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To evaluate the effects over 2 years of a weight loss program combining several weight loss strategies on weight loss and diabetes control in overweight subjects with type 2 diabetes.

• 30-70 years
• diagnosis of type 2 diabetes with HbA_1c between 7.0 and 10.0%
• BMI between 27 and 50kg/m²
• stable weight for the previous 3 months
• constant doses of any diabetes, hypertension, and lipid medications for at least 1 month

• current use or use in the previous 6 months of insulin
• prior use of sibutramine
• use of any weight loss product or participation in any formal weight loss program in the previous month
• significant abnormality on screening tests
• history of heart disease or stroke
• prior bariatric surgery
• lactose intolerance
• any chronic disease or therapy that would make adherence to the study protocol difficult

Recruitment

not given

Design: randomized controlled trial

Blinding used (if applicable): Implied for laboratory measures.

Intervention (if applicable)

• Randomization was stratified by sex.
• Standard/Combination (S/C) Therapy: Subjects in both groups received individual counseling by a registered dietitian. At baseline, each subject's basal energy requirement was calculated and resting energy expenditure was measured. Using these data and an estimate of the subject's typical activity level, the dietitian prescribed an individualized diet that would promote a 500- to 1,000-kcal reduction in daily energy intake. Subjects also received an individualized exercise prescription that included, at a minimum, walking for 30 minutes three times weekly added to usual activity. All subjects received an educational program of dietary, exericse, and behavioral strategies to facilitate weight loss using a commercially available dietary and lifestyle modification resource. After 1 year on standard therapy, this group was crossed over to combination therapy for the 2nd year of the study.
• Combination (C) Therapy: In addition to the standard therapy program described, the combination therapy weight loss program consisted of the following interventions: 1) 10 mg sibutramine daily with the option to increase to 15 mg daily after 6 months if BMI remained >/=27 kg/m²; 2) low-calorie diets providing 900-1,300 kcal per day made up exclusively of meal replacement products (meal shakes or meal bars, 220 kcal/serving, four to six servings daily) for 7 consecutive days every 2 months; and 3) between low-calorie-diet weeks, use of one meal replacement product and one snack bar daily (120 kcal/snack bar) to replace one usual meal and snack and thereby facilitate achievement of the goal of a 500- to 1,000-kcal/day reduction in energy intake. Meal replacement products and snack bars were provided by Slim Fast Foods Company. Two years of continuous combination therapy.
• Diabetes, hypertension, and lipid medications were adjusted, added or stopped according to a pre-established protocol.
• All subjects were to attempt to achieve HbA_1c values <7% through weight loss.
• Diabetes medication was initiated or increased if there were symptoms attributable to hyperglycemia or if HbA_1c was >10.0%. Diabetes medication was reduced or discontinued if symptomatic hypoglycemia occurred more than two times per week or home blood glucose values were frequently <80 mg/dL.
• Cost of program was about $6 per day, from which the cost of usual meals and snacks that were omitted (two to six per day) should be substracted.

Statistical Analysis

• Data from subjects who discontinued study participation before 24 months were excluded from the analysis.
• Changes from baseline to 24 months in study parameters were compared with a treatment group by a paired t test.
• A chi-square test was used to compare categorical data.
• Relationships between weight loss with C therapy and baseline parameters were examined by least squares linear regression.

Timing of Measurements

• Baseline and follow-up visits at 1 month, 2 months, and every 2 months thereafter. Subjects were also seen after each low-calorie-diet week for measurement of weight, pulse, and blood pressure.
• Blood samples for fasting glucose, lipids, and HbA_1c were obtained at baseline and 2, 4, 6, 8, 10, 12, 16, 20, and 24 months.
• Body composition was assessed at baseline and at 2, 6, 12, 16, and 24 months.

Dependent Variables

• weight and change in weight: electronic scale with subjects wearing light clothing and no shoes
• height: stadiometer
• blood pressure and pulse: automated blood pressure cuff after subjects were seated for 5 min; three readings were obtained and the average of the last two was recorded
• fasting plasma glucose
• HbA_1c
• fasting plasma total cholesterol
• HDL cholesterol
• triglycerides
• LDL cholesterol: calculated unless fasting plasma triglycerides exceeded 400 mg/dL
• body composition: total-body-dual energy X-ray absorptiometry using a Lunar Prodigy
• resting energy expenditure: measured using a DeltaTrac II Metabolic Monitor 

Independent Variables

• C therapy: combination therapy
• S/C therapy: standard therapy and then crossed over to combination therapy

Control Variables

 none listed

Initial N: 61 were enrolled

Attrition (final N):

Two subjects in S/C group withdrew before their first follow-up visit

54 completed 1 year of the study (27 in each group)

48 completed 2 years of the study (23 in C therapy, 11 women and 12 men; 25 in S/C therapy)

Reasons for early study termination were inability to keep study visits (three subjects), desire to undergo bariatric surgery (one subject), desire to start a commercial weight loss program (two subjects), personal reasons (four subjects), and death as a passenger in a motor vehicle accident (one subject).

Age: only given for the C therapy group; 51 ± 2

Ethnicity: not given

Other relevant demographics: not given

Anthropometrics

data only given for C therapy group

See Table 1 

Duration of diabetes (years): 4 ± 1

Location:

Subjects were evaluated in the University of Minnesota General Clinical Research Center.

