Achieving significant weight loss and glycemic control in diabetic patients remains a challenging task.
This study compared the effects of a soy-based meal replacement (MR) plan vs an individualized diet plan (IDP; as recommended by the American Diabetes Association) on weight loss and metabolic profile.
A total of 104 subjects were randomized prospectively to the two treatments for a total of 12 months.
In all, 77 of the 104 subjects completed the study. Percentage weight loss in MR group (4.57±0.81%) was significantly greater (P<0.05) than in IDP group (2.25±0.72%). Fasting plasma glucose was significantly reduced in MR group (126.4±4.9 mg/dl) compared with IDP group (152.5±6.6 mg/dl, P<0.0001) at 6 months but not at 12 months. Controlling for baseline levels, hemoglobin Alc level improved by 0.49±0.22% for those receiving MR when compared to IDP group (P<0.05). A greater number of subjects in MR group reduced their use of sulfonylureas (P<0.0001) and metformin (P<0.05) as compared to IDP group. High-sensitivity C-reactive protein (hs-CRP) decreased −26.3% (P=0.019) in MR group compared to −7.06% (P=0.338) in IDP group at 6 months. Similar changes were observed at 12 months with MR groups, with hs-CRP decreasing by −25.0% (P=0.019) compared to −18.7% (P=0.179) in IDP group.
This study demonstrates that MR is a viable strategy for weight reduction in diabetic patients, resulting in beneficial changes in measures of glycemic control and reduction of medications.
Obesity and type II diabetes mellitus (DM) coexist in a significant number of patients. It has been estimated that more than 70% of those with type II DM are overweight, while 33% are obese (National Institute of Health Publication, 1995). It is well known that obesity can worsen the metabolic abnormalities often associated with DM including hyperinsulinemia, hyperglycemia, hypertension, and hyperlipidemia (Colditz et al, 1990; Chan et al, 1994; Ford et al, 1997; Maggio & Pi-Sunyer, 1997). A modest 5–10% weight loss in obese nondiabetic individuals has been shown to result in marked improvements in some of these metabolic disturbances (Wing et al, 1987; Goldstein, 1992; Davidson et al, 1999; Hollander et al, 1998).
The long-term health benefits of weight loss in obese type II DM patients have not been clearly defined. However, several clinical trials have documented short-term benefits of weight loss on glycemic control (Williamson et al, 2000; Hermansen et al, 2001). Agurs-Collins et al (1997) found that weight loss through diet and exercise was significantly greater at 6 months when compared to a control group who received standard diabetes care. Intentional weight loss was also found to be associated with substantial reduction in mortality of overweight individuals with diabetes (Williamson et al, 2000). The amount of weight loss in the intervention group (−2.4 kg) resulted in a significant decrease in hemoglobin Alc (HbAlc) of 2.4%. Heller et al (1988) reported similar results in a randomized study where a weight loss of 5 kg was achieved through diet, resulting in a significant reduction of HbAlc of 2% at 6 months.
A weight loss program utilizing meal replacements (MR) in place of one or two daily meals has been shown to improve compliance with a calorie-restricted diet by comparison to simply providing food plans in both overweight and obese individuals (Heber et al, 1994; Ditschuneit et al, 1999; Flechtner-Mors et al, 2000). A multicenter trial (Heber et al, 1994) using MR for weight loss in 301 individuals found a 7% weight loss in men and women who continued on the diet plan for 2 y. Ditschuneit et al (1999) in a prospectively randomized clinical study compared the effects of a liquid meal replacement used twice a day for 12 weeks with a conventional energy-restricted diet with the same number of calories per day. By 12 weeks, there was a significantly greater weight loss in those on the MR plan as compared to the calorie-restricted group.
Commonly used MR contain mono and disaccharides such as lactose (derived from milk), fructose, and sucrose. Hence, some health providers have expressed concerns about their use in patients with type II DM. Previously, it was shown that obese noninsulin-dependent DM (NIDDM) patients placed on an MR regimen lost significant amounts of weight when compared to standard dietary therapy. Additionally, significant improvements were observed in glycemic control, due to this weight loss, demonstrating that this strategy is safe for patients with NIDDM (Yip et al, 2001).
A recent meta-analysis of 38 controlled clinical trials indicated that soy protein was effective in lowering plasma cholesterol, LDL, and triglyceride (TG) concentrations (Anderson et al, 1995). In a small study, supplementation of soy protein had beneficial effects on cardiovascular risk markers in type II diabetic subjects (Hermansen et al, 2001).
