3Results

Prior Systematic Reviews

The National Institutes of Health (NIH) panel reviewed 29 counseling-based trials, with follow-up of at least 12 months, in which net weight loss (weight loss in intervention group minus weight loss in control group) could be calculated from evidence table data (Table 4). They found that average weight change in the intervention groups varied from a gain of 8 kg to a loss of 21.6 kg; corrected for change in control groups, weight change was +1.9 kg to -8.8 kg. In considering trials of ≥ 1 month duration, they found 38 in which counseling for low-calorie diets (1,000–1,200 kilo-calorie [kcal] per day) could reduce body weight by an average of 8% over 3 to 12 months and decrease abdominal fat.³ While very-low-calorie diets produced greater initial weight loss than low-calorie diets, effects were similar over follow-up beyond 1 year. Counseling for physical activity (in 24 RCTs) led to modest weight loss (2% to 3% of weight) and reduction in abdominal fat independent of the effect of caloric reduction. The combination of counseling for a reduced calorie diet and increased physical activity produced greater weight loss and reduction in abdominal fat than either approach alone. Review of 36 studies indicated that behavior therapy was a useful adjunct to other weight loss approaches over 1 year and that longer-term efficacy depended on continuing the intervention.

Upon review of 13 diet or behavioral therapy trials, the Canadian Task Force on Preventive Health Care found that weight reduction was most effective during supervised dietary treatment, with subsequent gradual weight regain. In 6 trials, with 24 to 60 months of follow-up, net weight change was 0 kg to -4.5 kg.⁴⁶

The UK National Health Service (NHS) likewise found that behavioral interventions, combined with diet or exercise, appear to be effective and may be more so if of longer duration.⁴⁷ In 24 studies, net weight change was similar to that found in other reviews: +1.4 to -10.6 kg over 12 to 60 months. The authors concluded that long-term follow-up and maintenance strategies should be an integral part of a weight loss program.⁴⁷

Studies of Efficacy of Counseling and Behavioral Interventions

We identified 17 randomized trials of fair or good quality in which interventions were based on counseling (including diet, exercise, or some combination of the 2) and delivered with or without behavioral therapy.^{52, 65–80} In 1 additional trial, the intervention or control activity was delivered by county of residence in a nonrandom fashion.⁸¹ Evidence Table 1, Appendix B, records details of these 18 studies. Sustained weight loss was defined as a change in body weight (in pounds, kilograms, or kilograms per meter squared of height [ie, BMI]) for at least 1 year.

We recorded the mode of intervention in Evidence Table 1 as well as the degree of intensity of the intervention. We considered interventions to be of moderate intensity if they involved monthly person-to-person contact with the participant, during the first 3 months of the intervention. Those with more frequent contact were considered high intensity and those with less frequent contact low intensity; cut-offs were driven by the distribution of program intensity we found represented in the literature. The following discussion takes up trials of high, medium, and low intensity in that order. We classified trials according to the type of intervention - ie, type of behavior counseled (diet or exercise [D, E respectively in Evidence Table 1]) and presence of a behavioral therapy component in the delivery of the intervention (B in Evidence Table 1). More detail on counseling interventions is presented in Appendix C.

Trials often entailed both weight loss and maintenance phases. These were analyzed separately from trials that involved either only a loss phase or only a maintenance phase (following successful weight loss). We break out the 2 maintenance-only trials in the discussion below.^{67, 72}

Comparison of effects is summarized in Figure 6. For this, we plotted the difference in mean weight change between intervention and control groups, at end-points as close as possible to 1 year, for all trials for which we could calculate the difference or the investigators could report the difference. If variance data were available in the articles or we could calculate them, we also depicted the 95% confidence intervals. Data are arrayed for high-, then moderate-, and then low-intensity studies; those with good internal validity are listed ahead of those with fair internal validity.

