Excessive accumulation of body fat
Obesity may be defined as a condition in which there is an excessive accumulation of body fat to state in which the health of the patient is compromised. It results from an imbalance between energy intake and energy expenditure. Various factors such as environmental and genetic factors can contribute to obesity. Environmental factors comprises of availability of high calorie diet or sedentary lifestyle, whereas genetic factors comprises of components such as family history of obesity.1
Obesity is associated with a large number of health problems, both independently and in association with other diseases such as type 2 diabetes, CHD. Besides that, it also causes an increased incidence of certain forms of cancer, obstructive sleep apnoea and osteoarthritis.2
The body mass index (BMI) gives a measure of relative weight and is commonly used for identifying individuals at increased risk of morbidity and mortality from obesity (Table 1). The anatomical distribution of body fat, with central (visceral) adiposity carrying a greater health risk than peripheral. For this reason, the measurement of the waist circumference in centimetres (Table 2) can be a useful method for identifying clinical risks associated with obesity.1
With an increased number of people being obese, the government's Foresight programme shows that over half of the UK adult population could be obese by 2050. Besides obesity's implication on health problem, its economical implications are also substantial. The NHS costs attributable to overweight and obesity are projected to double to £10 billion per year by 2050. The wider costs to society and business are estimated to reach £49.9 billion per year (at today's prices). 3
Owing to its increasing prevalence in both developing and developed countries, associated morbidity and mortality, and the enormous healthcare costs, obesity has become a major concern, therefore it has been a therapeutic and research goal for pharmaceutical companies to develop strategies to reduce the obesity epidemic as well as to develop safe and effective antiobesity drugs.
In this essay, we shall review the current state of antiobesity drugs and their safety concerns, as well as highlight new therapeutic targets and mechanisms by understanding the pathology / physiology of obesity.
Orlistat (Xenical®) has been licensed in the UK since September 1998 as an anti-obesity drug, and was approved by the Food and Drug Administration in April 1999. Orlistat inhibits gastric and pancreatic lipases as well as the hydrolysis of dietary triglycerides, resulting in limited absorption of monoglycerides and free fatty acids. The compound is a partly hydrated endogenous lipstatin produced by Streptomyces toxytricini. 6 It is normally indicated for patients with a BMI of = 30 kg/m2, or a BMI of = 28 kg/m2 in the presence of other risk factors, such as hypertension, diabetes or hyperlipidaemia.
Orlistat is contraindicated in patients with chronic malabsorption syndrome or cholestasis, in pregnancy or while breastfeeding as well as in patients with known hypersensitivity to orlistat.7
I. Efficacy in clinical trials
In a recent published Cochrane review on the long term effects of approved antiobesity medications in clinical trials of at least one year duration, 16 orlistat studies ( n = 10,631 ), patients were either given orlistat 60 mg, 120 mg and placebo.
Compared to placebo, orlistat reduced weight by 2.9 kg ( 95% confidence interval (Cl) 2.5 to 3.2 kg ) was achieved. Active drug therapy showed patients were more likely to achieve a 5% and 10% weight loss thresholds to that of placebo controlled weight losses which were much lower in diabetic patients.
Orlistat reduced diabetes incidence from 9.0% to 6.2% (hazard ratio 0.63, 95% CI 0.46 to 0.86) in the XENDOS trial as well as improved total cholesterol, LDL-cholesterol, blood pressure 1.5 mm Hg (95% CI 0.9 to 2.2 mm Hg; in 13 studies) and diastolic blood pressure reductions of 1.4 mm Hg (95% CI 0.7 to 2.0 mm Hg; in 12 studies)., and glycaemic control in patients.8
II. Adverse effects
Orlistat therapy was associated with gastrointestinal ( GI ) events which were the most common side effects. In this review, the categorization of the outcomes and detail of those who reported GI adverse side effects varied between trials. Over 80% of orlistat treated patients were reported to have experienced at least one GI side effect, absolute frequency that was 24% (95% CI 20% to 29%; 14 studies) higher than patients on placebo.
The most commonly reported GI events were fatty/oily stool, faecal urgency and oily spotting, which occurred at frequency rate of 15% to 30% in most studies. Approximately 5% of these patients discontinued therapy due to GI side effects, which was 2% ( 95% CI 1% to 3%; 12 studies) higher than patients taking placebo.8
Sibutramine (Reductil®) is a centrally acting inhibitor of noradrenaline, serotonin, and to a lesser degree, dopamine reuptake, which was originally developed as an antidepressant however instead of it improving mood, it led to weight loss.
It acts mainly as an appetite suppressant and it may also increase energy expenditure resulting in weight loss during chronic treatment which normally occurs during the first six months. However further treatment does not causes further weight loss but helps to maintain body weight. Due to moderate effect, the drug was approved by the FDA and introduced into the US market in 1997 and in the European Union in 1999.9
Sibutramine is indicated in patients with a BMI of 30 kg/m2 or more (and no associated co-morbidity), or in those with a BMI of 27 kg/m2 or more in the presence of other risk factors such as type-2 diabetes or hypercholesterolaemia. It is contraindicated in patients with uncontrolled hypertension, CHD, congestive heart failure or stroke. 7
I. Efficacy in clinical trials
In a recent published Cochrane review on the long term effects of approved antiobesity medications in clinical trials of at least one year duration, 10 sibutramine studies ( n = 2,623 ), patients were either given dose of sibutramine ranged between 10 to 20 mg, with the most common dose being 15 mg.
