Drug treatments for obesity

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This page was written by a group of 4 Final Year Physiology Undergraduates at The University of Edinburgh as part of an elective we worked on (September - December 2009) called 'Appetite and Obesity'. It is the culmination of 8-10 weeks of work and is based on our studies both inside and outside the course.

Introduction

Limited Efficacy

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Serotonin & Noradrenaline Related Drugs

By Bruce McLintock

Endocannabinoids

By Neil R. J. Watson

One method of pharmaceutically tackling obesity is to give cannabinoid receptor type 1 (CB1 receptor) antagonists such as rimonabant. Mice genetically engineered to be deficient in CB-1 receptors have been shown to be resistant to diet induced obesity [1] Numerous clinical trials have demonstrated weight loss in obese subjects, as well as improving the ratio of good (HDL) to bad (LDL) cholesterol. However, a major issue in using CB1 antagonists is the incidence of psychiatric problems, in particular, depression (unfortunately several suicides occured during trials [2]). As a result, the FDA has not approved the use of rimonabant in the United States. The European Medicines Agency (EMEA) has recommended the marketing authorisation of rimonabant be suspended across the EU, and consequently NICE has withdrawn its guidance for the use of the drug [3].

'The prevalence of obesity and associated metabolic/cardiovascular disease has reached epidemic proportions in industrialized and developing countries. Dietary and behavioural approaches are insufficient to maintain weight loss and to fight this trend. Therefore, effective and safe new pharmacological therapies are absolutely required to overcome this obesity burden. One promising new strategy is the blockade of the endocannabinoid system which is involved in the regulation of energy balance, food intake, and lipid/glucose metabolism.' [N1]

'Many different diets have been tried to treat obesity, and weight loss occurs with all of them. There is currently no evidence that clearly supports a superiority of one macronutrient composition for diets used for weight loss. The principal effect seems to be the degree of adherence to the prescribed calorie reduction. Lifestyle strategies to modify eating behavior can be used in individual counseling sessions or in groups, both of which are important in helping patients modify their patterns of eating. Physical activity is particularly important in helping patients maintain a weight loss once achieved and is less valuable for weight loss itself. Food intake is controlled through many different mechanisms, but only a few drugs have been developed that tap these mechanisms. Orlistat, which blocks intestinal lipase, is one; sibutramine, a serotoninnorepinephrine reuptake inhibitor, is a second. Surgical approaches provide the most dramatic weight loss and have been demonstrated to reduce long-term mortality and reduce the incidence of diabetes.' [N2

Lifestyle and Pharmacological Approaches to Weight Loss: Efficacy and Safety [N2]

'The European Medicines Agency (EMEA), the European Union (EU) body which is responsible for monitoring the safety of medicines, has recommended the suspension of the marketing authorisation for rimonabant (acomplia) from Sanofi-Aventis. The EMEA has concluded that the benefits of rimonabant no longer outweigh its risks and the marketing authorisation should be suspended across the EU. The EMEA has advised that patients who are currently taking rimonabant should consult their doctor or pharmacist at a convenient time to discuss their treatment. The EMEA has advised that there is no need for patients to stop treatment with rimonabant immediately, but patients who wish to stop can do so at any time.' [N3]

http://eurheartj.oxfordjournals.org/cgi/reprint/ehn255v1.pdf [N1] Lifestyle and Pharmacological Approaches to Weight Loss: Efficacy and Safety [N2] http://www.nice.org.uk/TA144 [N3]

Peripheral Drugs

By Rachael Kirkbride

[REMINDER TO SELF: NEED BIT MORE ON METHOD OF ACTION, AND OTHER PERIPHERAL DRUGS]

‘Peripherally acting anti-obesity drugs’ are another class of medication aimed at causing weight loss in overweight and obese individuals. These work by reducing the calorie intake from food, or altering the metabolism of it in the gastrointestinal system (gut). There is currently only one drug of this kind that is approved for use globally - Orlistat (Xenicol) - and it works by inhibiting the enzyme lipase that breaks down fat in the gut, meaning that the fat cannot be absorbed from food, and instead it is excreted out of the body.[R3]. Studies have shown that is can reduce the amount of fat absorbed from the gut by 30%, causing a decreased calorie intake and therefore weight loss. The weight loss from taking this medication is found to be between 5-10% on average.[R2][R6]. As well as weight loss, Orlistat has been shown to improve several other cardiovascular risk-factors. Low-density lipoproteins (LDL) and triglyceride levels were shown to be reduced by 10% more than expected for the weight loss, as well as blood pressure, waist circumference and lipids being reduced.[R2][R5]. Some research also suggests that Orlistat reduces fasting glucose and HbA1c levels in type 2 diabetics by more than predicted for the weight loss, with suggested methods including increased insulin sensitivity and glucagon-like peptide-1 secretion in the small intestine. Orlistat also helps to reduce the risk of type 2 diabetes in obese subjects by 37.3%. [R2].

