Introduction

Behavior modification with lifestyle intervention, notably recommendation of a hypocaloric diet, is a cornerstone of overweight and obesity clinical management. However, the magnitude of weight loss in behaviorally managed groups is modest and long-term success rates tend to be low. These observations provide the foundation for supplementing conventional management with pharmacotherapy.

Two presently approved medications for weight loss treatment are orlistat and sibutramine. Orlistat, an inhibitor of gastrointestinal and pancreatic lipases, promotes weight loss and negative energy balance through fat malabsorption (1, 2). Orlistat (tetrahydrolipstatin) works by forming a covalent bond with the active serine site of gastric and pancreatic lipases and prevents these enzymes from hydrolyzing dietary triglycerides into absorbable free fatty acids and monoglycerols (3, 4). Sibutramine is a selective inhibitor of the reuptake of norepinephrine and serotonin and, to a lesser extent, dopamine, which facilitates weight loss through both suppression of food intake and augmentation of energy expenditure (5, 6). Both drugs significantly increase weight loss above that of lifestyle interventions (7, 8, 9, 10, 11).

While the orlistat and sibutramine development programs were initiated over two decades ago, rapid advances in our understanding of energy homeostasis over the ensuing years have provided greater insight into the central pathways that regulate food intake and energy expenditure. These advances offer the promise of a greater therapeutic range of intervention, and novel targets are beginning to be critically evaluated with translational research. In this respect, neuropeptide Y (NPY)¹ has been characterized as a potent orexigenic factor that is a key component of an anabolic network that promotes food intake and decreases energy expenditure (12, 13, 14, 15, 16). NPY is thought to mediate its orexigenic effects through two 7 transmembrane G-protein coupled receptor subtypes, the NPY Y1 and NPY Y5 receptors (NPY1R and NPY5R), which are expressed in the central nervous system (17, 18, 19, 20, 21, 22, 23, 24, 25, 26). However, controversy has arisen regarding the relative contribution of these two NPY receptor subtypes to NPY-induced feeding (27, 28), and genetic manipulations in mice have failed to definitively resolve this controversy. Both NPY1R- /- and NPY5R- /- mice have relatively normal feeding patterns and, counter-intuitively, develop mild obesity with age (29, 30, 31). Adding to this controversy is the observation that mice with germline deletion of the NPY gene are not lean (32). There is evidence that the phenotype of the germline NPY knockout could result from developmental compensation during embryogenesis (33), and similar arguments could be invoked to explain the phenotypes of NPY1R and NPY5R knockout mice.

MK-0557 is a highly selective NPY5R antagonist that induced modest, dose-dependent weight loss in a 12-week proof-of-concept clinical trial [ least squares (LS) mean change from baseline - 0.6, - 1.3, - 1.9, - 1.7, and - 1.9 kg for placebo, 0.2, 1, 5, and 25 mg MK-0557, respectively; p = 0.054 compared with placebo for the 0.2 mg dose; p 0.003 compared with placebo for the 1, 5, and 25 mg dose] in obese patients (34). This dose-ranging study combined with receptor occupancy data from positron emission tomography established 1 mg as the appropriate daily dose of MK-0557 for clinical studies. As part of our evaluation of MK-0557 as a clinical candidate, we examined the weight-loss effects of this NPY5R antagonist when co-administered with orlistat and sibutramine. Our experimental protocol also provided the opportunity for a head-to-head comparison of orlistat and sibutramine.

Research Methods and Procedures

Hypotheses and Study Design

The primary hypotheses tested were that in obese patients, MK-0557 1 mg every day (q.d.) co-administered with 1) sibutramine 10 mg q.d. for 24 weeks reduces body weight more than sibutramine alone; 2) orlistat 120 mg three times a day (TID) for 24 weeks reduces body weight more than orlistat alone; and 3) sibutramine or orlistat for 24 weeks is safe and well tolerated. Secondary hypotheses were 1) in obese patients, sibutramine 10 mg q.d. for 24 weeks reduces body weight more than placebo; and 2) in obese patients, orlistat 120 mg TID for 24 weeks reduces body weight more than placebo.

