Original Article | Published:

Clinical Studies and Practice

A comparative study of five centrally acting drugs on the pharmacological treatment of obesity

International Journal of Obesity volume 38, pages 10971103 (2014) | Download Citation

Abstract

Context:

No long-term studies have compared centrally acting drugs for treating obesity.

Objective:

To compare the efficacy and safety of diethylpropion (DEP), fenproporex (FEN), mazindol (MZD), fluoxetine (FXT) and sibutramine (SIB) in promoting weight loss.

Design and Setting:

A prospective, randomized, placebo (PCB)-controlled study conducted at a single academic institution.

Patients:

A total of 174 obese premenopausal women.

Intervention:

Participants randomly received DEP 75 mg (n=28), FEN 25 mg (n=29), MZD 2 mg (n=29), SIB 15 mg (n=30), FXT 20 mg (n=29) or PCB (n=29) daily over 52 weeks. Diet and physical activity were encouraged.

Main Outcome Measures:

The primary endpoints were changes in body weight and the proportion of women who achieved at least 5% weight loss by week 52 in the intent-to-treat population. Other measurements included anthropometry, safety, metabolic and cardiovascular parameters.

Results:

Weight loss was greater than PCB (−3.1±4.3 kg) with DEP (−10.0±6.4 kg; P<0.001), SIB (−9.5±5.9 kg; P<0.001), FEN (−7.8±6.9 kg; P<0.01) and MZD (−7.4±4.9 kg; P<0.01) but not with FXT (−2.5±4.1 kg). Ten (33.3%) women lost5% of their initial weight with PCB, compared with 20 (71.4%; P<0.001) with DEP, 20 (69%; P<0.02) with FEN, 21 (72.4%; P<0.01) with MZD, 22 (73.3%; P<0.001) with SIB and 10 (35.5%) with FXT. Each medically treated group experienced more adverse events compared with PCB (P<0.001). Compared with PCB, constipation was more prevalent with DEP, SIB and MZD (P<0.01); anxiety was more prevalent with DEP (P=0.01); and irritability occurred more frequently with DEP and FEN (P=0.02). Significant improvements in the depression and anxiety scores, binge-eating episodes and quality of life correlated with weight loss.

CONCLUSION:

The centrally acting drugs DEP, FEN, MZD and SIB were more effective than PCB in promoting weight loss in obese premenopausal women, with a satisfactory benefit–risk profile.

Introduction

Obesity is associated with several morbidities and reduced life expectancy.1, 2 Weight loss improves metabolic abnormalities and reduces cardiovascular and cancer risk in obese subjects.3, 4, 5 A reduction in body weight can be achieved with non-pharmacological strategies, but such approaches are often unsuccessful and associated with weight regain.6

Different pharmacological therapies have been employed for helping people to lose weight. Many anti-obesity drugs are centrally acting agents, whose mechanisms of action involve cerebral circuits that control food intake and energy expenditure.7, 8, 9, 10 The fear of adverse events and abuse associated with anti-obesity drugs has prevented or limited their use in most countries.11

In Brazil, when this study was performed, drugs such as diethylpropion (DEP; Aché Pharmaceuticals, Sau Paulo, Brazil), fenproporex (FEN; Aché Pharmaceuticals), mazindol (MZD; Apparenza Drugstore, Curitiba, Brazil) and sibutramine (SIB; Medley Pharmaceuticals, Sau Paulo, Brazil) were used to counteract obesity. DEP acts on the central nervous system (CNS); this drug increases the release of noradrenaline in the synaptic cleft of the hypothalamic neurons, thus stimulating noradrenergic receptors and inhibiting hunger.12, 13, 14 FEN (hydrochloride methyl-1-phenyl-2-ethyl-3-amino propionitrile) also acts on the CNS as an appetite-suppressing drug by increasing catecholamine action.15, 16 MZD is a non-amphetaminic, tricyclic derivative that blocks the reuptake of norepinephrine in the presynaptic neurons and reduces food intake by suppressing neurons in the lateral hypothalamus.16, 17, 18 SIB is the newest of these drugs; it acts as a reuptake inhibitor of serotonin and noradrenaline in the CNS.19, 20 FXT (Medley Pharmaceuticals) is indicated for the treatment of depression and bulimia nervosa, with no formal indication for the treatment of obesity.21 However, it is sometimes employed off-label by physicians to promote weight loss due to an acute effect via selective inhibition of serotonin reuptake in the presynaptic neurons.22, 23