The present study was undertaken to evaluate the long-term (1 y) safety and efficacy of an MR strategy in a population of obese patients with NIDDM in comparison to an individualized exchange diet plan (IDP) conforming to the macronutrient recommendations of the American Diabetes Association (ADA). The MR evaluated in this study was based on soy protein isolate as the protein source and was significantly lower in total sugars than the more popular products on the market.
Study 1: Assessment of dietary intervention
In all, 104 obese male and female subjects previously diagnosed and being treated for type II DM were recruited and randomized to either an MR diet plan or an individualized diet plan (IDP) for 12 months. Throughout the 12-month study period, body weight, glycemic control, insulin, lipid levels, and high-sensitivity C-reactive protein (hs-CRP) were measured. Adjustments in medication levels and use were made by research physicians and the subjects’ primary care physicians. Adverse events (AEs) were monitored and recorded. The Institutional Review Board of the University of California, Los Angeles, approved the study protocol. The study was carried out strictly in accordance with ethical standards as outlined by the University of California, Los Angeles.
Inclusion and exclusion criteria
Subjects, 30 y and older at screening, who were being treated for NIDDM with oral hypoglycemic agents were recruited. Subjects were required to have a BMI of 27–40 kg/m2, HbA1c of 7–12% inclusive, and no change in their diabetic medications for 3 months prior to entry into the trial. Subjects were excluded if they had been on insulin therapy, or if they had significant diabetes-related complications such as diabetic retinopathy, neuropathy, or proteinuria. Subjects were also excluded if they had a history of psychiatric or other major medical conditions such as liver disease, kidney disease, and coronary artery disease.
Randomization and power calculation
A random, permuted, block design was utilized for placement of subjects into the two treatment groups. The eligible subjects were equally assigned to either MR or control group. This was a 52-week 2-arm randomized clinical trial to examine the safety and efficacy of using a meal replacement for weight loss in patients with type II diabetes by comparison to individualized dietary plans. Assuming a dropout rate of 20%, there is greater than an 80% probability of detecting a significant difference from baseline in body weight in the meal replacement group when the Student's t-test is conducted at a significance level of 0.05, and using the data on weight loss reviewed in the preliminary work.
Dietary intervention protocol
Each participant received individual consultation with a registered dietitian at baseline, weeks 2, 4, 6, 8 and then monthly for the duration of the 1-y study. For the first 5 days of the study, subjects randomized into the MR group replaced three meals per day with a soy MR (Slim·Fast Food Company, Inc. West Palm Beach, FL 33401, USA). They also were instructed to add fruits and vegetables to their dietary intake. Thereafter, the MR group replaced two meals with the soy MR with continuing use of fruits and vegetables as snacks, plus a sensible third meal for three additional months. After the 3 months, subjects in the MR group were instructed to replace one to two meals per day with the soy shakes and consume correspondingly one to two sensible meals for the duration of the study. Subjects randomized into the IDP group were instructed on the use of food exchanges based on goals that met the criteria as recommended by the American Diabetes Association (ADA). This was based on the consumption of less than 30% calories from fat, 10–20% from protein and 55–65% from carbohydrates (Clinical Practice Recommendation, 1997). For both groups, an individualized caloric target was calculated to achieve a daily caloric deficit of 500 calories per day below estimated resting metabolic rates. Twenty-four-hour recall was reviewed and food portions were discussed at each visit for compliance with meeting with the dietitian.
Weight was measured with a balanced-beam doctor's scale calibrated to 0.11 kg and height was measured with a wall-mounted stadiometer to the nearest 0.318 cm. Glucose was measured using a spectrophotometric technique at an absorbance of 505 nm and insulin was measured using a commercial double antibody I125 method. Plasma total cholesterol (TC), triglyceride (TG) and high-density lipoprotein cholesterol (HDL) concentrations were determined by using standard enzymatic methods established in the UCLA Center for Human Nutrition Biomarker Research Laboratory. The inter-assay coefficients of variation are less than 4% and intra-assay variation is less than 2%. The HDL (α) alpha cholesterol concentrations were determined after precipitation of apoprotein B-rich lipoproteins with heparin and manganese chloride. The LDL-cholesterol concentrations were calculated by using the Friedewald equation (Friedewald et al, 1972), which assumes that circulating VLDLs consist of 80% TGS and 20% cholesterol. High sensitivity-CRP (hs-CRP) measurement was performed by Quest Diagnostic Laboratory. The laboratory is certified by the Centers for Disease Control Lipid Standardization Program, Lab No. LSP266.
