Welchol (Page 5 of 6)

14.2 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 type 2 diabetes mellitus who were treatment-naïve 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 HbA1c 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
FPG = fasting plasma glucose
*
Least-squares mean change calculated from an Analysis of Covariance model
Nominal p=value, not controlled for multiplicity testing
HbA1c (%), Mean
N 175 169
Baseline 8.25 8.17
Change from baseline * -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 baseline * -4.6 5.7
Treatment difference (p-value) -10.3 (p=0.037)
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 TG
*
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.
Median % change from baseline
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.)
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

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 HbA1c 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 HbA1c of 0.5% compared to placebo. Similar placebo-corrected reductions in HbA1c 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 HbA1c of 0.32% compared to placebo. In the metformin, pioglitazone, and sulfonylurea trials, treatment with WELCHOL also resulted in statistically significant reductions in FPG of at least 14 mg/dL compared to placebo.

WELCHOL had consistent effects on HbA1c across subgroups of age, gender, race, body mass index, and baseline HbA1c. WELCHOL’s effects on HbA1c 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 (4)] , and periodic monitoring of lipid parameters including TG is recommended [see Warnings and Precautions (5.1) and Adverse Reactions (6.1)].

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 HbA1c 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 Anti-diabetic Agents
WELCHOL 3.8 g/day Placebo WELCHOL 3.8 g/day Placebo WELCHOL 3.8 g/day Placebo
*
Least-squares mean change calculated from an Analysis of Covariance model
HbA1c (%), Mean
N 148 152 79 76 69 76
Baseline 8.1 8.1 8.2 8.2 8.1 8.0
Change from baseline * -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 baseline * -3 11 -7 8 0 13
Treatment difference (p-value) -14 (p=0.01) -14 (p=0.07) -14 (p=0.10)
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 TG
*
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.
Median % change from baseline
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.)
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 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 HbA1c 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
*
Least-squares mean change calculated from an Analysis of Covariance model
HbA1c (%), Mean
N 271 276
Baseline 8.2 8.1
Change from baseline * -0.34 -0.02
Treatment difference (p-value) -0.32 (0.0001)
FPG (mg/dL), Mean
N 268 270
Baseline 155 157
Change from baseline * -4.8 +9.9
Treatment difference (p-value) -14.7 (<0.0001)
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 TG
*
The N given represents the smallest number of patients included in the analysis for any parameter.
Median % change from baseline
p<0.001 for lipid parameters compared to placebo
Total Patient Cohort
WELCHOL 3.8 g 262 -3 -9 -5 +3 -5 +14
Placebo 262 +3 +7 +4 +1 +5 +2

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 HbA1c 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
*
Least-squares mean change calculated from an Analysis of Covariance model
HbA1c (%), Mean
n 218 218 69 80 149 138
Baseline 8.2 8.3 8.2 8.4 8.2 8.3
Change from baseline * -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 baseline * -4 10 3 15 -11 4
Treatment difference (p-value) -14 (p=0.009) -12 (p=0.18) -14 (p=0.03)
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 TG
*
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.
Median % change from baseline
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.)
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 HbA1c (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
*
Least-squares mean change calculated from an Analysis of Covariance model
HbA1c (%), Mean
n 144 136 54 55 90 81
Baseline 8.3 8.2 8.2 8.3 8.3 8.2
Change from baseline * -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 baseline * 2 16 8 17 -4 14
Treatment difference (p-value) -15 (p=0.08) -9 (p=0.51) -18 (p=0.09)
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 TG
*
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.
Median % change from baseline
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.)
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

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