Lifestyle Diseases

















Pharmacotherapy of obesity
 

The WHO projects that by 2015, around 2.3 billion adults worldwide will be
overweight and more than 700 million will be obese. As of 2005 the WHO
estimated that at least 20 million children under the age of 5 years were overweight
globally. And although lifestyle changes including healthy diet and increased physical
activity are considered the key to fighting obesity, compliance to these lifestyle
changes is generally quite low. Sandeep Saluja, MD, looks at pharmacotherapy as an
alternative treatment for obesity.

One does not need the help of statistics to understand the magnitude of the problem of obesity. A visit to the market place is enough! We are also well conversant with the associated health risks which extend far beyond the field of cardiovascular medicine such as cancers, arthritis and depression.

The Obesity Society has declared that obesity is a disease in its own right rather than just being a risk factor. Lifestyle management remains the cornerstone of therapy. Apart from exercise and caloric restriction, much research has been done on dietary composition. Both low carbohydrate and high protein diets have been shown to be helpful.

Although lifestyle management is the crux of therapy for obesity as well as diabetes, hypertension and dyslipidemia, most clinicians will attest to the limitations of this approach and point out that in the absence of potent drugs and their combinations it would be very difficult to manage these diseases.

However, in obesity management pharmaceutical treatment is still not widely used. The medical profession and the lay public are both scared of the experience of fenfluramine and phentermine. They are both anorectic agents (appetite suppressants). A 1990 study which combined phentermine and fenfluramine showed an association with Valvular Heart Disease. Fenfluramine was withdrawn from the United States market. Available drugs

Although current weight loss drugs result in only a small loss of weight, it has been shown that only a 5-10% reduction of initial body weight has a significant impact on associated comorbidities including diabetes and dyslipidemia(1).

The NIH (National Institute of Health, USA), suggests drug therapy for patients with a body mass index (BMI) greater than 30 if lifestyle changes fail for these patients over a six-month period or for individuals with a BMI greater than 27 if weight related co-morbidities are present. The WHO defines “overweight” as a BMI equal to or more than 25, and “obesity” as a BMI equal to or more than 30. (You can check your BMI online here: www.nhlbisupport.com/bmi)

Clinicians are generally happy that a 5-10% weight loss yields clinical benefits, however desperate patients are usually not satisfied and often look to surgical methods to reduce their weight. There are three options: gastric banding leads to a 20% weight loss over a two-year period; gastric bypass is associated with 30% loss; and biliopancreatic bypass with a 35% loss(2).

There is emerging evidence that suggests gastric bypass and gastric banding may reverse type 2 diabetes (See page 42). However surgery is not an ideal solution because of the scale of the problem – there are simply too many overweight and obese people to offer surgery as treatment for all.

Nonetheless, surgery for treating obesity has spurred interest in better under standing of the pathophysiological mechanisms of such interventions as well as new drug regimes. There is a better understanding of the key role gastrointestinal hormones play in weight loss.

Nature has an exquisite mechanism to maintain body weight despite wide variation in energy intake and expenditure. While weight gain or loss is a function of the interaction of various hormonal, environmental and genetic factors, it is now increasingly recognised that all of these converge on the neurohormonal gut brain axis(3). The hypothalamus especially the arcuate nucleus is the main centre controlling appetite integrating signals to co-ordinate feeding and energy expenditure. The hind brain especially area postrema and nucleus tractus solitarius are also the focus of current research(4). While short term regulation of appetite appears to be a function of neuronal pathways, long term control seems to be vested in hormonal stimuli released by the gastro-intestinal tract and adipose tissue(5). Research into these pathways has opened many exciting possibilities.

Drug options
1. Rimonabant
, is an anorectic, anti-obesity drug that targets the endocannabanoid system. It is an inverse agonist for the cannaboid receptor CB1. Its effect is to reduce appetite.

CB1 receptors influence various aspects of feeding behaviour and energy utilisation acting on the cortex, amygdala, nucleus accumbens and other areas of the limbic system as also the gastrointestinal tract, muscle, adipose tissue, liver, pituitary, thyroid, adrenals and testis(6). Thus, apart from weight loss, it has a favourable impact on the lipid profile (16.4% elevation in HDL cholesterol 6.9% fall in triglycerides)(7), fall in fasting insulin and elevation of adiponectin levels. Over half of the impact of rimonabant on lipids is not due to weight loss. It is thus said to be a drug for metabolic syndrome and cardiovascular risk reduction rather than just an antiobesity drug. The ongoing CRESCENDO trial is examining the effect on stroke, myocardial infarction and cardiovascular mortality. The STADIVARIUS trial is looking at the impact on atherogenesis. The RIO studies have shown a weight loss of 6.5 kg in a year with a major impact on visceral fat which correlates most with cardiovascular risk. An average reduction in waist circumference of 6.4 cm in a year was recorded(8).

