Pharmacotherapy

Key Points

• Orlistat, sibutramine, and rimonabant all promote weight loss and its maintenance over time.
• Lifestyle changes and drug interventions have an additional impact on weight loss.
• Rimonabant is the only drug that has been shown to improve the metabolic profile beyond that expected from weight loss alone, likely because it works directly on peripheral metabolic pathways.
• Rimonabant has been tested specifically in individuals at risk for CVD. Investigation of any weight reduction drug should include at-risk individuals, with special focus on intra-abdominal obesity and its response to treatment.
• Further study is required to determine the long-term benefits and side effects of pharmacotherapy and its impact on clinical cardiovascular endpoints relevant to obesity-related morbidity and mortality.

Foreword

Diet and physical activity are the cornerstones of weight loss therapy. Despite longstanding evidence from intervention studies that it is possible to lose weight through a standardized and well-supervised program featuring moderate caloric restriction and regular physical activity (1, 2), this approach calls for significant material and human resources as well as close patient supervision with regular follow-up (3). The literature is unequivocal in this regard: the more systematic and frequent the patient supervision, the greater the compliance with and efficacy of treatment (3). Though weight loss is possible as part of well-supervised clinical studies, this situation rarely applies to day-to-day clinical practice, where family physicians often work on their own and do not have access to a multidisciplinary team of health professionals such as dietitians and kinesiologists. This gap between our understanding of obesity’s etiology and treatment and the limited means of everyday clinical practice helps explain the rise of obesity and the medical community’s inability to treat obesity efficiently. This relative failure largely justifies the development of pharmacological means to treat obesity, not to meet aesthetic goals but to manage at-risk obesity. A wide array of pharmaceuticals products to manage the metabolic complications of intra-abdominal (visceral) obesity (hypertension, type 2 diabetes, dyslipidemia) has been available for a long time. However, drugs capable of treating the problem at its source (i.e., by reducing at-risk obesity through mobilization of intra-abdominal adipose tissue that causes such complications) have come to light only recently.

Patients must be properly selected for weight management medications, and health improvement should be the goal of therapy. It is generally accepted (4) that body mass index (BMI) should be 30 kg/m² or greater for pharmacological treatment of obesity to be considered. If there is a comorbid condition (hypertension, type 2 diabetes, hyperlipidemia), BMI should be 27 kg/m² or greater. Many experts recommend that the metabolic syndrome should also be included as a comorbid condition (5, 6). As an indication for pharmacotherapy, the metabolic syndrome diagnosis may be useful because the criteria identify individuals with levels of lipids, blood pressure, and fasting glucose that are somewhat lower than the traditional values used to identify risk for individual diseases, and because weight loss is likely to reduce overall risk for type 2 diabetes and cardiovascular disease (CVD) (7). The metabolic syndrome also includes waist circumference, an important criterion to consider (5, 7-10). However, because clinical diagnosis of the metabolic syndrome relies on variable criteria and because the underlying cause(s) of this condition is (are) poorly understood, it has been justifiably claimed that such a diagnosis cannot currently be considered an indication for pharmacotherapy (10). There is an obvious need for further research aimed at identifying individuals most likely to benefit from pharmacological treatment of obesity.

This section reviews the three major drugs currently approved by major supervising bodies for long-term treatment of obesity: orlistat, sibutramine, and rimonabant. The reader is referred elsewhere for review of additional drugs approved for short-term use or early-phase investigational agents (11-18).

Orlistat

Mechanism of Action
Approved in 1998, orlistat inhibits the activity of gastric and pancreatic lipases to reduce the digestion and absorption of dietary fat by approximately 30% (19). The inhibitor is a derivative of a natural lipstatin produced by Streptomyces toxytricini. Typically, the drug is taken (120 mg) three times a day with meals. Half-strength orlistat is currently being assessed by the American Food and Drug Administration (FDA) for over-the-counter use in the USA. Because of low systemic absorption and first-pass hepatic metabolism, the bioavailability of orlistat is very low (<1%). The drug therefore acts entirely within the digestive tract and is mostly excreted unchanged in feces (20).

