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STUDY DESIGN: This was a double-blind randomized placebo-controlled parallel-group comparative study of sibutramine 10 mg or 15 mg (or placebo) once daily for 1 year, given with dietary advice.
POPULATION: A total of 485 obese men and women with uncomplicated obesity were included (mean age=42 years; mean body mass index=32.7 kg/m2).
OUTCOMES: measured The outcomes were mean weight loss, percentage losing more than 5% or 10% of their body weight, and adverse drug effects.
RESULTS: Among patients completing the study, those taking sibutramine 10 mg or 15 mg had greater mean weight loss compared with placebo at 12-month assessment (P <.001). Changes in body weight from baseline to end point were -1.6 kg for those taking placebo, -4.4 kg for those taking sibutramine 10 mg (P <.01, last observation carried forward [LOCF]), and -6.4 kg for those taking sibutramine 15 mg (P <.001, LOCF). For placebo patients, 20% lost 5% or more of their body weight compared with 39% of patients taking sibutramine 10 mg and 57% taking sibutramine 15 mg. Only 7% of the patients taking placebo lost 10% or more of their body weight, compared with 19% taking sibutramine 10 mg and 34% taking sibutramine 15 mg (P <.001 for both 10 mg and 15 mg vs placebo, and for both Ž5% and Ž10%).
CONCLUSIONS: Sibutramine 10 mg or 15 mg once daily given with dietary advice produces and maintains statistically and clinically significantly greater weight loss than dietary advice alone (placebo) throughout a 12-month treatment period, and is safe and well tolerated.
Obesity is a common problem, with significant health costs and associated morbidity; rates of overweight and obesity continue to increase in the United States1,2 and Europe.3 In a typical general practice setting of 10,000 patients in the United Kingdom, approximately 1600 men and 1300 women could be expected to be overweight, and another 360 men and 700 women would need management of their obesity.4 Obesity predisposes patients to cardiovascular disease and hypertension,5 diabetes mellitus,6 hormone-related cancers,7 gallbladder disease,8 musculoskeletal disorders,9 sleep apnea,10 and generalized bodily pain.11 It has a detrimental effect on social well-being,12 decreases longevity,13 and imposes a tremendous financial and time burden on health care systems14; yet even a moderate amount of intentional weight loss (approximately 5%-10%) may significantly reduce the risk of mortality among subjects with medical complications of obesity.15
Increasingly, the major share of the primary effort to lower weight is falling on the general practice physician.16 Despite this, only 42% of obese patients seeking medical help are advised by their health professionals to lose weight; however, this telephone survey may suffer from a significant recall bias.17 Within the medical specialties, including family practice, internal medicine, and endocrinology, approximately 50% of physicians express interest in treating obesity in their practices.16,18
Current treatment plans include mostly behavioral interventions, such as diet and exercise, along with behavior modification.19 These generally have a poor success rate, and in one study, long-term follow-up of weight maintenance after a 12-week very-low-calorie diet showed that patients regained the weight lost at a rate of 2.5% per month.20 Although pharmacotherapy can be an important component of a weight loss program, safety issues have led to the withdrawal of some medications from the market. Studies with these have shown, however, that weight loss with pharmacotherapy can result in significant health benefits.21-26
Sibutramine (Meridia; Knoll Pharmaceuticals, Nottingham, United Kingdom) is a new pharmacotherapy alternative. It is a serotonin-norepinephrine reuptake inhibitor (SNRI) that produces dose-related weight loss by enhancing postingestive satiety and by increasing energy expenditure.21,27-29 Twelve months after weight reduction on a 4-week very-low-calorie diet, 75% of the patients taking sibutramine maintained 100% of their weight loss. This is a significantly greater percentage than the 42% who maintained 100% of weight loss in the nonsibutramine control group (P <.01).30,31 Our study of sibutramine, carried out in a primary care general practice setting, was designed to determine the long-term efficacy, tolerability, and safety of dosages of 10 mg and 15 mg of sibutramine, which have been identified as effective and well tolerated in previous studies.31,32 We also carried out analysis of improvements in risk factors resulting from 5% and 10% body weight loss.
Methods
The Nottinghamshire Independent Ethics Committee (Boots) approved our study, and all patients gave informed consent in writing. Our study was conducted in accordance with the Declaration of Helsinki (1983 revision).
Patients
We sought healthy male and female general practice patients, aged 18 to 65 years, who were mildly to moderately obese (body mass index [BMI] = 27 to 40 kg/m2), who had not lost more than 3 kg of weight during the previous 3 months, whose obesity was not of endocrine origin, and who did not have diabetes mellitus. All patients we enrolled were identified by primary care physicians. They had to have a seated pulse rate of 100 beats per minute or lower and a seated diastolic blood pressure of 100 mm Hg or lower. Hypertensive patients were included only if the condition had been stabilized with medication for 6 months. Patients receiving laxatives, anorectic agents, diuretics (except where stabilized for 6 months or more), bulking agents, antidepressants, or any other medication that in the opinion of the investigator might alter body weight were excluded. The patients completed the self-assessment Clinical Global Impressions questionnaire32,33 and the Beck Depression Inventory. The objective of this was to identify patients who might be likely to have unusual weight changes in the context of the trial because of depression, and was not done for psychiatric evaluation. Those assessed by the investigator to be more than borderline depressed were excluded.
Trial Protocol
Because of the lack of a clear definition of obesity at the time of the initiation of our study and the lack of a clear definition of the patients for whom sibutramine treatment would be appropriate, protocol amendments permitted enrollment of a few patients with BMIs of 25 to 44 kg/m2 (BMI Ž40 kg/m2 is considered extremely obese). Depression and anxiety inventories were completed by a subset of patients at the study outset.34 The investigator carried out a dietary inquiry for each eligible patient, and these patients were given standardized dietary advice and dietary advice sheets to be followed throughout the study. They were told to include certain foods in their diet each day: 12 oz of vegetables and fresh fruit; 6 oz of bread, cereal, potatoes, or rice; and 10 oz of skim milk; and they were told to substitute low-calorie foods such as fresh fruits and baked potatoes for sugary and fried foods such as chocolate and biscuits. The patients’ overall success in complying with dietary advice was assessed by the investigator using a 10-cm visual analog question scale labeled with opposite and extreme answers at either end (“easy to follow dietary advice” to “unable to follow dietary advice”).
Eligible patients then entered a 2-week single-blind placebo run-in period. At the end of the run-in period (month 0), those who still met the entry criteria entered the 12-month double-blind treatment phase of the study. Entry was restricted to those able to follow dietary advice as determined by the investigator. The patients were randomized in a double-blind fashion to once-daily treatment with placebo or sibutramine 10 mg or 15 mg dispensed in identical capsules, which were prepackaged and coded by the sponsor according to a computer-generated randomization list. The patients were assessed at monthly visits (month 0-month 12) during treatment and 1 week and 1 month after the completion of treatment. Patients withdrawing during treatment were assessed at that time and again 1 month after withdrawal. Beck Depression and State Anxiety inventories were performed on a subset of patients at the last treatment visit and at the 1-week follow-up visit to confirm lack of residual psychological changes due to medications.
At each visit, the investigator recorded the patient’s weight in indoor clothing. Waist and hip circumferences were measured at months 0, 6, and 12. Heart rate and blood pressure were recorded at every visit, and details of reported adverse events were recorded. Electrocardiograms and routine laboratory safety tests were performed at screening, 6 months, and 12 months.
Outcome Measures
The primary end point was the study outcome (measured on a categorical scale) on the basis of either the percentage weight loss at the end of the study or the reason for premature withdrawal.35 The outcome measures were weight loss (kg), percentage weight loss, weight loss of at least 5% and at least 10%, change in BMI, and change in waist/hip ratio.
Statistical Analysis
Calculations were performed on the difference between treatment groups in weight change between baseline and month12. Eighty-three patients completing treatment in each study group would be required to detect a difference in weight change of 4.0 kg with 90% power at the 5% significance level, assuming a standard deviation of 7.38 kg. Allowing for a forecast withdrawal rate of 45%, the desired sample size at enrollment was 184 patients per group or 552 for the entire study.
All statistical tests were two-tailed, with significance determined by reference to the 5% level. The null hypothesis was that the treatments were equivalent. The principal measure of efficacy was analyzed using the Kruskal-Wallis test,36 including a factor for treatment group. Given that this result was significant at the 5% level, pairwise comparisons between the treatment groups were made by the large-sample normal approximation to the Wilcoxon rank sum test.35
The methods we used to analyze differences between treatment groups were analysis of variance (ANOVA)34 with factors for treatment group, center, and treatment group-by-center interaction for weight loss, waist and hip circumference, waist/hip ratio, vital signs, glucose and triglycerides, and ranked ANOVA for BMI, cholesterol, and uric acid. The differences between groups in the proportion of patients losing at least 5% and 10% of their baseline body weight were analyzed by logistic regression with factors for treatment group and center. All efficacy analyses were performed using the last observation carried forward (LOCF) to replace missing data. All data collected were included except for assessments performed more than 14 days after the last dose of study medication. After 14 days postdose, it was thought body weights could have changed significantly.
Results
Of 510 patients who entered the run-in period, 485 continued into the double-blind phase Figure 1. This occurred because of a lack of a gold-standard definition of obesity at the outset of this study; a protocol amendment allowed data from these patients to be included in the analysis. No clinically significant differences were noted between treatment groups at baseline with respect to demographic profile or characteristics of obesity Table 1. Four patients had BMIs at screening that fell out of the original trial protocol, all in the sibutramine 10-mg treatment group (1 patient <27 and 3 patients >40 kg/m2). Reanalysis of the data excluding these 4 patients was carried out, and no differences affecting the results, outcomes, or conclusions of our study were found.
