SUPPLEMENTAL INFORMATION
Bupropion
Three long-term clinical trials have been conducted to evaluate the effectiveness of bupropion as a weight loss drug, two of which investigated the drug’s effect in depressed patients. For the studies investigating the drug’s use in depressed patients, one study of 422 obese adults (BMI = 30-44 kg/m2) not meeting criteria for major depression but with depressive symptoms (Beck Depression Inventory score 10-30) showed that those subjects who completed the study receiving bupropion-SR (300 mg/d) with a 500 kcal/d-deficit diet (n=109) lost an average of 5.8 kg (6.0 ± 0.5% body weight) vs. 2.8 kg (2.8 ± 0.5% body weight) for those on placebo (n=122) (p<0.001).1 The other clinical trial investigated the effect of bupropion-SR in patients with major depression, and enrolled 423 patients whose depression had responded to treatment with bupropion-SR. Subjects were separated into groups based on BMI, and those treated with bupropion-SR (300 mg/d) showed mean change-from-baseline weights as follows: BMI< 22, -0.1 kg; BMI 22-26, -0.6 kg; BMI ≥ 27, -1.4 kg; and BMI ≥ 30, -2.4 kg following 44 weeks of treatment.2
The trial of 327 non-depressed obese patients (BMI 30-44 kg/m2) participating in a lifestyle intervention program, including counseling on energy-restricted diets, meal replacements, and exercise, showed that subjects receiving bupropion-SR at doses of 300 mg/d and 400 mg/d displayed weight loss of 7.2% and 10.1% initial body weight, respectively, compared to 5.0% loss for placebo following 24 weeks of therapy. A loss of ≥5% of body weight was observed in 46%, 59%, and 83% of placebo-, bupropion-SR 300-, and bupropion-SR 400-treated subjects, respectively (p<0.0001 vs placebo), while a loss of ≥10% of body weight was observed in 20%, 33%, and 46% of placebo-, bupropion-SR 300-, and bupropion-SR 400-treated subjects (p=0.0008 vs placebo). Finally, subjects receiving bupropion-SR 300 or bupropion-SR 400 maintained weight loss of 7.5% and 8.6%, respectively, following 48 weeks of therapy.3
Bupropion was well-tolerated in these trials, but, as bupropion activates the noradrenergic system, there was an increase in dry mouth, with a non-significant increase in diarrhea and constipation.4 Cardiovascular effects, such as a rise in blood pressure and tachycardia are usually mild, and the risk of seizure, which was high with the original bupropion formulation, has been significantly reduced with the advent of bupropion-SR and bupropion-ER.
Fluoxetine & Sertraline
Both fluoxetine and sertraline are FDA-approved for the treatment of clinical depression. In a meta-analysis of 7 studies of fluoxetine treatment reporting weight loss outcomes at ≥6 months, 6 of the 7 studied reported significant weight loss in fluoxetine-treated patients at 6 months, with weight losses ranging from 0.9 kg to 9.1 kg, and 3 studies reported significant weight loss in fluoxetine-treated patients at 12 months, with weight losses ranging from 0.4 kg gained to 14.5 kg lost.4 Fluoxetine dosage for weight loss was 60 mg, which is 3-times higher than the dosage used for depression (20 mg). In another review of four RCTs investigating the utility of fluoxetine as a long-term anti-obesity therapeutic, fluoxetine-treated subjects lost an average of 2.6 kg and 0.6 kg more weight than placebo-treated patients, at 6 months and 12 months, respectively.5 Both reviews indicate that fluoxetine-treated patients, on average, lose weight during the first 6 months of treatment but experience weight regain thereafter, indicating that the drug loses its effectiveness on inducing weight loss following 6 months of therapy.
One study investigated the use of sertraline and relapse prevention training in maintaining weight loss following treatment by a very low-calorie diet. In this study a total of 53 women who had lost a mean of 22.9 ± 7.1 kg were assigned to a 54-week weight maintenance program and administered sertraline (200 mg/d) or placebo. Sertraline-treated subjects lost significantly more weight and showed greater reductions in hunger during the first 6 weeks of therapy, but women in both treatment groups steadily regained weight thereafter, and no significant differences in the degree of weight regain between setraline- and placebo-treated women remained by the end of the 54 week study.6 These data suggest that these drugs are not effective as long-term anti-obesity pharmacotherapeutics, as they lose their efficacy over the course of weeks to months. However, these drugs may be useful in treating obese patients suffering from depression or depressed individuals who are concerned about gaining weight from anti-depressant medication.
