. However, the effect of colesevelam on the absorption of fat-soluble vitamins has not been studied in pregnant women. This drug should be used during pregnancy only if clearly needed.

In animal reproduction studies, colesevelam revealed no evidence of fetal harm when administered to rats and rabbits at doses 50 and 17 times the maximum human dose, respectively. Because animal reproduction studies are not always predictive of human response, this drug should be used in pregnancy only if clearly needed.

8.3 Nursing Mothers

Colesevelam hydrochloride is not expected to be excreted in human milk because colesevelam hydrochloride is not absorbed systemically from the gastrointestinal tract.

8.4 Pediatric Use

The safety and effectiveness of WELCHOL as monotherapy or in combination with a statin were evaluated in children, 10 to 17 years of age with heFH [See Clinical Studies (14.1)]. The adverse reaction profile was similar to that of patients treated with placebo. In this limited controlled study, there were no significant effects on growth, sexual maturation, fat-soluble vitamin levels or clotting factors in the adolescent boys or girls relative to placebo [See Adverse Reactions (6.1) ].

Due to tablet size, WELCHOL for Oral Suspension is recommended for use in the pediatric population. Dose adjustments are not required when WELCHOL is administered to children 10 to 17 years of age.

WELCHOL has not been studied in children younger than 10 years of age or in pre-menarchal girls.

8.5 Geriatric Use

Primary Hyperlipidemia:  Of the 1350 patients enrolled in the hyperlipidemia clinical studies, 349 (26%) were ≥65 years old, and 58 (4%) were ≥75 years old. No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out.

Type 2 Diabetes Mellitus:  Of the 1128 patients enrolled in the four diabetes studies, 249 (22%) were ≥65 years old, and 12 (1%) were ≥75 years old. In these trials, WELCHOL 3.8 g/day or placebo was added onto background anti-diabetic therapy. No overall differences in safety or effectiveness were observed between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out.

8.6 Hepatic Impairment

No special considerations or dosage adjustments are recommended when WELCHOL is administered to patients with hepatic impairment.

8.7 Renal Impairment

Type 2 Diabetes Mellitus:  Of the 1128 patients enrolled in the four diabetes studies, 696 (62%) had mild renal insufficiency (creatinine clearance [CrCl] 50-<80 mL/min), 53 (5%) had moderate renal insufficiency (CrCl 30-<50 mL/min), and none had severe renal insufficiency (CrCl <30 mL/min), as estimated from baseline serum creatinine using the Modification of Diet in Renal Disease (MDRD) equation. No overall differences in safety or effectiveness were observed between patients with CrCl <50 mL/min (n=53) and those with a CrCl≥50 mL/min (n=1075).

10 Overdosage

Doses of WELCHOL in excess of 4.5 g/day have not been tested. Because WELCHOL is not absorbed, the risk of systemic toxicity is low. However, excessive doses of WELCHOL may cause more severe local gastrointestinal effects (e.g., constipation) than recommended doses.

11 Description

WELCHOL (colesevelam hydrochloride) is a non-absorbed, polymeric, lipid-lowering and glucose-lowering agent intended for oral administration. Colesevelam hydrochloride is a high-capacity bile acid-binding molecule.

Colesevelam hydrochloride is poly(allylamine hydrochloride) cross-linked with epichlorohydrin and alkylated with 1-bromodecane and (6-bromohexyl)-trimethylammonium bromide. The chemical name (IUPAC) of colesevelam hydrochloride is allylamine polymer with 1-chloro-2,3-epoxypropane, [6-(allylamino)-hexyl]trimethylammonium chloride and N-allyldecylamine, hydrochloride. The chemical structure of colesevelam hydrochloride is represented by the following formula:

wherein (a) represents allyl amine monomer units that have not been alkylated by either of the 1-bromodecane or (6-bromohexyl)-trimethylammonium bromide alkylating agents or cross-linked by epichlorohydrin; (b) represents allyl amine units that have undergone crosslinking with epichlorohydrin; (c) represents allyl amine units that have been alkylated with a decyl group; (d) represents allyl amine units that have been alkylated with a (6-trimethylammonium) hexyl group, and m represents a number ≥ 100 to indicate an extended polymer network. A small amount of the amines are dialkylated, and are not depicted in the formula above. No regular order of the groups is implied by the structure; cross-linking and alkylation are expected to occur randomly along the polymer chains. A large amount of the amines are protonated. The polymer is depicted in the hydrochloride form; a small amount of the halides are bromide. Colesevelam hydrochloride is hydrophilic and insoluble in water.

WELCHOL Tablets are an off-white, oval, film-coated, solid tablet containing 625 mg colesevelam hydrochloride. In addition, each tablet contains the following inactive ingredients: magnesium stearate, microcrystalline cellulose, silicon dioxide, HPMC (hydroxypropyl methylcellulose), and acetylated monoglyceride. The tablets are imprinted using a water-soluble black ink.