Our analysis takes the patients who withdrew from the study into account.32 Pooled rates of withdrawal for any reason were similar in the 3 treatment groups: placebo, 83 patients (51%); sibutramine 10 mg, 79 (49%); and sibutramine 15 mg, 67 (42%). The completion rate for the 1-year study was 53%, which is generally consistent with weight loss programs.37 Regarding the primary outcome analysis, fewer patients in the sibutramine groups than in the placebo group withdrew for lack of efficacy or adverse events. Using the log-rank test, there was no statistically significant difference between treatment groups in time to withdrawal, overall withdrawal rate, or withdrawal rate due to adverse events or lack of efficacy. Both sibutramine-treated groups had more patients in each category of weight loss above 5% (P=.001; Table 2. Pairwise comparisons showed a statistically significant difference versus placebo in favor of sibutramine 10 mg (P=.04) and sibutramine 15 mg (P <.001).
A significantly greater proportion of patients in the 2 sibutramine groups lost at least 5% and 10% of their baseline body weight Table 2. Mean weight reduction was significantly greater in the sibutramine groups than in the placebo group. Mean reductions in BMI reflected those in body weight and were significantly greater with 10 mg sibutramine (1.7 kg/m2) and 15 mg sibutramine (2.4 kg/m2) than with placebo (0.6 kg/m2; P <.001). The reduction in BMI was significantly greater with 15 mg sibutramine than 10-mg sibutramine (P <.05).
Patients treated with 10 mg or 15 mg sibutramine once daily lost more weight at each monthly assessment than those treated with placebo Figure 2. Weight loss was dose related, and maximal weight loss occurred by month 6 in all treatment groups. During the 4 weeks after treatment cessation (at whatever time this occurred), there were small weight increases in all treatment groups. Ten (6%) patients in the placebo group withdrew because of lack of efficacy compared with 5 (3%) in the sibutramine 10 mg group and 2 (1%) in the sibutramine 15-mg group.
Dose-related reductions in mean waist and hip circumferences achieved by month 6 were maintained at month 12. In the placebo group at month 12 (LOCF), the reductions were similar for waist and hip (2.4 cm and 2.6 cm, respectively), while in the 10- and 15-mg sibutramine groups, waist reduction was greater than hip reduction (6.4 cm and 3.8 cm at 10 mg and 7.4 cm and 5.2 cm at 15 mg). The reductions on active treatment were significantly greater than with placebo (P <.05 for overall comparison). The mean reduction in waist/hip ratio at month 12 (LOCF) was significantly greater with 10 mg sibutramine (-0.04) and 15 mg sibutramine (-0.03) than with placebo (-0.01; P <.05; least significant difference, .02).
There were statistically significant changes in triglycerides compared with placebo (+3.2%) at month 6 for the sibutramine 10- and 15-mg treatment groups (-10.8%, P <.05 and -10.0%, P <.01, respectively). Uric acid levels were also significantly reduced at month 6 for both sibutramine treatment groups (10 mg, -6.0% [P <.05] and 15 mg, -6.2% [P <.05] compared with placebo, -1.9%). Decrease in uric acid was the only laboratory-reported variable that was statistically significantly greater in the sibutramine-treated patients than in the placebo-treated patients at end point Table 3. These changes are more closely associated with disease end points than with patient outcomes.
Among adverse events occurring with a frequency of more than 5% in any treatment group, only dry mouth occurred significantly more frequently with 10 mg sibutramine (19 patients) or 15 mg sibutramine (21 patients) than with placebo (2 patients; P <.001). Eight serious adverse events led to early withdrawal during the double-blind phase of the study (2 in each of the sibutramine groups and 4 in the placebo group). Two were considered possibly related to sibutramine. The first was a 49-year-old woman with a history of epilepsy with no seizures during the previous 4 years, who was withdrawn after 126 days of treatment with 10 mg sibutramine because she had had 4 “drop attacks” within 2 weeks. The second was a 32-year-old woman who was withdrawn after 246 days of treatment with 15 mg sibutramine because of palpitations due to frequent ventricular ectopic beats. No evidence was found of any withdrawal effect during the follow-up period, when active treatment was over. Patient psychological status was evaluated both at the end of the double-blind treatment (63 patients completed all assessments) and at follow-up 1 week after stopping treatment (67 patients completed all assessments). There were no statistically or clinically significant differences between the treatment groups for change in either the Beck Depression Inventory or the State Anxiety Inventory studied from the end of the double-blind treatment period to the follow-up. All 3 groups showed a mean improvement in the depression inventory.
Mean changes in vital signs averaged over all post-baseline double-blind assessments adjusted for center and treatment-by-center are shown in Table 3. Differences in mean changes in blood pressure were not statistically significant for the sibutramine treatment groups from placebo, except for the mean increase in diastolic blood pressure in the sibutramine 10 mg treatment group Table 3. Statistically significant changes in pulse rate in the sibutramine 15 mg treatment group compared with the placebo treatment group were consistent with the mechanism of action of sibutramine as an SNRI.
Discussion
Weight loss, obesity, and overweight are important topics,16 and today an increasing proportion of obesity is first encountered in the family practice setting.38 Our study shows that in the context of a family practice setting, a patient’s diet, along with sibutramine treatment, will cause more loss of weight than changes in diet alone. Increased levels of total serum cholesterol are associated with an increased risk of coronary heart disease, and although difficult to quantify, a reduction of 0.6 mmol per L has been observed to be associated with a 54% lower risk.39 This was calculated in a retrospective analysis of results of several clinical studies. Patients in this study losing 10% of their body weight over 6 months taking sibutramine 10 mg once daily reduced serum cholesterol by 0.23 mmol per L and may contribute to an overall benefit for patients as part of a risk reduction program. Similarly, the recently recommended target for reduction of triglycerides is a reduction of 1.7 mmol per L.40 In our study, a reduction of 0.63 mmol per L in triglycerides was accomplished among those patients who received sibutramine 10 mg who lost at least 10% of body weight. Mean changes in blood pressure observed during the 6 months of our study were not great enough to increase the category of patient risk for coronary heart disease.41 Although weight loss can be associated with decreased mortality,13 the extent to which a weight reduction of 10% can augment other medical approaches to risk reduction long-term is only now being defined.
In this 1-year placebo-controlled study carried out in the primary care setting, sibutramine given with dietary advice was significantly superior in all weight loss efficacy assessments to dietary advice alone (placebo). These efficacy assessments included the ranked weight reduction outcomes analysis. Sibutramine was consistently superior to placebo across all categories of weight loss in this ranked analysis that takes subject withdrawals into account. The results of this study confirm the findings previously reported.30
The plateau in weight loss observed at 6 months and maintained while having treatment is consistent with observations in other long-term studies of drug treatment in uncomplicated obese patients.26,37 On the basis of other studies of weight loss, the regain of weight after cessation of treatment is not unexpected. The rates of completion of the study, although low, probably reflect what might be expected to occur in a general practice setting and are consistent with completion rates of weight loss programs in general.37
The response rate at the 5% and 10% weight-reduction thresholds, with changes in waist circumference and in waist/hip ratio, were chosen for analysis in part because weight loss at these levels may ameliorate obesity-related disease.37-42 Sustained moderate weight loss may be expected to bring about a reduction in blood pressure, hypertension, and dyslipidemia.43 The small mean changes in blood pressure seen in the sibutramine groups were not unexpected given the norepinephrine-reuptake inhibitory properties of sibutramine. In clinical practice, any clinically significant changes that may occur should be detected by routine monitoring of vital signs. Of note, even in the current setting, where approximately 8% of patients were being treated with concomitant therapies related to cardiovascular disease, no patients were withdrawn (0%) because of elevated blood pressure.
Limitations
There were limitations to the general applicability of our study results to family practice. The treatment was limited to those patients who first demonstrated they could adhere to a weight loss program. Although the family practitioner may have some background information concerning this capability for a candidate for sibutramine treatment, general documentation may not be available for all candidates. Also, only 53% of the randomized patients completed this 1-year weight loss study. In addition, generally patients who stop weight loss treatment gain weight; however, the Sibutramine Trial in Obesity Reduction and Maintenance44 demonstrated that weight loss can be maintained safely with sibutramine for up to 2 years. Another limitation to applicability of the study is the detailed depression and anxiety profile carried out for some patients enrolled. Such analysis is not practical or needed before sibutramine use in a family practice setting, and this analysis is not included in recently initiated studies. This was a generally healthy obese patient population with few comorbidities, and they were not depressed or anxious. That may limit the ability to generalize these findings to obese patients overall.
Conclusions
Dosages of sibutramine 10 mg or 15 mg administered once daily in a primary care general practice setting to patients with mild to moderate uncomplicated obesity produced statistically and clinically significant weight reduction that was maintained over a 12-month treatment period. Sibutramine was safe and well tolerated at both 10-mg and 15-mg once-daily doses. Further studies in patients with medical complications of obesity are under way to evaluate the efficacy of sibutramine-induced weight loss on the comorbidities and risk factors associated with obesity.
Acknowledgments
The author would like to thank the Sibutramine Clinical Study 1047 Team for their contributions, especially J Hosie, I James, and SP Jones. Competing interests: This study was funded by Knoll Pharmaceuticals, the manufacturer of sibutramine.
1. Kuczmarski RJ, Flegal KM, Campbell SM, Johnson CL. Increasing prevalence of overweight among US adults: the National Health and Nutrition Examination Surveys, 1960 to 1991. JAMA 1994;272:205-11.
2. Mokdad AH, Serdula MK, Dietz WH, Bowman BA, Marks JS, Koplan JP. The spread of the obesity epidemic in the United States, 1991-1998. JAMA 1999;282:1519-22.
3. WHO Expert Committee on Physical Status Physical status: the use of and interpretation of anthropometry report of a WHO expert committee. Geneva, Switzerland: Geneva World Health Organization; 1995. WHO technical report series 854.
4. Her Majesty’s Stationery Office Health Survey for England 1994. London, England: HMSO; 1996.
5. Hubert HB, Feinleib M, McNamara PM, Castelli WP. Obesity as an independent risk factor for cardiovascular disease: a 26-year follow-up of participants in the Framingham Heart Study. Circulation 1983;67:968-77.
6. Chan JM, Rimm EB, Colditz GA, Stampfer MJ, Willett WC. Obesity, fat distribution, and weight gain as risk factors for clinical diabetes in men. Diabetes Care 1994;17:961-69.
