Recent New Experience With Antiobesity Drugs

Centrally Active Drugs: Sibutramine

Sibutramine (Figure 31.1) is a centrally acting agent that dose-dependently inhibits serotonin and noradrenaline reuptake (49). Sibutramine's action in inhibiting the reuptake of serotonin enhances satiety and thus decreases energy intake (50). By inhibiting noradrenaline reuptake, sibutramine enhances sympathetic outflow, including to brown adipose tissue, leading to increased thermogenesis and thus increased energy expenditure.



Figure 31.1 Structure of sibutramine and orlistat, two recent drugs developed for the treatment of obesity

The sibutramine parent molecule is efficiently absorbed from the gastrointestinal tract and undergoes an extensive first-pass metabolism. Hepatic metabolism of the parent molecule by the cytoch-rome P450 enzyme system leads to the formation of two active metabolites, termed metabolite 1 and metabolite 2 (51). Metabolite 1 is a secondary amine and metabolite 2 is a primary amine. These two metabolites mediate the pharmacological activity of the sibutramine molecule. Further metabolism yields inactive glucoronidases, which are excreted in the urine. As metabolites 1 and 2 have half-lives of 14 h and 16 h, respectively, sibutramine can be given as a once-daily dose (51).

The pharmacological activity of sibutramine does not appear to be a result of increased serotonin release; this differentiates it from the actions of dex-fenfluramine, a predominantly serotonin-releasing compound, and dexamphetamine, which predominantly releases dopamine and noradrenaline. This might explain why sibutramine has not been associated with cardiac valve insufficiency. This was illustrated in a study of 210 obese patients with late-onset diabetes treated with sibutramine or placebo, in which the rate of valve problems was 2.3% in the sibutramine group and 2.6% in the placebo group (52). In in vitro studies as well as trials conducted in animals and humans, sibutramine and its metabolites also showed no significant potential for inducing dopamine release, unlike dexam-phetamine. This may account for the lack of abuse potential with sibutramine.

Given the role of the liver in sibutramine metab olism, administration of sibutramine to patients with severe hepatic disease is inadvisable, at least until further information becomes available. It would also seem wise to exercise caution regarding the use of sibutramine in conjunction with other drugs requiring the cytochrome P450 enzyme system (53).

Both pre- and postsynaptic ^-adrenoceptors in brain tissue appear to be rapidly downregulated by sibutramine. The effect of sibutramine on clonidine-induced hypoactivity and mydriasis was used in mice to measure the activity of the drug at, respectively, pre- and postsynaptic ^-adrenoceptors (54). Sibutramine significantly reduced these activities after 3 days (P < 0.01 vs. placebo) with a greater effect on post- than presynaptic ^-adrenoceptors (42 vs. 15% reduction after 14 days' sibutramine administration) (55). Daily administration of sibutramine (3mg/kg) reduced the total number of adrenoceptors in rat cortex by 23% after 3 days and by 38% after 10 days; this was exclusively via reduction of the ^-adrenoceptor subset (56). Data regarding the effects of sibutramine on food behaviour via a variety of a- and ^-adrenergic receptors seems conflicting. Studies of the hypophagic effects of sibutramine support an a-adrenergic and ^- adrenergic but not ^-adrenergic effect of the drug. There are few published primary data on the effects of sibutramine on ^-adrenoceptors (55,57).

Sibutramine has no effect on the binding affinity or number of dopamine (58,59) or dopamine D2 receptors (60) in rat striatal membranes. Sibut-ramine's weight-reducing efficacy is comparable with that of earlier appetite-suppressant norad-renergic and serotonergic compounds (55).

Most clinical trials in obese patients combined sibutramine administration with a reduction in calorie intake, an increase in daily physical activity and advice on eating behaviour (61,62). Indeed, the drug should be administered in conjunction with a reduced calorie intake. Most clinical trials investigating the effects of sibutramine followed a similar protocol: a 1- to 3-week single-blind placebo run-in period followed by a double-blind placebo-controlled treatment period. The single-blind run-in period observed the effects of diet and/or behavioural changes. The treatment phase lasted 8-52 weeks and was commonly followed by a second singleblind placebo period to assess weight change after drug discontinuation (55).

