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Objective: To evaluate the safety and efficacy of sibutramine 15 mg by mouth once per day in obese patients over a period of 6 months.
Research Methods and Procedures: A monocenter, double-blind, placebo controlled, parallel, prospective clinical trial was carried out. Sixty-nine male and female obese patients (body mass index [BMI] > 30 kg/m2) aged 16 to 65 years entered the trial.
Results: 22 of 35 patients in the sibutramine group and 9 of 34 patients in the placebo group completed the trial. The high dropout rate in the sibutramine group was due to adverse events in 3 cases, lack of efficacy (as judged by patients) in 7, loss to follow-up in 2, and an orthopedic device being worn in 1; in the placebo group the dropouts were ascribed to lack of efficacy (as judged by patients) in 17 cases and to loss to follow-up in 8 cases. Using the method of last observation carried forward, the weight loss in the sibutramine group was 10.27 kg (95% confidence intervals [95% CI] 7.66; 13.07) and 1.26 kg (95% CI 0.3; 2.23) in the placebo group. The BMI loss was 4.17 kg/m2 (95% CI 3.11; 5.22) in the sibutramine group and 0.53 kg/m2 (95% CI 0.13; 0.92) in the placebo group. The waist circumference reduction was 12.51 cm (95% CI 9.25; 15.77) in the sibutramine group and 3.26 cm (95% CI 1.38; 5.14) in the control group (p < 0.05 by paired Student's t test for all the intragroup comparisons). Twenty-three sibutramine patients had 34 adverse events, the most frequent adverse events in the sibutramine group were upper respiratory tract infections (n = 6) and constipation (n = 6); 16 placebo patients had 21 adverse events. Three sibutramine patients withdrew their informed consent when they had adverse events.
Discussion: The results show that sibutramine induces significant loss of body weight and waist circumference. Cardiovascular function was not significantly affected by sibutramine. Sibutramine was well tolerated by most of the patients.
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The prevalence of obesity varies among ethnic groups in the United States; black and Hispanic populations (particularly Mexican Americans) have a higher prevalence of overweight and obesity than the non-Hispanic white group (1, 2).
Overweight and obesity have a different impact on cardiovascular risk factors in the ethnic groups. For instance, Mexican Americans are more susceptible to impaired glucose tolerance and diabetes than non-Hispanic whites (3). On the other hand, Mexican Americans have lower mean systolic and diastolic blood pressure than non-Hispanic whites or blacks, as well as a lower prevalence of hypertension (4).
The lower prevalence of hypertension in Hispanics may be connected to similar or lower rates of stroke mortality (5) and to lower cardiovascular disease mortality (6) compared to the non-Hispanic white and general population, despite the high prevalence of other risk factor such as obesity, diabetes, and low socioeconomic status in this ethnic group.
It is considered that Mexican Americans and Mexicans have the same gene pool, and that these genetic influences may predominate to determine insulin levels, but not triglycerides and HDL-C levels (7).
Sibutramine (Meridia; Knoll Pharmaceutical Co., Mt. Olive, NJ) is a serotonin (5-hydroxytriptamine, 5HT) and noradrenaline reuptake inhibitor, which produces weight loss by enhancing satiety and increasing the metabolic rate in rodent systems. The dual mechanism of action depends on the balanced inhibition of the serotonin and noradrenaline reuptake. Sibutramine does not release monoamines and has no affinity for their receptors. The effects of sibutramine are mediated by two active demethylated metabolites (8, 9).
The hypophagic effect of sibutramine has been demonstrated in humans (10). The thermogenic effect in humans is unclear, because one study did not find differences in the resting metabolic rate 3 hours postdose between placebo and sibutramine 10 and 30 mg once per day, after 8 weeks (11). Yet, a second trial indicated that sibutramine 10 mg once per day limited the decrease in resting metabolic rate during a weight loss program of 6 months (12). Additionally, a third study demonstrated that a dose of 30 mg of sibutramine caused a significant increase in the energy expenditure during a period of 5.5 hours, during fed and fasted states, as compared to placebo (13).