An analysis of adverse effects observed in RCTs investigating fluoxetine use in obesity reported that fluoxetine-treated patients experienced increased nervousness, sweating, and tremors (relative risk, 6.37), nausea and vomiting (relative risk, 2.68), fatigue, asthenia, hypersomnia, and somnolence (relative risk, 2.36), insomnia (relative risk, 2.06), and diarrhea (relative risk, 1.74) compared to placebo-treated patients.4 These same side effects have been associated with sertraline use.
Lorcaserin HCl
Lorcaserin has been shown to be a full agonist of the 5-HT2C receptor and to bind to the 5-HT2C receptor with 18- and 104-fold selectivity over 5-HT2A and 5-HT2B receptors, respectively. Further, it was shown to induce a reduction in food intake in rats, which was abolished by pre-treatment with the 5-HT2C, but not a 5-HT2A, antagonist, and to induce weight loss over a 4-week period, with weights returning to baseline following discontinuation of the drug.7 In a 12-week RCT enrolling 469 obese subjects (BMI = 30-45 kg/m2), individuals were administered placebo, lorcaserin (10 mg q.d.), lorcaserin (15 mg q.d.), or lorcaserin (10 mg b.i.d.) and were instructed to maintain their normal diet and exercise patterns. Weight losses of 0.3 kg, 1.8 kg, 2.6 kg, and 3.6 kg were observed for the placebo, 10 mg q.d., 15 mg q.d., and 10 mg b.i.d. groups, respectively (p < 0.001 for each group), and the percentage of patients completing the trial who lost ≥5% of their initial body weight was 2.3%, 12.8%, 19.5%, and 31.2% for the placebo, 10 mg q.d., 15 mg q.d., and 10 mg b.i.d. groups, respectively.8
The serotonergic drug fenfluramine was removed from the market due to incidences of heart valve disease with use of the drug. Since lorcaserin is a serotonergic drug, the effect of lorcaserin use on heart valve function was investigated. Echocardiograms showed no drug-related effects on cardiac valves or pulmonary arterial pressure. The only side effects which were reported more frequently in the lorcaserin-treated subjects were transient headache, nausea, and dizziness.8
Cetilistat
Cetlistat is a novel lipase inhibitor which is currently the furthest in the clinical development. In a 5-day trial of cetilistat treatment in 90 healthy volunteers, cetilistat was associated with a 3- to 7-fold increase in fecal fat with only 11% of subjects experiencing >1 episode of oily stool. Thus it had the potential to be more tolerable than orlistat. In a 12-week trial, patients were prescribed a hypocaloric diet (500 kcal deficit) for a 2-week run-in period and were then randomized to placebo or cetilistat (60, 120, or 240 mg t.i.d.) groups and treated for 12 weeks. Treatment with cetilistat was observed to reduce weight to similar extents in each cetilistat dosage groups (60 mg t.i.d. 3.3 kg, p<0.03; 120 mg t.i.d. 3.5 kg, p=0.02; 240 mg t.i.d. 4.1 kg, p<0.001). Total and LDL cholesterol were also reduced by 3-11% in all three dosage groups. Importantly, the frequency of withdrawal due to adverse events was similar between cetilistat-treated (5.3-7.6%) and placebo (7.6) groups.9
A recent trial compared efficacy and safety of cetilistat and orlistat relative to placebo in obese patients with type II diabetes, on metformin. Following a 2-week run-in, subjects were randomized to placebo, cetilistat (40, 80, or 120 mg t.i.d.), or orlistat (120 mg t.i.d.) for 12 weeks. The 80 mg and 120 mg cetilistat groups showed similar significant reductions in weight relative to placebo compared to the orlistat group (3.85 kg, p=0.01; 4.32 kg, p=0.0002; 3.78 kg, p=0.008, respectively). Further, significant reductions in waist circumference relative to placebo were observed in the cetilistat 80 and 120 mg groups (4.3 cm, p=0.033; 4.5 cm, p = 0.037 vs. 3.2 cm) and in the orlistat group (4.4 cm; p=0.019). Significant reductions in HbA1c levels were also observed in the cetilistat 80 mg and 120 mg as well as the orlistat group. Thus, cetilistat (80 mg or 120 mg t.i.d.) appeared to be similarly efficacious to orlistat (120 mg t.i.d.) in this study, but importantly, while the proportion of patients in the orlistat group reporting adverse events (93%) was similar to that in the cetilistat groups, the patients in the orlistat group reported more events (541 AEs vs. 428 AEs in the 120 mg cetilistat group, p=0.0148), with more being severe (55 vs. 31 in the 120 mg cetilistat group, p=0.0546).10