7. Lew EA, Garfinkel L. Variations in mortality by weight among 750,000 men and women. J Chron Dis 1979;32:563-76.
8. Friedman GD, Kannel WB, Dawber TR. The epidemiology of gallbladder disease: observations in the Framingham Study. J Chron Dis 1966;19:273-92.
9. Spector TD, Hart DJ, Doyle DV. Incidence and progression of osteoarthritis in women with unilateral knee disease in the general population: the effect of obesity. Ann Rheum Dis 1994;53:565-68.
10. Kopelman PG. Sleep-apnea and hypoventilation in obesity. Int J Obes 1992;16:S37-42.
11. Fontaine KR, Cheskin LJ, Barofsky I. Health-related quality of life in obese persons seeking treatment. J Fam Pract 1996;43:265-70.
12. Enzi G. Socioeconomic consequences of obesity-the effect of obesity on the individual. PharmacoEconomics 1994;5:54-57.
13. Manson JE, Willett WC, Stampfer MJ, et al. Body weight and mortality among women. N Engl J Med 1995;333:677-85.
14. Wolf AM, Colditz GA. Current estimates of the economic cost of obesity in the United States. Obes Res 1998;6:97-106.
15. Goldstein DJ. Beneficial health effects of modest weight loss. Int J Obes Relat Metab Disord 1992;16:397-415.
16. Williamson DF. The prevention of obesity. N Engl J Med 1999;341:1140-41.
17. Galuska DA, Will JC, Serdula MK, Ford ES. Are health care professionals advising obese patients to lose weight? JAMA 1999;282:1576-78.
18. Kristeller JL, Hoerr RA. Physician attitudes toward managing obesity: differences among six specialty groups. Prev Med 1997;26:542-49.
19. Garrow JS. Treatment of obesity. Lancet 1992;340:409-13.
20. Anderson JW, Vichitbandra S, Qian W, Kryscio RJ. Long-term weight maintenance after an intensive weight-loss program. J Am Coll Nutr 1999;18:620-27.
21. Heal DJ, Aspley S, Prow MR, Jackson HC, Martin KF, Cheetham SC. Sibutramine: a novel anti-obesity drug. A review of the pharmacological evidence to differentiate it from d-amphetamine and d-fenfluramine. Int J Obes Relat Metab Disord 1998;22(suppl 1):S18-28.
22. US Department of Health and Human Services Cardiac valvulopathy associated with exposure to fenfluramine or dexfenfluramine: US Department of Health and Human Services Interim Public Health Recommendations, November 1997. MMWR Morb Mortal Wkly Rep 1997;46:1061-66.
23. Joint National Committee on Prevention Detection Evaluation and Treatment of High Blood Pressure The sixth report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure. Arch Intern Med 1997;157:2413-46.
24. Bray GA. A case for drug treatment of obesity. Hospital Practice 1994;29:53,57-60.
25. Wooley SC, Garner DM. Dietary treatments for obesity are ineffective. BMJ 1994;309:655-56.
26. Goldstein DJ, Potvin JH. Long-term weight loss: the effect of pharmacologic agents. Am J Clin Nutr 1994;60:647-57.
27. Ryan DH, Kaiser P, Bray GA. Sibutramine: a novel new agent for obesity treatment. Obes Res 1995;3(suppl 4):553S-59S.
28. Connoley IP, Liu Y-L, Frost I, Reckless IP, Heal DJ, Stock MJ. Thermogenic effects of sibutramine and its metabolites. Br J Pharmacol 1999;126:1487-95.
29. Walsh KM, Leen E, Lean MEJ. The effect of sibutramine on resting energy expenditure and adrenaline-induced thermogenesis in obese females. Int J Obes Relat Metab Disord 1999;23:1009-15.
30. Apfelbaum M, Vague P, Ziegler O, Hanotin C, Thomas F, Leutenegger E. Long-term maintenance of weight loss after a very-low-calorie diet: a randomized blinded trial of the efficacy and tolerability of sibutramine. Am J Med 1999;106:179-84.
31. Bray GA, Ryan DH, Gordon D, Heidingsfelder S, Cerise F, Wilson K. A double-blind randomized placebo-controlled trial of sibutramine. Obes Res 1996;4:263-70.
32. Gould AL. A new approach to the analysis of clinical drug trials with withdrawals. Biometrics 1980;36:721-27.
33. Guy W. CGI global impression ECDEU assessment manual for psychopharmacology. Washington, DC: Department of Health, Education, and Welfare; 1976.
34. Winer BJ. In: Winer BJ, ed. Statistical principles in experimental design. 2nd ed. New York, NY: McGraw-Hill; 1971;261-308.
35. Hollander M, Wolfe DA. The two-sample location problem. In: Hollander M, Wolfe DA, eds. Nonparametric statistical methods. New York, NY: John Wiley & Sons; 1973;67-82.
36. Hollander M, Wolfe DA. The one-way layout. In: Hollander M, Wolfe DA, eds. Nonparametric statistical methods. New York, NY: John Wiley & Sons; 1973;114-20.
37. National Task Force on the Prevention and Treatment of Obesity Long-term pharmacotherapy in the management of obesity. JAMA 1996;276:1907-15.
38. Noel M, Hickner J, Ettenhofer T, Gauthier B. The high prevalence of obesity in Michigan primary care practices: an UPRNet study. J Fam Pract 1998;47:39-43.
39. Guidelines Subcommittee of the World Health Organization-International Society of Hypertension Mild Hypertension Liaison Committee. 1999 World Health Organization-International Society of Hypertension guidelines for the management of hypertension. J Hypertens 1999;17:151-83.
40. Assmann G, Carmena R, Cullen P, et al. Coronary heart disease: reducing the risk. A worldwide view. Circulation 1999;100:1930-38.
41. Hansson L. The Hypertension Optimal Treatment Study and the importance of lowering blood pressure. J Hypertens 1999;17(suppl 1):S9-13.
42. Lapidus L, Bengtsson C, Larsson B, Pennert K, Rybo E, Sjostrom L. Distribution of adipose tissue and risk of cardiovascular disease and death: a 12-year follow-up of participants in the population study of women in Gothenburg, Sweden. BMJ 1984;289:1257-61.
43. Larsson B, Svärdsudd K, Welin L, Wilhelmsen L, Björntorp P, Tibblin G. Abdominal adipose tissue distribution, obesity, and risk of cardiovascular disease and death: 13-year follow-up of participants in the study of men born in 1913. BMJ 1984;288:1401-04.
44. James WPT, Astrup A, Finer N, et al. Effect of sibutramine on weight maintenance after weight loss: a randomized trial. Lancet 2000;356:2119-25.
STUDY DESIGN: This was a double-blind randomized placebo-controlled parallel-group comparative study of sibutramine 10 mg or 15 mg (or placebo) once daily for 1 year, given with dietary advice.
POPULATION: A total of 485 obese men and women with uncomplicated obesity were included (mean age=42 years; mean body mass index=32.7 kg/m2).
OUTCOMES: measured The outcomes were mean weight loss, percentage losing more than 5% or 10% of their body weight, and adverse drug effects.
RESULTS: Among patients completing the study, those taking sibutramine 10 mg or 15 mg had greater mean weight loss compared with placebo at 12-month assessment (P <.001). Changes in body weight from baseline to end point were -1.6 kg for those taking placebo, -4.4 kg for those taking sibutramine 10 mg (P <.01, last observation carried forward [LOCF]), and -6.4 kg for those taking sibutramine 15 mg (P <.001, LOCF). For placebo patients, 20% lost 5% or more of their body weight compared with 39% of patients taking sibutramine 10 mg and 57% taking sibutramine 15 mg. Only 7% of the patients taking placebo lost 10% or more of their body weight, compared with 19% taking sibutramine 10 mg and 34% taking sibutramine 15 mg (P <.001 for both 10 mg and 15 mg vs placebo, and for both Ž5% and Ž10%).
CONCLUSIONS: Sibutramine 10 mg or 15 mg once daily given with dietary advice produces and maintains statistically and clinically significantly greater weight loss than dietary advice alone (placebo) throughout a 12-month treatment period, and is safe and well tolerated.
Obesity is a common problem, with significant health costs and associated morbidity; rates of overweight and obesity continue to increase in the United States1,2 and Europe.3 In a typical general practice setting of 10,000 patients in the United Kingdom, approximately 1600 men and 1300 women could be expected to be overweight, and another 360 men and 700 women would need management of their obesity.4 Obesity predisposes patients to cardiovascular disease and hypertension,5 diabetes mellitus,6 hormone-related cancers,7 gallbladder disease,8 musculoskeletal disorders,9 sleep apnea,10 and generalized bodily pain.11 It has a detrimental effect on social well-being,12 decreases longevity,13 and imposes a tremendous financial and time burden on health care systems14; yet even a moderate amount of intentional weight loss (approximately 5%-10%) may significantly reduce the risk of mortality among subjects with medical complications of obesity.15
Increasingly, the major share of the primary effort to lower weight is falling on the general practice physician.16 Despite this, only 42% of obese patients seeking medical help are advised by their health professionals to lose weight; however, this telephone survey may suffer from a significant recall bias.17 Within the medical specialties, including family practice, internal medicine, and endocrinology, approximately 50% of physicians express interest in treating obesity in their practices.16,18
Current treatment plans include mostly behavioral interventions, such as diet and exercise, along with behavior modification.19 These generally have a poor success rate, and in one study, long-term follow-up of weight maintenance after a 12-week very-low-calorie diet showed that patients regained the weight lost at a rate of 2.5% per month.20 Although pharmacotherapy can be an important component of a weight loss program, safety issues have led to the withdrawal of some medications from the market. Studies with these have shown, however, that weight loss with pharmacotherapy can result in significant health benefits.21-26
Sibutramine (Meridia; Knoll Pharmaceuticals, Nottingham, United Kingdom) is a new pharmacotherapy alternative. It is a serotonin-norepinephrine reuptake inhibitor (SNRI) that produces dose-related weight loss by enhancing postingestive satiety and by increasing energy expenditure.21,27-29 Twelve months after weight reduction on a 4-week very-low-calorie diet, 75% of the patients taking sibutramine maintained 100% of their weight loss. This is a significantly greater percentage than the 42% who maintained 100% of weight loss in the nonsibutramine control group (P <.01).30,31 Our study of sibutramine, carried out in a primary care general practice setting, was designed to determine the long-term efficacy, tolerability, and safety of dosages of 10 mg and 15 mg of sibutramine, which have been identified as effective and well tolerated in previous studies.31,32 We also carried out analysis of improvements in risk factors resulting from 5% and 10% body weight loss.