The aim of this trial was to evaluate the safety and efficacy of sibutramine in obese Hispanic patients undergoing a program that included dietary advice over a period of 6 months.
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A double-blind, placebo-controlled, parallel, prospective clinical trial was conducted in order to evaluate the safety and efficacy of sibutramine in the treatment of obesity.
Male and female patients aged 16 to 65 years with a body mass index (BMI) greater than 30 kg/m2 were included. Written informed consent was obtained from the patients. Exclusion criteria were: subjects suffering from endocrine diseases other than type 2 diabetes, uncontrolled hypertension, secondary hypertension, autoimmune diseases, ischemic heart disease, arrhythmia, lactating or pregnant women, psychosis, and those requiring drugs acting on the central nervous system, cathartics, thyroid supplements, or diuretics.
Patients' participation was stopped if they became pregnant, presented with a concomitant severe disease, suffered from severe adverse events, withdrew the informed consent, or failed to attend the clinic appointments.
Based on the study of Bray et al. (14), we predicted that patients taking 15 mg of sibutramine for 24 weeks would lose 7.68 ± 1.56 (mean ± SE) kg. Using the sample size calculation described by Glantz (15), the sample size was 20 per group. A loss of 5% of the initial body weightwas considered clinically significant. Seventy patientswere admitted to the study considering an attrition of40%. The subjects were outpatients attending to the Clínica 10 del Instituto Mexicano del Seguro Social (Mexican Social Security).
Patients were randomized to either the group taking sibutramine 15 mg orally once per day or the group taking placebo. In order to randomize the participants, we prepared a computer list of 80 random numbers in eight different blocks of ten. For each block the proportion of even/odd numbers by group was 3/2 or 2/3, with no more than three consecutive positions. The patients were assigned a consecutive number after they completed the initial laboratory safety test and electrocardiogram to confirm the selection criteria. For each number there was a box containing 19 packages with 10 capsules each (two blisters of five capsules), and an opaque sealed envelope with the drug code, all the materials for a patient were identified by the patient number. The materials were prepared by an investigator, who did not know the identity of the patients. Another investigator received the trial materials without any knowledge of the procedures or order in the random number list. The first patient entered the trial by January ’97, and the last patient finished the trial by June 1998.
The appearances of the boxes, packages, blisters, and capsules were similar.
Patients were recommended to complete a diet of 30 kcal/kg of ideal body weight, according to height and weight charts for Mexican adults (16). The suggested diet had about 50% of the calories from carbohydrates, 30% form lipids, and 20% from proteins. Patients received a list of the allowed and not allowed foods with the recommended portions and the possible combinations.
Patients received standard printed material and individual counseling at the beginning of the trial by family care physicians. All the patients were literate and able to understand the directions. Patients were counseled on following the diet at each clinic visit, but they did not have any additional dietary reinforcement in order to assess the effect of sibutramine with minimal dietary counseling.
Visits were scheduled 15 days before the beginning of the study medication, and then monthly up to 6 months of treatment. In these visits the primary and secondary end-points were registered, as well as heart rate and blood pressure. Additionally, the appearance of adverse events were recorded and the diet was re-emphasized.
The primary endpoints for the trial were body weight and BMI, the secondary endpoints were the waist circumference and waist/hip ratio. Waist and hip circumferences were measured with the patient standing; waist circumference was measured at the midpoint between the highest point of the iliac crest and the lowest part of the costal margin at the mid-axillary line; hip circumference was measured at the level of the greater femoral trochanter.
Appetite, satiety, and diet adherence were also evaluated. For the appetite, the visual analog scale was a line of 155 mm with 10% divisions from 0% with the quotation “very hungry” on the left, up to 100% “without hunger” on the right. In the case of Satiety, the scale was similar but the 0% mark on the left corresponded to the legend “extremely full” and the right mark of 100% to “sensation of emptiness.” The scale for assessing compliance with the diet had the legend “impossible to follow” corresponding to 0% on the left and “easy to comply with” on the right mark of 100%. All the described parameters were evaluated at each visit.
