Randomized Controlled Trial

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POSITIVE: See Quality Criteria Checklist below.

To evaluate the effects of sibutramine (15 and 20 mg/day) on weight, metabolic control, and blood pressure in metformin-treated obese subjects with type 2 diabetes.

• Type 2 diabetes (absence of ketonuria, rapid preceding weight loss, or need for insulin treatment);
• diabetes duration >6 months, BMI >/=27 kg/m²;
• duration of metformin treatment of 3 months to 2 years;
• fasting serum glucose 7.0-15.0 mmol/L; and,
• age 25-70 years.

• Current or previous evidence of ischemic heart disease, heart failure, or stroke;
• seated pulse rate >100 bpm;
• diastolic blood pressure >95mmHg;
• total fasting serum cholesterol >7.8 mmol/L;
• fasting serum triglycerides >5.6 mmol/L;
• serum creatinine >120 umol/L;
• serum liver enzymes or bilirubin levels that exceeded twice the upper limit of normal;
• weight change of >3 kg during the preceding 3 months;
• malignancy; and,
• significant neurological or psychiatric disturbances, including alcohol or drug abuse.

Women were excluded if they were pregnant, lactating or of child-bearing potential while not taking adequate contraceptive precautions.

Excluded medications (within the previous 3 months) were anorectic agents, laxatives, B-agonists (other than inhalers), cyproheptadine, phenothiazines, anti-depressants, anti-serotoninergics, barbiturates, anti-pyschotics, and oral corticosteroids.

Antihypertensive and lipid-lowering drugs were permitted if treatment was stable for at least 3 months.

Recruitment

Subjects were recruited from primary and secondary care centers in England, Canada, France, and Belgium.

Design

Multicenter randomized placebo-controlled double-blind trial

Blinding used (if applicable)

Double-blind

Intervention (if applicable)

• Placebo, 15 mg sibutramine per day, or 20 mg sibutramine per day for 12 months
• Subjects in the 20 mg sibutramine group initially took 15 mg daily for the first 2 weeks because of tolerability issues
• Patients were reviewed every 4 weeks, when dietetic advice was reinforced, medication compliance checked by capsule count, and adverse events and medication changes recorded.
• Metformin dosage was adjusted if necessary.

Statistical Analysis

• Power analysis indicated 60 subjects per group were needed to have a 90% power at the 5% significance level to detect a treatment effect of 0.8% in HbA_1c, assuming a variability of 1.3%.
• Analyses were based on the intention-to-treat populations using the last observation carried forward.
• Changes from baseline to end point in body weight, anthropometry, and metabolic measures were analyzed using ANCOVA, with factors for treatment group and country and the relevant baseline as a covariate.
• Pairwise comparisons between each sibutramine group and placebo were carried out using Fisher's protected least-squares difference test.
• Metabolic measures were ranked before analysis and Hodges-Lehmann estimates of treatment differences were determined.
• Analyses were also carried out on within-group changes, stratified by weight loss (<5, >/=5, and >/=10%), using one-sample t tests. The proportions of subjects within these categories were compared between sibutramine and placebo groups using Chi-square tests. All tests were two-tailed and carried out at the 5% level.

Timing of Measurements

• Height, weight (in light clothes), and BMI were recorded at screening and weight was measured every 4 weeks thereafter.
• At randomization and at 6 and 12 months, waist and hip circumference were measured and waist-to-hip ratio was calculated.
• Fasting blood samples and urine were collected at screening and then every 3 months.

Dependent Variables

• Weight in light clothes; change in body weight
• BMI
• Circumference: waist (cm); hip (cm); and waist-to-hip ratio
• Fasting glucose, HbA_1c, insulin, C-peptide, triglycerides, total cholesterol, HDL cholesterol
• LDL cholesterol was calculated.
• blood pressure
• pulse rate

Independent Variables

• Placebo
• 15 mg sibutramine per day
• 20 mg sibutramine per day

Control Variables

• Factors for treatment group and country and the relevant baseline measure were used as covariates.
• Tobacco and alcohol history were recorded.

 

Initial N:

85 men (44%) and 109 women (56%)

64 in the placebo group, 68 in 15 mg sibutramine group, and 62 in 20 mg sibutramine group

Attrition (final N):

Intent to treat analyses was performed; therefore, the final N remained the same even after withdrawals.

Fifty subjects withdrew prematurely; 18 in the placebo group; 19 in the 15 mg sibutramine group; and, 13 in the 20 mg sibutramine group.