High-Intensity Interventions for Weight Loss. In all, 11 RCTs employed high-intensity interventions at the group or individual level.^{52, 65, 66, 68, 69, 71, 73, 74, 76, 79, 80} Of these, 6 RCTs compared high-intensity counseling intervention with a true control (no-intervention) group. Four achieved significant reductions in weight in the treatment groups (average loss: 2.7–5.5 kg improvement over controls at 12 months to more than 2 years of follow-up).^{65, 66, 69, 79}

Of these, a Finnish trial is of particular note: individual-based diet and exercise advice with a behavioral component (7 sessions over the first year) led the intervention group to lose 3.4 kg more than controls over the first year.⁶⁶ The investigators noted a high frequency of response (where response was defined as 5% weight loss): 43% of the intervention group versus 5% of the controls.⁶⁶ Similar results were subsequently found for the participants in the Diabetes Prevention Program in the United States: high-intensity counseling for diet and exercise, with behavioral therapy, led to an average 5.5 kg loss in the intervention group versus controls over an average of 2.8 years.⁷⁹

Two trials with a true control were less successful. One, with a group-based approach, showed borderline-significant reduction in weight in the treatment groups.⁷⁴ Another combined an intense individual and group approach; the treatment group had improved weight at 6 months, but did not differ significantly from controls at 12 to 30 months of follow-up.⁶⁸

Because prior studies have shown that combinations of diet, exercise, and behavioral therapy tend to be more effective than a single treatment, we evaluated 5 additional trials in which 1 combination of treatments was found to be superior to another, even in the setting of no true control (ie, no treatment) arm.^{52, 71, 73, 76, 80} One study evaluating choice of behavioral interventions found that a diet and exercise approach combined with behavioral choice treatment led to, on average, 5.8 kg of additional weight loss compared with traditional behavioral therapy.⁷³ Another trial examined different exercise regimens in the setting of diet and behavioral therapy: people who were supplied with treadmill machines for use at home, and instructed to do short bouts of exercise, lost more weight (4.3 kg more) over 18 months than those with similar instructions but no home equipment.⁷¹ A trial comparing various 1-year, 26-session counseling programs found that combining meal replacements with a dietician-led group intervention was more effective than such counseling alone; short counseling sessions (10 to 15 minutes) with a health care provider combined with meal replacements led to similar degrees of weight loss as 1-hour dietician-led group sessions.⁸⁰

A single trial examined the combination of counseling and behavioral therapy with pharmacotherapy for obesity.⁵² Compared with sibutramine alone, the addition of a lifestyle intervention (behavioral therapy) led to a 7.3 kg weight reduction, and the further addition of a portion-controlled low-calorie diet led to weight loss of 12.8 kg over 1 year. Finally, Wing and Anglin studied weight change by race, rather than weight loss per se. The data in Figure 6 thus reflect differences between black and white populations estimated from their graph-based results.⁷⁶ Graphical data (significance not noted) suggest that weight loss was greater with behavioral therapy and an intermittent very-low-calorie diet than with behavioral therapy with a continuous low-calorie diet for white and black participants. However, over the 1-year follow-up, weight loss was lower in blacks than whites, primarily from faster regain.

Three studies (1 with 2 different physical activity interventions) reported weight change results first at 12 to 18 months, and then with prolonged follow-up.^{66, 69, 74} As seen in prior reviews, subjects showed a tendency towards weight regain. However, in 3 of the 4 interventions, a modest statistically significant weight loss of at least 2 kg was maintained 24 to 36 months after initiation.^{65, 66, 74} Two programs specifically included long-term maintenance interventions.^{65, 74}

Moderate-Intensity Interventions for Weight Loss. We identified 2 moderate-intensity, counseling-based weight loss interventions, both with a behavioral component.^{70, 77} A 1-year, group-focused intervention showed effectiveness similar to that of the nonpharmacological high-intensity interventions (3.5 kg).⁷⁰ A second intervention for multiple issues related to cardiac risk showed no significant improvement in weight at 18 months.⁷⁷

Low-Intensity Interventions for Weight Loss. The low-intensity weight loss interventions that we reviewed were not effective. In 1 RCT, Jeffrey and French looked at the difference in weight change between intervention and control groups; this study was designed for weight gain prevention and showed no difference in men or in women of 2 socioeconomic strata at the end of 1 year.⁷⁵

Two other studies (not shown in Figure 6) also investigated low-intensity approaches.^{78, 81} An RCT that did not measure baseline weight for controls found that, after 3 years, skilled manual laborers who underwent either a single or an annual nurse-run preventive medicine examination weighed 0.4 kg less than coworkers who received no health checks.⁷⁸ Finally, a group-based study, delivered according to nonrandomized intervention or control counties, was likewise ineffective.⁸¹