Blood pressure and heart rate were taken in the morning as the mean of three resting readings after 5 minutesseated. Systolic pressure was determined by the first Korotkoff sound and diastolic blood pressure by the fifth Korotkoff sound.
Adverse events were reported as they were detected. Patients were encouraged to call the investigators if they had any question or complaint at any time. Additionally, the patients were asked if “something unusual has happened since your last visit” at all the visits, in order to collect any possible complaints from the patients.
Blood cytology, blood chemistry urinalysis, and electrocardiograph examinations were performed before the beginning of the medication and at 3 and 6 months of medication.
The proposed statistical analysis for the endpoints included the intent-to-treat ANOVA for repeated measures looking for the effect of repetition and for the interaction between repetition and study medication, and the intragroup comparison of the values at the baseline with those in the last visit by the paired Student's t test. A similar analysis was performed with the last observation carried forward (LOCF) of the endpoints, where the last observation replaced the missing values. For this analysis, only patients who completed at least 1 month of treatment with the corresponding endpoint evaluation were considered.
The rate of patients achieving 5% and 10% loss from baseline weight in each group was compared using the Kaplan-Meier statistics, including the inverse of the Survival Curve. The odds ratio was calculated for the sibutramine patients with a loss of 5% and 10% of the initial body weight with respect to the placebo patients.
For the rest of the interval measurements, the intragroup comparisons were tested by the paired Student's t test, whereas the intergroup comparisons were performed using the unpaired Student's t test, and in the case of nominal scales in the intergroup comparisons, the χ2 test, with continuity correction in the 2 × 2 tables, was used.
The protocol was approved by the local investigation and ethics committee, the national investigation committee of the Instituto Mexicano del Seguro Social (National Social Security System), and the Mexican Ministry of Health. The protocol complied with Mexican regulations and with the European Good Clinical Practice guidelines.
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Eighty-one subjects were considered to have entered the trial. Of these, two were eliminated because of a move and job duties, one due to a positive pregnancy test, one due to severe type 2 diabetes with peripheral neuropathy, one due to severe uncontrolled hypertension and arrhythmia, and six failed to show up at the initial laboratory safety tests. Another patient withdrew the informed consent in the run-in period; this patient had been allocated to the placebo group. Therefore, 69 patients started the trial medication as shown in Figure 1.
Twenty-two patients in the sibutramine group finished the trial, and only nine in the placebo group. The time and cause of attrition are shown in Table 1. Seven (20%) sibutramine patients withdrew their informed consent for lack of efficacy, as did 17 (50%) placebo patients.
Table 1. Cause of attrition throughout the trial; n (%)
| ||Last visit registered|
|Sibutramine|| || || || || || || |
|Adverse events*|| || || ||2 (5.7)||1 (2.9)|| || |
|Lack of efficacy†|| ||1 (2.9)||2 (5.7)||1 (2.9)||2 (5.7)||1 (2.9)|| |
|Lost to follow-up|| || || || || ||1 (2.9)||1 (2.9)|
|Wearing orthopedic device|| || || || || || ||1 (2.9)|
|Total||—||1 (2.9)||2 (5.7)||3 (8.6)||3 (8.6)||2 (5.7)||2 (5.7)|
|Cumulative||—||1 (2.9)||3 (8.6)||6 (17.1)||9 (25.7)||11 (31.4)||13 (37.1)|
|Placebo|| || || || || || || |
|Lack of efficacy†|| ||2 (5.9)||3 (8.8)||4 (11.8)||4 (11.8)||3 (8.8)||1 (2.9)|
|Lost to follow-up|| ||1 (2.9)||2 (5.9)||2 (5.9)||—||2 (5.9)||1 (2.9)|
|Total||—||3 (8.8)||5 (14.7)||6 (17.6)||4 (11.8)||5 (14.7)||2 (5.9)|
|Cumulative||—||3 (8.8)||8 (23.5)||14 (41.2)||18 (52.9)||23 (67.7)||25 (73.5)|
The demographics of the patients are described in Table 2. Except for the presence of whites in the sibutramine group, both groups are statistically similar, so the randomization and concealment were considered successful.