These hypotheses were examined in a multicenter, double-blind, randomized, placebo-controlled study. Before randomization, there was a 2-week diet and single blind placebo run-in period. Patients were instructed to follow a diet 500 kcal/d below their weight maintenance requirements, based on an estimation of energy expenditure (35), and to limit fat consumption to <30% of total daily calories. Eligible patients were then randomized equally to each of 5 treatment arms (placebo; sibutramine 10 mg q.d.; MK-0557 1 mg q.d. plus sibutramine 10 mg q.d.; orlistat 120 mg TID; MK-0557 1 mg q.d. plus orlistat 120 mg TID) and continued diet counseling. MK-0557 1 mg or placebo was administered orally once daily at any time of day; 10 mg sibutramine or placebo was administered orally once daily at any time of day; and 120 mg orlistat or placebo was administered orally 3 times daily with meals. Patients provided a physical activity history at baseline and follow-up visits and when low they were encouraged to modestly increase these levels. Patients were also required to take a once-daily multivitamin 2 hours after the administration of orlistat (or placebo), not to exceed 1 multivitamin tablet in any given day. To maintain blinding across the treatment arms, all patients were provided five matched pills per day for ingestion as with the orlistat/vitamin plus MK-0557 group.

The primary measure of efficacy was change from baseline in body weight. Exploratory measures included change from baseline in waist circumference, systolic and diastolic blood pressure, fasting plasma lipid profile (total cholesterol, high-density lipoprotein-cholesterol, low-density lipoprotein-cholesterol, non-high-density lipoprotein cholesterol, triglycerides), fasting plasma glucose, thyroid function (thyroid-stimulating hormone, free T4, total T3), and assessment of appetite/satiety and patient-reported outcomes by questionnaires.

Before initiation of this study, the effects of co-administration of orlistat on the plasma pharmacokinetics of MK-0557 were assessed in a 2-period, crossover study in healthy adult male and female patients. The mean plasma concentration profiles of a single oral 1 mg dose of MK-0557 administered alone or when co-administered with orlistat were found to be similar. The geometric mean MK-0557 area under the plasma concentration curve from time 0 to and maximum plasma concentration ratios for the combination relative to the MK-0557 treatment alone [ with 90% confidence intervals (CIs)] were 1.03 (0.98, 1.08) and 1.12 (0.99, 1.27), respectively. The mean apparent terminal half-life of MK-0557 (28 hours) was also unaltered by orlistat.

Patients

Obese patients with BMI between 30 kg/m² and 43 kg/m², between the ages of 18 and 65 years, inclusive, and who met other entry criteria were eligible to participate. Patients with diabetes mellitus, hypertension, or a history of significant cardiovascular, pulmonary, gastrointestinal, renal, or neurological disorders were excluded from this study. Patients requiring monoamine oxidase inhibitors or medications that could influence serotonin levels were also excluded.

For each patient, a baseline clinical evaluation was completed, including a physical examination, electrocardiogram, and laboratory assessment as specified above.

Clinical Measurements

Patients were instructed to remain fasting for at least 8 hours before the measurement of body weight. Body weight was measured in gowned patients after voiding. Measurements were obtained to the nearest 0.1 kg on a calibrated digital scale throughout the study and were collected until three consecutive measurements were within 0.25 kg of each other. The same digital scale was used for weighing patients at each site throughout the study.

Height was measured to within the nearest millimeter without shoes using a stadiometer fitted with a vertical backboard, fixed floorboard, and a movable headboard. Waist circumference was measured as described in the National Health and Nutrition Examination Survey III protocol using a tension-controlled measuring tape. When possible, the same nurse or study coordinator measured waist circumference at each visit to ensure consistency.

All blood pressure measurements were taken with a mercury sphygmomanometer as patients sat in position for at least 5 minutes. The same arm was used to obtain all readings over the course of the study. Sitting systolic and diastolic blood pressures were estimated by averaging 3 replicate measurements obtained 1 to 2 minutes apart.

Quality of life was assessed using the Impact of Weight on Quality of Life (36), the Medical Outcomes Trust Short Form, version 2 (37), and the EuroQoL questionnaires (38).

Statistical Analysis

The primary analysis population for the key endpoints (e.g., body weight) was an all-patients-treated (APT) population that consisted of patients who were randomized and who received at least one dose of study medication. For evaluation of change from baseline, patients who had both a baseline and at least one post-baseline measurement were included in the analysis. Missing data were imputed using the last observation carried forward (LOCF) (39).

The efficacy hypotheses were evaluated by comparing the mean change from baseline in body weight using an analysis of covariance (ANCOVA) model with terms for weight loss during the run-in, baseline body weight, treatment, and center. The hypotheses were evaluated using linear contrasts on the ANCOVA model. LS mean differences (i.e., adjusted for the covariates) with corresponding 95% CIs are reported. Both primary hypotheses were tested at the 0.05 level with a two-tailed level.