Interventions for Weight Loss in the Overweight. Limited data address the efficacy of counseling-based interventions in the overweight. A well-done high-intensity intervention on participants with baseline mean BMI levels of 25 promoted weight loss in a range similar to that found in trials including only obese participants.⁶⁵ However, 1 low- and 1 moderate-intensity intervention in which participants' baseline BMI was in the upper range of overweight were ineffective.^{75, 77}

Interventions for Maintenance of Weight Loss. Two trials, neither with a true control group, evaluated counseling and behavioral plans for weight maintenance only.^{67, 72} In the high-intensity trial, members of a weight-focused treatment arm regained 2.1 kg less over 18 months than those receiving exercise-focused treatment.⁷² Weight-focused participants maintained, on average, 90% of their weight loss over that time (compared with 54% in the exercise-focused arm). A low-intensity weight maintenance intervention also found a significant difference between treatments:⁶⁷ among self-selected women who had already lost more than 20 pounds, the prescription of pre-measured low-calorie liquid meal replacements led to an average of 5 kg lower weight over 1 year.

Summary of the Effectiveness of Counseling and Behavioral Treatment

Data on effectiveness of counseling and behavioral interventions must be understood in light of several caveats. Although several trials were of “good” quality (internal validity), most were judged only “fair,” with limitations such as small sample size, potential selection bias (trials often enrolled volunteers), and high drop-out rates. Studies tended to report mean group weight change (eg, an average weight change of -5 kg in a group of 50 participants) and not frequency of response to the interventions (eg, 15 [30%] of 50 participants achieved loss of 10% of their initial body weight). We were not able to assess differences by sex or ethnic background in response to counseling and behavioral interventions; most trials included only women and either did not specify ethnicity or involved primarily white samples. One study did examine weight loss in black and white participants; initial weight loss in the black groups was followed by rapid weight regain, so that at the end of the study, sustained weight loss was considerably greater in white participants.⁷⁶ Finally, the vast majority of these trials enrolled either only obese participants or samples in which average baseline BMI was in the high-overweight range. We were not able to assess the effectiveness of interventions specifically for those who are overweight but not obese.

Our findings agreed with those of the prior systematic reviews: generally, the counseling and behavioral interventions showed small to moderate degrees of weight loss sustained over at least 1 year. In the updated searches, higher-intensity trials and combinations of interventions appeared to promote better outcomes. However, treating patients with individual- versus group-based approaches did not appear to have a strong influence on success. As previous reviews have noted, trials with follow-up beyond 1 year tended to show a loss of effect; several studies, however, have shown modest weight loss maintained at 24 to 36 months. In addition, the success of weight maintenance trials is encouraging. Weight loss methods may need to be paired with longer-term maintenance interventions for sustained improvement.

Prior Systematic Reviews

Pharmacological treatment options for obesity are intended either to help promote or to sustain weight loss, in coordination with lifestyle change. Drug options have changed markedly since the major prior systematic reviews for obesity. The evidence concerning sibutramine (a dopamine, norepinephrine, and serotonin re-uptake inhibitor) and orlistat (a gastrointestinal lipase inhibitor) has increased. Both are approved by the U.S. Food and Drug Administration (FDA) for weight loss and weight maintenance after prior weight loss, in persons with BMI > 30 or persons with BMI > 27 with other risk factors such as hypertension, diabetes, or dyslipidemia; they should be used in conjunction with a reduced-calorie diet. FDA approval was based upon studies of up to 2 years' duration. Because of safety concerns, dexfenfluramine, fenfluramine, phenylpropanolamine, and the combination of fenfluramine/phentermine—previously central players in the pharmacotherapy of obesity—are no longer available in the United States.

Because available medications have changed so substantially since the publication of the 3 earlier large comprehensive obesity reviews, we do not present their findings here, although we did review relevant content. For example, we reviewed the 1996 National Task Force on the Prevention and Treatment of Obesity systematic review of clinical trials up to 6 months of drugs available at that time. Arterburn and Noel had also reviewed these same articles in 2001,⁸² so we focused on the more recent review. In our data synthesis step, we included the findings of the systematic reviews along with the additional studies that we reviewed in detail.