Efficacy
A few studies lasting two or more years have examined the efficacy of orlistat. Pooled two-year data from four of these studies showed dose-dependent weight loss with orlistat (optimal dose: 120 mg, three times a day) (5, 7). When combined with a rather stringent lifestyle modification program, an average cumulative maximal weight loss (–9.5%) was attained at 6-9 months, followed by a slow regain in all experimental groups, including placebo. Weight loss after two years was approximately 7% below baseline in the 120 mg orlistat group.

In a longer-term, four-year double-blind placebo-controlled randomized study of 3,305 Swedish obese patients, orlistat reduced weight by an average of 2.7 kg over placebo (21) (Figure 1). The greatest reduction in body weight occurred during the first year and was –11% below baseline in the orlistat-treated group vs. –6% below baseline in the placebo-treated group. There was some weight regain over the remaining three years, with orlistat-treated patients ending up at –6.9% below baseline compared to –4.1% for those receiving placebo.

Figure 1: Effect of orlistat on body weight in a four-year randomized, placebo-controlled clinical trial

Figure 1: Effect of orlistat on body weight in a four-year randomized, placebo-controlled clinical trial

In a meta-analysis of 11 placebo-controlled, one-year trials involving a total of 6,021 overweight or obese patients, orlistat was found to reduce weight by 2.9% over placebo (13). There were 21% more orlistat-treated patients who achieved 5% placebo-subtracted weight loss and 12% more who reached 10% weight loss compared to placebo. Orlistat also significantly reduced systolic and diastolic blood pressure (1.6-1.8 mm Hg), LDL cholesterol (0.27 mmol/l), and fasting glucose in patients with diabetes (0.8 mmol/l). No clinically significant effect on triglycerides or HDL cholesterol was observed. Other meta-analyses of one- and two-year studies indicate that, compared to placebo treatment, orlistat causes an additional weight loss of some 3 kg within that time frame (5).

The most marked clinical improvement associated with orlistat-induced weight loss was a reduced incidence of type 2 diabetes relative to placebo, with a 37% reduction (9.0% vs. 6.2%) in the conversion of patients from impaired glucose tolerance to diabetes (22). Other studies on weight reduction also showed a greater improvement in glucose/insulin homeostasis with orlistat relative to placebo. All of the clinical studies with orlistat have found a small but significant decrease in serum cholesterol and LDL cholesterol that usually was modestly greater than that which could be accounted for by weight loss alone (23). This effect is likely because orlistat interferes with intestinal cholesterol absorption. In contrast, orlistat does not appear to have a significant impact on triglyceride or HDL cholesterol levels. However, most studies of orlistat have mainly been conducted in obese women at fairly low risk of CVD and not in intra-abdominally obese men with atherogenic dyslipidemia, who would be at much higher risk for CVD.

Weight maintenance with orlistat after diet-induced weight loss was evaluated in a one-year study of patients who had previously lost >8% of their body weight over six months by adhering to a calorie-restricted diet (24). After the one-year treatment with 120 mg orlistat three times per day, the placebo-treated patients had regained 56% of their body weight compared to 32% in the group treated with orlistat. Smaller doses of the drug did not prevent weight regain better than placebo.

Adverse Side Effects
The main adverse effects of orlistat are gastrointestinal. Fatty and oily stool, fecal urgency, and oily spotting occur in 15 to 30% of orlistat-treated patients (2 to 7% with placebo) (25). Fecal incontinence is observed in 7% of orlistat-treated patients vs. 1% in those receiving placebo (13, 25). These gastrointestinal symptoms are common initially but subside as patients learn to use the drug (23). To prevent possible deficiencies in fat-soluble vitamins, the absorption of which is also reduced by orlistat, prescription of a daily multivitamin is recommended. Because gut absorption of orlistat is minimal, there are virtually no systemic adverse effects. Past concerns regarding increased risk of breast cancer in orlistat-treated patients are no longer considered relevant (20).

Sibutramine

Figure 2: Effect of a six-month treatment with sibutramine on body weight

Figure 2: Effect of a six-month treatment with sibutramine on body weight

Mechanism of Action
Sibutramine was approved in the USA in 1997 and in the European Union in 1999. Originally developed as an antidepressant, sibutramine is a centrally acting, highly selective inhibitor for the reuptake at nerve endings of norepinephrine, serotonin, and, to a lesser degree, dopamine. It is a so-called “selective” serotonin norepinephrine reuptake inhibitor. This action increases satiety, thereby reducing food intake (26). In animals, sibutramine also stimulates thermogenesis, but data is conflicting in human beings. If sibutramine increases energy expenditure in humans, it is in the order of 100 kcal/day (27).