Diazoxide
In an 8-week RCT of diazoxide use in overweight and obese individuals, subjects were administered diazoxide (2 mg/kg/d, maximum 200 mg/d) or placebo, and it was observed that diazoxide-treated subjects decreased insulin and C-peptide responses to glucose but did not improve glycemic control or experience weight loss.11 However, another 8-week RCT of diazoxide (2 mg/kg/d, maximum 200 mg/d) therapy administered in combination with a low-calorie diet to obese, hyperinsulinemic adults reported more promising results, as subjects treated with diazoxide over 8 weeks experienced greater weight loss (9.5 ± 0.69% vs. 4.6 ± 0.61%, p < 0.001) and a greater decrease in body fat with no effect on glycemic control.12 A study investigating the effectiveness of high-dose diazoxide in combination with moderate calorie restriction (30% deficit) and increased physical activity to induce weight loss in obese, hyperinsulinemic men also reported positive results. Subjects were administered diazoxide (50 mg t.i.d.) and had their dosage increased by 50 mg per dose every 4 weeks, up to a maximum of 300 mg t.i.d. over a 6-month period. Subjects treated with diazoxide experienced an average weight loss of 9.4 kg (95% CI: 5.6–13.2 kg, p < 0.001), waist circumference reduction of 9.2 cm (95% CI: 5.3–12.9 cm, p < 0.001) and total body fat mass decrease of 23.3% (95% CI: 13.7–32.9%, p < 0.001). The degree of fat loss was inversely correlated to fasting insulin levels (r = −0.76, p < 0.002). Furthermore, diastolic blood pressure decreased by 10.9 mmHg (95% CI: 6.5–15.4 mmHg, p < 0.002) in the diazoxide-treated patients, presumably due to weight loss in combination with the ability of diazoxide to induce relaxation of vascular smooth muscle.13
L-796568 – β3AR Agonist
In 2000, a selective human β3-agonist, L-796568, was developed14 and in 2002 a single 1000mg dose was shown to significantly increase energy expenditure by ~8%. The drug also increased plasma levels of glycerol and free fatty acids, markers of lipolysis, in overweight human subjects during a 4-hr period.15 However, a clinical trial investigating the efficacy of chronic use of L-796568 revealed that overweight and obese non-diabetic men (BMI = 28-35 kg/m2) receiving the drug (350 mg/d) do not display any significant changes in body composition or 24-hour energy expenditure over a 28-day trial period.16 The cause for the ineffectiveness of β3-adrenreceptor activation to induce significant and sustained lipolysis in humans may be explained by studies revealing the differential expression of the receptor between rodent and human adipocytes. Human brown adipose tissue (BAT) expresses 3-fold lower β3-adrenoreceptors compared to rodent BAT and human white adipose tissue express minimal levels of β3-adrenoreceptors, determined by specific ligand-binding analyses.17 Furthermore, β3-adrenoreceptor activation has been observed to play a weak role in lipolysis of human subcutaneous adipose tissue, compared to β1- and β2-adrenoreceptor activation.18
11β-HSD1 Inhibtors
Pharmacologic inhibition of 11β-HSD1 in humans with the nonselective 11β-HSD inhibitor, carbenoxolone (100 mg every 8 hrs for 7 days), improved whole body insulin sensitivity in seven healthy male volunteers, measured by euglycemic hyperinsulinemic clamp studies.19 However, in a trial of lean and obese individuals, obese subjects were observed to have more rapid conversion of cortisone to cortisol in adipose tissue, and carbenoxolone treatment did not inhibit adipose 11β-HSD1 activity or improve insulin sensitivity.20
Sirtuin 1 Activators