Table 2. Characteristics of the patients at the beginning of the study
|Number of patients (n)||35||34|| |
|Sex|| || ||0.139†|
|Male, n (%)||2 (5.7)||7 (20.6)|| |
|Female, n (%)||33 (94.3)||27 (79.4)|| |
|Age years; mean± SD||38.44 ± 10.09||38.62 ± 9.12||0.937‡|
|Weight kg; mean± SD||85.96 ± 11.78||90.07 ± 18.66||0.277‡|
|Height cm; mean± SD||155.54 ± 8.33||158.12 ± 9.56||0.237‡|
|BMI kg/m2; mean± SD||35.54 ± 4.21||35.97 ± 6.96||0.755‡|
|Race|| || ||0.022§|
|Caucasian, n (%)||7 (20)||—|| |
|Mestizo, n (%)||27 (77.1)||33 (97.1)|| |
|Indian, n (%)||1 (2.9)||1 (2.9)|| |
|Physical activity|| || ||0.061§|
|Light, n (%)||32 (91.4)||24 (70.6)|| |
|Moderate, n (%)||2 (5.7)||9 (26.5)|| |
|Severe, n (%)||1 (2.8)||1 (2.9)|| |
|Current tobacco use (%)||15 (42.9)||16 (47.1)||0.913†|
|Familial obesity (%)||31 (88.6)||27 (79.4)||0.298†|
|Previous number of weight-loss|| || || |
|attempts as reported by the|| || || |
|patients; mean± SD||2.97 ± 2.31||3.18 ± 2.64||0.732‡|
|median (range)||3 (0–10)||3 (0–10)||0.860¶|
|Concomitant chronic diseases reported by the patients at the beginning of the trial|| || || |
|Hypertension||4 (11.4)||4 (11.8)||1.000†|
|Type 2 diabetes||2 (5.7)||4 (11.8)||0.612†|
|Dyslipidemia||2 (5.7)||2 (5.9)||1.000†|
|Concomitant chronic diseases found in physical examination and laboratory tests|| || || |
|Hypertension||4 (11.4)||4 (11.8)||1.000†|
|Type 2 diabetes||8 (22.9)||6 (17.6)||0.590†|
|Hypercholesteremia||2 (5.9)||4 (11.8)||0.673†|
|Hypertriglyceridemia||12 (34.3)||13 (40.6)||0.777†|
Based on the empty blisters packets, the compliance of the patients was considered to be at least 90%.
Figure 1 represents the flow of the patients throughout the trial. Twenty-two out of 35 patients completed the trial in the sibutramine group. Only nine of 34 patients in the placebo group completed the trial.
The evolution of the endpoints (body weight, BMI, waist circumference, and waist hip ratio) expressed as mean ± SD are in the Table 3. The effects of the trial medication on the endpoints are shown in Table 4. The sibutramine group reached significant reductions using either the intent-to-treat and the LOCF analysis.