However, this drug does not come without some side-effects. Oily-spotting, flatulence, abdominal cramps, faecal urgency/incontinence and liquid stools are the common adverse effects of Orlistat, due to an increase of fat in the gut and stools.[R3]. These side-effects are reported to only be experienced during the early stages, “but they subside as patients learn to use the drug”.[R4]. Orlistat also prevents some absorption of fat-soluble vitamins (A,E,D,K), and so patients are recommended to take supplements.[R3]. The drug does not have any systemic side-effects as it is contained in the gut, however it does affect the absorption of acyclovir, and they shouldn’t be used at the same time. [R4].

In 2001 the NHS National Institute for Health and Clinical Excellence (NICE) issued a press release on guidance for Orlistat use, and it states that it is cost effective to the NHS.[R8]. Studies have also shown that Orlistat is a cost-effective drug in obese adults.[R2].

Other Drug Therapies

Off Label Uses of Prescribed Medication

There are certain drugs, that are not primarily indicated for use as weight loss therapies; however they may be effective in this role. Below is a list of drugs and the evidence to support or disprove their usefulness as anti-obesity agents.

Anti-Diabetic Medication

Metformin & Acarbose

In patients with type II diabetes, there is evidence to support the use of metformin and acarbose as weight loss agents [M2]. The role of metformin in stabilising blood glucose levels has been shown to aid weight loss and also - perhaps by another mechanism - to reduce appetite [M3]. Acarbose is believed to simply slow nutrient digestion and interact with Glucagon-like Peptide-1 to aid a slight weight loss [M2].

In contrast to this, patients without type II diabetes will not benefit to the same extent [M1]. In The Diabetes Prevention Program, the weight loss achieved in a group of non-diabetic patients taking metformin was approximately half of that of a 'lifestyle modification' group. And the mean weight loss was only slightly higher than in the placebo group [M4]. Acarbose is of even less use in this context, neither helping with weight loss or with maintaining a healthy weight.

M1 - Reference: Review: Role of metformin for weight management in patients without type 2 diabetes. 2008. [Desilets A. R.]

M2 - Reference: Review: Is there a role for metformin or acarbose as a weight-loss agent in the absence of diabetes? 2003. [Siraj E. S.]

M3 - Reference: Article: Metformin decreases food consumption and induces weight loss in subjects with obesity with type II non-insulin-dependent diabetes. 1998. [Lee A.]

M4 - Reference: Article: Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin. 2002.[Diabetes Prevention Program Research Group]

Diuretics

Diuretics, cause an increase in fluid loss (e.g. by means of hypo-absorption in the nephron), and as such have no role in weight loss by reducing body fat stores. They are abused, however as means of a 'quick-fix' pseudo-weight loss, giving the impression of a reduction in body weight whilst in reality, they are simply causing dehyrdration. They have been used for some time in the sporting world, particularly boxing, for boxers to 'make the weight' or simply to reduce likelihood of other drugs being found by urine testing [M5]. The are also used by women suffering from pre-menstrual water retention [M6].

M5 - Reference: Review: Abuse of Drugs Associated with Eating Disorders. 1992. [Bulik C.]

M6 - Reference: Review: Enhancement of athletic performance with drugs. An overview. 1991. [Wagner J]

Thyroid Hormones

M4 - Reference: Review: Thyroid hormones in the pathogenesis and treatment of obesity [Krotkiewski M.]

M5 - Reference: Review: New Targets for Obesity Pharmacotherapy [Aronne L. J.]

Caffeine

M6 - Reference: Review: The safety and efficacy of pharmaceutical and herbal caffeine and ephedrine use as a weight loss agent [Greenway et Al.]

M7 - Reference: Review: Obesity and thermogenesis related to the consumption of caffeine, ephedrine, capsaicin, and green tea [Diepvens et Al.]

Amphetamines & Cocaine

M8 - Article: Paper: Hypothalamic CART is a new anorectic peptide regulated by leptin [Kristensen et Al.]

Ephedrine

M9 - Reference: Review: Obesity and thermogenesis related to the consumption of caffeine, ephedrine, capsaicin, and green tea [Diepvens et Al.]