A report of a 24-week dose-ranging study, recent

Figure 31.2 Percentage of patients obtaining a weight loss of 10% or more of baseline weight in clinical trials after 1 year of treatment with dexfenfluramine (63), orlistat (64) and sibutramine (65). Adapted from Scheen and Lefebvre (13)

ly published, indicated that sibutramine administered once daily for 24 weeks in the weight loss phase of treatment for uncomplicated obesity produced dose-related weight loss and was well tolerated (36), leading to a mean weight loss of up to 9-10% from baseline weight. With 10 mg sibutramine, almost 60% of patients could obtain 5% weight loss and 17.2% reached the clinically important 10% weight loss (36) (see also Figure 31.2).

Long-term clinical trials indicate that sibutramine given for 6 months induces a significant dosage-dependent reduction in body weight, which for dosages ranging from 10 to 20mg/day was 3 to 5 kg greater than the loss of body weight with placebo.

Following a very low calorie diet, sibutramine-treated patients lost more weight than placebo-treated patients during the subsequent 12 months. A substantial tendency to regain weight was observed in the placebo group, compared with additional weight loss in the sibutramine group (66). This time-course of weight loss is similar to that observed in the 20 long-term weight-reduction studies reviewed by Goldstein and Potvin (67). Sibut-

ramine helped greater proportions of patients to maintain > 100%, > 50%, or 25% of weight loss following a very low calorie diet and was associated with decreases in waist circumference (66).

The STORM trial, a 2-year sibutramine trial of obesity reduction and maintenance, and presented at the most recent European Congress (68), assessed the usefulness of the drug in maintaining substantial weight loss in a randomized controlled doubleblind trial. Over 600 obese individuals were studied in eight European centres for a 6-month period of weight loss with sibutramine, combined with an individualized 600 kcal deficit programme based on measured basal metabolic rates. Seventy-seven per cent of patients with > 5% weight loss after 6 months were randomized 3:1 to sibutramine (10mg/day) and placebo groups to study weight maintenance over a further 18 months. Sibutramine was increased up to 20mg/day if weight regain occurred. Initially weight loss progressed to a total of — 11.3 kg after 6 months. After randomization the placebo group regained weight to — 4.7 + 7.2 kg at 2 years; the sibutramine group only showed slight weight regain to — 10.2 kg + 9.3 kg at 2 years (Fig

Figure 31.3 The Sibutramine Trial of Obesity Reduction and Maintenance (STORM) (68). Mean weight changes during the 6-month weight loss phase under open drug therapy and the 18-month double-blind placebo-controlled weight maintenance phase

ure 31.3). Marked and sustained falls occurred with sibutramine over the first 6 months in cardiovascular risk factors such as triglycerides, very low density lipoprotein (VLDL), insulin, C-peptide and uric acid. An important finding was the rise in high density lipoprotein (HDL) cholesterol in the second year with overall increases of 20.7% (sibutramine) and 11.7% (placebo). Adverse events were modest: only 20 (3%) patients were withdrawn with blood pressure problems (68).

Sibutramine is, in some preliminary studies at least, also able to stimulate thermogenesis (69) and to reduce significantly the amount of visceral fat (70). Energy expenditure was significantly increased during the 5-hour period after administration of sibutramine 30 mg compared with placebo in healthy volunteers (71). Energy expenditure, as measured by indirect calorimetry, was increased during the fasted and the fed states by 152 and 34% versus placebo, respectively. These sibutramine-in-duced increases were accompanied by increases in plasma catecholamines and glucose concentrations, heart rate and diastolic blood pressure. Resting energy expenditure was decreased from baseline values by about half as much with sibutramine 10mg as with placebo (by 5.3 vs. 9.4%; not statistically significantly different) in obese female patients (55,72). It is thought that this smaller decrease in resting energy expenditure may contribute to the long-term maintenance of weight seen with sibut-ramine (55).