Table 3. Data for the endpoints
| ||Days from start|
| ||Day −15||Day 0||Day 30||Day 60||Day 90||Day 120||Day 150||Day 180|
|Number of patients|| || || || || || || || |
|Body Weight|| || || || || || || || |
|Sibutramine||86.0 ± 11.8||85.7 ± 11.7||82.2 ± 11.1||80.5 ± 10.2||79.1 ± 10.5||76.0 ± 8.8||74.8 ± 9.4||73.6 ± 10.4|
|Placebo||90.1 ± 18.7||90.0 ± 18.7||88.8 ± 19.2||87.4 ± 20.1||88.0 ± 18.9||83.8 ± 15.5||85.8 ± 15.5||87.1 ± 15.4|
|BMI|| || || || || || || || |
|Sibutramine||35.5 ± 4.21||35.5 ± 4.3||34.1 ± 4.2||33.2 ± 4.2||32.4 ± 4.4||31.2 ± 4.2||30.5 ± 4.7||29.8 ± 5.0|
|Placebo||36.0 ± 7.0||35.9 ± 7.0||35.4 ± 6.9||35.1 ± 7.2||34.6 ± 6.0||33.1 ± 4.1||32.4 ± 2.6||32.3 ± 2.4|
|Waist|| || || || || || || || |
|Sibutramine||104.8 ± 10.6||103.9 ± 9.8||99.1 ± 8.9||97.1 ± 8.6||95.4 ± 8.8||93.2 ± 8.8||91.8 ± 9.0||90.6 ± 9.4|
|Placebo||106.1 ± 13.3||105.9 ± 12.7||102.1 ± 13.1||101.8 ± 13.6||102.3 ± 13.0||99.3 ± 10.9||100.4 ± 10.8||101.8 ± 9.8|
|Waist/Hip ratio|| || || || || || || || |
|Sibutramine||0.87 ± 0.07||0.86 ± 0.06||0.84 ± 0.05||0.83 ± 0.05||0.83 ± 0.05||0.83 ± 0.05||0.83 ± 0.05||0.82 ± 0.05|
|Placebo||0.87 ± 0.06||0.88 ± 0.06||0.84 ± 0.07||0.85 ± 0.05||0.86 ± 0.05||0.86 ± 0.04||0.87 ± 0.05||0.88 ± 0.53|
Table 4. Effect of the trial medication on the endpoints
| ||Intent-to-treat (6 month completers)||LOCF|
|Weight, kg|| || || || |
|(95% CI)||(11.5; 17.2)*||(−0.8; 2.8)||(7.7; 13.1)*||(0.3; 2.2)*|
|% of the baseline weight mean± s||83.8± 7.6||98.7± 2.7||88.2± 8.7||98.6 ± 2.7|
|(95% CI)||(87.0; 80.6)*||(100.4; 96.9)||(91.1; 85.2)*||(99.5; 97.6)*|
|BMI, kg/m2|| || || || |
|(95% CI)||(4.5; 6.8)*||(−0.3; 1.1)||(3.1; 5.2)*||(0.1; 0.9)*|
|Waist circumference, cm|| || || || |
|(95% CI)||(14.6; 20.8)*||(−0.8; 4.4)||(9.2; 15.8)*||(1.4; 5.1)*|
|Waist/hip ratio|| || || || |
|(95% CI)||(0.04; 0.08)*||(−0.05; 0.03)||(0.02; 0.06)*||(−0.005; 0.03)|
The intent-to-treat ANOVA for multiple measures of the body weight, BMI, waist circumference, and waist/hip ratio showed the effect of time and interaction of the effect of time with the kind of medication, p < 0.001 for the first three parameters, and p < 0.022 for the waist/hip ratio.
The ANOVAs for repeated measures using LOCF were similar to the results in the intent-to-treat analysis.
Figure 2 shows the absolute reduction on the body weight and BMI using LOCF throughout the trial.
Figure 2. Body weight and BMI reduction throughout the trial using LOCF. Shown are the mean ± SEM of the absolute weight loss in kg (left scale) and BMI loss in kg/m2 (right scale), at the different times of the study.
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In the intent-to-treat analysis, the rate of patients losing 5% of their initial body weight, at any time, was 26/35 (74.3%) for the sibutramine group and 5/34 for the control group (14.7%). Considering the LOCF, the number of patients reaching the 5% goal, by the end of trial medications, was 26/34 (76.5%) for the sibutramine group, and 3/31 (9.7%) for the placebo group, because some placebo patients regained weight over the trial. The odds ratio for the sibutramine group to achieve the 5% goal was 7.9, with 95% confidence limits being 2.65 to 23.54.