Secondary efficacy endpoints included assessments of changes from baseline in waist circumference, lipid profile, and glycemic parameters. For safety, a multitiered approach was taken to address the adverse experiences; the effect of MK-0557 on pre-specified adverse events (in general, cardiovascular-related events for sibutramine, and gastrointestinal events for orlistat) was assessed.

A longitudinal repeated measures ANCOVA was also used to analyze the observed data (i.e., without LOCF imputation); results were consistent with the LOCF analysis and are, thus, not reported here. A per-protocol patient population, consisting of patients who completed 24 weeks of treatment and who followed the rules of the protocol was also performed. As with the longitudinal analysis of the APT population, results were generally consistent in the primary analysis and are, thus, not reported here.

This study was powered to detect a 2.3 (2.0) kg difference after 24 weeks of treatment with 90% (80% ) power, assuming a standard deviation of 4.76 kg, level 0.05 for the primary hypotheses and 90 patients per treatment arm. The expected one-half width of the 95% CI was 1.4 kg.

Results

Patients

Patient characteristics are summarized in Table 1. Race, gender, age, weight, BMI, and waist circumference were generally similar across the five study groups. Overall, the study consisted mainly of white (75% to 83% ) women (80% to 85% ) who were moderately obese with a baseline BMI of 35 kg/m².

Table 1. - Patient baseline characteristics for all randomized patients.

Full table

Patient disposition is outlined in Figure 1. A total of 719 patients were screened and, from these 719 patients, 497 patients were randomized to placebo (n = 101), sibutramine (n = 100), MK-0557 plus sibutramine (n = 98), orlistat (n = 99), and MK-0557 plus orlistat (n = 99). At completion of the protocol, 73% (n = 368) of the 497 patients remained in the study, 71% (n = 72) in the placebo group, 76% (n = 76) in the sibutramine group, 79% (n = 77) in the MK-0557 plus sibutramine group, 69% (n = 68) in the orlistat group, and 76% (n = 75) in the MK-0557 plus orlistat group. Nine randomized patients, who were lost to follow-up after initial therapy, were excluded from the APT population.

Figure 1:.

Patient disposition.

AE, adverse event.

Full figure and legend (88K)

MK-0557 Plus Sibutramine vs. Sibutramine Alone

After 24 weeks of treatment, MK-0557 did not induce significant weight loss when co-administered with sibutramine compared with sibutramine alone (p = 0.892) (Table 2; Figure 2). In the APT population, the LS mean difference (95% CI) between MK-0557 plus sibutramine and sibutramine alone was - 0.1 (- 1.6, 1.4) kg. No significant differences were observed in the per-protocol population or in the 5% and 10% responder analyses.

Figure 2:.

Mean change from baseline in body weight (kg) over 24 weeks of treatment using LOCF (all-patients-treated population). †LS mean estimates (84% CI) based on ANCOVA model with terms for treatment, baseline body weight, center, and run-in weight change. p Values for comparisons are provided in Table 2 and in "Results."

Full figure and legend (108K)

Table 2. - Metabolic and cardiovascular outcomes for the APT population and treatment group comparisons for the metabolic and cardiovascular outcomes in the APT population.

Full table

For pre-specified general adverse experiences and cardiovascular-related events, there were no significant differences in rates between MK-0557 plus sibutramine and sibutramine alone (Table 3).

Table 3. - Summary of pre-specified adverse experiences and treatment comparison for pre-specified adverse experiences.

Full table

MK-0557 Plus Orlistat vs. Orlistat

After 24 weeks of treatment, MK-0557 did not induce significant weight loss when co-administered with orlistat compared with orlistat alone (p = 0.250) (Table 2; Figure 2). In the APT population, the LS mean difference (95% CI) between MK-0557 plus orlistat and orlistat alone was - 0.9 (- 2.4, 0.6) kg. No significant differences were observed in the per-protocol population or in the 5% and 10% responder analyses.

For pre-specified adverse experiences of general and gastrointestinal events, there were no significant differences in rates between MK-0557 plus orlistat and orlistat alone (Table 3).

Sibutramine vs. Orlistat

The LS mean change in body weight (95% CI) was - 5.9 (- 6.9, - 4.9) kg in the sibutramine group and - 4.6 (- 5.7, - 3.6) kg in the orlistat group, as compared with a mean change of - 1.8 (- 2.9, - 0.8) kg for placebo (Figure 2; Table 2). Both sibutramine and orlistat induced statistically significant changes in body weight (p < 0.001 for both compounds vs. placebo), and the difference between the two compounds approached significance (p = 0.097) (Table 2). No significant differences between sibutramine and orlistat were observed in the per-protocol population or in the 5% and 10% responder analyses.