Sibutramine undergoes extensive hepatic first-pass metabolism to active primary (M1) and secondary (M2) amine metabolites, which are more potent than the parent compound (26). Most of the drug and its active metabolites are excreted by the kidney.

Efficacy
Sibutramine has been evaluated extensively in several multicentre trials. In a six-month dose-ranging study of 1,047 patients, 67% treated with sibutramine achieved a >5% weight loss from baseline, and 35% lost 10% or more. There was a clear dose–response effect, and patients regained weight when the drug was stopped, indicating that the drug remained effective while used (Figure 2). A number of other studies have reported that sibutramine can reduce weight by 3 to 6 kg more than placebo over a one- to two-year treatment period and that this effect is reproducible (5, 7, 28).

Figure 3: Effects of adding a lifestyle modification program to sibutramine therapy on body weight loss

Figure 3: Effects of adding a lifestyle modification program to sibutramine therapy on body weight loss

Other trials have assessed the ability of sibutramine to prevent regain of body weight. The two-year Sibutramine Trial of Obesity Reduction and Maintenance provided evidence that sibutramine had a positive effect on weight maintenance after weight loss (29). A selective subgroup of patients who had successfully lost more than 8 kg after six months of taking sibutramine 10 mg/day were randomly assigned to continue sibutramine or switch to placebo. In the 18 months that followed, the placebo-treated patients steadily regained weight, maintaining only 20% of their weight loss after two years. Sibutramine-treated subjects maintained 80% of their initial weight loss after two years.

A one-year trial tested the efficacy of intermittent vs. continuous therapy with sibutramine on weight loss (30). The patients randomized to sibutramine received either continuous treatment (15 mg/day) for one year or were subjected to two six-week periods of sibutramine withdrawal during the one-year treatment. A small weight regain was observed during the two placebo periods, and the weight was lost when the drug was resumed. At the end of the trial, both regimens had lost the same amount of weight.

Because sibutramine enhances satiety, a dietary program that takes advantage of this is likely to spur greater weight loss than the drug alone. This was shown to be the case in a one-year study in which obese adults received sibutramine alone, sibutramine plus regular visits to a physician, intensive group lifestyle modification counselling alone, or sibutramine plus intensive lifestyle modification counselling (31). Those in the sibutramine plus intensive lifestyle modification program lost the most weight, an average of 12.1 kg compared to 5.0 kg with sibutramine alone and around 7 kg with the comprehensive lifestyle modification program alone. This indicates that pharmacological and behavioural interventions have a strong additive effect (Figure 3). Interestingly, subjects who recorded their food intake more frequently lost more than twice as much weight as those who did not (18.1 vs. 7.7 kg). It would not be surprising to find that intensive counselling can improve the efficacy of any weight-reduction drug. Despite differences in the magnitude of weight loss among the four experimental groups (drug alone, drug plus regular visits to physician, intensive lifestyle modification program, and drug plus intensive lifestyle modification program), no difference was found in the response of metabolic and CVD risk variables across the four groups. This is most likely because the sample mainly included obese women who had a normal risk factor profile and were presumably at low risk of CVD.

In long-term studies, sibutramine per se (beyond its effect on weight loss) has not been found to have a significant impact on LDL cholesterol and glycemic control, whereas variable effects (no change to mild improvement) on blood triglycerides and HDL cholesterol have been reported (28). In contrast, a meta-analysis of studies in diabetic patients receiving sibutramine showed improvement in glucose, HbA1c, triglycerides, and HDL cholesterol (32).

Adverse Side Effects
Common side effects of sibutramine include insomnia, nausea, dry mouth, and constipation. A 10 mg/day single dose is recommended as a starting level, with titration up or down depending on response. Patients with a better initial weight loss are more likely to achieve greater loss in the long term (7). Sibutramine has been linked to increases in blood pressure and pulse rate (33). The drug is therefore not recommended for patients with uncontrolled hypertension, pre-existing CVD, or tachycardia (34, 35).