In the intent-to-treat analysis, the rate of patients losing 10% of their initial body weight, at any time, was 19/35 (54.3%) in the sibutramine group and none in the placebo. Considering the LOCF, the number of patients reaching the 10% goal was 19/34 (55.9%) in the sibutramine group, and none in the placebo group.
Figure 3 shows the cumulative rate of patients reaching the 5% and 10% goals throughout the study. They correspond to the inverse of the Kaplan-Meier statistics Survival Curve. The difference in the cumulative incidence of the event (5% and 10% loss of the initial weight) is highly significant; p < 0.001 by the log rank, Breslow, and Tarone-Ware tests.
Figure 3. Kaplan-Meier statistics graphic of the cumulative incidence of 5% and 10% responders. Depicted is the cumulative rate of patients who achieved the 5% and 10% loss of their initial body weight throughout the study. The solid line corresponds to the sibutramine 5% responders; the broken line with asterisk markers to the placebo 5% responders; and the bold broken line with diamond markers to the sibutramine 10% responders. There were no placebo 10% responders.
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On the analog visual scales, patients on sibutramine reported decreased appetite, increased satiety, and a better compliance with the diet from the first month of treatment on, and these remained constant up to the end of the trial. On the other hand, the effects for the placebo group were only observed in the first 2 months of treatment for appetite and satiety and during the first month for diet adherence. The sibutramine group had better scores considering each one of the months of treatment (see Table 5).
Table 5. Appetite, satiety, and adherence to the recommended diet
| ||Mean days from start of study|
|Appetite, %|| ||*||*||*||*||*||*|
|Sibutramine||44.6 ± 16.5||75.9 ± 12.6†||74.2 ± 14.3†||70.0 ± 21.9†||71.4 ± 17.4†||75.8 ± 16.7†||75.4 ± 17.6†|
|Placebo||45.9 ± 15.2||55.7 ± 20.4†||53.1 ± 19.1†||49.0 ± 20.0||46.9 ± 24.4||46.4 ± 21.1||43.3 ± 18.0|
|Satiety, %|| ||*||*||*||*||*||*|
|Sibutramine||64.3 ± 16.7||28.5 ± 15.4†||28.4 ± 15.5†||32.1 ± 22.4†||30.0 ± 18.3†||25.4 ± 19.6†||25.4 ± 17.6†|
|Placebo||65.9 ± 14.2||50.3 ± 21.6†||52.7 ± 20.3†||60.0 ± 19.2||62.5 ± 22.7||60.0 ± 18.4||61.1 ± 16.2|
|Adherence, %|| || ||*||*||*||*||*|
|Sibutramine||57.7 ± 13.1||72.9 ± 17.8†||74.1 ± 11.6†||71.5 ± 15.9†||70.0 ± 17.4†||72.1 ± 15.6†||71.8 ± 15.9†|
|Placebo||58.2 ± 13.1||64.7 ± 15.9†||56.1 ± 16.0||54.0 ± 13.9||48.7 ± 14.5||51.8 ± 9.8||50.0 ± 15|
There were no differences in the systolic blood pressure between the sibutramine and placebo groups at any time. Sibutramine patients showed a small decrease in the third month of treatment regarding the baseline assessments (p < 0.05 by paired Student's t test) (see Figure 4).
There were no differences in the diastolic blood pressure between sibutramine and placebo groups at any time. Sibutramine patients showed a small decrease in 2nd, 3rd, 4th, 5th month of treatment regarding baseline assessments (p < 0.05 by paired Student's t test) (see Figure 4).
Only one patient in each group presented increased blood pressure of >140/90 mmHg. In both cases, they were patients with known hypertension, who failed to take the antihypertensive medication for several days. They recovered the normal blood pressure levels when they re-initiated the antihypertensive treatment.
