Weighing up anti-obesity medications

To achieve weight loss, the most important and valuable treatment is the development of a healthy diet and exercise regime and helping your patient to maintain these lifestyle changes. That said, many patients will benefit from the help of pharmacological anti-obesity agents in order to lose the initial weight.1 Studies have repeatedly reported that the weight loss associated with lifestyle changes combined with pharmacotherapy is greater than weight loss from lifestyle changes alone.2

Treatment with weight loss medication has been shown to exert its most predominant effects on initial and short-term weight loss, yet there is a high prevalence of weight regain once the medication has been discontinued.³ Weight regain is a highly undesirable outcome as it can have serious and devastating psychological adverse effects associated with failure, leading to depression.⁴ Therefore it is very important that patients are made aware of the likelihood of weight regain and reminded not to be discouraged in the event of relapse.⁵

Obesity is an increasing epidemic in Western societies. In 2005, 18% of Australian adults were obese (about 3.1 million people) compared to 13% in 1995.^6,7 It is estimated that this obesity epidemic is costing Australia approximately $1,721 million per year.⁶ The main aims in the treatment of obesity are to lose weight, maintain weight loss and prevent any further weight gain,² focusing especially on reducing cardiovascular and metabolic risk.¹ Weight loss and maintenance can be defined as a 10% reduction of weight loss maintained for one year, or a 5% weight reduction maintained for 2 years.⁴ It is reported that only a small percentage of overweight people are successful in losing weight and keeping it off long term.³

The Australian Department of Health and Ageing recommends prescribing weight loss drugs to patients who have a BMI greater than 30 kg/m² and have not adequately responded to an appropriate weight reducing lifestyle regimen alone.⁸ If a patient presents with lifestyle risk factors, the acceptable BMI for weight loss medication use is lowered to 27 kg/m², which is in the pre-obese range.^8-9

Exercise and diet are the first-line treatment for obesity. Failing this, pharmacological agents can be used to aid weight loss, in conjunction with a reduced calorie intake (500–1000 kcal/day deficit) and a daily exercise regime (at least 30 minutes per day).² The drugs are not "wonder pills" that will make the weight disappear and under no circumstance should they be prescribed as stand alone treatment.²

In order to determine whether a patient is responding optimally to a drug, an evaluation of the patient’s weight loss and adherence to lifestyle modifications should be conducted within six weeks to three months of starting therapy.¹ Often the success of the therapy can be determined by the initial response to the drug, with greater initial weight loss predicting better overall weight loss and maintenance.⁴ If patients have not lost at least 1.5 kg in the first six weeks, or 5% of their body weight within six months, pharmacotherapy with that particular agent should be reconsidered.¹

Drugs that decrease food intake do so centrally. Activating noradrenergic, serotonergic and dopaminergic receptors in the hypothalamus will induce appetite suppression and early satiety.⁹  

Professor Joseph Proietto of the Endocrine Specialist Centre in Heidelberg, Victoria, said 

"Appetite suppressants in theory should all be good for weight maintenance. An obese individual has gone to a lot of trouble to lose a lot of weight. He’s then faced with being hungry and being surrounded by food. That’s why nearly everybody gains weight. That’s why we have to tackle the hunger. Anything that suppresses the drive to eat could be useful for weight maintenance."

Phentermine (Duromine) is a sympathomimetic agent available for weight loss in obese patients (BMI≥30) or overweight patients at an increased risk of morbidity (BMI 25–29.9).¹² The longest phentermine trial, conducted in 1968, resulted in an average weight reduction of 12.6 kg over a period of 36 weeks for both continuous and intermittent use (weight loss in the placebo group was 4.8 kg). Participants also adhered to a calorie-controlled, low-carbohydrate diet regimen (1000 kcal/day).^2,11

Phentermine increases activity in both the dopaminergic and noradrenergic nervous systems.¹² Although increased dopamine activity is commonly associated with drug abuse and dependence, no reports of addiction or tolerance have been found with the drug.^3,13

Patients taking phentermine continuously or intermittently must be encouraged to have regular medical monitoring and a full medical review after three months.¹² Phentermine’s effects last approximately 12–14 hours,² so should be taken once daily with breakfast.¹² Phentermine is metabolised by the liver.¹² The recommended dose is between 15 and 40 mg, titrated depending on patient response to the drug and adverse effect profile.^2,12

Dr Proietto said "phentermine works fairly quickly, and the side effects appear fairly early on."