Arterburn and Noel concluded that limited evidence shows that sibutramine is more effective than placebo in promoting modest weight loss (2.8–4.2 kg in 7 RCTs over 0.5–24 months) in healthy adults, and in those with controlled hypertension, but that subjects regain weight after stopping treatment.⁵¹ Orlistat was found to have a modest effect on body weight (an average of 3.5 kg loss in 10 RCTs). Both medications lacked long-term evidence of safety. Phentermine (7.4 kg average loss in 1 RCT) and mazindol (3.8 kg average loss in 1 RCT) caused modest weight loss in adults who were more than 15% overweight; again, these drugs lacked long-term evidence on safety. Small RCTs found limited and inconsistent evidence for the efficacy of diethylpropion (2 RCTs) and fluoxetine (2 RCTs) for weight loss compared with placebo.

Pharmacotherapy Intervention Studies Reviewed

We identified 13 RCTs of the efficacy of pharmacotherapy for weight loss that had been published since the 1996 USPSTF guidelines and that fit our inclusion criteria. Of these, 6 trials evaluated sibutramine,^83–88 6 covered orlistat,^89–94 and 1 involved metformin.⁹⁵ We did not re-review any trials that Arterburn and Noel had covered.⁵¹ We added 1 medication, metformin, to the list of drugs reviewed previously, as we had located several trials addressing its use specifically for weight loss. Evidence Tables 2, 3, and 4 in Appendix B present details on trials of sibutramine, orlistat, and metformin, respectively.

Inclusion criteria for our review included (a) fair or good quality, placebo-controlled RCTs on humans; (b) body weight or BMI as a primary trial outcome; (c) trial duration of at least 6 months; (d) trial population generalizable to a typical U.S. primary care population; (e) English language; and (f) no review by Arterburn and Noel. We categorized studies as either “weight loss” (minimum of 6-month follow-up) or “weight maintenance” (minimum of 1-year follow-up after successful weight loss). Eight weight-loss trials and 3 weight-maintenance trials were judged to be of fair or good quality (1 study had both a loss and a maintenance arm).

To depict the various findings from the trials focused on weight loss, we record in Figures 7 and 8 the mean weight changes and the percentage frequency of response (10% weight loss), respectively.

Pharmacotherapy Interventions for Weight Loss

Sibutramine. Of the 6 sibutramine trials (Evidence Table 2),^83–88 5 concerned weight loss and lasted 6 to 12 months.^84–88 Sibutramine-treated participants achieved an average of 2.8 kg to 4.8 kg more weight loss than placebo (Figure 7). Four trials recorded frequency of response; for example, 27% to 65% of sibutramine-treated patients achieved 5% weight loss and 6% to 38% of patients lost 10% of their initial body weight.^{84, 86–88} Sibutramine-treated participants achieved 5% of total body weight loss 19% to 37% more often than controls (depending on drug dose). As shown in Figure 8, patients on sibutramine achieved a 10% weight loss 5% to 27% more often than controls (Figure 8, right hand panel). Differences by dose of drug or mode of use (Figure 8, left-hand panel) were also of interest; however, by and large dosage did not materially affect outcomes. For instance, in 1 trial, weight loss obtained with sibutramine therapy did not differ between people treated with continuous therapy and those treated with intermittent therapy.⁸⁷

Orlistat. Of the 6 orlistat trials (see Evidence Table 3),^{89–93, 96} we reviewed 5 assessing weight loss over 6 to 12 months duration; orlistat-treated participants treated in the normal dosing range (120 mg 3 times a day [Figure 7]) lost significantly more weight than controls: on average, 2.8 kg to 4.5 kg (or 1.2–1.5 kg/m²) more than control participants.^89–93 In 1 small study (n = 55), the average weight of orlistat treated patients dropped 5.8 kg more than that of controls, but the difference was not statistically significant.⁹⁴ Only 2 of the orlistat trials we reviewed reported frequency of response.^{89, 93} In these trials, a 10% weight loss response occurred in 23% to 38% of orlistat-treated participants depending on dose (Figure 8, left-hand panel). Between 9% and 19% more of orlistat group members were able to achieve 10% loss of their body weight than members of the control group (Figure 8, right-hand panel).