Resting metabolic rates were estimated based on lean body mass as measured by bioelectrical impedance analysis according to the Cunningham equation estimate of 13.8 kcal/day/pound of lean body mass.
Study 2: Assessment of glucose response to MR
A separate study was designed to compare the glucose and insulin response of one serving (48 g in 237 ml) of a soy-based MR (Slim·Fast Soy, SlimFast Foods Company, West Palm Beach, FL, 33401, USA) with a serving (237 ml) of a liquid nutritional supplement specifically designed for those with diabetes (Glucerna™ Ross Lab). In all, 18 subjects were randomized in a cross-over design to either receive the soy-based MR on day 1 and the nutritional supplement on day 4 or the nutritional supplement on day 1 and the soy-based MR on day 4. The nutritional composition of the two products is presented in Table 1. Each test session was initiated between 08:00 and 09:00 on each test day. An intravenous catheter was placed in an arm vein using the aseptic technique. Serum glucose levels for the 2 test days were required to be within 20 mg/dl of each other prior to initiation of the test meal, or the subject was rescheduled. Serum glucose and insulin levels were measured at baseline (prior to test meal consumption), 15, 30, 60, 90, 120, 150, 180, 210, 240, 270, and 300 min. For each subject and each type of breakfast, the area under glucose (insulin) level over time was calculated.
Data from subjects who returned for their initial follow-up visit after randomization were analyzed on an intention-to-treat basis. Data from subjects who discontinued study participation before 12 months were included through their last study visit. Baseline data and 12-month changes from baseline data were compared between treatment groups using Student’s t-test for two independent samples. A X2 test was used to compare categorical data. All data are presented as mean±s.e.m. unless otherwise stated. P-values <0.05 were considered significant.
In this randomized study, the outcome variables were repeatedly measured over time. Weight, BMI, insulin, glucose, HbA1c, serum lipids, and hs-CRP were measured at baseline, months 3, 6, and 12, respectively. Descriptive statistics, such as means and standard deviation, were used to summarize the outcomes for each study group at each time point. Change of each outcome variable from baseline within each diet group was tested using paired t-test. The differences among the diet groups at each time point were examined using a general linear model with the baseline value as covariate. A mixed model was used to test the overall diet effect:
where Y is the outcome; Baseline Y is the baseline measurement; γg is the diet effect for group g after taking baseline value into account; ɛ is a vector of error, ɛ∼MVN ( 0, R), R is block diagonal with a block for each subject. Each block has a compound symmetric covariance structure. Log transformation was taken for some Y and baseline Y due to non-normality. The data is analyzed as a 2-arm study with direct comparison of IDP vs MR using the above intent-to-treat model.
Study 1. Diet intervention study
In this study, a total of 104 subjects were randomized to treatment. In all, 11 subjects (three in MR and eight in IDP) dropped out during the screening and/or baseline visits. An additional 11 subjects (eight in the IDP group and three in MR group) were lost to the study within the first 6 months. These 22 subjects were excluded from the analysis. During the second 6 months, there were an additional five dropouts, (one in the IDP group, four in the MR group). No subjects withdrew from the study due to serious AEs. Intention-to-treat analysis was also performed including all 104 subjects that showed same statistical results. Table 2 shows the baseline characteristics of the subject population of study 1. There were no statistical differences between the two study groups with respect to the baseline demographics.
Subjects in both the MR and the IDP groups lost clinically significant amounts of weight over the 12-month study. For the MR and IDP groups the average weight loss was −5.24±4.08 and −2.85±4.04 kg at 6 months and −4.35±5.28 and 2.36±4.92 kg at 12 months. Similar decreases were observed in BMI with the MR group having decreased 1.44±1.77 units in the MR group compared to 0.77±1.49 units in the IDP at 12 months (Table 3). This translated to an average percentage loss at the end of the 12 months of −4.57±5.26 and 2.25±4.27% (P=0.039) for MR and IDP, respectively. At each study time point, the percentage of weight loss in the MR group was statistically higher than in the IDP group (Figure 1). During the entire study period, the mean % weight loss for the MR group is 2.28+0.64% higher than the IDP group (P=0.0004).