In rodent studies, mice administered chow supplemented with RSV (400 mg/kg/d) for 15 weeks were protected from both diet-induced obesity and insulin resistance. These mice displayed increased endurance, enhanced mitrochondrial activity in brown adipose tissue and skeletal and enhanced aerobic capacity of skeletal muscle, which are all presumably effects due to increased PGC-1α activity.21 Moreover, mice started on a diet containing RSV (400-2400 mg/kg food) at 12 months of age exhibited improvements in aortic elasticity, motor coordination, bone mineral density, as well as reduced albuminuria, inflammation, apoptosis in vascular endothelium, and cataract formation. However, RSV-treated elderly mice did not exhibit increased survival.22
Beyond inducing SIRT1 activation, RSV has also been observed to activate both AMP-activated protein kinase (AMPK) and mitochondrial superoxide dismutase (MnSOD), among other effects.23 However, mice treated with SRT1720, a potent, selective synthetic activator of SIRT1, were observed to be resistant to diet-induced obesity and obesity and insulin resistance due to enhanced oxidative metabolism in skeletal muscle, liver, and brown adipose tissue, indicating the positive metabolic consequences of specific SIRT1 activation.24
Contrave (Bupropion + Naltrexone)
In one trial, 238 obese subjects randomized to 4 groups: placebo + placebo (P+P), BUP (300 mg) + placebo (BUP + P), NTX (50 mg) + placebo (NTX + P), and BUP (300 mg) + NTX (50 mg) (BUP + NTX) groups. Over the 24-week trial, the BUP+NTX exhibited sustained weight loss which did not plateau. The weight loss curve of the BUP+NTX diverged from the NAL+P (p<0.01) and P+P (p<0.001) curves at week 16 and diverged from the BUP+P curve by week 24 (p<0.05).25
In a subsequent 24-week trial, three doses of naltrexone (16, 32, and 48 mg) combined with bupropion 400 mg/day all produced significant weight loss (4.3, 5.4, and 5.4%, respectively vs. 0.8% for placebo).26 On this basis, four 56-week phase III trials investigating BUP+NTX (Contrave) combination therapy in producing weight loss in obese patients with and without type II diabetes were undertaken. The results of one trial of 793 obese patients receiving Contrave-32 [BUP (360 mg/d) + NTX (32 mg/d)] or placebo along with behavior modification intervention indicated that those subjects receiving Contrave-32 achieved 9.3% weight loss vs. 5.1% in the placebo group. Also, twice as many Contrave-32 subjects lost ≥10% of their baseline weight compared the placebo group (41.5 vs. 20.2%).26
In July 2009, the Contrave trial sponsor, Orexigen, announced the results of the three other trials. In one trial, obese patients receiving Contrave-32 along with a diet and exercise regimen experienced a mean weight loss of 8.1%, compared to only 1.8% in the placebo group. Another trial of 1,496 obese subjects yielded similar results with no significant difference in patients treated with Contrave-32 vs. Contrave-48 [BUP (360 mg/d) + NTX (48 mg/d)]. Finally, in a trial of 505 obese patients with type II diabetes, subjects treated with Contrave-32 along with a diet and exercise regimen experienced a mean weight loss of 5.9% vs. 2.2% in the placebo group.27
Empatic (Bupropion + Zonisamide)
A 12-week trial was undertaken comparing the effectiveness of zonisamide monotherapy to a combination of bupropion and zonisamide in reducing the weight of 18 obese women. All subjects were prescribed a hypocaloric diet (500 kcal deficit) and half the subjects were administered zonisamide (100 mg/d gradually increased to 400 mg/d) while the other half were administered a combination of zonisamide (same dosing) and bupropion (100 mg/d gradually increased to 200 mg/d). Following 12-weeks, the combination therapy group exhibited significantly greater weight loss (8.1 ± 1.4 kg (8.5%) vs. 3.0 ± 0.9 kg (3.3%) in the zonisamide group).28 This trial prompted further studies of bupropion-zonisamide combination therapy in combating obesity.