Metformin. Only 1 metformin trial met quality criteria (Evidence Table 4).⁹⁵ It included patients with diabetes who had inadequate blood glucose control despite oral therapy for at least 1 year. Metformin-treated patients did no better than controls in terms of weight loss.

Pharmacotherapy Interventions for Maintenance of Weight Loss

Sibutramine. James et al reported weight change from baseline through 6 months of successful treatment with sibutramine, followed by an 18-month period of sibutramine maintenance therapy.⁸³ Over the 2 years, sibutramine-treated participants lost, on average, 4 kg more than their placebo-treated counterparts. They were also more likely (41% of sibutramine vs 14% of placebo participants) to maintain 80% of their initial weight loss.

Orlistat. In the trial conducted by Karhunen et al, participants received 2 years of therapy: orlistat for 2 years, placebo for 2 years, or 1 year of each.⁹¹ The investigators did not record orlistat versus placebo results. Patients who were treated with orlistat for 1 or 2 years obtained “significantly more” weight loss over 2 years than participants treated with placebo. During the second year of treatment, orlistat was no more effective than placebo, on average, and discontinuing orlistat appeared to lead to excess weight regain. That is, those treated with orlistat for the first year and then changed to placebo had a mean 6.3 kg weight gain during the second year, whereas those treated with placebo throughout gained, on average, only 3 kg over the second year of the study.

In another trial, initiated after 6 months of successful dieting, participants treated with an orlistat dose of at least 60 mg 3- times a day lost more weight over 1 year and were less likely to experience marked weight regain than placebo-treated patients.⁹⁰ Those treated with 120 mg 3- times daily also achieved a larger percentage of weight change and were more likely to maintain 75% of their initial weight loss than placebo-treated patients.

Summary of the Efficacy of Pharmacotherapy

Again, findings must be interpreted in light of several considerations. One is internal validity: most trials were of fair quality, although a few were judged to be of good quality. A second is the degree to which participants were overweight in the trials. These trials did not assess drug effectiveness by degree of overweight. Some included participants with baseline BMI in the high 20s, but average baseline weight was consistently in the obese range (ie, BMI ≥ 30), and pharmacotherapy for weight loss is approved only for the obese. As with pharmacotherapy trials, participants were primarily women of European origin. We evaluated several pharmacotherapy trials with relatively short-term follow-up (less than 1 year); although their findings were generally within the range seen for the longer studies, sustained weight loss was not established in so short a time.

Finally, although most trials did employ a form of intention-to-treat analysis, typically the investigators analyzed their data according to a “last observation carried forward” protocol—the final weight outcome available was used as the final weight for those participants who dropped out of the study. As weight loss tends to be maximal within the first 6 months of therapy, failure to measure body weight at the endpoint of longer trials risks overestimating the tendency towards sustained weight loss. We would prefer to review such results alongside analysis of trial “completers,” but such an approach was infrequent.

Overall, fairly long-term data for sibutramine and orlistat suggested that these drugs have modest but potentially prolonged effects. Although average weight loss was consistently modest, the percentage of patients achieving clinically significant loss (5%–10% of body weight) was frequently substantial. Weight maintenance trials suggested that prolonged drug therapy confers some benefit but that discontinuation of pharmacotherapy may lead to rapid weight regain.

Prior Systematic Reviews

The 3 previous obesity reviews all evaluated the impact of surgery on people with obesity. Because of practical and ethical constraints to a true randomized, blinded, placebo-controlled surgical obesity trial, high-quality evidence for obesity surgery is limited. Reviews have relied primarily on randomized unblinded trials in which neither arm was a true control (eg, comparisons between surgical techniques). Here, we summarize their findings for current procedures with at least 1 year of follow-up. The Canadian Task Force on Preventive Health Care analyzed 4 randomized trials and 1 prospective cohort study.⁴⁶ In these studies, mean weight loss following surgery was 17 kg to 46 kg after 2 to 5 years. Postoperative mortality and morbidity rates were low; 1 surgery-related death occurred (0.002% of subjects), and post-operative morbidity was less than 5%. The Centre for Reviews and Dissemination from the University of York's review of 6 trials showed weight loss of 9.7 kg to 57.9 kg.⁴⁷ In the NIH National Heart, Lung and Blood Institute review, 5 randomized surgical trials led to weight loss of 10 kg to 159 kg over 12 to 48 months.³