Glucose, HbA1c, and insulin levels
Table 4 presents the changes over time for serum glucose, insulin and HbA1c. Adjusting for baseline values, the MR group had significantly lower glucose concentrations than the IDP group at 3 (P=0.04) and 6 (P=0.002) months but not at 12 months. Comparing within treatment groups, those using MR averaged significantly lower glucose concentrations for each time point with the exception of month 12, whereas the IDP group only trended to lower values. Insulin values were unchanged in both groups.
The HbA1c levels at months 3, 6, and 12 in the IDP group were reduced but were not significantly lower than starting levels. Adjusting for baseline HbA1c level, the mean HbA1c was 0.49±0.22 lower than the IDP group for the entire study period (P=0.0291) by repeated measurement analysis.
Total cholesterol, triacylglycerol, LDL, and HDL
Reponses to the dietary interventions over time for lipids and lipoproteins are also presented in Table 4. There were no significant differences between treatment groups at any time point for TC, TG, LDL-C, and HDL-C. However, there were within treatment differences when compared to the respective baselines for both the MR and IDP groups.
Change in hs-CRP
Of the 77 patients who completed 12 months, hs-CRP level was measured in 50 subjects (24 in IDP group and 26 in MR group). A total of 27 patients were excluded for recent history of systemic infection/inflammation or did not consent to this specific test. Patients on statins for treatment of dyslipidemia were included in the analysis. There was no significant difference in baseline demographics and observed weight loss in those excluded when compared to the overall analysis population.
Baseline levels of hs-CRP were similar in both groups (MR 3.69±0.75 mg/l, IDP 3.66±0.69 mg/l, P=0.861). Subset analysis based on comparison of subjects with or without statin use revealed no difference in baseline hs-CRP level in IDP group (with statin (n=12): 3.55±0.91 mg/l, without statin (n=12): 3.76±1.07 mg/l, P=0.977) as well as in the MR group (with statin (n=12): 3.71±0.99 mg/l, without statin (n=14): 3.61±1.24 mg/l, P=0.980).
Change in medication
All the study subjects were taking at least one oral hypoglycemic agent at study entry. The medication profiles were compatible between the two groups. In the MR group, significant number of subjects had a reduction of their sulfonylurea (P<0.0001) and metformin (P<0.05) use by 12 months (McNemar's Test, Figure 2). Changes of this nature were not seen in the IDP group. There were no significant dosage changes with regard to hypertension medication and cholesterol lowering agents in either group.
Study 2: MR glucose response test
The blood glucose and insulin response test demonstrated that the consumption of the soy-based MR resulted in similar effects on glucose levels when compared to Glucerna use. Figures 3 and 4 show the average glucose and insulin levels after a single MR consumption for all the subjects over time. Since the carry-over effect and the sequence effects were very insignificant, Wilcoxon sign-rank test was used to examine the difference in area under the curve (AUC) for glucose and insulin with the soy-based MR and Glucerna. There were no statistically significant differences in the AUC when comparing the consumption of the two products, when parameters glucose (P=0.8603) and insulin (P=0.9799) were analyzed. It should be noted that while there are 30% additional calories in Glucerna, contribution of total carbohydrate to overall calories remains constant between the two MRs.
Obesity is now an epidemic in the United States, affecting one out of every three Americans (Flegal et al, 1998; National Institute of Health Publication, 1998). The increasing prevalence of obesity over the past two decades is alarming since it translates into increased medical care and disability costs because of the relationship between excess body weight and several risk factors for disease. Obese subjects with type II DM pose a significant challenge for the clinicians responsible for their care (Maggio & Pi-Sunyer, 1997). There is increasing scientific evidence suggesting that excess visceral fat in obese type II DM patients may play a key role in the evolution of the metabolic abnormalities manifested in this population. Several recent clinical trials have shown that weight loss in obese type II DM can result in a favorable correction of several key metabolic disturbances (Agurs-Collins et al, 1997; Hollander et al, 1998). However, successful weight management in this population is often difficult to achieve. Weight reduction through nutritional and pharmaceutical intervention as a primary approach for treatment of type II DM is starting to receive more attention nationally. The Diabetes Primary Prevention Trial demonstrated that changes in diet and lifestyle can prevent progression from impaired glucose tolerance to a diagnosis of DM. The study was terminated after 3 y due to the significant improvements in the subjects’ health as a result of dietary and lifestyle changes. In fact, weight losses of 5–7% and implementation of regular exercise resulted in a significantly lower rate of progression to DM (14%) than pharmacotherapy alone with metformin (29% progression to DM) (The Diabetes Prevention Program, 1999).