Rimonabant is available in many markets.

Adverse effects

In clinical practice, many patients report adverse effects but only 13.8% patients on 20mg rimonabant discontinued due to adverse events vis-a vis 7.2% on placebo(9). Most adverse events generally occur in the first few months and are mild and transient. Common side effects include nausea, dizziness and diarrhea. Side effects of greatest concern are depression, anxiety(10).

2. Sibutramine is an appetite suppressant. It is a centrallyacting serotonin-norepinephrine reuptake inhibitor. Sibutramine has been clinically shown to significantly reduce caloric intake after 7 days of treatment(11). The starting dose is 10 mg/day and can be increased to 15 mg/day after a month.

Adverse affects
It has cardiostimulatory effects and can lead to increase in blood pressure and heart rate(12). All patients treated with sibutramine should have regular monitoring of blood pressure and pulse. Milder effects include nausea, vomiting, headache, sweating, constipation and insomnia. Occasional cases of panic attacks, mania in bipolar patients, psychosis, QT prolongation and arrhythmia have been reported(13).

Contraindications


It should not be used in patients on monoamine oxidase inhibitors (now seldom used), those with cardiovascular disease or stroke and pregnant and lactating women.

3) Orlistat works by preventing the absorption of fats from diet and thus reducing caloric intake. The drug does this by inhibiting pancreatic, gastric and carboxyl ester lipases & phospholipase A2. Without this enzyme, triglycerides from the diet are prevented from being hydrolyzed into absorbable free fatty acids and are excreted undigested. Only trace amounts of orlistat are absorbed systemically; the primary effect is local lipase inhibition within the GI tract after oral dose.

At the standard prescription dose of 120mg three times daily before meals, orlistat prevents approximately 30% of dietary fat from being absorbed(14).

Orlistat has been shown to reduce the development of type 2 diabetes by 37% during a 4 year study(15). And diabetic patients show an improvement in glycemic control(16).

Side effects


Side effects are limited to sequlae of malabsorption of dietary fat including diarrhea, oily spotting and evacuation, fecal urgency and flatus with discharge. These effects generally wane with time(17), though this may be due to greater compliance with a low-fat diet. It may lead to a deficiency of fat soluble vitamins and supplementation may be helpful(17).

Development

Some new anti-obesity drugs in the pipeline include:

1) Leptin. Rare individuals are leptin deficient and replacement can be curative. In most obese individuals leptin resistance exists and leptin may only help maintain weight loss. Leptin receptor agonists are being developed. Intranasal delivery may bypass a saturable transport system conferring resistance.

2) Atomexitine. It is a central norepinephrine uptake inhibitor used in the treatment of attention deficit hyperactivity disorder. Short term studies have shown about 5% weight loss

3) Ciliary neurotrophic factor. This is produced by glial cells and is being tried as an agent for neurodegenerative disorders. In trials it resulted in a 10-15% weight loss (18).

4) Betahistine is a centrally acting histamine H1 agonist with partial H3 antagonistic activity. It has been conventionally used as a vasodilator for Meniere’s disease, cluster headache and vascular dementia. Understanding the key role of histamine as a neurotransmitter in regulating feeding behaviour, it is being explored as an antiobesity agent.

Apart from the above, nonconventional approaches are being taken and some of them are already available in many international markets. They include:

1) Conjugated linoleic acid (CLA). Small but significant weight reduction of about 0.6kg/m2 in BMI associated with change in body composition (less adipose tissue) has been recorded when it is administered as a triglyceride. The effect is also dependent on isomers used.

2) Probiotics. Gut microbiota have been shown to influence nutrient acquisition and energy regulation and gut microbes have been shown to differ between obese and non-obese individuals. Further, bacterial lipopolysacharides may influence inflammatory responses in metabolic syndrome induced by a high fat diet. Animal studies have shown the potential beneficial effect of probiotics in reducing weight(19). This is worth further study considering the clinical safety of these products and their other health benefits.

Future options
Combination drug therapy is also expected to play an increasingly important role. Just as many patients with diabetes or hypertension receive more than one drug, the same may apply for obesity.

Going forward, current research points to a greater a application of pharmacogenetics – that is personalised medicine where pharmaceuticals are designed to treat disease according to an individual’s specific genetic makeup – ensuring greater efficacy and fewer side-effects.

Sandeep Saluja MD is a Senior Consultant at Apollo Hospital, Agra, India.


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ate of upload: 16th November 2008

                                  
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