In most countries, the clinical use of these old anorectic drugs is prohibited or limited to no more than 3 months, which is counterintuitive in a chronic disease such as obesity. These limitations are frequently based on empirical decisions because there is a lack of long-term, well-designed studies that evaluate the long-term efficacy and safety of these agents. More recently, SIB was withdrawn from the market due to safety issues related to cardiovascular risks.24 The main goal of the present study was to compare, in a single-blind, randomized, placebo-controlled design, the efficacy and safety of a 52-week (wk) therapeutic program with DEP, FEN, MZD, FXT or SIB for promoting weight loss in a group of obese premenopausal women.

Patients and methods

Study design and population

This trial was a prospective, randomized, placebo-controlled study conducted by a multidisciplinary team at the Obesity Outpatient Clinic of the Endocrine Division (SEMPR) of the Parana Federal University Hospital, in Curitiba, Brazil. The main goal of the study was to compare the efficacy and safety of five different centrally acting medications used to treat obesity during a follow-up period of 52 wks. Efficacy was evaluated by the differences in weight loss promoted by medications and placebo and the proportion of patients in each arm who experienced a reduction in the baseline body weight of at least 5% or 10% after 52 wks. The secondary endpoints included changes from the baseline values in anthropometric measures (that is, waist circumference (WC), body mass index (BMI)). Safety was evaluated by reports of adverse events in the follow-up visits, with an emphasis on serious events and events that led to the patient’s discontinuation. Key secondary safety endpoints included changes from the baseline in measures of blood pressure, heart rate, serum lipids (total cholesterol, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol and triglycerides (TGs)), glycemic variables (fasting glucose, fasting insulin, glycated hemoglobin and the homeostasis model assessment of insulin resistance) and quality of life (QoL).

Eligible subjects included premenopausal women with ages between 18 and 50 years with a BMI of at least 30 and no more than 40 kg m−2 who were weight stable within the previous 3 months (variation not greater than 3 kg). The exclusion criteria were male gender; previous bariatric surgery; menopause; pregnancy or lactation; desire to become pregnant during the study; uncontrolled hypertension (>160/100 mm Hg at the time of enrollment); diabetes mellitus; clinically significant history of gastrointestinal, cardiac, renal, hepatic, pulmonary, neurological, neoplastic or endocrine diseases; diagnosis of major depressive, bipolar, generalized anxiety or eating disorders; alcoholism or drug abuse; use of medications that could alter body weight or appetite; elevation of aspartate aminotransferase and alanine aminotransferase more than twofold the upper limit of reference range; creatinine levels more than 1.5-fold the upper limit of the reference range; and TG above 6.78 mmol l−1. Informed consent was obtained from all participants, and the protocol was approved by the Ethics Committee for Human Research of our institution and conducted under the guidelines of the Declaration of Helsinki.

All visits were performed in the morning after an overnight fast. There were two screening assessments at wk 2 and wk 1 before randomization; then, the patients were re-evaluated every 4 wks during the duration of the trial. The eligible participants were randomly assigned in equal numbers to one of the six following treatment arms: placebo (PCB; Apparenza Drugstore); DEP at 75 mg per day; FEN at 25 mg per day; MZD at 2 mg per day; SIB at 15 mg per day; FXT at 20 mg per day. The regimens were based on the most common daily doses used for each medication, which were directly obtained from the manufacturers because they were usually commercialized. A sample of each medication was originally covered by gel to obtain identical capsules for a double-blind study design. These gel-covered capsules were then analyzed by the Parana Institute of Technology (TECPAR, Curitiba, Brazil), but the results showed a different pharmacokinetic pattern in comparison with the original medications. For this reason, the double-blind design could not be employed in our protocol, and uncoated capsules were utilized.