In previous studies, liquid MRs have been shown to be a useful tool for both weight loss and weight maintenance in obese subjects (Ditschuneit et al, 1999; Flechtner-Mors et al, 2000). There are concerns, however, that the high sugar content in most MRs may cause adverse glycemic excursions in patients with type II DM. As a result of this, we published a 12-week study comparing the safety and efficacy of a popular liquid MR marketed for weight loss, which contains high levels of mono- and disaccharides, with an exchange diet based on the recommendations of the American Diabetic Association (Yip et al, 2001). As reported in this study, significant reductions in body weight were accompanied by significantly improved glycemic control despite the high level of sugars.
The present study is an extension of the previous short-term study (Yip et al, 2001) and was undertaken to evaluate the efficacy and safety of a meal replacement strategy for weight loss in the type II DM patient. This is the first study to demonstrate the long-term efficacy of a soy-based liquid meal replacement in type II DM as the sole therapy.
The use of soy-based MR diets for weight loss in rigorously conducted clinical trials is limited. Allison et al (2003) recently reported that soy-based MR formula is well tolerated and effective for short-term weight loss in obese individuals. In this study, the MR group was given five packages of MR and fruit and vegetables. At 12 weeks, soy MR group lost 7.1 vs 2.9 kg in control group. The present study used a soy-based MR to replace one or two meals per day over a 1-y period. The weight loss at 3 months was comparable to the above study with a 5.6 kg weight loss in the MR group compared to a 2.9 kg in the IDP group. At 12 months, the soy-based MR group still maintained a significantly higher percentage of weight loss than the IDP group.
Obese type II DM patients with excess intra-abdominal fat are at increased risk for negative health consequences. A growing body of evidence suggests that adipose tissue, specifically visceral fat, is a key regulator of inflammatory responses. Elevated levels of hs-CRP have been shown to be associated with increased risk for coronary events, independent of traditional lipid risk factors (Mendall et al, 1996; Mojiminiyi et al, 2002).
There are no significant changes in insulin levels except for the MR group at month 3. All the subjects in this study were in good glycemic control at the beginning of the study. The baseline HbA1c level was 7.53% for the IDP group and 7.63% for MR group, which is very close to normal. Hypoglycemic medications were closely monitored and changed by the study physician and subject's primary care physicians in accordance with the subject's change in caloric intake and successful weight loss. This may explain the steady level of insulin found at each study time point. Furthermore, we were able to reduce oral hypoglycemic medications in many of our participants as they were losing weight. By doing so, the potential side effects of these medications, that is, weight gain, were decreased improving the success of the dietary program.
The dropout rate of this study was 26% over the study period with the majority of the loss during screening and initial visits. Most of the subjects who dropped out at this time did so because they were not randomized into the MR group, although they were informed of the possibility due to randomization, or they realized the time commitment of the study was not manageable. The rate decreased to 6% after the initial dropout in the first month of the study. These retention results are excellent for this type of clinical trial. Overall, the meal replacements were very well tolerated. Subjects were compliant with the MR plan throughout the study even though only one flavor of the product was provided for the entire year. Subjects did report ‘taste fatigue’ particularly after the first 6 months, which may have contributed to weight regain and loss of some of the metabolic profile improvements after 6 months.
In conclusion, the use of soy-based MR in a structured strategy of a reduced calorie diet plan provided clinically significant weight losses in individuals with noninsulin-dependent type II DM. Due to the overall good compliance of the participants to the dietary regimen, significant changes were made in their medications that control for blood glucose. These changes may, in part, have blunted the significant improvements seen in glycemic control over time.
Financial support information
Meal replacements provided by SlimFast Foods Co. Inc. (West Palm Beach, FL). All serology studies processed by Quest Diagnostics (Van Nuys, CA).
Guarantor: Z Li.
Contributors: ZL and KH—manuscript preparation and data analysis. PS, MB and GT—data collection and patient evaluation. SD, H-JW and RE—statistical analysis. YL—data collection and processing. DH—principle investigator, manuscript preparation and data analysis.
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