Rimonabant

Mechanism of Action
The ability of Cannabis sativa (marijuana) to stimulate appetite generated interest in the endogenous cannabinoid (or endocannabinoid) system as a target for weight-related disorders. The endocannabinoid system has two major receptors (CB1 and CB2) and two major endogenous ligands (anandamide and 2-arachidonoyl-glycerol (2-AG)) (36, 37). Endocannabinoids are polyunsaturated phospholipid-derived eicosanoids produced on demand from arachidonic acid that elicit many biological responses, including counteracting stressful stimuli such as food deprivation, aversive memories, and pain (37). The CB1 receptor is a G-protein coupled receptor that is extensively expressed in the central nervous system (CNS), including in areas involved in food intake (38). Endocannabinoids interact with several anorexic and orexigenic pathways within the CNS, increasing motivation to eat and stimulating food intake (38).

Rimonabant, the first CB1-receptor blocker, has been approved by the European Agency for the Evaluation of Medicinal Products (EMEA). As of August 2007, it is now approved for clinical use in 42 countries. Rimonabant is a potent, selective CB1 antagonist (39). The drug is metabolized in the liver and excreted in bile.

Rimonabant produces a dose-dependent reduction in food intake, body weight, and fat accretion in various rodent models (40-42). In addition, unlike other weight-reducing drugs, rimonabant improves the metabolic profile beyond what can be explained by weight loss alone, as suggested by pair feeding studies in rodents (43). This can be explained by the fact that the CB1 receptor can also be expressed outside the CNS in several peripheral tissues, including adipose tissue, liver, gut, and skeletal muscle (43, 44). Animal studies have suggested there are several peripheral mechanisms responsible for rimonabant’s food intake-independent benefits. These include enhanced thermogenesis via increased oxygen consumption in skeletal muscle (45), diminished hepatic (46) and adipocyte lipogenesis (43), promotion of vagally-mediated cholecystokinin-induced satiety (38, 47), inhibition of preadipocyte proliferation coupled with increased adipocyte maturation without lipid accumulation (48), and increased circulating adiponectin levels via enhanced adipose tissue expression (49). Modulation of adiponectin levels by rimonabant is of particular interest given the insulin-sensitizing properties of this adipokine (50), as is the drug’s anti-lipogenic effects, which can reduce both fat cell hypertrophy and hepatic steatosis. Most of the individual mechanisms by which rimonabant acts on peripheral metabolism (as suggested by animal studies) await confirmation in humans.

Figure 4: Effect of rimonabant on body weight over two years

Figure 4: Effect of rimonabant on body weight over two years

Overall, 29 to 39% of patients achieved 5% and 10% placebo-subtracted weight loss, and this percentage was 17 to 25% higher with rimonabant treatment than with placebo (49, 51, 52). In RIO-North America, rimonabant-treated patients given placebo during the second year of the trial regained weight, whereas those who continued to receive the 20 mg dose kept off the weight lost during the first year of therapy (52) (Figure 4). Compared to placebo, rimonabant again lowered waist circumference, reduced plasma triglycerides, and increased HDL cholesterol. These changes in metabolic parameters reduced metabolic syndrome prevalence in all four trials (e.g., in RIO-Europe: placebo –34%, rimonabant –65%) (49, 51, 52) (53). Rimonabant also increased LDL particle size (49). RIO-Lipids confirmed the increase in plasma adiponectin levels associated with rimonabant treatment previously reported in animal models (49). Indicators of inflammation (e.g., C-reactive protein (CRP)) also dropped in the 20 mg rimonabant groups vs. placebo (49, 53). Rimonabant significantly decreased (0.7%) placebo-subtracted HbA1c in RIO-Diabetes (53).