Methods
The Nottinghamshire Independent Ethics Committee (Boots) approved our study, and all patients gave informed consent in writing. Our study was conducted in accordance with the Declaration of Helsinki (1983 revision).
Patients
We sought healthy male and female general practice patients, aged 18 to 65 years, who were mildly to moderately obese (body mass index [BMI] = 27 to 40 kg/m2), who had not lost more than 3 kg of weight during the previous 3 months, whose obesity was not of endocrine origin, and who did not have diabetes mellitus. All patients we enrolled were identified by primary care physicians. They had to have a seated pulse rate of 100 beats per minute or lower and a seated diastolic blood pressure of 100 mm Hg or lower. Hypertensive patients were included only if the condition had been stabilized with medication for 6 months. Patients receiving laxatives, anorectic agents, diuretics (except where stabilized for 6 months or more), bulking agents, antidepressants, or any other medication that in the opinion of the investigator might alter body weight were excluded. The patients completed the self-assessment Clinical Global Impressions questionnaire32,33 and the Beck Depression Inventory. The objective of this was to identify patients who might be likely to have unusual weight changes in the context of the trial because of depression, and was not done for psychiatric evaluation. Those assessed by the investigator to be more than borderline depressed were excluded.
Trial Protocol
Because of the lack of a clear definition of obesity at the time of the initiation of our study and the lack of a clear definition of the patients for whom sibutramine treatment would be appropriate, protocol amendments permitted enrollment of a few patients with BMIs of 25 to 44 kg/m2 (BMI Ž40 kg/m2 is considered extremely obese). Depression and anxiety inventories were completed by a subset of patients at the study outset.34 The investigator carried out a dietary inquiry for each eligible patient, and these patients were given standardized dietary advice and dietary advice sheets to be followed throughout the study. They were told to include certain foods in their diet each day: 12 oz of vegetables and fresh fruit; 6 oz of bread, cereal, potatoes, or rice; and 10 oz of skim milk; and they were told to substitute low-calorie foods such as fresh fruits and baked potatoes for sugary and fried foods such as chocolate and biscuits. The patients’ overall success in complying with dietary advice was assessed by the investigator using a 10-cm visual analog question scale labeled with opposite and extreme answers at either end (“easy to follow dietary advice” to “unable to follow dietary advice”).
Eligible patients then entered a 2-week single-blind placebo run-in period. At the end of the run-in period (month 0), those who still met the entry criteria entered the 12-month double-blind treatment phase of the study. Entry was restricted to those able to follow dietary advice as determined by the investigator. The patients were randomized in a double-blind fashion to once-daily treatment with placebo or sibutramine 10 mg or 15 mg dispensed in identical capsules, which were prepackaged and coded by the sponsor according to a computer-generated randomization list. The patients were assessed at monthly visits (month 0-month 12) during treatment and 1 week and 1 month after the completion of treatment. Patients withdrawing during treatment were assessed at that time and again 1 month after withdrawal. Beck Depression and State Anxiety inventories were performed on a subset of patients at the last treatment visit and at the 1-week follow-up visit to confirm lack of residual psychological changes due to medications.
At each visit, the investigator recorded the patient’s weight in indoor clothing. Waist and hip circumferences were measured at months 0, 6, and 12. Heart rate and blood pressure were recorded at every visit, and details of reported adverse events were recorded. Electrocardiograms and routine laboratory safety tests were performed at screening, 6 months, and 12 months.
Outcome Measures
The primary end point was the study outcome (measured on a categorical scale) on the basis of either the percentage weight loss at the end of the study or the reason for premature withdrawal.35 The outcome measures were weight loss (kg), percentage weight loss, weight loss of at least 5% and at least 10%, change in BMI, and change in waist/hip ratio.
Statistical Analysis
Calculations were performed on the difference between treatment groups in weight change between baseline and month12. Eighty-three patients completing treatment in each study group would be required to detect a difference in weight change of 4.0 kg with 90% power at the 5% significance level, assuming a standard deviation of 7.38 kg. Allowing for a forecast withdrawal rate of 45%, the desired sample size at enrollment was 184 patients per group or 552 for the entire study.
All statistical tests were two-tailed, with significance determined by reference to the 5% level. The null hypothesis was that the treatments were equivalent. The principal measure of efficacy was analyzed using the Kruskal-Wallis test,36 including a factor for treatment group. Given that this result was significant at the 5% level, pairwise comparisons between the treatment groups were made by the large-sample normal approximation to the Wilcoxon rank sum test.35
The methods we used to analyze differences between treatment groups were analysis of variance (ANOVA)34 with factors for treatment group, center, and treatment group-by-center interaction for weight loss, waist and hip circumference, waist/hip ratio, vital signs, glucose and triglycerides, and ranked ANOVA for BMI, cholesterol, and uric acid. The differences between groups in the proportion of patients losing at least 5% and 10% of their baseline body weight were analyzed by logistic regression with factors for treatment group and center. All efficacy analyses were performed using the last observation carried forward (LOCF) to replace missing data. All data collected were included except for assessments performed more than 14 days after the last dose of study medication. After 14 days postdose, it was thought body weights could have changed significantly.
Results
Of 510 patients who entered the run-in period, 485 continued into the double-blind phase Figure 1. This occurred because of a lack of a gold-standard definition of obesity at the outset of this study; a protocol amendment allowed data from these patients to be included in the analysis. No clinically significant differences were noted between treatment groups at baseline with respect to demographic profile or characteristics of obesity Table 1. Four patients had BMIs at screening that fell out of the original trial protocol, all in the sibutramine 10-mg treatment group (1 patient <27 and 3 patients >40 kg/m2). Reanalysis of the data excluding these 4 patients was carried out, and no differences affecting the results, outcomes, or conclusions of our study were found.
Our analysis takes the patients who withdrew from the study into account.32 Pooled rates of withdrawal for any reason were similar in the 3 treatment groups: placebo, 83 patients (51%); sibutramine 10 mg, 79 (49%); and sibutramine 15 mg, 67 (42%). The completion rate for the 1-year study was 53%, which is generally consistent with weight loss programs.37 Regarding the primary outcome analysis, fewer patients in the sibutramine groups than in the placebo group withdrew for lack of efficacy or adverse events. Using the log-rank test, there was no statistically significant difference between treatment groups in time to withdrawal, overall withdrawal rate, or withdrawal rate due to adverse events or lack of efficacy. Both sibutramine-treated groups had more patients in each category of weight loss above 5% (P=.001; Table 2. Pairwise comparisons showed a statistically significant difference versus placebo in favor of sibutramine 10 mg (P=.04) and sibutramine 15 mg (P <.001).
A significantly greater proportion of patients in the 2 sibutramine groups lost at least 5% and 10% of their baseline body weight Table 2. Mean weight reduction was significantly greater in the sibutramine groups than in the placebo group. Mean reductions in BMI reflected those in body weight and were significantly greater with 10 mg sibutramine (1.7 kg/m2) and 15 mg sibutramine (2.4 kg/m2) than with placebo (0.6 kg/m2; P <.001). The reduction in BMI was significantly greater with 15 mg sibutramine than 10-mg sibutramine (P <.05).
Patients treated with 10 mg or 15 mg sibutramine once daily lost more weight at each monthly assessment than those treated with placebo Figure 2. Weight loss was dose related, and maximal weight loss occurred by month 6 in all treatment groups. During the 4 weeks after treatment cessation (at whatever time this occurred), there were small weight increases in all treatment groups. Ten (6%) patients in the placebo group withdrew because of lack of efficacy compared with 5 (3%) in the sibutramine 10 mg group and 2 (1%) in the sibutramine 15-mg group.
Dose-related reductions in mean waist and hip circumferences achieved by month 6 were maintained at month 12. In the placebo group at month 12 (LOCF), the reductions were similar for waist and hip (2.4 cm and 2.6 cm, respectively), while in the 10- and 15-mg sibutramine groups, waist reduction was greater than hip reduction (6.4 cm and 3.8 cm at 10 mg and 7.4 cm and 5.2 cm at 15 mg). The reductions on active treatment were significantly greater than with placebo (P <.05 for overall comparison). The mean reduction in waist/hip ratio at month 12 (LOCF) was significantly greater with 10 mg sibutramine (-0.04) and 15 mg sibutramine (-0.03) than with placebo (-0.01; P <.05; least significant difference, .02).
There were statistically significant changes in triglycerides compared with placebo (+3.2%) at month 6 for the sibutramine 10- and 15-mg treatment groups (-10.8%, P <.05 and -10.0%, P <.01, respectively). Uric acid levels were also significantly reduced at month 6 for both sibutramine treatment groups (10 mg, -6.0% [P <.05] and 15 mg, -6.2% [P <.05] compared with placebo, -1.9%). Decrease in uric acid was the only laboratory-reported variable that was statistically significantly greater in the sibutramine-treated patients than in the placebo-treated patients at end point Table 3. These changes are more closely associated with disease end points than with patient outcomes.