There were no significant group differences in reasons or numbers of withdrawals, and an imputation analysis indicated that this drop-out rate is unlikely to have influenced the outcome.

Age:

range: 27-69 years

placebo: 51±1.1 years (mean±SE)

15 mg sibutramine: 49±1.0 years

20 mg sibutramine: 48±1.0 years

Ethnicity: not given

Other relevant demographics: not given

Anthropometrics

weight (kg): placebo 110.7±2.6; 15 mg sibutramine 103.5±2.2; 20 mg sibutramine 104.3±2.9

BMI (kg/m²): placebo 36.2±0.8; 15 mg sibutramine 36.3±0.7; 20 mg sibutramine 37.5±1.0

 

Disease and medication information:

Duration of diabetes (years: median, range): placebo 1.8 (0.4-13); 15 mg sibutramine 2.0 (0.4-17); 20 mg sibutramine 2.0 (0-22)

Duration of metformin (years: median, range): placebo 0.6 (0.2-2.0); 15 mg sibutramine 0.6 (0.1-2.9); 20 mg sibutramine 0.6 (0.1-2.0)

Fasting plasma glucose (mmol/L): placebo 9.1 (6.2-16.2); 15 mg sibutramine 9.5 (5.7-15.4); 20 mg sibutramine 9.2 (5.7-17.1)

HbA_1c (%): placebo 9.73±0.3; 15 mg sibutramine 9.75±0.3; 20 mg sibutramine 9.14±0.2

There were no significant differences between centers in sex distribution, age, diabetes duration, or the dosage (mean 1,250 mg/day) or duration of metformin treatment.

Seventy subjects (36%) were hypertensive according to World Health Organization criteria, and 56 (29%) were taking antihypertensive treatment, with 17 (9%) receiving lipid-lowering drugs.    

Location:

Two centers were in the U.K. (n=28); eight were in Canada (n=116); five were in France (n=21); and, six were in Belgium (n=30).

 Table 2 - Overall effects on weight and anthrometry

Variable Treatment group	Baseline	Change	Dc	95% CI for Dc
Weight (kg)
Placebo	100.7 ± 2.6	-0.2 ± 0.5	-	-
15 mg sibutramine	103.5 ±2.2	-5.5 ± 0.6***	-5.1 ± 0.9*	-7.0 to -3.3
20 mg sibutramine	104.3 ± 2.9	-8.0 ± 0.9***	-7.8 ± 1.0*	-9.7 to -5.9
BMI (kg/m2)
Placebo	36.2 ± 0.8	-0.1 ± 0.2	-	-
15 mg sibutramine	36.3 ± 0.7	-2.0 ± 0.2***	-1.9 ± 0.3*	-2.6 to -1.2
20 mg sibutramine	37.5 ± 1.0	-2.9 ± 0.3***	-2.9 ± 0.3*	-3.6 to -2.2
Circumference Waist (cm)
Placebo	112.0 ± 2.0	0.2 ± 0.6	-	-
15 mg sibutramine	113.5 ± 1.6	-4.7 ± 0.7***	-4.9 ± 0.9*	-6.7 to -3.0
20 mg sibutramine	113.0 ± 1.9	-6.6 ± 0.7***	-6.8 ± 1.0*	-8.7 to -4.9
Hip (cm)
Placebo	119.4 ± 1.6	0.0 ± 0.7	-	-
15 mg sibutramine	116.9 ± 1.6	-3.0 ± 0.6***	-3.0 ± 1.0*	-5.0 to -1.0
20 mg sibutramine	119.1 ± 2.1	-6.1 ± 1.0**	-6.1 ± 1.0*	-8.2 to - 4.1
Waist to hip ratio
Placebo	93.9 ± 1.2	-0.3 ± 0.7	-	-
15 mg sibutramine	97.5 ± 1.2	-1.6 ± 0.6**	-1.4 ± 0.9	-3.1 to 0.3
20 mg sibutramine	95.3 ± 1.2	-1.1 ± 0.7	-0.9 ± 0.9	-2.6 to 0.8

 Data are means ± SE or medians (range). D^c, treatment group difference (i.e., sibutramine minus placebo). ^*P<0.001, ^**P<0.01, ^***  (rev: no P-value was given)