As reported previously, sibutramine (10 mg), is associated with an increase in heart rate (3 to 6 beats/min) and systolic blood pressure (2mmHg). This effect of sibutramine is in keeping with its noradrenergic action. This effect seems to be attenuated the more (visceral) fat is lost. The most frequently reported adverse events included dry mouth, anorexia, constipation, insomnia, dizziness and nausea.

Pre-absorptive Nutrient Partitioning: Orlistat

Due to their high energy content and low potential for inducing satiety, high fat diets are very conducive to weight gain, particularly in individuals who are relatively inactive. Indeed, humans are much more likely to become obese through the excessive consumption of dietary fat than by excess consumption of carbohydrate (73). It is rational, therefore, to decrease the proportion of fat, as well as the total number of calories. By reducing fat absorption after ingestion, a continued calorie deficit may be maintained more easily over the long term than by dieting alone.

Orlistat, the first of a new class of agents specifically designed for the long-term management of obesity, is a chemically synthesized derivative of lipstatin (a natural product of Streptomyces toxyt-ricini). Orlistat is an inhibitor of gastric and pancreatic lipases, which are instrumental in the digestion and absorption of fat from the gastrointestinal tract. Inhibition of lipase activity has the effect of decreasing fat absorption by 30%, independent of the amount of fat intake, and increasing the excretion of triglycerides in the faeces (74,75).

In vitro studies showed that the concentration of orlistat required to produce 50% inhibition of lipases present in human duodenal juice was low (76). The actual pharmacodynamic interaction between lipase and orlistat is complex (77). The extent of enzyme inhibition by the drug is time and concentration dependent (76). Orlistat is highly lipophilic and distributes into the lipid phase of an aqueous/oil partition model. In vitro experiments suggest that inhibition of pancreatic lipase by orlistat is practically irreversible (76). The effects of orlis-tat on hydrolases other than lipases have been investigated in vitro. The drug had no effect on other enzymes such as phospholipase or amylase and a minimal effect on trypsin (16,76).

The systemic absorption of orlistat is minimal. After oral administration of a single dose of 360 mg 14C-labelled orlistat to healthy or obese volunteers, peak plasma radioactivity levels were reached approximately 6 to 8 hours after the dose (78,79). Plasma concentrations of intact orlistat were small, indicating negligible systemic absorption of the drug (79). Pooled data from five long-term (6 months to 2 years) clinical trials with orlistat 180 to 720mg/day in obese patients indicated that there was a dose-related increase in plasma concentrations of orlistat in several clinical studies. However, these plasma concentrations were generally below the level of assay detection (16).

No pharmacodynamic or pharmacokinetic interactions were observed with orlistat 360 mg/day and warfarin (80) or glyburide (81) in healthy volunteers or with pravastatin in patients with mild hyper-cholesterolaemia (82). No pharmacokinetic interactions were reported with orlistat and digoxin (83), nifedipine (84) or phenytoin (85). Orlistat did not interfere with oral contraceptive medication in healthy women (86). Orlistat had no clinically significant effects on the pharmacokinetics of captop-ril, nifedipine, atenolol or frusemide in healthy volunteers (85). Short-term treatment with orlistat had no effect on ethanol pharmacokinetics, nor did ethanol interfere with the ability of orlistat to inhibit dietary fat absorption in healthy male volunteers (16,87).

A number of short-term trials have revealed that orlistat promotes weight loss and improves hypercholesterolemia in obese patients. The weight-reducing effect of orlistat was initially shown in a short-term multiple dose study involving almost 200 healthy, obese subjects. Weight reduction was statistically significant in those subjects receiving orlistat 120 mg three times daily (tid) compared to those dieting alone (74,88). Initial studies on healthy volunteers have shown that the maximum amount of fat excreted in the faeces following doses of orlistat at 400 mg/day is approximately 32% of fat ingested. Orlistat (10-20 mg tid) has also been shown to improve the lipid profile of non-obese and obese patients with primary hyperlipidaemia.

A European dose-ranging study, conducted by our own research group, indicated that among 676 obese male and female subjects orlistat treatment resulted in a dose-dependent reduction in body weight, with orlistat 120 mg tid representing the optimal dosage regimen (89).