Studies of the Effectiveness of Surgical Interventions for Weight Loss

Randomized Trials. Our review of randomized trials with comparison arms included trials of fair to good quality with follow-up of at least 1 year and weight loss or BMI change as an outcome. We identified 2 trials that had not been reported by the previous systematic reviews.^{97, 98} Details are in Evidence Table 5. One compares laparoscopic versus open banding techniques,⁹⁷ and the other, 2 laparoscopic banding techniques.⁹⁸

In the de Wit et al study, 50 obese (BMI >40) patients were randomized to either open or laparoscopic adjustable silicone gastric banding.⁹⁷ Both groups showed large average weight declines over 1 year: 35 kg in the laparoscopic and 34 kg in the open surgical group. Accordingly, BMI dropped from 51.3 to 39.7 in the laparoscopic group and from 49.7 to 39.1 in the open group. Complications included incisional hernias (14.3%), umbilical hernia (2%), and infection (2%); no subject died.

Weiner et al randomized 101 consecutive patients to 1 of 2 groups of laparoscopic gastric banding—retrogastric placement (RGP) or esophagogastric placement (EGP).⁹⁸ Weight loss was substantial in both groups: more than 40 kg in both groups at 18 months. Post-operative complications included 3 band slippages (3%, which were subsequently corrected with additional laparoscopic surgery), 1 pouch dilation (1%), vomiting in 6 patients (6%), and dysphagia in 6 patients (6%); no patient died. Of note, results from a quality-of-life questionnaire revealed that more than 96% of participants reported excellent well-being at the 18-month follow-up.

Cohort Studies. We used well-designed cohort studies as a second form of evidence for obesity surgery. RCTs are the preferable form of evidence, but because the constraints against a large RCT for obesity surgery are extensive, this may be a situation in which carefully evaluated cohort data are appropriate. We searched for controlled cohort studies with weight loss as a primary outcome, in which the patient population was well described, and identified a single large on-going study - the Swedish Obese Subjects (SOS) study.^{99, 100} In addition, we examined extensive uncontrolled cohort (case series) evidence to assess the safety of obesity surgical techniques and their applicability to primary care populations.

The SOS study provides the best cohort evidence: a large ongoing multi-center trial with nonrandomized matched controls involving volunteers at 750 primary health care centers and 26 county and university hospitals in Sweden. The surgical arm is divided equally among 3 surgical techniques: gastric banding, vertical banded gastroplasty, and gastric bypass. Controls are treated with “the best non-surgical options available” (p. S3).¹⁰⁰

Two-year data revealed weight loss of 28 kg (23% of total weight) among the surgical patients and 0.5 kg among controls. The percentages of weight reduction after gastric banding, vertical banded gastroplasty, and gastric bypass were 21%, 23%, and 33%, respectively. Eight-year follow-up data showed a 20-kg weight loss (16.5% of total weight) for 251 patients in the surgical group; over this same period, the 232 control patients gained 0.7 kg.¹⁰⁰ The reported post-operative mortality rate was 0.2%. As in the randomized trials, morbidity was low; among 1,164 patients, complications included bleeding (0.9%), wound complications (1.8%), abdominal infection (2.1%), thromboembolic events (0.8%), pulmonary symptoms (6.2%), and miscellaneous events (4.8%).¹⁰⁰

Summary of Effectiveness of Surgical Treatment

Overall, considering RCTs, controlled cohort studies, and uncontrolled cohort studies, the degree of weight reduction obtained with surgical interventions is consistently dramatic. Cohort evidence suggests that this weight loss may be prolonged and that it can be achieved in patient populations with multiple comorbidities.

We must, however, note some limitations to this literature. Surgical data are limited by the lack of placebo-controlled RCT evidence, and the internal validity of the trials we reviewed was of only fair quality. Again, the investigators tended to report average treatment effect, rather than frequency of response.

Finally, obesity surgery has been performed for only a select group of patients; the NIH obesity panel recommends it only for those people with a BMI >40 or a BMI of 35 to 40 with at least 1 obesity-related comorbidity.³ National data indicate that 5% to 6% of the general population has a BMI in this range,¹² so a substantial number of people may meet these criteria.