There was a difference in the heart rate between the two groups during the first month of treatment (p < 0.05 by unpaired Student's t test). Sibutramine patients showed a small increase in 1st, 2nd, 3rd, and 4th months of treatment regarding the baseline assessments (p < 0.05 by paired Student's t test) (Figure 5). Three patients in the sibutramine group were detected to have tachycardia. All patients recovered without any additional treatments.
The electrocardiogram did not show significant variations between groups. Clinical laboratory tests did not disclose any abnormality in the trial participants, except one control patient with known hypercholesteremia reported in the adverse event section.
Table 6 describes the adverse events during the trial. In the sibutramine group, 23 patients reported 34 adverse events. The most frequent adverse events were upper respiratory tract infection (n = 6) and constipation (n = 6); 15 adverse events occurred in the first month of treatment and 5 in the second. Sixteen patients in the placebo group had 21 adverse events.
Table 6. Adverse events presented
|Upper respiratory tract infections||6||2|
|Edema of lower legs||1||2|
|Other (one case each)||Polydipsia-dry mouth and constipation||Lipoma abscess|
| ||Ovarian cyst||Menstrual syndrome|
| ||Neck sprain by trauma||Hypercholesterenemia|
| ||Insomnia-anxiety-tiredness and headache||Metacarpus fracture|
| ||Discoidectomy T5||Dry nasal mucosa|
| ||Dry mouth, headache and palpitations||Thyroid node detected|
| ||Tooth abscess||Migraine|
| ||Sweating and flush sensation||Flatulence|
| ||Neurodermatitis exacerbation||Dizziness and vertigo|
| ||Wrist fracture|| |
| ||Profuse sweating|| |
| ||Insomnia|| |
Three patients in the sibutramine group withdrew their informed consent when they experienced adverse events (Patient 29; insomnia, anxiety, tiredness and headache, Patient 41; dry mouth, headache and palpitations, and Patient 59 profuse sweating and insomnia).
The envelopes with the codes of the following sibutramine patients were opened due to adverse events Patient 14 (lower leg edema), Patient 17 (neck sprain by trauma), Patient 41 (dry mouth, headache, and palpitations), Patient 59 (profuse sweating and insomnia), meanwhile in the placebo group the following envelopes were opened: Patient 8 (lipoma abscess), Patient 37 (thyroid node detected), and Patient 69 (hypotension). The rest of the sealed envelopes were returned with the rest of the unused trial medications.
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Obesity is a serious medical condition requiring treatment as do other chronic diseases. The main goal of treatment is maintenance of a long-term healthy weight in order to avoid health risks (17).
The benefits of weight loss have been shown for the comorbidities associated to obesity (18). Yet, after an initial successful weight loss, most patients tend to regain weight (19). Pharmacological agents have been tried in an effort to improve success of long-term weight maintenance. Sibutramine is a new drug approved for the long-term treatmentof obesity.
Previously, the safety and efficacy of sibutramine has been reported in dose-ranging trials. The effect of long-term 15-mg therapy for 12 weeks was a reduction of 4.9 ± 0.5 kg with 55% of the patients losing at least 5% of their initial body weight (20), and over a 24-week treatment period, a weight loss of 7.68 ± 1.56 kg (male patients) with 52% of the patients losing at least 5% of their initial weight (14) and in another 24-week trial the completers had an absolute weight loss of 7.0 kg with 70% of the patients reaching the 5% goal (21).
In this trial using LOCF, after 3 months of treatment, sibutramine patients had a weight loss of 7.07 ± 4.94 kg, 95% CI (5.345; 8.796), with 23/34 (67.6%) patients achieving the 5% goal. After 6 months of treatment, the weight loss in the sibutramine patients was 10.3676 ± 7.759 kg, 95% CI (7.66; 13.07), with 26/34 (76.5%) patients reaching the 5% goal. The results in this trial were therefore superior to previous reports on the patients taking sibutramine 15 mg once per day.