In a subsequent 24-week RCT, obese subjects receiving zonisamide (400 mg/d) + bupropion (300 mg/d) achieved more weight loss than zonisamide (400 mg), bupropion (300 mg), or placebo (-9.2, -6.6, -3.6, and -0.4%, respectively).29 A Phase IIb trial investigated the efficacy of different ratios of bupropion and zonisamide in the combination, and every different combination elicited significant more weight loss compared to placebo, with bupropion (360 mg) + zonisamide (360 mg) having the greatest efficacy (8.6% weight loss vs. 1.1% for placebo).26
Another Phase IIb trial investigated the efficacy of Empatic-360 (bupropion 360 mg/zonisamide 120 mg) and Empatic-120 (bupropion 360 mg/zonisamide 120 mg) vs. placebo. In this trial of 729 obese subjects, those receiving either Empatic-360 or Empatic-120 experienced significantly greater weight loss compared to the placebo group (9.9%, 7.7% vs. 1.7%, respectively (p<0.001)). There were also a significantly greater number of subjects losing ≥5% and ≥10% baseline weight in the Empatic-360 and Empatic-120 groups compared to the placebo group (82.6%, 59.3% vs. 18.9%, respectively (p<0.001) and 47.7%, 35.2% vs. 5.7%, respectively (p<0.001)). Thus, both drugs appear effective, with Empatic-360 having slightly greater efficacy. Adverse events were similar to those reported for each of the individual drugs, with headache, nausea, insomnia, anxiety and dry mouth being the most commonly reported adverse events.26
Qnexa (Topiramate + Phentermine)
In a 24-week RCT involving 200 obese patients, the efficacy of topiramate + phentermine (100 mg/15 mg) compared to topiramate (100 mg), phentermine (15 mg), and placebo revealed that combination treatment led to a mean weight loss of 11.4 kg, which is significantly greater than the mean weight losses observed with topiramate (6.6 kg), phentermine (5.3 kg), or placebo (2.2 kg)30. In a subsequent 28-week RCT, 756 obese patients were randomized to receive topiramate (92 mg or 46 mg), phentermine (15 mg or 7.5 mg), combination therapy (92 mg/15 mg or 46 mg/7.5 mg), or placebo. High-dose combination therapy was effective in achieving a mean weight loss of 9.2%, compared to high-dose topiramate (6.4%), high-dose topiramate (6.1%), and placebo (1.7%). Low-dose combination therapy was also effective in achieving a mean weight loss of 8.5%, compared to low-dose topiramate (5.1%), low-dose phentermine (5.5%), and placebo (1.7%).31
A 56-week RCT in which obese subjects with type II diabetes were randomized to either placebo or combination topiramate + phentermine therapy, reported that subjects receiving combination therapy achieved a mean weight loss of 9.4% compared to 2.7% in the placebo group. Furthermore, combination therapy led to a mean 1.6% decrease in HbA1c, compared to a 1.1% decrease in the placebo group.32
As reported by the sponsor, Vivus, Inc., in a 24-week trial 756 obese subjects were randomized to receive mid-dose Qnexa (46 mg topiramate/7.5 mg phentermine), full-dose Qnexa (92 mg topiramate/15 mg phentermine), topiramate (46 mg or 92 mg), phentermine (7.5 mg or 15 mg), or placebo groups. Subjects receiving mid-dose and full-dose Qnexa experienced mean weight losses of 8.5% and 9.2%, compared to 1.7% in the placebo group (p<0.0001). The proportion of subjects losing ≥5% their baseline weight for mid-dose and full-dose Qnexa was 62% and 66%, respectively, compared to 15% in the placebo group (p<0.0001). The proportion of subjects losing ≥10% their baseline weight for mid-dose and full-dose Qnexa was 39% and 41%, respectively, compared to 7% in the placebo group (p<0.0001).33
Two 1-year phase III trials of Qnexa therapy for the treatment of obesity were completed in 2009. In the first study, 1,267 morbidly obese (mean BMI = 42.1 kg/m2) were randomized to receive mid-dose Qnexa, full-dose Qnexa, or placebo along with a hypocaloric diet (500 kcal deficit) and advised to implement a lifestyle modification program. For those who completed the 52-week study, subjects receiving mid-dose and full-dose Qnexa experienced mean weight losses of 7.0% and 14.7%, respectively, compared to 2.5% in the placebo group (p<0.0001). In the second study, 2,487 overweight and obese patients with high blood pressure, high cholesterol, or type II diabetes were placed on the same regimen, and mid-dose and full-dose Qnexa subjects who completed the study experienced mean weight losses of 10.5% and 13.2%, respectively, compared to 2.4% in the placebo group (p<0.0001). Qnexa therapy was also associated with significant improvements in blood pressure, triglycerides, and HbA1c levels.34
ReferenceS
(1) Jain, A.K. et al. Bupropion SR vs. placebo for weight loss in obese patients with depressive symptoms. Obesity 10, 1049-56 (2002).