Table 3 - Overall effects on metabolic measures

Variable Treatment group	Baseline	Change	Dc	95% CI for Dc
Fasting glucose (mmol/L)
Placebo	9.1 (6.2-16.2)	0.2 (-6.8 to 9.3)	-	-
15 mg sibutramine	9.5 (5.7-15.4)	-0.3 (-6.3 to 8.5)	-0.2	-1.0 to 0.7
20 mg sibutramine	9.2 (5.7-17.1)	-0.1 (-5.7 to 7.7)	-0.2	-1.0 to 0.5
HbA1c (%)
Placebo	9.73 ± 0.27	-0.22 ± 0.24	-	-
15 mg sibutramine	9.75 ± 0.26	-0.56 ± 0.27	-0.34 to 0.33	-0.99 to 0.31
20 mg sibutramine	9.14 ± 0.24	-0.32 ± 0.23	-0.10 to 0.34	-0.76 to 0.57
Fasting insulin (pmol/L)
Placebo	108.0 (30-402)	-3.0 (-210 to 228)	-	-
15 mg sibutramine	114.0 (30-372)	-7.2 (-168 to 246)	-6.0	-24.0 to 12.0
20 mg sibutramine	96.0 (30-540)	-33.0 (-492 to 84)	-18.0*	-30.0 to 0.0
Cholesterol (mmol/L)
Placebo	5.8 (3.5-7.3)	-0.2 (-1.3 to 1.4)	-	-
15 mg sibutramine	5.4 (3.4-7.4)	-0.1 (-2.6 to 1.1)	0.0	-0.2 to 0.3
20 mg sibutramine	5.5 (2.8-8.0)	0.0 (-1.6 to 1.3)	0.1	-0.1 to 0.3
HDL
Placebo	1.1 (0.6-5.7)	0.0 (-4.9 to 0.3)	-	-
15 mg sibutramine	1.0 (0.3-2.3)	0.1 (-1.4 to 0.6)*	0.1	0.0 to 0.2
20 mg sibutramine	1.1 (0.7-2.3)	0.1 (-0.8 to 0.7)**	0.1	0.0 to 0.1
LDL
Placebo	3.5 (1.1-5.4)	-0.2 (-1.8 to 1.2)	-	-
15 mg sibutramine	3.2 (0.6-5.2)	-0.2 (-2.1 to 0.9)	0.0	-0.2 to 0.3
20 mg sibutramine	3.2 (1.1-5.8)	-0.1 (-1.2 to 1.1)	0.1	-0.1 to 0.3
Total cholesterol-to-HDL cholesterol ratio
Placebo	5.0 (1.1-10.2)	0.0 (-1.8 to 7.1)	-	-
15 mg sibutramine	5.8 (2.8-13.3)	-0.3 (-3.3 to 13.5)	-0.5***	-0.9 to -0.2
20 mg sibutramine	4.8 (2.2-7.9)	-0.5 (-8.5 to 2.8)	-0.2	-0.5 to 0.1
Triglycerides (mmol/L)
Placebo	2.4 (0.6-5.7)	0.1 (-1.8 to 3.4)	-	-
15 mg sibutramine	2.4 (0.6-7.2)	-0.2 (-3.3 to 3.4)	-0.2	-0.6 to 0.1
20 mg sibutramine	2.2 (0.6-4.2)	-0.2 (-1.7 to 6.3)**	-0.3**	-0.6 to 0.0

 Data are means ± SE or median (range). D^c, treatment group difference (i.e., sibutramine minus placebo). ^*P<0.001, ^**P<0.05, ^***P<0.01.

 Table 4 - Overall cardiovascular effects (seated vital signs) 

Variable Treatment group	Baseline	Change	Dc	95% CI for Dc
Systolic blood pressure (mmHg)
Placebo	132.9 ± 1.9	-0.2 ± 2.0
15 mg sibutramine	131.5 ± 2.1	4.4 ± 1.9*	4.6 ± 2.2**	0.3 to 8.8
20 mg sibutramine	130.5 ± 2.0	-1.5 ± 2.0	-1.3 ± 2.2	-5.6 to 3.1
Diastolic blood pressure (mmHg)
Placebo	82.1 ± 1.1	0.5 ± 1.1
15 mg sibutramine	82.8 ± 1.2	3.3 ± 1.1**	2.8 ± 1.2**	0.4 to 5.3
20 mg sibutramine	81.3 ± 1.2	0.4 ± 1.0	0.0 ± 1.3	-2.5 to 2.4
Pulse (bpm)
Placebo	74.8 ± 1.0	-0.8 ± 1.2
15 mg sibutramine	76.4 ± 1.3	5.1 ± 1.5*	5.9 ± 1.7*	2.5 to 9.4
20 mg sibutramine	75.0 ± 1.2	5.0 ± 1.4***	5.8 ± 1.8***	2.3 to 9.3

 Data are means ± SE or median (range). D^c, treatment group difference (i.e., sibutramine minus placebo). ^*P<0.001, ^**P<0.05, ^***P<0.01.