It is important to note that patients on sibutramine lost weight even in the last month of treatment. This observation is consistent with previous sibutramine studies by Bray et al. (14, 21), and Smith et al. (22).
Lack of efficacy was reported on 7/35 sibutramine patients and on 17/34 placebo patients. The major shortcoming of this study was the high drop-out rate in the placebo group.
We found a low rate of responders in the placebo group, maybe because the dietary advice was not strict enough and food diaries were not included as part of the patient support. In our study, the patients received minimal dietary advice consisting of standard printed material and individual counseling at the beginning of the trial by family care physicians, but no special emphasis was paid to dietary reinforcement.
We may speculate that differences in weight loss may be a result of the predominance of Hispanic mestizos in the trial population or due to differences in the Mexican way of living. Mexicans, as well as Mexican Americans, have a genetic admixture of white and Amerindian genes, but it seems that much of the genetic susceptibility to obesity, insulin resistance, and type 2 diabetes may be ascribed to the Amerindian heritage (7, 23, 24). On the other hand, the diet for the population of Mexico City relies more on carbohydrate consumption, 68% to 72% of the calorie intake, and less on fat, 18% to 21% of the calories (23, 25).
At baseline, patients presented a very low prevalence of hypertension (11.6%), since a prevalence of 17.1% has been reported in the general population of Mexico City (26); the prevalence of diabetes (20.3%) was higher than that reported for the general population (12%) (27), and the rates for hypercholesteremia (8.7%) and hypertriglyceridemia (36.2%) were, respectively, lower and higher than those of hospital workers in Mexico City (14.9% and 21.1%) (28).
The profile of the adverse events observed was relatedto the mode of action of the drug and reflects the activation of the sympathetic system. Most of the adverse events inthe sibutramine group occurred in the first 2 months of treatment.
These adverse events suggested that these patients were taking sibutramine. Surprisingly, dry mouth was presented only by one patient; dry mouth is frequently reported for the patients on sibutramine treatment (29).
No important cardiovascular effects related to the study drug, however, were found. An important factor in this may be the relatively low baseline blood pressure. Low blood pressures for Mexican obese patients have been reported previously (26).
Previous studies (29, 30, 31) have found an average of 2-mmHg increases in systolic and diastolic blood pressures in the patients taking 10 or 15 mg of sibutramine, with an increase of 3 to 6 beats per minute in the heart rate. In the present study, the blood pressure did not increase, in fact, in some months it showed a small but significant reduction. Heart rate increased significantly in the first 4 months of treatment but returned to basal levels in the patients completing the 5th and 6th months of treatment. Except for the three described cases of transitory tachycardia, patients with heart rate increase did not go beyond 90 beats per minute. Thus, the cardiovascular tolerance was good, and it is not a serious limitation to extending the period of treatment.
Although, sibutramine is generally well-tolerated, it could be convenient to down-titrate on those presenting adverse events and to up-titrate in patients showing a minor weight loss or those showing weight regain during the maintenance period.
According to Bray (32), the characteristics of an ideal weight loss drug are those that: 1) are orally active, 2) have few or no side effects, 3) have dose-dependent reduction in body fat, 4) are visceral fat reducing, 5) are inexpensive, 6) are long acting, and 7) are non-toxic. In this study, sibutramine has shown effectiveness producing and maintaining weight loss for up to 6 months, with significant changes in the waist circumference and in the waist/hip ratio. The side effects were tolerated by most of the patients, with minimal effects on the cardiovascular function evaluated: blood pressure, heart rate, and electrocardiogram. Sibutramine seems to cover most of the features of an ideal drug for the treatment of obesity, but additional trials are necessary to probe the effect on special groups of patients, as well as the effect on visceral fat.
Taking into account the health risks of obesity in contrast to efficacy and tolerance of sibutramine, we consider that sibutramine can be used to complement a program of diet, exercise, and behavioral therapy.