Among adverse events occurring with a frequency of more than 5% in any treatment group, only dry mouth occurred significantly more frequently with 10 mg sibutramine (19 patients) or 15 mg sibutramine (21 patients) than with placebo (2 patients; P <.001). Eight serious adverse events led to early withdrawal during the double-blind phase of the study (2 in each of the sibutramine groups and 4 in the placebo group). Two were considered possibly related to sibutramine. The first was a 49-year-old woman with a history of epilepsy with no seizures during the previous 4 years, who was withdrawn after 126 days of treatment with 10 mg sibutramine because she had had 4 “drop attacks” within 2 weeks. The second was a 32-year-old woman who was withdrawn after 246 days of treatment with 15 mg sibutramine because of palpitations due to frequent ventricular ectopic beats. No evidence was found of any withdrawal effect during the follow-up period, when active treatment was over. Patient psychological status was evaluated both at the end of the double-blind treatment (63 patients completed all assessments) and at follow-up 1 week after stopping treatment (67 patients completed all assessments). There were no statistically or clinically significant differences between the treatment groups for change in either the Beck Depression Inventory or the State Anxiety Inventory studied from the end of the double-blind treatment period to the follow-up. All 3 groups showed a mean improvement in the depression inventory.
Mean changes in vital signs averaged over all post-baseline double-blind assessments adjusted for center and treatment-by-center are shown in Table 3. Differences in mean changes in blood pressure were not statistically significant for the sibutramine treatment groups from placebo, except for the mean increase in diastolic blood pressure in the sibutramine 10 mg treatment group Table 3. Statistically significant changes in pulse rate in the sibutramine 15 mg treatment group compared with the placebo treatment group were consistent with the mechanism of action of sibutramine as an SNRI.
Discussion
Weight loss, obesity, and overweight are important topics,16 and today an increasing proportion of obesity is first encountered in the family practice setting.38 Our study shows that in the context of a family practice setting, a patient’s diet, along with sibutramine treatment, will cause more loss of weight than changes in diet alone. Increased levels of total serum cholesterol are associated with an increased risk of coronary heart disease, and although difficult to quantify, a reduction of 0.6 mmol per L has been observed to be associated with a 54% lower risk.39 This was calculated in a retrospective analysis of results of several clinical studies. Patients in this study losing 10% of their body weight over 6 months taking sibutramine 10 mg once daily reduced serum cholesterol by 0.23 mmol per L and may contribute to an overall benefit for patients as part of a risk reduction program. Similarly, the recently recommended target for reduction of triglycerides is a reduction of 1.7 mmol per L.40 In our study, a reduction of 0.63 mmol per L in triglycerides was accomplished among those patients who received sibutramine 10 mg who lost at least 10% of body weight. Mean changes in blood pressure observed during the 6 months of our study were not great enough to increase the category of patient risk for coronary heart disease.41 Although weight loss can be associated with decreased mortality,13 the extent to which a weight reduction of 10% can augment other medical approaches to risk reduction long-term is only now being defined.
In this 1-year placebo-controlled study carried out in the primary care setting, sibutramine given with dietary advice was significantly superior in all weight loss efficacy assessments to dietary advice alone (placebo). These efficacy assessments included the ranked weight reduction outcomes analysis. Sibutramine was consistently superior to placebo across all categories of weight loss in this ranked analysis that takes subject withdrawals into account. The results of this study confirm the findings previously reported.30
The plateau in weight loss observed at 6 months and maintained while having treatment is consistent with observations in other long-term studies of drug treatment in uncomplicated obese patients.26,37 On the basis of other studies of weight loss, the regain of weight after cessation of treatment is not unexpected. The rates of completion of the study, although low, probably reflect what might be expected to occur in a general practice setting and are consistent with completion rates of weight loss programs in general.37
The response rate at the 5% and 10% weight-reduction thresholds, with changes in waist circumference and in waist/hip ratio, were chosen for analysis in part because weight loss at these levels may ameliorate obesity-related disease.37-42 Sustained moderate weight loss may be expected to bring about a reduction in blood pressure, hypertension, and dyslipidemia.43 The small mean changes in blood pressure seen in the sibutramine groups were not unexpected given the norepinephrine-reuptake inhibitory properties of sibutramine. In clinical practice, any clinically significant changes that may occur should be detected by routine monitoring of vital signs. Of note, even in the current setting, where approximately 8% of patients were being treated with concomitant therapies related to cardiovascular disease, no patients were withdrawn (0%) because of elevated blood pressure.
Limitations
There were limitations to the general applicability of our study results to family practice. The treatment was limited to those patients who first demonstrated they could adhere to a weight loss program. Although the family practitioner may have some background information concerning this capability for a candidate for sibutramine treatment, general documentation may not be available for all candidates. Also, only 53% of the randomized patients completed this 1-year weight loss study. In addition, generally patients who stop weight loss treatment gain weight; however, the Sibutramine Trial in Obesity Reduction and Maintenance44 demonstrated that weight loss can be maintained safely with sibutramine for up to 2 years. Another limitation to applicability of the study is the detailed depression and anxiety profile carried out for some patients enrolled. Such analysis is not practical or needed before sibutramine use in a family practice setting, and this analysis is not included in recently initiated studies. This was a generally healthy obese patient population with few comorbidities, and they were not depressed or anxious. That may limit the ability to generalize these findings to obese patients overall.
Conclusions
Dosages of sibutramine 10 mg or 15 mg administered once daily in a primary care general practice setting to patients with mild to moderate uncomplicated obesity produced statistically and clinically significant weight reduction that was maintained over a 12-month treatment period. Sibutramine was safe and well tolerated at both 10-mg and 15-mg once-daily doses. Further studies in patients with medical complications of obesity are under way to evaluate the efficacy of sibutramine-induced weight loss on the comorbidities and risk factors associated with obesity.
Acknowledgments
The author would like to thank the Sibutramine Clinical Study 1047 Team for their contributions, especially J Hosie, I James, and SP Jones. Competing interests: This study was funded by Knoll Pharmaceuticals, the manufacturer of sibutramine.
STUDY DESIGN: This was a double-blind randomized placebo-controlled parallel-group comparative study of sibutramine 10 mg or 15 mg (or placebo) once daily for 1 year, given with dietary advice.
POPULATION: A total of 485 obese men and women with uncomplicated obesity were included (mean age=42 years; mean body mass index=32.7 kg/m2).
OUTCOMES: measured The outcomes were mean weight loss, percentage losing more than 5% or 10% of their body weight, and adverse drug effects.
RESULTS: Among patients completing the study, those taking sibutramine 10 mg or 15 mg had greater mean weight loss compared with placebo at 12-month assessment (P <.001). Changes in body weight from baseline to end point were -1.6 kg for those taking placebo, -4.4 kg for those taking sibutramine 10 mg (P <.01, last observation carried forward [LOCF]), and -6.4 kg for those taking sibutramine 15 mg (P <.001, LOCF). For placebo patients, 20% lost 5% or more of their body weight compared with 39% of patients taking sibutramine 10 mg and 57% taking sibutramine 15 mg. Only 7% of the patients taking placebo lost 10% or more of their body weight, compared with 19% taking sibutramine 10 mg and 34% taking sibutramine 15 mg (P <.001 for both 10 mg and 15 mg vs placebo, and for both Ž5% and Ž10%).
CONCLUSIONS: Sibutramine 10 mg or 15 mg once daily given with dietary advice produces and maintains statistically and clinically significantly greater weight loss than dietary advice alone (placebo) throughout a 12-month treatment period, and is safe and well tolerated.
Obesity is a common problem, with significant health costs and associated morbidity; rates of overweight and obesity continue to increase in the United States1,2 and Europe.3 In a typical general practice setting of 10,000 patients in the United Kingdom, approximately 1600 men and 1300 women could be expected to be overweight, and another 360 men and 700 women would need management of their obesity.4 Obesity predisposes patients to cardiovascular disease and hypertension,5 diabetes mellitus,6 hormone-related cancers,7 gallbladder disease,8 musculoskeletal disorders,9 sleep apnea,10 and generalized bodily pain.11 It has a detrimental effect on social well-being,12 decreases longevity,13 and imposes a tremendous financial and time burden on health care systems14; yet even a moderate amount of intentional weight loss (approximately 5%-10%) may significantly reduce the risk of mortality among subjects with medical complications of obesity.15
Increasingly, the major share of the primary effort to lower weight is falling on the general practice physician.16 Despite this, only 42% of obese patients seeking medical help are advised by their health professionals to lose weight; however, this telephone survey may suffer from a significant recall bias.17 Within the medical specialties, including family practice, internal medicine, and endocrinology, approximately 50% of physicians express interest in treating obesity in their practices.16,18
Current treatment plans include mostly behavioral interventions, such as diet and exercise, along with behavior modification.19 These generally have a poor success rate, and in one study, long-term follow-up of weight maintenance after a 12-week very-low-calorie diet showed that patients regained the weight lost at a rate of 2.5% per month.20 Although pharmacotherapy can be an important component of a weight loss program, safety issues have led to the withdrawal of some medications from the market. Studies with these have shown, however, that weight loss with pharmacotherapy can result in significant health benefits.21-26
Sibutramine (Meridia; Knoll Pharmaceuticals, Nottingham, United Kingdom) is a new pharmacotherapy alternative. It is a serotonin-norepinephrine reuptake inhibitor (SNRI) that produces dose-related weight loss by enhancing postingestive satiety and by increasing energy expenditure.21,27-29 Twelve months after weight reduction on a 4-week very-low-calorie diet, 75% of the patients taking sibutramine maintained 100% of their weight loss. This is a significantly greater percentage than the 42% who maintained 100% of weight loss in the nonsibutramine control group (P <.01).30,31 Our study of sibutramine, carried out in a primary care general practice setting, was designed to determine the long-term efficacy, tolerability, and safety of dosages of 10 mg and 15 mg of sibutramine, which have been identified as effective and well tolerated in previous studies.31,32 We also carried out analysis of improvements in risk factors resulting from 5% and 10% body weight loss.
Methods
The Nottinghamshire Independent Ethics Committee (Boots) approved our study, and all patients gave informed consent in writing. Our study was conducted in accordance with the Declaration of Helsinki (1983 revision).