The efficacy of orlistat has meanwhile been evaluated in obese patients aged 18 to 78 years in seven randomized, double-blind, placebo-controlled multicentre US and European trials of 12 weeks to 2 years duration. Generally, patients were obese but otherwise healthy although one trial evaluated the efficacy of orlistat in obese patients with type 2 diabetes mellitus (90). Obesity was classified according to BMI; mean BMI values were 31 to 36 kg/m2. Patients were also prescribed a hypocaloric weight loss diet (500 to 800 kcal/day deficit) consisting of 30% of calories as fat, 50% as carbohydrate, 20% as protein, and a maximum of 300 mg per day of cholesterol (16).

In the 2-year randomized double-blind placebo-controlled trial with orlistat conducted recently by Sjostrom and colleagues, 38.8% of patients treated with orlistat lost > 10% of their initial body weight versus 17.7% in the placebo group (64) (Figure 31.4). This indicates that orlistat can be considered as a valuable adjunct to dietary therapy in patients on weight maintenance.

However, as emphasized by the authors, 'the use of orlistat beyond 2 years needs careful monitoring with respect to efficacy and adverse events' (64).

A comparable 2-year orlistat trial, conducted in 18 US research centres, confirmed the Sjostrom data: orlistat treatment in addition to dietary approaches promotes significant weight loss, decreases weight regain and improves some obesity-related disease risk factors. During the first year

Orlistat Body Weight Eucaloric

Figure 31.4 Mean percentage change in body weight in a 2-year trial with orlistat studying weight loss and prevention of weight regain in obese patients. In the first year patients were assigned double-blind to treatment with orlistat 120 mg tid or placebo together with a 600 kcal deficit diet. In the second year patients were reassigned to orlistat or placebo with a eucaloric diet. * Chi-square P < 0.05 (vs. placebo). Adapted from Sjostrom et al. (64)

Figure 31.4 Mean percentage change in body weight in a 2-year trial with orlistat studying weight loss and prevention of weight regain in obese patients. In the first year patients were assigned double-blind to treatment with orlistat 120 mg tid or placebo together with a 600 kcal deficit diet. In the second year patients were reassigned to orlistat or placebo with a eucaloric diet. * Chi-square P < 0.05 (vs. placebo). Adapted from Sjostrom et al. (64)

obesity treated subjects lost approximately 3 kg more weight than did placebo subjects (91). Also in subjects with type 2 diabetes, a beneficial effect of orlistat has been proven, despite the usually very limited successes with weight loss in diabetics (90). The results showed a weight loss superior in diabetics compared to placebo, improvement of metabolic control and a decrease in the concomitant ongoing anti-diabetic therapy (90).

The most reported adverse effects consisted of abdominal pain, liquid stools, faecal incontinence with oily stools, nausea, vomiting and flatulence, but these symptoms were in general mild and transient. There was also some trend towards a decrease in lipid-soluble vitamin levels, but only the decrease in vitamin E levels was statistically significant, while remaining within normal ranges.

growth hormone therapy have been shown to have positive effects on body fat and body fat distribution. Studies evaluating the effect of growth hormone replacement therapy in multiple pituitary hormone deficiencies (92,93) or isolated growth hormone deficiency (94,95) show that growth hormone is an important regulator of intra-abdominal fat mass. Recently two studies showed that growth hormone treatment reduces the size of total abdominal fat (95) subcutaneous fat (94), as well as intra-abdominal fat mass (94,95). Marin et al. (96) treated 23 middle-aged abdominally obese men with oral testosterone supplements for 8 months. Visceral fat mass, measured by computerised tomography, decreased significantly without a change in body mass, subcutaneous fat mass or lean body mass.

Post-absorptive Nutrient Partitioning: Testosterone and Growth Hormone

Another potential target for drug treatment is modulation of metabolic processes. Although not yet tested in large clinical trials, testosterone and


Long-term results of weight loss programmes are often disappointing. This was shown by the work of

Table 31.5 Long-lasting effects of drug therapy on weight: 1- and 2-year trials


Dose (mg/day)

Subjects (n) Drug / Placebo

Weight change (kg) Drug/Placebo

Weight change (%) Drug/Placebo


Dexfenflur amine

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