The changes in waist circumference with treatment paralleled those of body weight across the placebo, sibutramine, and orlistat groups (Table 2).

Low-density lipoprotein-cholesterol increased from baseline levels in placebo, sibutramine, and orlistat groups (Table 2) with the largest relative increase observed in the placebo group (7.8% ; 95% CI, 3.9% , 11.6% ) and the smallest in the orlistat group (0.5% ; 95% CI, - 3.5% , 4.5% ). The change in low-density lipoprotein-cholesterol for the orlistat group was significantly different from the change in placebo (p = 0.010) (Table 2); the LS mean difference (95% CI) between orlistat and placebo was - 7.3% (- 12.8% , - 1.8% ) The levels of high-density lipoprotein-cholesterol also increased in all three groups, with the largest effect observed in the sibutramine group (3.5% ; 95% CI, 0.8% , 6.2% ) and the smallest effect observed in the orlistat alone group (0.5% ; 95% CI, - 2.3% , 3.4% ). Triglyceride levels also increased in the placebo group (3.3% ; 95% CI, - 5.8% , 12.4% ) but decreased in the orlistat (- 2.2% ; 95% CI, - 9.6% , 5.3% ) and sibutramine (- 9.0% ; 95% CI, - 16.1% , - 1.8% ) groups.

Systolic and diastolic blood pressures were almost unchanged over 24 weeks in the placebo group (Table 2). Orlistat treatment was accompanied by a small reduction in both systolic and diastolic blood pressure (- 1.4 and - 1.2 mm Hg, respectively), whereas sibutramine treatment was accompanied by a 2.1 mm Hg elevation in systolic blood pressure. The systolic blood pressure difference for orlistat and sibutramine (3.5 mm Hg; 95% CI, 0.9, 6.1 mm Hg) was significant (p = 0.008), whereas no significant treatment difference was observed in diastolic blood pressure. The temporal relations in systolic blood pressure changes over the study period are shown from the per-protocol population in Figure 3.

Figure 3:.

Change from baseline in systolic blood pressure (mm Hg) over 24 weeks of treatment (all-patients-treated population). Observed data plotted from Week - 2 to 24. Sample size corresponds to Week 24; 84% CI shown on Week 24. p Values for comparisons are provided in Table 2 and in "Results."

Full figure and legend (111K)

There were no serious drug-related adverse events (Table 4). The highest proportions of patients with drug-related adverse experiences were in the orlistat groups (40.4% for orlistat alone and 51.5% for orlistat plus MK-0557) followed by the sibutramine (28.0% for sibutramine alone and 31.6% for sibutramine plus MK-0557) and placebo (17.8% ) groups. Of the patients discontinuing due to a drug-related adverse experience, 4% were in the orlistat alone and 1% in both the sibutramine alone and placebo groups. The study dropout rate (Figure 4) was highest in the orlistat alone group (31% ) and lowest in the sibutramine plus MK-0557 group (21% ).

Figure 4:.

Cumulative dropout rate over time by treatment group.

Full figure and legend (94K)

Table 4. - Clinical adverse experience summary.

Full table

Clinical adverse experiences organized by system organ class are summarized in Table 5. The most common reported clinical adverse experiences for the sibutramine group were dry mouth (6% vs. 1% in placebo and 1% in orlistat groups) and constipation (11% vs. 4% in placebo and 2% in orlistat groups). Diarrhea (17.2% vs. 3% in placebo and 5% in sibutramine groups), loose stools (8.1% vs. 2% in placebo and 1% in sibutramine groups), and other related gastrointestinal effects were the most common adverse events in the orlistat group. The orlistat-related gastrointestinal events tended to occur within the first 4 weeks of treatment (Figure 5).

Figure 5:.

Time to first event per patient, expressed as cumulative incidence rate, of gastrointestinal adverse experiences by treatment group for the all-patients-treated population.

Full figure and legend (133K)

Table 5. - Selected clinical averse experiences by system organ class (incidence 5% in one or more treatment group).