Patients
We sought healthy male and female general practice patients, aged 18 to 65 years, who were mildly to moderately obese (body mass index [BMI] = 27 to 40 kg/m2), who had not lost more than 3 kg of weight during the previous 3 months, whose obesity was not of endocrine origin, and who did not have diabetes mellitus. All patients we enrolled were identified by primary care physicians. They had to have a seated pulse rate of 100 beats per minute or lower and a seated diastolic blood pressure of 100 mm Hg or lower. Hypertensive patients were included only if the condition had been stabilized with medication for 6 months. Patients receiving laxatives, anorectic agents, diuretics (except where stabilized for 6 months or more), bulking agents, antidepressants, or any other medication that in the opinion of the investigator might alter body weight were excluded. The patients completed the self-assessment Clinical Global Impressions questionnaire32,33 and the Beck Depression Inventory. The objective of this was to identify patients who might be likely to have unusual weight changes in the context of the trial because of depression, and was not done for psychiatric evaluation. Those assessed by the investigator to be more than borderline depressed were excluded.
Trial Protocol
Because of the lack of a clear definition of obesity at the time of the initiation of our study and the lack of a clear definition of the patients for whom sibutramine treatment would be appropriate, protocol amendments permitted enrollment of a few patients with BMIs of 25 to 44 kg/m2 (BMI Ž40 kg/m2 is considered extremely obese). Depression and anxiety inventories were completed by a subset of patients at the study outset.34 The investigator carried out a dietary inquiry for each eligible patient, and these patients were given standardized dietary advice and dietary advice sheets to be followed throughout the study. They were told to include certain foods in their diet each day: 12 oz of vegetables and fresh fruit; 6 oz of bread, cereal, potatoes, or rice; and 10 oz of skim milk; and they were told to substitute low-calorie foods such as fresh fruits and baked potatoes for sugary and fried foods such as chocolate and biscuits. The patients’ overall success in complying with dietary advice was assessed by the investigator using a 10-cm visual analog question scale labeled with opposite and extreme answers at either end (“easy to follow dietary advice” to “unable to follow dietary advice”).
Eligible patients then entered a 2-week single-blind placebo run-in period. At the end of the run-in period (month 0), those who still met the entry criteria entered the 12-month double-blind treatment phase of the study. Entry was restricted to those able to follow dietary advice as determined by the investigator. The patients were randomized in a double-blind fashion to once-daily treatment with placebo or sibutramine 10 mg or 15 mg dispensed in identical capsules, which were prepackaged and coded by the sponsor according to a computer-generated randomization list. The patients were assessed at monthly visits (month 0-month 12) during treatment and 1 week and 1 month after the completion of treatment. Patients withdrawing during treatment were assessed at that time and again 1 month after withdrawal. Beck Depression and State Anxiety inventories were performed on a subset of patients at the last treatment visit and at the 1-week follow-up visit to confirm lack of residual psychological changes due to medications.
At each visit, the investigator recorded the patient’s weight in indoor clothing. Waist and hip circumferences were measured at months 0, 6, and 12. Heart rate and blood pressure were recorded at every visit, and details of reported adverse events were recorded. Electrocardiograms and routine laboratory safety tests were performed at screening, 6 months, and 12 months.
Outcome Measures
The primary end point was the study outcome (measured on a categorical scale) on the basis of either the percentage weight loss at the end of the study or the reason for premature withdrawal.35 The outcome measures were weight loss (kg), percentage weight loss, weight loss of at least 5% and at least 10%, change in BMI, and change in waist/hip ratio.
Statistical Analysis
Calculations were performed on the difference between treatment groups in weight change between baseline and month12. Eighty-three patients completing treatment in each study group would be required to detect a difference in weight change of 4.0 kg with 90% power at the 5% significance level, assuming a standard deviation of 7.38 kg. Allowing for a forecast withdrawal rate of 45%, the desired sample size at enrollment was 184 patients per group or 552 for the entire study.
All statistical tests were two-tailed, with significance determined by reference to the 5% level. The null hypothesis was that the treatments were equivalent. The principal measure of efficacy was analyzed using the Kruskal-Wallis test,36 including a factor for treatment group. Given that this result was significant at the 5% level, pairwise comparisons between the treatment groups were made by the large-sample normal approximation to the Wilcoxon rank sum test.35
The methods we used to analyze differences between treatment groups were analysis of variance (ANOVA)34 with factors for treatment group, center, and treatment group-by-center interaction for weight loss, waist and hip circumference, waist/hip ratio, vital signs, glucose and triglycerides, and ranked ANOVA for BMI, cholesterol, and uric acid. The differences between groups in the proportion of patients losing at least 5% and 10% of their baseline body weight were analyzed by logistic regression with factors for treatment group and center. All efficacy analyses were performed using the last observation carried forward (LOCF) to replace missing data. All data collected were included except for assessments performed more than 14 days after the last dose of study medication. After 14 days postdose, it was thought body weights could have changed significantly.
Results
Of 510 patients who entered the run-in period, 485 continued into the double-blind phase Figure 1. This occurred because of a lack of a gold-standard definition of obesity at the outset of this study; a protocol amendment allowed data from these patients to be included in the analysis. No clinically significant differences were noted between treatment groups at baseline with respect to demographic profile or characteristics of obesity Table 1. Four patients had BMIs at screening that fell out of the original trial protocol, all in the sibutramine 10-mg treatment group (1 patient <27 and 3 patients >40 kg/m2). Reanalysis of the data excluding these 4 patients was carried out, and no differences affecting the results, outcomes, or conclusions of our study were found.
Our analysis takes the patients who withdrew from the study into account.32 Pooled rates of withdrawal for any reason were similar in the 3 treatment groups: placebo, 83 patients (51%); sibutramine 10 mg, 79 (49%); and sibutramine 15 mg, 67 (42%). The completion rate for the 1-year study was 53%, which is generally consistent with weight loss programs.37 Regarding the primary outcome analysis, fewer patients in the sibutramine groups than in the placebo group withdrew for lack of efficacy or adverse events. Using the log-rank test, there was no statistically significant difference between treatment groups in time to withdrawal, overall withdrawal rate, or withdrawal rate due to adverse events or lack of efficacy. Both sibutramine-treated groups had more patients in each category of weight loss above 5% (P=.001; Table 2. Pairwise comparisons showed a statistically significant difference versus placebo in favor of sibutramine 10 mg (P=.04) and sibutramine 15 mg (P <.001).
A significantly greater proportion of patients in the 2 sibutramine groups lost at least 5% and 10% of their baseline body weight Table 2. Mean weight reduction was significantly greater in the sibutramine groups than in the placebo group. Mean reductions in BMI reflected those in body weight and were significantly greater with 10 mg sibutramine (1.7 kg/m2) and 15 mg sibutramine (2.4 kg/m2) than with placebo (0.6 kg/m2; P <.001). The reduction in BMI was significantly greater with 15 mg sibutramine than 10-mg sibutramine (P <.05).
Patients treated with 10 mg or 15 mg sibutramine once daily lost more weight at each monthly assessment than those treated with placebo Figure 2. Weight loss was dose related, and maximal weight loss occurred by month 6 in all treatment groups. During the 4 weeks after treatment cessation (at whatever time this occurred), there were small weight increases in all treatment groups. Ten (6%) patients in the placebo group withdrew because of lack of efficacy compared with 5 (3%) in the sibutramine 10 mg group and 2 (1%) in the sibutramine 15-mg group.
Dose-related reductions in mean waist and hip circumferences achieved by month 6 were maintained at month 12. In the placebo group at month 12 (LOCF), the reductions were similar for waist and hip (2.4 cm and 2.6 cm, respectively), while in the 10- and 15-mg sibutramine groups, waist reduction was greater than hip reduction (6.4 cm and 3.8 cm at 10 mg and 7.4 cm and 5.2 cm at 15 mg). The reductions on active treatment were significantly greater than with placebo (P <.05 for overall comparison). The mean reduction in waist/hip ratio at month 12 (LOCF) was significantly greater with 10 mg sibutramine (-0.04) and 15 mg sibutramine (-0.03) than with placebo (-0.01; P <.05; least significant difference, .02).
There were statistically significant changes in triglycerides compared with placebo (+3.2%) at month 6 for the sibutramine 10- and 15-mg treatment groups (-10.8%, P <.05 and -10.0%, P <.01, respectively). Uric acid levels were also significantly reduced at month 6 for both sibutramine treatment groups (10 mg, -6.0% [P <.05] and 15 mg, -6.2% [P <.05] compared with placebo, -1.9%). Decrease in uric acid was the only laboratory-reported variable that was statistically significantly greater in the sibutramine-treated patients than in the placebo-treated patients at end point Table 3. These changes are more closely associated with disease end points than with patient outcomes.
Among adverse events occurring with a frequency of more than 5% in any treatment group, only dry mouth occurred significantly more frequently with 10 mg sibutramine (19 patients) or 15 mg sibutramine (21 patients) than with placebo (2 patients; P <.001). Eight serious adverse events led to early withdrawal during the double-blind phase of the study (2 in each of the sibutramine groups and 4 in the placebo group). Two were considered possibly related to sibutramine. The first was a 49-year-old woman with a history of epilepsy with no seizures during the previous 4 years, who was withdrawn after 126 days of treatment with 10 mg sibutramine because she had had 4 “drop attacks” within 2 weeks. The second was a 32-year-old woman who was withdrawn after 246 days of treatment with 15 mg sibutramine because of palpitations due to frequent ventricular ectopic beats. No evidence was found of any withdrawal effect during the follow-up period, when active treatment was over. Patient psychological status was evaluated both at the end of the double-blind treatment (63 patients completed all assessments) and at follow-up 1 week after stopping treatment (67 patients completed all assessments). There were no statistically or clinically significant differences between the treatment groups for change in either the Beck Depression Inventory or the State Anxiety Inventory studied from the end of the double-blind treatment period to the follow-up. All 3 groups showed a mean improvement in the depression inventory.
Mean changes in vital signs averaged over all post-baseline double-blind assessments adjusted for center and treatment-by-center are shown in Table 3. Differences in mean changes in blood pressure were not statistically significant for the sibutramine treatment groups from placebo, except for the mean increase in diastolic blood pressure in the sibutramine 10 mg treatment group Table 3. Statistically significant changes in pulse rate in the sibutramine 15 mg treatment group compared with the placebo treatment group were consistent with the mechanism of action of sibutramine as an SNRI.