WELCHOL for Oral Suspension is a citrus-flavored, white to pale yellow powder containing yellow granules packaged in single-dose packets containing either 1.875 gram or 3.75 gram colesevelam hydrochloride. In addition, each packet contains the following inactive ingredients: lemon flavor, orange flavor, propylene glycol alginate, simethicone, aspartame, citric acid, medium chain triglycerides, and magnesium trisilicate.

PHENYLKETONURICS: WELCHOL for Oral Suspension contains 24 mg phenylalanine per 1.875 gram dose and 48 mg phenylalanine per 3.75 gram dose.

12 Clinical Pharmacology

12.1 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.

12.2 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.

12.3 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 digoxin, fenofibrate, lovastatin, metoprolol, quinidine, valproic acid, pioglitazone, and warfarin. The results of additional in vivo drug interactions of WELCHOL are presented in Table 5.

Drug interactions between WELCHOL and other commonly co-administered drugs in patients with type 2 diabetes (including rosiglitazone maleate, glimepiride, glipizide, sitagliptin phosphate, angiotensin converting enzyme inhibitors, angiotensin receptor blockers, sustained-release formulations of anti-diabetic and anti-hypertensive drugs, and aspirin) have not been evaluated.

Table 5 Mean Change in Drug Exposure (AUC_0-∞ and C_max) when Administered with WELCHOL (3.75 g)^a

a With verapamil, the dose of WELCHOL was 4.5 g
b Should be administered at least 4 hours prior to WELCHOL. [See Drug Interactions (7)]
* Oral contraceptive containing norethindrone and ethinyl estradiol.
N/A — Not Available
Drug	Dose	Co-administered		1 hr prior toWELCHOL		4 hr prior toWELCHOL
		AUC0-∞ Cmax		AUC0-∞ Cmax		AUC0-∞ Cmax
Verapamil sustained-release	240 mg	-31%	-11%	N/A	N/A	N/A	N/A
Glyburideb	3 mg	-32%	-47%	-20%	-15%	-7%	4%
Levothyroxineb	600 µg	-22%	-33%	6%	-2%	1%	8%
Norethindrone*b	1 mg	-1%	-20%	5%	-3%	6%	7%
Ethinyl Estradiol*b	0.035 mg	-24%	-24%	-18%	-1%	-12%	0%
Repaglinide	2 mg	-7%	-19%	-6%	-1%	N/A	N/A
Cyclosporine	200 mg	-34%	-44%	N/A	N/A	N/A	N/A

13 Nonclinical Toxicology

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenesis:  A 104-week carcinogenicity study with colesevelam hydrochloride was conducted in CD-1 mice, at oral dietary doses up to 3 g/kg/day. This dose was approximately 50 times the maximum recommended human dose of 4.5 g/day, based on body weight, mg/kg. There were no significant drug-induced tumor findings in male or female mice. In a 104-week carcinogenicity study with colesevelam hydrochloride in Harlan Sprague-Dawley rats, a statistically significant increase in the incidence of pancreatic acinar cell adenoma was seen in male rats at doses >1.2 g/kg/day (approximately 20 times the maximum human dose, based on body weight, mg/kg) (trend test only). A statistically significant increase in thyroid C-cell adenoma was seen in female rats at 2.4 g/kg/day (approximately 40 times the maximum human dose, based on body weight, mg/kg).

Mutagenesis:  Colesevelam hydrochloride and 4 degradants present in the drug substance have been evaluated for mutagenicity in the Ames test and a mammalian chromosomal aberration test. The 4 degradants and an extract of the parent compound did not exhibit genetic toxicity in an in vitro bacterial mutagenesis assay in S.typhimurium and E. coli (Ames assay) with or without rat liver metabolic activation. An extract of the parent compound was positive in the Chinese Hamster Ovary (CHO) cell chromosomal aberration assay in the presence of metabolic activation and negative in the absence of metabolic activation. The results of the CHO cell chromosomal aberration assay with 2 of the 4 degradants, decylamine HCl and aminohexyltrimethyl ammonium chloride HCl, were equivocal in the absence of metabolic activation and negative in the presence of metabolic activation. The other 2 degradants, didecylamine HCl and 6-decylamino-hexyltrimethyl ammonium chloride HCl, were negative in the presence and absence of metabolic activation.

Impairment of Fertility:  Colesevelam hydrochloride did not impair fertility in rats at doses up to 3 g/kg/day (approximately 50 times the maximum human dose, based on body weight, mg/kg).

13.2 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.