Diethylpropion (Tenuate), like phentermine, is recommended as a short-term adjunct to lifestyle changes, as part of a holistic weight loss program. Average weight loss when using diethylpropion is around 3 kg more than placebo. However, some studies have not shown significant weight loss with this drug.⁸

Sibutramine (Reductil) is a serotonin and noradrenaline reuptake inhibitor (SNRI).¹ Its weight loss effects are attributed to increased satiety and decreased appetite.^2,8 On average, sibutramine treatment with diet and exercise will result in a 4.5 kg greater weight loss than diet and exercise alone;³ weight loss over one to two years can total anywhere between 5 and 17 kg (mean = 10.8 kg) when combined with lifestyle modifications.⁸ Sibutramine is approved for extended use; the patient may continue to take the drug as long as the weight loss exceeds 5% of the total body mass, or if the comorbid risk factors are responding positively to the treatment.⁹ However, the safety of prolonged use (more than 2 years) has not been demonstrated.⁸

The second major mechanism of pharmacologically treating obesity is increasing the metabolism of food; this is achieved through the use of pancreatic and gastric lipase inhibitors.

Orlistat (Xenical) is a potent medication in this class.⁸ Orlistat prevents the absorption of approximately 30% of fat from diets in which 30% of the energy is supplied by fat.⁹ After one or two years, the average weight loss with a combination of orlistat and lifestyle changes is approximately 8.5 kg.¹ Patients have reported an improved quality of life while on orlistat treatment despite the presence of gastro disturbances.⁹ Orlistat is available in Australia as an over-the-counter medicine from pharmacies.¹

Comparing the drugs

Each drug has its own constellation of side effects which need to be taken into consideration for each patient.

The results of a recent meta-analysis indicated a weighted mean difference between sibutramine and orlistat of 2.2 kg in favour of sibutramine. The eight trials ranged between 3 and 12 months and averaged 7 months. Sibutramine was found to be significantly more effective in weight loss versus orlistat therapy. Trials comparing sibutramine and orlistat use as a combination therapy were more effective than orlistat alone but not sibutramine alone.¹⁴

Sibutramine use is associated with increased levels of HDL cholesterol, whereas orlistat slightly decreases HDL levels and has been shown to improve LDL cholesterol levels. Orlistat improves blood pressure, whereas sibutramine increases both blood pressure and heart rate.¹⁵

Neither phentermine nor sibutramine are recommended for patients with certain heart conditions and hypertension;^8,12 orlistat should be used with caution in patients with vitamin deficiencies and gastrointestinal problems.¹⁶

Phentermine is not as well studied as sibutramine or orlistat.¹⁷ Recently meta-analysis of weight loss medications concluded that further research is needed on the long term effects of all medications.¹⁷ Hence, patients need to be closely monitored if they will be using phentermine for over 3 months.

Professor Proietto said, "Phentermine is a very old drug. It’s been on the market for 40 years.

"It is effective, it has a few side effects, but we don’t know the long term safety."

Perhaps a major cost and side effect profile advantage of phentermine is that it can successfully be used intermittently. Theoretically, intermittent phentermine use could help with tolerability of the drug as well as the associated side effects. Continuous phentermine use over a 36 week period had no significant weight loss advantage over intermittent use, which uses half the amount of drug over the same period.¹¹

Recent research directions

Recent anti-obesity medication research involves investigating the characteristics and personalities that will respond best to which type of weight loss drug. Although the findings are preliminary and provide only tentative suggestions, certain personality and psychological traits were found to respond to particular drugs better than others.¹⁸

It has been proposed that people who are less able to control binge eating, or who eat in response to stress and emotions, are more likely to benefit from sibutramine’s appetite suppressant effects, whereas patients who are more able to restrain their eating with cognitive control are more likely to benefit from orlistat’s reduced fat absorption. Patients who show more organisation, self-discipline and deliberation are also more likely to benefit from orlistat, which requires strict adherence to a medication schedule.¹⁸

Dr Andrew Dean, Consultant Physician, said:

"Phentermine helps establish a break in the habit of over-eating. In doing so, it allows significant weight loss in the first week or two which can then encourage people to continue to eat healthily – it is particularly useful as part of a dietary and behaviour modification plan."  

All this said, regardless of personality correlates the ultimate factor determining the optimal pharmacological agent lies with the individual tolerance of the medications.¹⁷

References

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2. Schnee DM, Zaiken K, McCloskey WW. An update on the pharmacological treatment of obesity. Curr Med Res Opin. 2006; 22(8): 1463-74.  
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8. NHMRC. Clinical practice guidelines for the management of overweight and obesity in adults [online]. Commonwealth Government of Australia, Department of Health and Ageing. 12 November 2003 [cited 20 August 2008]. Available from URL: http://www.health.gov.au/ internet/ main/ publishing.nsf/ Content/ obesityguidelines-guidelines-adults.htm  
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14. Neovius M, Johansson K, Rössner S. Head-to-head studies evaluating efficacy of pharmaco-therapy for obesity: A systematic review and meta-analysis. Obes Rev. 2008; 9(5): 420-7.
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16. Faucher MA. How to lose weight and keep it off: What does the evidence show? Nurs Womens Health. 2007; 11(2): 170-9.
17. Li Z, Maglione M, Tu W, Mojica W, Arterburn D, Shugarman LR, et al. Meta-analysis: Pharmacologic treatment of obesity. Ann Intern Med. 2005; 142(7): 532-46.
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