Discussion
Weight loss, obesity, and overweight are important topics,16 and today an increasing proportion of obesity is first encountered in the family practice setting.38 Our study shows that in the context of a family practice setting, a patient’s diet, along with sibutramine treatment, will cause more loss of weight than changes in diet alone. Increased levels of total serum cholesterol are associated with an increased risk of coronary heart disease, and although difficult to quantify, a reduction of 0.6 mmol per L has been observed to be associated with a 54% lower risk.39 This was calculated in a retrospective analysis of results of several clinical studies. Patients in this study losing 10% of their body weight over 6 months taking sibutramine 10 mg once daily reduced serum cholesterol by 0.23 mmol per L and may contribute to an overall benefit for patients as part of a risk reduction program. Similarly, the recently recommended target for reduction of triglycerides is a reduction of 1.7 mmol per L.40 In our study, a reduction of 0.63 mmol per L in triglycerides was accomplished among those patients who received sibutramine 10 mg who lost at least 10% of body weight. Mean changes in blood pressure observed during the 6 months of our study were not great enough to increase the category of patient risk for coronary heart disease.41 Although weight loss can be associated with decreased mortality,13 the extent to which a weight reduction of 10% can augment other medical approaches to risk reduction long-term is only now being defined.
In this 1-year placebo-controlled study carried out in the primary care setting, sibutramine given with dietary advice was significantly superior in all weight loss efficacy assessments to dietary advice alone (placebo). These efficacy assessments included the ranked weight reduction outcomes analysis. Sibutramine was consistently superior to placebo across all categories of weight loss in this ranked analysis that takes subject withdrawals into account. The results of this study confirm the findings previously reported.30
The plateau in weight loss observed at 6 months and maintained while having treatment is consistent with observations in other long-term studies of drug treatment in uncomplicated obese patients.26,37 On the basis of other studies of weight loss, the regain of weight after cessation of treatment is not unexpected. The rates of completion of the study, although low, probably reflect what might be expected to occur in a general practice setting and are consistent with completion rates of weight loss programs in general.37
The response rate at the 5% and 10% weight-reduction thresholds, with changes in waist circumference and in waist/hip ratio, were chosen for analysis in part because weight loss at these levels may ameliorate obesity-related disease.37-42 Sustained moderate weight loss may be expected to bring about a reduction in blood pressure, hypertension, and dyslipidemia.43 The small mean changes in blood pressure seen in the sibutramine groups were not unexpected given the norepinephrine-reuptake inhibitory properties of sibutramine. In clinical practice, any clinically significant changes that may occur should be detected by routine monitoring of vital signs. Of note, even in the current setting, where approximately 8% of patients were being treated with concomitant therapies related to cardiovascular disease, no patients were withdrawn (0%) because of elevated blood pressure.
Limitations
There were limitations to the general applicability of our study results to family practice. The treatment was limited to those patients who first demonstrated they could adhere to a weight loss program. Although the family practitioner may have some background information concerning this capability for a candidate for sibutramine treatment, general documentation may not be available for all candidates. Also, only 53% of the randomized patients completed this 1-year weight loss study. In addition, generally patients who stop weight loss treatment gain weight; however, the Sibutramine Trial in Obesity Reduction and Maintenance44 demonstrated that weight loss can be maintained safely with sibutramine for up to 2 years. Another limitation to applicability of the study is the detailed depression and anxiety profile carried out for some patients enrolled. Such analysis is not practical or needed before sibutramine use in a family practice setting, and this analysis is not included in recently initiated studies. This was a generally healthy obese patient population with few comorbidities, and they were not depressed or anxious. That may limit the ability to generalize these findings to obese patients overall.
Conclusions
Dosages of sibutramine 10 mg or 15 mg administered once daily in a primary care general practice setting to patients with mild to moderate uncomplicated obesity produced statistically and clinically significant weight reduction that was maintained over a 12-month treatment period. Sibutramine was safe and well tolerated at both 10-mg and 15-mg once-daily doses. Further studies in patients with medical complications of obesity are under way to evaluate the efficacy of sibutramine-induced weight loss on the comorbidities and risk factors associated with obesity.
Acknowledgments
The author would like to thank the Sibutramine Clinical Study 1047 Team for their contributions, especially J Hosie, I James, and SP Jones. Competing interests: This study was funded by Knoll Pharmaceuticals, the manufacturer of sibutramine.
1. Kuczmarski RJ, Flegal KM, Campbell SM, Johnson CL. Increasing prevalence of overweight among US adults: the National Health and Nutrition Examination Surveys, 1960 to 1991. JAMA 1994;272:205-11.
2. Mokdad AH, Serdula MK, Dietz WH, Bowman BA, Marks JS, Koplan JP. The spread of the obesity epidemic in the United States, 1991-1998. JAMA 1999;282:1519-22.
3. WHO Expert Committee on Physical Status Physical status: the use of and interpretation of anthropometry report of a WHO expert committee. Geneva, Switzerland: Geneva World Health Organization; 1995. WHO technical report series 854.
4. Her Majesty’s Stationery Office Health Survey for England 1994. London, England: HMSO; 1996.
5. Hubert HB, Feinleib M, McNamara PM, Castelli WP. Obesity as an independent risk factor for cardiovascular disease: a 26-year follow-up of participants in the Framingham Heart Study. Circulation 1983;67:968-77.
6. Chan JM, Rimm EB, Colditz GA, Stampfer MJ, Willett WC. Obesity, fat distribution, and weight gain as risk factors for clinical diabetes in men. Diabetes Care 1994;17:961-69.
7. Lew EA, Garfinkel L. Variations in mortality by weight among 750,000 men and women. J Chron Dis 1979;32:563-76.
8. Friedman GD, Kannel WB, Dawber TR. The epidemiology of gallbladder disease: observations in the Framingham Study. J Chron Dis 1966;19:273-92.
9. Spector TD, Hart DJ, Doyle DV. Incidence and progression of osteoarthritis in women with unilateral knee disease in the general population: the effect of obesity. Ann Rheum Dis 1994;53:565-68.
10. Kopelman PG. Sleep-apnea and hypoventilation in obesity. Int J Obes 1992;16:S37-42.
11. Fontaine KR, Cheskin LJ, Barofsky I. Health-related quality of life in obese persons seeking treatment. J Fam Pract 1996;43:265-70.
12. Enzi G. Socioeconomic consequences of obesity-the effect of obesity on the individual. PharmacoEconomics 1994;5:54-57.
13. Manson JE, Willett WC, Stampfer MJ, et al. Body weight and mortality among women. N Engl J Med 1995;333:677-85.
14. Wolf AM, Colditz GA. Current estimates of the economic cost of obesity in the United States. Obes Res 1998;6:97-106.
15. Goldstein DJ. Beneficial health effects of modest weight loss. Int J Obes Relat Metab Disord 1992;16:397-415.
16. Williamson DF. The prevention of obesity. N Engl J Med 1999;341:1140-41.
17. Galuska DA, Will JC, Serdula MK, Ford ES. Are health care professionals advising obese patients to lose weight? JAMA 1999;282:1576-78.
18. Kristeller JL, Hoerr RA. Physician attitudes toward managing obesity: differences among six specialty groups. Prev Med 1997;26:542-49.
19. Garrow JS. Treatment of obesity. Lancet 1992;340:409-13.
20. Anderson JW, Vichitbandra S, Qian W, Kryscio RJ. Long-term weight maintenance after an intensive weight-loss program. J Am Coll Nutr 1999;18:620-27.
21. Heal DJ, Aspley S, Prow MR, Jackson HC, Martin KF, Cheetham SC. Sibutramine: a novel anti-obesity drug. A review of the pharmacological evidence to differentiate it from d-amphetamine and d-fenfluramine. Int J Obes Relat Metab Disord 1998;22(suppl 1):S18-28.
22. US Department of Health and Human Services Cardiac valvulopathy associated with exposure to fenfluramine or dexfenfluramine: US Department of Health and Human Services Interim Public Health Recommendations, November 1997. MMWR Morb Mortal Wkly Rep 1997;46:1061-66.
23. Joint National Committee on Prevention Detection Evaluation and Treatment of High Blood Pressure The sixth report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure. Arch Intern Med 1997;157:2413-46.
24. Bray GA. A case for drug treatment of obesity. Hospital Practice 1994;29:53,57-60.
25. Wooley SC, Garner DM. Dietary treatments for obesity are ineffective. BMJ 1994;309:655-56.
26. Goldstein DJ, Potvin JH. Long-term weight loss: the effect of pharmacologic agents. Am J Clin Nutr 1994;60:647-57.
27. Ryan DH, Kaiser P, Bray GA. Sibutramine: a novel new agent for obesity treatment. Obes Res 1995;3(suppl 4):553S-59S.
28. Connoley IP, Liu Y-L, Frost I, Reckless IP, Heal DJ, Stock MJ. Thermogenic effects of sibutramine and its metabolites. Br J Pharmacol 1999;126:1487-95.
29. Walsh KM, Leen E, Lean MEJ. The effect of sibutramine on resting energy expenditure and adrenaline-induced thermogenesis in obese females. Int J Obes Relat Metab Disord 1999;23:1009-15.
30. Apfelbaum M, Vague P, Ziegler O, Hanotin C, Thomas F, Leutenegger E. Long-term maintenance of weight loss after a very-low-calorie diet: a randomized blinded trial of the efficacy and tolerability of sibutramine. Am J Med 1999;106:179-84.
31. Bray GA, Ryan DH, Gordon D, Heidingsfelder S, Cerise F, Wilson K. A double-blind randomized placebo-controlled trial of sibutramine. Obes Res 1996;4:263-70.
32. Gould AL. A new approach to the analysis of clinical drug trials with withdrawals. Biometrics 1980;36:721-27.
33. Guy W. CGI global impression ECDEU assessment manual for psychopharmacology. Washington, DC: Department of Health, Education, and Welfare; 1976.