At the randomization visit (V0), all women were instructed to take one capsule every day at 1000 hours. Adherence was defined as the consumption of at least 80% of the capsules, which were counted at all visits. The women received instructions from a trained nutrition counselor to follow a balanced hypocaloric diet based on individual energy expenditure, which was calculated by the Harris–Benedict formula multiplied by the activity factor 1.3 (activity factor−sedentary) with a daily energy deficit of 800 kcal. Additionally, they were encouraged to maintain at least 150 min per wk of moderate physical activity. They were also asked to avoid any other medications, especially medications that were likely to affect body weight.

Study procedures

At the follow-up visits, the inclusion and exclusion criteria were reviewed, and the use of concomitant medication was checked. The patients were asked about compliance and adverse effects. The research staff evaluated vital signs and anthropometric measurements with an emphasis on weight and WC. After the medical assessment, the participants were interviewed by the trained nutrition counselor for dietary reassessments.

At baseline and at wk 52, all participants were evaluated by a psychologist and responded to the following tests: the Beck Depression Inventory25 and the Beck Anxiety Inventory,26 which evaluate the levels of depression and anxiety, respectively; the Binge Eating Scale,27 a self-administered questionnaire to assess the severity of binge eating in obese individuals; the Short-Form Health Survey (SF-36), a general health questionnaire;28, 29 and the Impact of Weight on Quality of Life (IWQOL-LITE).30 IWQOL-LITE scores range from 0 to 100, with higher scores indicating a better QoL. At these visits, blood samples were collected in the morning after an overnight fast to determine the serum levels of glucose, aminotransferase, alanine aminotransferase, total cholesterol, high-density lipoprotein, low-density lipoprotein, TG, insulin and TSH. Insulin resistance was calculated in accordance with the Homeostasis Model Assessment.31 An electrocardiogram (ECG) was performed before the start of the study and was repeated if clinically indicated. Transthoracic echocardiography was performed at baseline and at the end of the study by the same operator, with all patients in the left lateral decubitus position, using the same equipment (Sonos 5500, Hewlett-Packard, Andover, MA, USA) with an electronic multifrequential transducer of 2–4 MHz.

Statistical analysis

To compare the efficacy of the different drugs in promoting weight loss, a 52-wk placebo-subtracted total weight loss of at least 5% was considered. It was assumed that roughly 10% of patients in the placebo group would have a weight loss of 5% at the end of the study and the magnitude of the effect (the minimum difference between treatment arms to be considered clinically relevant) was assumed as 40%. Power was set as 0.8 with an alpha level of 0.05, resulting in an estimate minimum sample size of 30 patients per group. The initial analyses involved data from the intention-to-treat population and last-observation-carried-forward imputation for missing values.32 The analyses were performed with the outcomes obtained at baseline and 52 wks, and the variables were evaluated with the Student's t-test, Pearson’s chi-squared test, Fisher’s exact test and analysis of variance for repeated measurements. Duncan’s post-hoc multiple range test was performed to allow better discrimination among study groups and to reduce type I error. We also conducted a statistical analysis with only those patients who completed the study using the same tests described above. All statistical analyses were two-tailed and performed with the use of Statistica, version 7.1 StatSoft. P-values<0.05 were considered significant. No statistical imputation was performed for the missing data.

Results

Patients and study completion

Of the 507 recruited subjects, 327 subjects were excluded during the screening phase because they did not fulfill the inclusion and exclusion criteria (Figure 1). A total of 180 women were randomized to one of the treatment arms, but six withdrew consent at the initial visit and were excluded from the final analysis. The final intention-to-treat population consisted of 174 women who were grouped as follows: PCB (n=29); DEP (n=28); FEN (n=29); MZD (n=29); SIB (n=30); FXT (n=29) (Figure 1). In the whole group, the mean (±s.d.) age was 36.7±7.2 years (range, 20.7–47.7 years); the mean weight, BMI and WC were 89.2±9.7 kg, 34.6±2.6 kg m−2 and 108.3±8.0 cm, respectively. There were no significant differences in the baseline characteristics among the groups (Table 1).

Figure 1
Figure 1

Trial profile.

Table 1: Baseline characteristics of the study groups

One hundred and twenty-nine (74.1%) women completed the whole period of the study with a dropout rate of 25.9%, mostly during the first 6 months of treatment. The highest dropout rates occurred in the PCB group (n=14; 48.2%) and the FXT group (n=11; 35.5%). There were no differences in the causes of dropouts among the groups (Figure 1).