Full table

Discussion

NPY-Associated Weight Effects

The current study was designed to investigate whether antagonism of the NPY5R with MK-0557 leads to additional weight loss when co-administered with either of two marketed weight loss drugs, sibutramine and orlistat. Our main observation in this randomized, controlled clinical trial is that NPY5R antagonism with MK-0557 did not lead to additional weight loss beyond that observed with either sibutramine or orlistat alone. Our study was predicated in part on earlier clinical trials that had demonstrated MK-0557 resulted in small, but statistically significant, weight loss compared with placebo (34, 40). Moreover, results from our Phase IIa proof-of-concept dose-ranging and positron emission tomography brain NPY5R occupancy studies indicated that the 1-mg dose used in this study is the optimal dose of MK-0557 for investigational use from a pharmacokinetic and pharmacodynamic standpoint, with >95% NPY5R occupancy at 24 hours and no greater weight loss efficacy at higher doses (34).

Although there appeared to be a trend for greater weight loss in the MK-0557 plus orlistat group vs. the orlistat alone group (Figure 2), this difference was not statistically significant. Based on the results of the pre-study pharmacokinetic analysis, malabsorption of MK-0557 when co-administered with orlistat is unlikely to be the explanation for the lack of additional weight loss observed.

One possible explanation for the lack of additional weight loss with MK-0557 plus sibutramine as compared with sibutramine alone is the recognized interaction between the serotonin [ 5-hydroxytryptamine (5-HT)] and NPY pathways. In rats, the 5-HT antagonist methysergide stimulates feeding and increases NPY mRNA levels and secretion in the paraventricular nucleus of the hypothalamus, an important brain region involved in energy homeostasis (41). In contrast, the 5-HT_{1B/2C-receptor} agonist meta-chlorophenylpiperazine reduces food intake and NPY levels in the paraventricular nucleus of rats (42). Similarly, in rats, the serotonergic drug fenfluramine reduces food intake and increases NPY levels in the ventromedial and dorsomedial nuclei and the lateral hypothalamic area, which are additional brain regions involved in energy homeostasis that have been implicated to be involved in the hyperphagic effects of NPY (43). Moreover, it has been demonstrated that sibutramine dose-dependently reduces feeding caused by NPY microinjection into the paraventricular nucleus (44). Therefore, it is possible that increased brain serotonin levels in the sibutramine-treated patients in this study reduced the orexigenic effects mediated by the NPY pathway to a sufficient extent such that NPY5R antagonism by MK-0557 had no additional effect. The results of our other 3 clinical trials that indicate NPY5R blockade alone has only modest weight loss efficacy (34, 40) are supportive of the argument that the effect of NPY5R blockade might be obscured by increased 5-HT antagonism of the NPY pathway. Co-administration studies performed in rodents are also supportive of this explanation. Co-administration of another NPY5R antagonist with sibutramine tended to produce less weight gain than sibutramine alone in a model of diet-induced obesity, but the difference between groups was not statistically significant (45, 46).

Another explanation for the lack of additive effect of MK-0557 with orlistat or sibutramine has a statistical basis. At the time that this study was initiated, we did not know the long-term weight loss of MK-0557 when used as monotherapy, which we later learned was 1.1 kg above placebo at 52 weeks (34, 40). Our current protocol was powered (90% /80% ) to detect a weight loss of 2.3/2.0 kg, and our experiment was, therefore, not designed to observe the relatively small weight loss observed in those studies.

Orlistat-Sibutramine Comparisons

The current investigation is one of the first randomized, double-blind studies that include a head-to-head comparison of orlistat and sibutramine. In the present 24-week study, orlistat alone or in combination with MK-0557 led to significant weight loss compared with placebo of 2.8 and 3.7 kg, respectively. Li et al. conducted a meta-analysis of orlistat studies and reported a similar 24-week weight loss of 2.59 kg (95% CI, 1.74 to 3.46 kg) (9). At 12 months, weight loss with orlistat increased further to 2.89 kg (2.27 to 3.51 kg).

The respective weight loss above placebo at 24 weeks observed in our study for sibutramine with or without MK-0557, 4.2 kg and 4.0 kg, was greater than that with orlistat, although the differences were not statistically significant. The magnitude of weight loss observed with sibutramine treatment is consistent with meta-analyses and systematic reviews of 12-month studies that report placebo-subtracted weight loss in the range of 4.18 kg (3.21 to 5.14 kg) to 4.45 kg (3.62 to 5.29 kg) (9, 11, 47, 48, 49).