(2) Croft, H. et al. Effect on body weight of bupropion sustained-release in patients with major depression treated for 52 weeks. Clinical Therapeutics 24, 662-72 (2002).
(3) Anderson, J.W., Greenway, F.L., Fujioka, K., Gadde, K.M., McKenney, J. & O'Neil, P.M. Bupropion SR enhances weight loss: a 48-week double-blind, placebo-controlled trial. Obesity 10, 633-41 (2002).
(4) Li, Z. et al. Meta-analysis: Pharmacologic treatment of obesity. Annals of Internal Medicine 142, 532-46 (2005).
(5) Goldstein, D.J. et al. Efficacy and safety of long-term fluoxetine treatment of obesity--maximizing success. Obesity Research 3 Suppl 4, (1995).
(6) Wadden, T.A. et al. Sertraline and relapse prevention training following treatment by very-low-calorie diet: a controlled clinical trial. Obesity Research 3, 549-57 (1995).
(7) Thomsen, W.J. et al. Lorcaserin, a novel selective human 5-hydroxytryptamine2C agonist: In vitro and in vivo pharmacological characterization. Journal of Pharmacology and Experimental Therapeutics 325, 577-87 (2008).
(8) Smith, S.R., Prosser, W.A., Donahue, D.J., Morgan, M.E., Anderson, C.M. & Shanahan, W.R. Lorcaserin (APD356), a selective 5-HT 2C agonist, reduces body weight in obese men and women. Obesity 17, 494-503 (2009).
(9) Kopelman, P. et al. Cetilistat (ATL-962), a novel lipase inhibitor: A 12-week randomized, placebo-controlled study of weight reduction in obese patients. International Journal of Obesity 31, 494-9 (2007).
(10) Kopelman, P. et al. Weight loss, HbA 1c reduction, and tolerability of cetilistat in a randomized, placebo-controlled phase 2 trial in obese diabetics: Comparison with orlistat (xenical). Obesity 18, 108-15 (2010).
(11) Due, A. et al. No effect of inhibition of insulin secretion by diazoxide on weight loss in hyperinsulinaemic obese subjects during an 8-week weight-loss diet. Diabetes, Obesity and Metabolism 9, 566-74 (2007).
(12) Alemzadeh, R., Langley, G., Upchurch, L., Smith, P. & Slonim, A.E. Beneficial effect of diazoxide in obese hyperinsulinemic adults. J Clin Endocrinol Metab 83, 1911-5 (1998).
(13) Boekel, G.v., Loves, S., Sorge, A.v., Ruinemans-Koerts, J., Rijnders, T. & Boer, H.d. Weight loss in obese men by caloric restriction and high-dose diazoxide–mediated insulin suppression. Diabetes, Obesity and Metabolism 10, 1195-203 (2008).
(14) Mathvink, R.J. et al. Discovery of a potent, orally bioavailable β3 adrenergic receptor agonist, (R)-N-[4-[2-[[2-Hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]-4-[4-[4-(tri fluoromethyl)phenyl]thiazol-2-yl]benzenesulfonamide. Journal of Medicinal Chemistry 43, 3832-6 (2000).
(15) Van Baak, M.A. et al. Acute effect of L-796568, a novel β3-adrenergic receptor agonist, on energy expenditure in obese men. Clinical Pharmacology and Therapeutics 71, 272-9 (2002).
(16) Larsen, T.M. et al. Effect of a 28-d treatment with L-796568, a novel β3-adrenergic receptor agonist, on energy expenditure and body composition in obese men. American Journal of Clinical Nutrition 76, 780-8 (2002).
(17) Deng, C. et al. Respective degree of expression of β1-, β2- and β3-adrenoceptors in human brown and white adipose tissues. British Journal of Pharmacology 118, 929-34 (1996).