Weight loss

At wk 52, the weight loss in the PCB group was −3.1±4.3 kg. In relation to PCB, weight loss was significantly greater in all drug-treated arms, except for FXT (−2.5±4.1 kg; P=0.55). The weight reductions in the DEP, FEN, MZD and SIB arms were −10.0±6.4 kg (P<0.001), −7.8±6.9 kg (P<0.01), −7.4±4.9 kg (P<0.01) and −9.5±5.9 kg (P<0.001), respectively (Figure 2). The weight loss with DEP, FEN, MZD and SIB was significantly greater than that observed with FXT (P<0.05). However, there were no statistical difference in weight loss promoted by DEP, FEN, MZD and SIB.

Figure 2
Figure 2

Effects of PCB, DEP, FEN, MZD, SIB and FXT on body weight. Mean change from baseline. Weight-change curves are plotted for completers for each visit using data from the intention-to-treat population.

At wk 52, 10 (33.3%) women treated with PCB lost 5% of their initial weight, compared with 20 (71.4%; P<0.001) women treated with DEP, 20 (69%; P<0.02) women treated with FEN, 21 (72.4%; P<0.01) women treated with MZD and 22 (73.3%; P<0.001) women treated with SIB. Only 10 (35.5%) women treated with FXT lost 5%; this percentage was not different than the percentage for PCB. A similar pattern was observed for weight loss of 10%: only 2 (7.45%) women in the PCB group attained this target, in comparison with 18 (64.3%; P<0.001) in the DEP, 10 (34.5%; P<0.02) in the FEN, 11 (37.9%; P<0.01) in the MZD, 15 (50%; P<0.001) in the SIB, and three (9.7%; P=NS) in the FXT groups (Figure 3). Again, the results obtained with DEP, FEN, MZD and SIB, were significantly different compared with FXT (P<0.05), but no difference was observed among them.

Figure 3
Figure 3

Percentage of obese women with at least 5% or 10% weight loss at wk 52 in the PCB, DEP, FEN, MZD, SIB, and FXT study groups.

The reduction of WC in the PCB group was −2.0±6.5 cm. The corresponding values in the DEP, FEN, MZD and SIB arms were −8.6±7.0, −6.6±9.1, −5.2±5.4 and −6.8±6.0 cm, respectively, all of which were greater than that for PCB (P<0.05). Once again, there was no difference in the FXT arm (−1.1±4.7 cm) (Table 2). Changes in WC were positively related to the changes in body weight (r=0.98; P<0.01).Weight loss 5% was associated with reduced total cholesterol, low-density lipoprotein, TG, insulin and homeostasis model assessment (P<0.01). Weight loss 10% was associated with a decrease in diastolic blood pressure and serum glucose levels (P<0.01). The changes in high-density lipoprotein cholesterol were significant in the DEP and SIB groups, whereas significant changes in TG occurred only in the DEP group (Table 2).

Table 2: Changes from baseline to week 52 in primary and secondary endpoints

Safety

As shown in Table 3, 23 distinct adverse events were reported by the participants during the follow-up. The total number of adverse events was significantly higher in each medically treated group in relation to PCB (P<0.001). At wk 4, dry mouth was the most prevalent adverse event (79 cases, 45.1%), and there was no difference in its frequency among the experimental and placebo groups. The second most common adverse event was constipation (36 cases, 20.6%), which was more frequent in the DEP, SIB and MZD users compared with the PCB users (P<0.01). Twenty-three patients (13.2%) reported anxiety, which was more prevalent in the DEP group compared with PCB (P=0.01), whereas irritability was more frequent with DEP and FEN in relation to PCB (P=0.02). All the other reported adverse events did not differ in frequency in women treated with medication compared with women treated with PCB. Most adverse events were mild, well-tolerated and either disappeared or progressively improved during the follow-up. No serious adverse events were noted during the study period. At 52 wks, there were significant improvements in the depression and anxiety scores, binge-eating episodes and QoL in all the study arms (P<0.001). These findings were related to weight loss and were more pronounced in women who lost 5% of their initial body weight.