Several earlier reports also describe comparative studies of orlistat and sibutramine. Kaya et al. (47) and Aydin et al. (50) reported in two separate papers a 12-week trial that included four groups with 20 patients in each arm who were randomized to diet alone, orlistat (120 mg TID) or sibutramine (10 mg/d) alone, and orlistat (120 mg TID) and sibutramine (10 mg/d) in combination. The weight loss (mean standard deviation) observed with sibutramine at the final 3-month visit (11.72 3.31 kg) exceeded that of orlistat (9.35 2.62 kg) (p = 0.02). The largest weight loss among the groups was for combination drug treatment, 13.68 4.25 kg, which was significantly greater than the weight loss observed in the diet alone and orlistat groups (both p < 0.001), but not in the sibutramine group.

Sari et al. (51) examined orlistat (n = 30; 120 mg TID), sibutramine (n = 29; 15 mg/d), and the two drugs together (n = 30) in a randomized trial of obese women over a 6-month treatment period that included an energy-deficit diet. Weight loss at 6 months in the three respective groups was (mean standard deviation) 5.5 4.9, 10.1 3.6, and 10.8 6.6 kg. The weight loss with sibutramine was significantly greater than that of orlistat (p < 0.003), but adding orlistat to sibutramine treatment did not significantly increase the weight loss above that of sibutramine alone.

Gokcel et al. (52) compared sibutramine (10 mg twice a day) with orlistat (120 mg TID) and metformin (850 mg twice a day) in a 24-week randomized double-blind trial of 150 female patients with BMI >30 kg/m². Sibutramine, orlistat, and metformin groups all showed significantly reduced BMI with treatment (13.57% , 9.06% , and 9.90% , respectively) and the magnitude of weight loss was significantly greater in the sibutramine group compared with the two other groups (p < 0.001). In contrast, Derosa et al. (48) in a randomized trial with hypertensive patients reported similar weight loss for sibutramine (10 mg/d) and orlistat (120 mg TID) at both 24 weeks (5.4 1.9, 5.5 2.1 kg) and 12 months (8.3 3.2, 8.4 3.6 kg) (45). In a second randomized trial with obese type 2 diabetic patients, Derosa et al. (53) reported similar BMI changes for sibutramine (n = 70) and orlistat (n = 71) at 12 months (33.1 1.4 to >29.5 0.5 vs. 33.6 1.3 to >29.7 0.6 kg/m²; p = not significant).

Our findings and those of these other head-to-head comparison studies suggest the overall weight loss efficacy of the two drugs is similar, with a small numerical advantage for sibutramine.

However, the two drugs were not equally well tolerated. In our study, dry mouth and constipation were the two most frequently reported adverse events with sibutramine and retention of patients in the two sibutramine groups was similar to the placebo group. In contrast, gastrointestinal adverse events were pervasive and most likely accounted for the relatively high early dropout rate in both orlistat groups. Blood pressure, as expected, declined modestly (1 to 2 mm Hg) with orlistat treatment and increased to about the same extent in the sibutramine-treated patients. These findings are consistent with earlier reports of both drugs (7, 8, 9, 10, 11).

In summary, our study demonstrated that the co-administration of a selective NPY5R antagonist with either of two conventional weight loss therapies, orlistat or sibutramine, was well tolerated but did not result in a statistically significant increase in weight loss beyond what was observed with orlistat or sibutramine alone. Our explanations for the lack of additive effect of MK-0557 co-administered with orlistat or sibutramine compared with either orlistat or sibutramine alone are somewhat conjectural. Plausible explanations are that our study lacked adequate power to detect a small weight loss effect of MK-0557 alone or that there was an overriding 5-HT effect in the case of MK-0557 plus sibutramine. The latter hypothesis introduces a topic that no doubt will become part of commonplace discussions as additional therapeutic agents become available for the treatment of obesity. That is, as more co-administration trials are undertaken in the future, discussions about which agents are likely to act additively or synergistically will become essential. Whether preliminary studies in rodents or short term (24-hour) food intake studies in humans will provide adequate guidance on this issue remains to be determined.

Notes

¹ Nonstandard abbreviations: NPY, neuropeptide Y; NPY1R, NPY Y1 receptor; NPY5R, NPY Y5 receptor; LS, least squares; TID, three times a day; q.d., every day; CI, confidence interval; APT, all-patients-treated; LOCF, last observation carried forward; ANCOVA, analysis of covariance; 5-HT, 5-hydroxytryptamine.

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Acknowledgments

The authors thank Sylvianne Roberge and Sheng Zhang for their statistical programming support of this study. This study was supported by Merck & Co.