34. Winer BJ. In: Winer BJ, ed. Statistical principles in experimental design. 2nd ed. New York, NY: McGraw-Hill; 1971;261-308.
35. Hollander M, Wolfe DA. The two-sample location problem. In: Hollander M, Wolfe DA, eds. Nonparametric statistical methods. New York, NY: John Wiley & Sons; 1973;67-82.
36. Hollander M, Wolfe DA. The one-way layout. In: Hollander M, Wolfe DA, eds. Nonparametric statistical methods. New York, NY: John Wiley & Sons; 1973;114-20.
37. National Task Force on the Prevention and Treatment of Obesity Long-term pharmacotherapy in the management of obesity. JAMA 1996;276:1907-15.
38. Noel M, Hickner J, Ettenhofer T, Gauthier B. The high prevalence of obesity in Michigan primary care practices: an UPRNet study. J Fam Pract 1998;47:39-43.
39. Guidelines Subcommittee of the World Health Organization-International Society of Hypertension Mild Hypertension Liaison Committee. 1999 World Health Organization-International Society of Hypertension guidelines for the management of hypertension. J Hypertens 1999;17:151-83.
40. Assmann G, Carmena R, Cullen P, et al. Coronary heart disease: reducing the risk. A worldwide view. Circulation 1999;100:1930-38.
41. Hansson L. The Hypertension Optimal Treatment Study and the importance of lowering blood pressure. J Hypertens 1999;17(suppl 1):S9-13.
42. Lapidus L, Bengtsson C, Larsson B, Pennert K, Rybo E, Sjostrom L. Distribution of adipose tissue and risk of cardiovascular disease and death: a 12-year follow-up of participants in the population study of women in Gothenburg, Sweden. BMJ 1984;289:1257-61.
43. Larsson B, Svärdsudd K, Welin L, Wilhelmsen L, Björntorp P, Tibblin G. Abdominal adipose tissue distribution, obesity, and risk of cardiovascular disease and death: 13-year follow-up of participants in the study of men born in 1913. BMJ 1984;288:1401-04.
44. James WPT, Astrup A, Finer N, et al. Effect of sibutramine on weight maintenance after weight loss: a randomized trial. Lancet 2000;356:2119-25.
1. Kuczmarski RJ, Flegal KM, Campbell SM, Johnson CL. Increasing prevalence of overweight among US adults: the National Health and Nutrition Examination Surveys, 1960 to 1991. JAMA 1994;272:205-11.
2. Mokdad AH, Serdula MK, Dietz WH, Bowman BA, Marks JS, Koplan JP. The spread of the obesity epidemic in the United States, 1991-1998. JAMA 1999;282:1519-22.
3. WHO Expert Committee on Physical Status Physical status: the use of and interpretation of anthropometry report of a WHO expert committee. Geneva, Switzerland: Geneva World Health Organization; 1995. WHO technical report series 854.
4. Her Majesty’s Stationery Office Health Survey for England 1994. London, England: HMSO; 1996.
5. Hubert HB, Feinleib M, McNamara PM, Castelli WP. Obesity as an independent risk factor for cardiovascular disease: a 26-year follow-up of participants in the Framingham Heart Study. Circulation 1983;67:968-77.
6. Chan JM, Rimm EB, Colditz GA, Stampfer MJ, Willett WC. Obesity, fat distribution, and weight gain as risk factors for clinical diabetes in men. Diabetes Care 1994;17:961-69.
7. Lew EA, Garfinkel L. Variations in mortality by weight among 750,000 men and women. J Chron Dis 1979;32:563-76.
8. Friedman GD, Kannel WB, Dawber TR. The epidemiology of gallbladder disease: observations in the Framingham Study. J Chron Dis 1966;19:273-92.
9. Spector TD, Hart DJ, Doyle DV. Incidence and progression of osteoarthritis in women with unilateral knee disease in the general population: the effect of obesity. Ann Rheum Dis 1994;53:565-68.
10. Kopelman PG. Sleep-apnea and hypoventilation in obesity. Int J Obes 1992;16:S37-42.
11. Fontaine KR, Cheskin LJ, Barofsky I. Health-related quality of life in obese persons seeking treatment. J Fam Pract 1996;43:265-70.
12. Enzi G. Socioeconomic consequences of obesity-the effect of obesity on the individual. PharmacoEconomics 1994;5:54-57.
13. Manson JE, Willett WC, Stampfer MJ, et al. Body weight and mortality among women. N Engl J Med 1995;333:677-85.
14. Wolf AM, Colditz GA. Current estimates of the economic cost of obesity in the United States. Obes Res 1998;6:97-106.
15. Goldstein DJ. Beneficial health effects of modest weight loss. Int J Obes Relat Metab Disord 1992;16:397-415.
16. Williamson DF. The prevention of obesity. N Engl J Med 1999;341:1140-41.
17. Galuska DA, Will JC, Serdula MK, Ford ES. Are health care professionals advising obese patients to lose weight? JAMA 1999;282:1576-78.
18. Kristeller JL, Hoerr RA. Physician attitudes toward managing obesity: differences among six specialty groups. Prev Med 1997;26:542-49.
19. Garrow JS. Treatment of obesity. Lancet 1992;340:409-13.
20. Anderson JW, Vichitbandra S, Qian W, Kryscio RJ. Long-term weight maintenance after an intensive weight-loss program. J Am Coll Nutr 1999;18:620-27.
21. Heal DJ, Aspley S, Prow MR, Jackson HC, Martin KF, Cheetham SC. Sibutramine: a novel anti-obesity drug. A review of the pharmacological evidence to differentiate it from d-amphetamine and d-fenfluramine. Int J Obes Relat Metab Disord 1998;22(suppl 1):S18-28.
22. US Department of Health and Human Services Cardiac valvulopathy associated with exposure to fenfluramine or dexfenfluramine: US Department of Health and Human Services Interim Public Health Recommendations, November 1997. MMWR Morb Mortal Wkly Rep 1997;46:1061-66.
23. Joint National Committee on Prevention Detection Evaluation and Treatment of High Blood Pressure The sixth report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure. Arch Intern Med 1997;157:2413-46.
24. Bray GA. A case for drug treatment of obesity. Hospital Practice 1994;29:53,57-60.
25. Wooley SC, Garner DM. Dietary treatments for obesity are ineffective. BMJ 1994;309:655-56.
26. Goldstein DJ, Potvin JH. Long-term weight loss: the effect of pharmacologic agents. Am J Clin Nutr 1994;60:647-57.
27. Ryan DH, Kaiser P, Bray GA. Sibutramine: a novel new agent for obesity treatment. Obes Res 1995;3(suppl 4):553S-59S.
28. Connoley IP, Liu Y-L, Frost I, Reckless IP, Heal DJ, Stock MJ. Thermogenic effects of sibutramine and its metabolites. Br J Pharmacol 1999;126:1487-95.
29. Walsh KM, Leen E, Lean MEJ. The effect of sibutramine on resting energy expenditure and adrenaline-induced thermogenesis in obese females. Int J Obes Relat Metab Disord 1999;23:1009-15.
30. Apfelbaum M, Vague P, Ziegler O, Hanotin C, Thomas F, Leutenegger E. Long-term maintenance of weight loss after a very-low-calorie diet: a randomized blinded trial of the efficacy and tolerability of sibutramine. Am J Med 1999;106:179-84.
31. Bray GA, Ryan DH, Gordon D, Heidingsfelder S, Cerise F, Wilson K. A double-blind randomized placebo-controlled trial of sibutramine. Obes Res 1996;4:263-70.
32. Gould AL. A new approach to the analysis of clinical drug trials with withdrawals. Biometrics 1980;36:721-27.
33. Guy W. CGI global impression ECDEU assessment manual for psychopharmacology. Washington, DC: Department of Health, Education, and Welfare; 1976.
34. Winer BJ. In: Winer BJ, ed. Statistical principles in experimental design. 2nd ed. New York, NY: McGraw-Hill; 1971;261-308.
35. Hollander M, Wolfe DA. The two-sample location problem. In: Hollander M, Wolfe DA, eds. Nonparametric statistical methods. New York, NY: John Wiley & Sons; 1973;67-82.
36. Hollander M, Wolfe DA. The one-way layout. In: Hollander M, Wolfe DA, eds. Nonparametric statistical methods. New York, NY: John Wiley & Sons; 1973;114-20.
37. National Task Force on the Prevention and Treatment of Obesity Long-term pharmacotherapy in the management of obesity. JAMA 1996;276:1907-15.
38. Noel M, Hickner J, Ettenhofer T, Gauthier B. The high prevalence of obesity in Michigan primary care practices: an UPRNet study. J Fam Pract 1998;47:39-43.
39. Guidelines Subcommittee of the World Health Organization-International Society of Hypertension Mild Hypertension Liaison Committee. 1999 World Health Organization-International Society of Hypertension guidelines for the management of hypertension. J Hypertens 1999;17:151-83.
40. Assmann G, Carmena R, Cullen P, et al. Coronary heart disease: reducing the risk. A worldwide view. Circulation 1999;100:1930-38.
41. Hansson L. The Hypertension Optimal Treatment Study and the importance of lowering blood pressure. J Hypertens 1999;17(suppl 1):S9-13.
42. Lapidus L, Bengtsson C, Larsson B, Pennert K, Rybo E, Sjostrom L. Distribution of adipose tissue and risk of cardiovascular disease and death: a 12-year follow-up of participants in the population study of women in Gothenburg, Sweden. BMJ 1984;289:1257-61.
43. Larsson B, Svärdsudd K, Welin L, Wilhelmsen L, Björntorp P, Tibblin G. Abdominal adipose tissue distribution, obesity, and risk of cardiovascular disease and death: 13-year follow-up of participants in the study of men born in 1913. BMJ 1984;288:1401-04.
44. James WPT, Astrup A, Finer N, et al. Effect of sibutramine on weight maintenance after weight loss: a randomized trial. Lancet 2000;356:2119-25.