Table 3: Adverse events in the intention-to-treat population

All baseline ECGs were normal or showed abnormalities that were considered not to be clinically significant. None of the women had a clinical indication to repeat an ECG during the follow-up. Baseline echocardiography was performed in 157 participants; mild mitral or tricuspid regurgitation was observed in 23 and 17 women, respectively. These alterations were not considered clinically significant by the examiner or the investigator, and they did not change in the ECG obtained at the end of the study (data not shown). At wk 52, the heart rate increased significantly in women treated with SIB compared with PCB (P<0.01; Table 2).

There were three pregnancies (PCB, DEP and FEN); two were carried to full term, resulting in healthy infants and one resulted in miscarriage at 23 wks of gestation (DEP). The miscarriage was the patient’s fourth pregnancy; the patient had a previous history of two abortions and one complicated pregnancy, in which cervical cerclage was performed.

Discussion

This is the first study to compare five centrally acting drugs for the treatment of obesity. We have shown that the treatment of obese premenopausal women with DEP, FEN, MZD or SIB as an adjunct to lifestyle intervention was more effective in promoting weight loss over 52 wks when compared with a lifestyle intervention plus PCB. Moreover, either 5% or 10% weight loss was achieved in a greater proportion of patients who received one of these agents as compared with PCB. As expected, weight loss was associated with beneficial reductions in WC and blood pressure and improvements in metabolic parameters.

In our PCB group, the mean weight reduction was 3.1 kg at 52 wks with 33.3% and 7.45% of women presenting with a 5% and 10% weight loss, respectively. The greatest weight reductions were observed with DEP and SIB. On average, women treated with DEP lost 6.9 kg more than women taking PCB; 71.4% lost more than 5% and 64.3% lost more than 10% of their initial weight. Our result in the DEP versus PCB users was more than double the mean of 3 kg (confidence interval 1.6–11.5 kg) reported in a meta-analysis of 13 studies with DEP, most of which lasted less than 20 wks,8 indicating that efficacy improves over time. Our SIB users lost 6.4 kg more than women treated with PCB, which represents a weight reduction that is greater than the 3.4–6.0 kg reported by trials with a follow-up ranging from 16 to 52 wks.33 The percentage of patients treated with SIB who lost 5% was 73.3%, and 50% of SIB-treated women lost 10% of their initial body weight, far exceeding the numbers in the PCB group. In fact, our results with SIB are comparable to the results seen with the higher dose of phentermine plus topiramate and are better if compared with the lower doses of these new combined drugs approved for the treatment of obesity.34 The permanent non-pharmacological, multidisciplinary approach employed in our protocol in association with drug therapy might have contributed to the greater weight loss seen in our patients in comparison with these other studies. The differences in weight loss in relation to PCB were also significantly greater in women treated with FEN (4.7 kg) and MZD (4.3 kg); a 5% and 10% decrease in body weight was observed in 69% and 34.5% of the FEN group and in 72.4% and 37.9% of the MZD group, respectively. There have been few published trials with FEN and MZD, and these studies have large variation in doses, duration and therapeutic outcomes, preventing a comparison with our results.9, 10, 11, 16, 17

FXT is the first highly specific serotonin uptake inhibitor used as an antidepressant. Initial short-term studies suggested that FXT could be effective in inducing weight loss, even though it has never been approved as an anti-obesity drug.22, 35, 36 We decided to include FXT in our trial because it is sometimes commonly used off-label with the aim of reducing weight. Our findings demonstrated that weight loss induced by FXT after 52 wks was not different compared with PCB, in agreement with the results of a systematic review.23