(18) Barbe, P., Millet, L., Galitzky, J., Lafontan, M. & Berlan, M. In situ assessment of the role of the β1-, β2- and β3-adrenoceptors in the control of lipolysis and nutritive blood flow in human subcutaneous adipose tissue. British Journal of Pharmacology 117, 907-13 (1996).
(19) Walker, B.R., Connacher, A.A., Lindsay, R.M., Webb, D.J. & Edwards, C.R.W. Carbenoxolone increases hepatic insulin sensitivity in man: A novel role for 11-oxosteroid reductase in enhancing glucocorticoid receptor activation. Journal of Clinical Endocrinology and Metabolism 80, 3155-9 (1995).
(20) Sandeep, T.C., Andrew, R., Homer, N.Z.M., Andrews, R.C., Smith, K. & Walker, B.R. Increased in vivo regeneration of cortisol in adipose tissue in human obesity and effects of the 11β-hydroxysteroid dehydrogenase type 1 Inhibitor carbenoxolone. Diabetes 54, 872-9 (2005).
(21) Lagouge, M. et al. Resveratrol improves mitochondrial function and protects against metabolic disease by activating SIRT1 and PGC-1[alpha]. Cell 127, 1109-22 (2006).
(22) Pearson, K.J. et al. Resveratrol Delays Age-Related Deterioration and Mimics Transcriptional Aspects of Dietary Restriction without Extending Life Span. Cell Metabolism 8, 157-68 (2008).
(23) Baur, J.A. et al. Resveratrol improves health and survival of mice on a high-calorie diet. Nature 444, 337-42 (2006).
(24) Feige, J.N. et al. Specific SIRT1 activation mimics low energy levels and protects against diet-induced metabolic disorders by enhancing fat oxidation. Cell Metabolism 8, 347-58 (2008).
(25) Greenway, F.L. et al. Rational design of a combination medication for the treatment of obesity. Obesity 17, 30-9 (2009).
(26) Gadde, K.M. & Allison, D.B. Combination therapy for obesity and metabolic disease. Current Opinion in Endocrinology, Diabetes and Obesity 16, 353-8 (2009).
(27) Contrave(R) obesity research phase 3 Program meets co-primary and key secondary endpoints; exceeds FDA efficacy benchmark for obesity treatments. Available from: http://ir.orexigen.com/phoenix.zhtml?c=207034&p=irol-newsArticle&ID=1308920&highlight.
(28) Gadde, K.M., Yonish, G.M., Foust, M.S. & Wagner Ii, H.R. Combination therapy of zonisamide and bupropion for weight reduction in obese women: A preliminary, randomized, open-label study. Journal of Clinical Psychiatry 68, 1226-9 (2007).
(29) Greenway, F., Anderson, J. & Atkinson, R. Bupropion and zonisamide for the treatment of obesity. Obes Res 14, (2006).
(30) Gadde, K.M., Yonish, G.M. & Foust, M.S. A 24-week randomized controlled trial of VI-0521, a combination weight loss therapy, in obese adults. Obesity 14, (2006).
(31) Aronne, L.J., Peterson, C. & Troupin, B. Weight loss with VI-0521 (phentermine/ controlled release topiramate) stops progression toward type 2 diabetes in obese nondiabetic subjects. Meeting Abstracts of the 69<sup>th</sup> Annual Meeting of the American Diabetes Association, June 5-9, 2009, New Orleans.
(32) Garvey, W.T., Troupin, B. & Tam, P. One-year treatment with VI-0521 in type 2 diabetes demonstrates continued glycaemic improvement and weight loss. Meeting Abstracts of the 69<sup>th</sup> Annual Meeting of the American Diabetes Association, June 5-9, 2009, New Orleans.
(33) Results from phase 3 EQUATE trial of Vivus' Qnexa highlighted at European Congress on Obesity. Available from: http://ir.vivus.com/releasedetail.cfm?ReleaseID=382339.
(34) VIVUS announces positive results from two phase 3 studies; obese patients on Qnexa achieve average weight loss up to 14.7% and significant improvements in co-morbidities. Available from: http://ir.vivus.com/releasedetail.cfm?ReleaseID=407933.
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