14 Clinical Studies

14.1 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

* p<0.05 for lipid parameters compared to placebo, for Apo B compared to baseline.
a Median % change 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

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

*p<0.05 for lipid parameters compared to placebo, for Apo B compared to baseline.
a Median % change from baseline.
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

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 Baseline^b at 6 Weeks)

*p≤0.0002 compared to placebo.
a For triglycerides, median % change from baseline.
b Treated Baseline: following 8-week treatment with open-label fenofibrate 160 mg.
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

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 naïve 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-naïve 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

*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.
a For triglycerides, median % change from baseline.
Results were based on the ITT population with LOCF
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

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.

14.2 Type 2 Diabetes Mellitus

WELCHOL has been studied in combination with metformin, sulfonylureas, and insulin. WELCHOL has not been studied as monotherapy.

The efficacy of WELCHOL 3.8 g/day in patients with type 2 diabetes mellitus was evaluated in 3 double-blind, placebo-controlled add-on therapy trials involving a total of 1018 patients with baseline A1C 7.5-9.5%. Patients were enrolled and maintained on their pre-existing, stable, background anti-diabetic regimen. WELCHOL and placebo were administered either as 3 tablets twice daily with lunch and dinner or as 6 tablets with dinner alone.

In these studies, the overall mean age was 57 years (range 24-81 years), 47% were women, and 59% of the patients were Caucasian, 23% were Hispanic, 14% were Black, 3% were Asian, and 1% were of other racial groups. Statin use at baseline was reported in 42% of the WELCHOL-treated patients and 50% of the placebo-treated patients.

In all 3 pivotal add-on therapy trials, 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 metformin and sulfonylurea trials, treatment with WELCHOL also resulted in statistically significant reductions in fasting plasma glucose (FPG) of 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), 106 mg/dL in the sulfonylurea study (range 41-264 mg/dL), and 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 and patients on a sulfonylurea, 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 (4)] and periodic monitoring of lipid parameters including TG and non-HDL-C levels is recommended [See Warnings and Precautions (5.2) and Adverse Reactions (6.1)].

Body weight did not significantly increase from baseline with WELCHOL therapy, compared with placebo, in any of the 3 pivotal clinical 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 10). WELCHOL also reduced TC, LDL-C, Apo B, and non-HDL-C (Table 11). 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 10 Glycemic Parameters in a 26-Week Placebo-Controlled Study of WELCHOL in Combination with Metformin in Patients with Type 2 Diabetes

a Least-squares mean change calculated from an Analysis of Covariance model.
A1C = hemoglobin A1C, FPG = fasting plasma glucose
	Total Patient Population		Metformin Alone		Metformin inCombination withOther OralAnti-Diabetic Agents
	WELCHOL   3.8 g/day	Placebo	WELCHOL3.8 g/day	Placebo	WELCHOL3.8 g/day	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)

Table 11 Percent Change in Lipid Parameters in a 26-Week Placebo-Controlled Study of WELCHOL in Combination with Metformin in Patients with Type 2 Diabetes

*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)
a Median % 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.
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

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 12). WELCHOL also reduced TC, LDL-C, Apo B, and non-HDL-C, but increased serum TG (Table 13). 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 12 Glycemic Parameters in a 26-Week Placebo-Controlled Study of WELCHOL in Combination with Sulfonylurea in Patients with Type 2 Diabetes

a Least-squares mean change calculated from an Analysis of Covariance model.
A1C = hemoglobin A1C, FPG = fasting plasma glucose
	Total Patient Population		Sulfonylurea Alone		Sulfonylurea inCombination withOther OralAnti-Diabetic Agents
	WELCHOL   3.8 g/day	Placebo	WELCHOL3.8 g/day	Placebo	WELCHOL3.8 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)

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

*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)
a Median % 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.
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

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 14). WELCHOL also reduced LDL-C and Apo B, but increased serum TG (Table 15). 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 14 Glycemic Parameters in a 16-Week Placebo-Controlled Study of WELCHOL in Combination with Insulin in Patients with Type 2 Diabetes

a Least-squares mean change calculated from an Analysis of Covariance model.
A1C = hemoglobin A1C, FPG = fasting plasma glucose
	Total Patient Population		Insulin Alone		Insulin inCombination withOther OralAnti-Diabetic Agents
	WELCHOL   3.8 g/day	Placebo	WELCHOL3.8 g/day	Placebo	WELCHOL3.8 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)

Table 15 Percent Change in Lipid Parameters in a 16-Week Placebo-Controlled Study of WELCHOL in Combination with Insulin in Patients with Type 2 Diabetes

*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)
a Median % 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.
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 Other Oral Anti-diabetic Agents
WELCHOL 3.8 g	83	-4	-13	-4	-1	-3	25*
Placebo	73	-1	-3	0	-1	-1	2