Other Findings

•  Placebo-treated patients showed no consistent weight change at any time; 88% of subjects (56 of 63) either gained weight or lost <5%, whereas only 12% lost >/=5%, and none lost >/=10%.
• With 15 mg sibutramine, average weight fell steadily over 6 months to 5.3 kg (~6%) below baseline and was then maintained throughout treatment.
• The 20-mg dose caused consistently greater weight loss, averaging 8 kg (~8%) below baseline from 8 months to the end of treatment.
• Significantly more sibutramine-treated subjects lost >/=5% weight (46 and 65% with 15 and 20 mg, respectively), whereas 14% of subjects receiving 15 mg/day and 27% of subjects taking 20 mg lost >/= 10%.
• Overall, HbA_1c concentrations did not change significantly among the treatment groups, but it fell significantly (0.7 ± 0.3%, P<0.02) in subjects who lost 5-10% of weight and significantly further (1.2 ± 0.4%, P<0.0001) in those losing >/= 10%.
• Among sibutramine-treated patients, percentage weight loss was significantly correlated with the fall in HbA_1c (r=0.43, P<0.001, for the 15-mg group and r=0.32, P<0.02, for the 20-mg group), but no correlation was seen in the placebo group, where average weight was unchanged (r=0.5, P=0.73).
• Fall in HbA_1c correlated significantly with percentage reduction in waist circumference in both sibutramine treatment groups (15 mg: r=0.43, P<0.001; 20 mg: r=0.30, P<0.05) and with placebo (r=0.51, P<0.001).
• Fasting plasma glucose decreased significantly by 1.8 mmol/L (P<0.001) in patients (sibutramine-treated only) who lost >/=10%.
• Metformin dosage was reduced in five patients (7%) receiving 15 mg sibutramine and in six patients (10%) with the 20-mg dosage, but in only one subject (2%) given placebo.
• In sibutramine subjects who lost >/=5 or >/=10% weight, total cholesterol-to-HDL cholesterol also showed modest but significant falls of 8% (P=0.011) and 16% (P=0.002), respectively.
• In subjects losing >/=5 and >/=10% weight, triglycerides fell significantly by 0.3 mmol/L (13%, P<0.01) and 0.8 mmol/L (29%, P<0.01), respectively.
• A few sibutramine-treated patients showed marked pressure rises, but systolic and diastolic blood pressure also rose in some placebo-treated pateints, being higher at completion than at baseline in over 40% of cases.
• Blood pressure rises during sibutramine treatment were more apparent when measured sitting; standing systolic pressure showed no consistent group differences.
• For a diastolic blood pressure rise of >/= mmHg, the corresponding figures were 43% with 15 mg sibutramine (P<0.05 vs placebo), 26% with 20 mg sibutramine (NS vs placebo), and 25% with placebo.
• With 15 mg sibutramine, systolic blood pressure did not change significantly in subjects who lost >/=5 or >/=10% weight, whereas the >/= 5% responders with 20 mg sibutramine showed a mean placebo-subtracted fall of 4.6 ± 2.0 mm Hg (P=0.053 vs all placebo subjects). 
• Placebo-treated subjects who lost >/=5% weight showed a systolic decrease of 3.3 ± 1.4 mmHg.
• For >5% weight loss, mean placebo-subtracted diastolic changes were 2.0 ± 1.5 with 15 mg sibutramine (NS vs placebo, 1.5 ± 1.0 mmHg) and -0.9 ± 1.4 mmHg (NS vs placebo) for 20 mg sibutramine.
• For >10% weight loss, mean placebo-subtracted changes were 1.7 ± 2.2 and 1.0 ± 1.8 mmHg, respectively (both NS vs placebo).

Sibutramine can be an effective adjunct to metformin treatment in selected obese type 2 diabetic subjects and improves metabolic control in individuals who lose weight.

Government:

Scottish Executive Dept. of Health