Reviewers note: main interest of investigators was to assess the long-term effects of combination therapy in the C therapy group

Table 1 - comparison of baseline and 2-year data for subjects on C therapy

Variables	Baseline	2-year	Change	P
Diabetes medications
none	2	1
One	7	5		0.62
Two or more	14	17
Weight (kg)	113.2 ± 4.4	108.6 ± 4.2	-4.6 ± 1.2	0.001
BMI (kg/m2)	38.5 ± 1.1	36.9 ± 1.0	-1.6 ± 0.4	0.001
Body fat (kg)	46.8 ± 2.5	44.8 ± 2.2	-2.0 ± 0.8	0.03
Lean body mass (kg)	62.6 ± 3.0	60.0 ± 2.9	-2.6 ± 0.8	0.002
Fasting glucose (mg/dL)	158 ± 9	148 ± 12	-9 ± 15	0.56
HbA1c	8.1 ± 0.2	7.6 ± 0.2	-0.5 ± 0.3	0.08
Resting pulse (bpm)	80 ± 2	79 ± 2	-1 ± 2	0.55
Systolic blood pressure (mmHg)	139 ± 2	132 ± 2	-7 ± 3	0.03
Diastolic blood pressure (mmHg)	77 ± 2	73 ± 2	-4 ± 2	0.06
Fasting cholesterol (mg/dL)	197 ± 10	185 ± 9	-12 ± 11	0.29
HDL cholesterol (mg/dL)	40 ± 2	38 ± 2	-1 ± 1	0.37
LDL cholesterol (mg/dL)*	115 ± 8	102 ± 6	-13 ± 9	0.14
Fasting triglycerides (mg/dL)	233 ± 32	225 ± 43	-8 ± 42	0.85

 ^*Excludes four subjects with fasting triglycerides >400 mg/dL at baseline.

Other Findings

•  Mean weight loss was greatest at 10 months in the C therapy group followed by a slow regain over the subsequent 14 months.
• A pattern of weight loss during low-calorie-diet weeks with subsequent weight regain in the period between low-calorie-diet weeks was observed through-out the study.
• The S/C therapy group lost little weight during year 1 of standard therapy. After starting combination therapy at the beginning of year 2, this group demonstrated a pattern of weight loss similar to that observed during year 1 in the C therapy group. Weight loss in the S/C therapy group at 2 years was 8.1 ± 1.6 kg (P < 0.001).
• Baseline HbA_1c was 8.1 ± 0.2% for both groups. HbA_1c at 2 years decreased 0.5 ± 0.3 % in the C therapy group (P=0.08) and 0.3 ± 0.2 % in the S/C therapy group (P=0.18).
• Compliance with the intermittent low-calorie-diet weeks was generally good, as evidenced by the repetitive demonstration of weight loss during these weeks. During the 2nd year of the study, there was less weight loss during low-calorie-diet weeks and more weight gain during intervening weeks. This led to a gradual increase in weight during the 2nd year of the study.
• Women had significantly greater weight loss than men after 12 months of C therapy (8.6 ± 1.5 vs 4.7 ± 0.9%, P=0.03).
• Percent body fat at baseline was also significantly correlated with weight loss (r = 0.49, P=0.02). Women had significantly greater percent body fat than men, so sex and body fat are not independent of each other.
• After 2 years, 14 subjects (61%) in the C therapy group were taking sibutramine (15 mg daily in 13 subjects and 10 mg daily in one subject). Sibutramine was discontinued by nine subjects for a variety of reasons, which included starting antidepressant therapy (one subject), possible side effects (constipation, dry mouth, and difficulty with urination, one subject each), concern over possible blood pressure effects (three subjects), and personal reasons (two subjects).
• No serious adverse events related to the study protocol.
• Some subjects experienced mild hypoglycemia during low-calorie-diet weeks and required temporary reductions in diabetes medications.

The weight regain may have been due to decreased adherence to the combination therapy program, perhaps because the novelty of the program decreased over time.

Overweight or obese people with type 2 diabetes receiving a weight loss intervention that combined intermittent low-calorie diets, daily meal replacements, and the medication sibutramine achieved and maintained significant weight loss over a 2-year period. This was accompanied by improvement in diabetes control.

Limitations as given by authors:

THe long-term treatment effect of combination therapy would have been better assessed if we had an appropriate control group throughout the entire study. The S/C therapy group provided an appropriate control for the initial study year, but not the second due to crossover to combination therapy.

The crossover was done for retention purposes because the investigators felt it unlikely that subjects would remain active participants in standard therapy for 2 years.

Because of study design, it was not possible to determine which component of combination therapy was most important in producing and sustaining weight loss.

 

Government:	NIH
Industry:	Abbott Labs, Slim Fast Food Company: Pharmaceutical/Dietary Supplement Company:

• One year results previously reported: Diabetes Care 26:2505-2511, 2003.
• Study design has problems as mentioned by the authors: unable to separate out effective component in C therapy; and, lack of an appropriate control for year 2.
• The changes in fasting glucose and HbA_1c were not statistically significant in the C therapy group and HbA_1c did not decrease below 7%.
• A possible conflict of interest exists as grants from Abbott Laboratories and Slim Fast Nutrition Institute supported the project.