The dropout rate in our study was 25.9% and occurred mainly during the first 6 months of treatment. This percentage is consistent with the rates noted in 52-wk-large weight-loss trials of pharmaceutical interventions and was lower than the roughly 50% dropout rates observed in phase 3 trials of lorcaserin and naltrexone plus bupropion, which are two new investigational drugs.37, 38 Nine of the fifteen (60%) women who stopped treatment due to therapeutic failure were in the PCB and FXT groups, which showed the poorest outcomes. Thirteen women discontinued treatment due to adverse events, and their numbers were similar among the groups. The total number of adverse events was significantly higher in the medically treated groups compared with the PCB group, but there were no serious adverse events observed throughout the period of our trial. The most common side effects were dry mouth and constipation, which were tolerable or manageable by other simple interventions. Dry mouth and constipation are well-known side effects of SIB and amphetamine-like analogs,39, 40 and they were also the most common side effects observed in the CONQUER trial with phentermine plus topiramate.34 In the SIB group, we observed a mean increase in heart rate of 6 beats per minute over the PCB group and a mean elevation in the diastolic blood pressure of 2.4 mm Hg, which is similar to previous reports.24, 33, 39 Systolic blood pressure decreased in all study groups. None of the women had to stop treatment due to uncontrolled hypertension, angina or arrhythmia. There were no significant changes in the echocardiographic parameters at the end of the study.

Anxiety and irritability occurred more frequently in patients treated with DEP and FEN but not with SIB or MZD. DEP has been available for inducing weight loss since the early 1960s; however, there have been few, if any, randomized clinical trials of its long-term use, especially in large cohorts. From the information available, the most common side effects of this drug are dry mouth and insomnia, which are more frequent in the first 3 months and become less apparent with continuing treatment.14, 40 In our trial, these adverse events were mild and occurred mainly in the first month of therapy, thereafter decreasing subsequently both in frequency and intensity. There were significant improvements in the scores of depression, anxiety and QoL and in the number of binge-eating episodes in all study arms. These improvements were clearly related to weight loss, suggesting that positive or negative results might also influence the level of anxiety and irritability.

A potential limitation of the study was the lack of a double-blind design. On principle, we did not want to manipulate the drugs in compounding pharmacies. For this reason, a sample of each medication was covered by gel to obtain identical capsules for a double-blind design. Unfortunately, the pharmacokinetic patterns of the gel-covered capsules differed from the original medications. As a consequence, we chose to pack the original capsules in identical bottles, which were tracked by codes. Other limitations were the restriction of the upper limit of BMI to 40 kg m2, age and the exclusion of men, which were due to the sample size for subgroup analysis and the potential impact of severe obesity and menopausal state in the results. All of these factors affect the generalization of our findings. On the other hand, a more homogeneous study group helps to prevent the interference of several confounding factors in the analysis of the results. As in any single-center trial, the sample size is always a major concern, especially considering our dropout rate of 25.9%. Although this problem does not invalidate our data on the efficacy of the studied medications, the sampling was small and dropout was too high for definitive conclusions regarding safety issues of the drugs.

Changes in lifestyle are fundamental in the therapeutic approach against obesity. A decrease of 5–10% of body weight is associated with significant improvements in the risk factors for type 2 diabetes and cardiovascular diseases.9, 10 However, weight regain is frequent, and medical options to promote sustained weight loss are very limited. In Brazil, DEP, MZD and FEN were recently banned from the market after 30 years of use with the justification of low efficacy and high risks for the patients. Bariatric surgery is an option for long-term weight loss, but it is generally indicated for selected subjects with complicated or severe obesity.4 In our hands, 52 wks of pharmacological treatment with the centrally acting drugs DEP, FEN, SIB and MZD showed a satisfactory benefit–risk profile for achieving sustained weight loss in obese premenopausal women. Thus, we believe that our study sheds new light on the importance to design long-term multicenter studies in larger groups of obese individuals, encouraging the regulatory agencies in Brazil and other countries to review the role of these older and cheaper agents in the fight against the obesity epidemic.

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Acknowledgements

SIB and FXT were generously provided by Medley Pharmaceuticals. FEN and DEP were generously provided by Aché Pharmaceuticals. MZD and PCB were prepared by Apparenza Drugstore, which was also responsible for packing all medications in identical bottles.

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  1. Endocrine Division (SEMPR), Department of Internal Medicine, Parana Federal University, Curitiba, Brazil

    • H Suplicy
    • , C L Boguszewski
    • , C M C dos Santos
    • , M do Desterro de Figueiredo
    • , D R Cunha
    •  & R Radominski

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The authors declare no conflict of interest.

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Correspondence to H Suplicy.

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DOI

https://doi.org/10.1038/ijo.2013.225

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