Table: Results of the Rimonabant In Obesity (RIO) program at 1 year

Table: Results of the Rimonabant In Obesity (RIO) program at 1 year

Efficacy
The Rimonabant In Obesity (RIO) program, which included four double-blind human trials, compared rimonabant 5 mg or 20 mg daily with placebo in more than 6,600 individuals. RIO-Europe (51), RIO-Lipids (49), RIO-North America (52), and RIO-Diabetes (53) have published first-year results, with RIO-North America including a second year in which rimonabant-treated patients were studied for an additional year with or without (placebo) rimonabant treatment. The lower dose was found not to be effective and only the higher dose (20 mg/day) is reviewed here. The RIO program enrolled patients with obesity (BMI > 30 kg/m²) or overweight (27 kg/m² < BMI < 30 kg/m²) and at least one CVD risk factor, such as dyslipidemia (high blood triglycerides or low HDL cholesterol), type 2 diabetes, or hypertension. Compared to placebo, rimonabant significantly lowered body weight by an average of 4.6 kg, reduced waist circumference (3.3 to 4.7 cm), and improved triglyceride (13 to 16%) and HDL cholesterol (7 to 9%) profiles (Table) (54).

In the context of treating CVD risk factors associated with intra-abdominal obesity, the RIO-Lipids study (49) is of special importance because, unlike most other weight-reducing drug studies, it specifically targeted subjects with atherogenic dyslipidemia and had several CVD risk factors and markers as major endpoints. For instance, the reduction in triglyceride levels, waist circumference, CRP levels, and blood pressure in hypertensive subjects; the increase in plasma adiponectin and HDL cholesterol levels; and the improved liver function (55) all suggest that CB1 antagonism could have a significant impact on the cluster of metabolic abnormalities of the metabolic syndrome by acting on its core cause. This is probably the most important consequence of targeting the endocannabinoid system. Multiple abnormalities can be addressed at once, and it is unnecessary to focus solely on a single marker (e.g., HDL cholesterol), a change to which does not always translate into clinical benefits when considered as an isolated target.

Rimonabant's beneficial metabolic effects (other than weight loss per se) are usually not seen with alternative pharmacological weight loss therapies and strongly suggest that at least some of its peripheral actions in rodent models also apply to humans. Several rimonabant studies examining clinical endpoints (myocardial infarction, stroke, cardiovascular death) and coronary atherosclerosis (by intravascular ultrasound) are currently underway. The largest of these (17,000 obese patients) is the Comprehensive Rimonabant Evaluation Study of Cardiovascular Endpoints and Outcomes (CRESCENDO) trial.

Adverse Side Effects
The most common adverse effects associated with rimonabant are nausea, dizziness, diarrhea, and insomnia, each occurring 1 to 9% more frequently than with placebo. Side effects leading to drug discontinuation occurred in 13 to 16% of patients taking the 20 mg dose (49, 51, 52). In RIO-Europe, RIO-North America, and RIO-Lipids, drug discontinuation due to psychiatric disorders (mainly depression) occurred in 6 to 7% of rimonabant-treated individuals or 2 to 5% over placebo (49, 51, 52). These figures are relatively modest but are derived from healthy volunteers. As with any centrally acting drug, the innocuity of rimonabant in patients with pre-existing mental dysfunction awaits further assessment.

Conclusions

Figure 5: The endocannabinoid system and cardiometabolic risk

Figure 5: The endocannabinoid system and cardiometabolic risk

As reviewed above, the studies on pharmacological treatment of obesity indicate that some drugs do promote body weight loss, possibly (and not surprisingly) even more so when used as a complement to lifestyle management. However, it is important to note that most studies have so far focused on weight loss alone and were conducted largely in women with relatively few metabolic abnormalities and at low risk of CVD. Given the well-established link between intra-abdominal obesity and CVD and type 2 diabetes risk, there is a definite need for more studies (RIO-Lipids being one example) that target at-risk individuals, men in particular.

Because of deeply entrenched prejudice regarding causality, physicians are understandably reluctant to treat obesity pharmacologically. But objective clinical reality and the environment in which many of us now live strongly suggest that willpower alone is not a viable solution and point to pharmacotherapy as a necessary complement to dietary and physical activity interventions.

Figure 6: The endocannabinoid system and CB1 mechanism of action

Figure 6: The endocannabinoid system and CB1 mechanism of action

Although the number of available tools remains limited, basic and clinical research has identified control systems that show great promise as targets for the successful treatment of at-risk obesity. Because of their additive effect on independent pathways, the systems that jointly improve central control of food intake and peripheral metabolic pathways associated with intra-abdominal adipose tissue metabolism are of particular interest. The endocannabinoid CB1 pathway is an example of such a system (Figures 5 and 6), and others are currently under intensive study.

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