In terms of weight loss, patients on sibutramine therapy lost 4.2 kg (95% CI 3.6 to 4.7 kg; 8 studies) or 4.3% (95% CI 3.7% to 5.0%; 10 studies) more weight than those taking placebo.8
In patients with diabetes, sibutramine reduced weight by 5.0% (95% CI 3.8 to 6.2%; 3 studies) or 4.9 kg (95% CI 3.6 kg to 6.2 kg; 3 studies) compared to placebo therapy.10 Overall, changes in glycaemic parameters were inconsistent and were not significantly different from placebo in any study even in patients with diabetes when reported. Sibutramine was also found to increase HDL cholesterol levels by 0.04 mmol/L (95%CI 0.01 to 0.08 mmol/L; 5 studies) and reduce triglyceride levels by 0.18 mmol/L (95% CI 0.07 to 0.30 mmol/L; 4 studies) compared to placebo-treated patients.8
II. Adverse effects
Common side effects observed during sibutramine treatment are headache, dry mouth, constipation, and insomnia. It also causes a dose-related increase in blood pressure. The mean increase in blood pressure was found to be about 2mm Hg systolic and diastolic at the 15 mg dose. Although the effect is modest, it has been estimated that a 2mm Hg change in diastolic blood pressure can increase the risk of coronary heart disease by 6% and the risk of stroke by 15%.11
In the same Cochrane review as above, sibutramine was found to have increased systolic blood pressure by 1.7mmHg (95% CI 0.1 to 3.3 mm Hg; 7 studies), diastolic blood pressure by 2.4 mm Hg (95% CI 1.5 to 3.3 mm Hg; 7 studies) and pulse rate by 4.5 beats/min (95% CI 3.5 to 5.6 beats/min; 7 studies) compared to placebo. 8
Recently the European Medicines Agency ( EMA ) completed a review on sibutramine on a large clinical trial to see whether the cardiovascular risks of sibutramine outweigh its benefits. The SCOUT trial carried out was a randomised, double blind, placebo controlled study in which approximately 10,000 obese and overweight patients with cardiovascular disease and/or type 2 diabetes were treated for over 6 years. Results showed that patients had a 16% increased risk of cardiovascular adverse events such as myocardial infarction and stroke compared with placebo treated patients (hazard ratio 1·161 [95% CI 1·029-1·311]; p=0·016).
Furthermore, silbutramine decreased body weight by approximately 2 - 4 kg more than placebo which may not be maintained after stopping. Therefore this trial concluded that the benefit of sibutramine as a weight loss aid does not outweigh the cardiovascular risks causing sibutramine to be SUSPENDED from the market until further trials have been carried out.12
Although studies in this Cochrane review showed a positive treatment effect, morbidity and mortality endpoints is considered to be an important measure, as a favourable benefit/risk ratio of antiobesity drugs which cause weight loss may not improve outcomes for long term treatment of obesity.8
FUTURE PHARMACOLOGICAL TREATMENT AND MANAGEMENT
Current available antiobesity drugs are modestly effective, however they may be associated with unacceptable and life threatening adverse effects. As a result there is a growing need for pharmaceutical companies to find effective, safe and well tolerated antiobesity drugs. In this section we will look at the potential molecular targets for antiobesity drugs in various stages of the preclinical and clinical development.
As discussed above, obesity arises as a result of how the body regulates energy intake/absorption, energy expenditure and energy storage. The size of body fat stores hence is determined by the net balance between energy intake and expenditure over an extended period of time. The energy intake and energy expenditure can be used as an approach to develop new antiobesity drugs. (Table 3)13
Appetite or satiation are normally influenced by peripheral signal by direct effects on certain areas of the brain or by indirect effects via the vagus nerve, or both. The signals normally originate from the adipose tissue (adiposity signals) or the gastrointestinal tract (satiety signals). Leptin which is an adiposity signal is mainly responsible for the long-term regulation of energy balance whereas satiety signals are normally involved in the short-term regulation from gastrointestinal tract. The different signals are integrated in the hypothalamus and can also modulate each other's efficacy and sensitivity.14
Leptin being the most important adiposity signal acts on specific receptors in the hypothalamus and the hindbrain. In the hypothalamus, leptin receptor activation leads to the stimulation of neurons containing pro-opiomelanocortin and cocaine and amphetamine-regulated transcript as well as the inhibition of neurons producing neuropeptide Y (NPY) and Agouti-related protein.
The downstream pathways also plays an important role in the regulation of energy balance. Activation of hypothalamic melanocortin-4 receptors leads to appetite suppression. Amongst other gastrointestinal hormones, ghrelin, which is produced from the stomach, is the only appetite-stimulating peptide. Ghrelin acts directly on NPY neurons in the hypothalamus but also through the vagal afferents. Several intestinal peptides such as cholecystokinin (CCK), pancreatic polypeptide (PP) and glucagon-like peptide 1 (GLP-1) are known to increase satiation during and after a meal. 14 Besides that, peptide YY and oxyntomodulin are also thought to influence satiety by mainly acting on the hypothalamus.
POTENTIAL FUTURE THERAPY FOR OBESITY
1. Central targets/ hypothalamic Mediators.
Leptin is a hormone which is released from the adipocytes that conveys message of energy availability to the hypothalamus. Leptin deficiency leads to severe obesity. It acts by means of its receptor to activate a Janus kinase/ signal transduction and translation ( JAK/STAT ) system, which ultimately leads to the decreased expression of neuropeptide Y ( NPY ), a potent appetite stimulant, and increased expression of anorexigenic neuropeptides.15
Leptin generated a lot of intense interest as a potential therapy however no agonists of leptin receptors are currently in clinical development since it has shown disappointing results in certain trials carried out in obese patients which is thought to be caused by leptin resistance found in most of these patients.16
However, mechanisms involved in the development of leptin resistance could become potential target for future drug development.
II. Neuropeptide Y ( NPY )
After the failure of in obesity drug development, the pathways downstream of leptin e.g. NPY and melanocortins became a focus in the drug discovery. Decreased brain leptin/insulin activity may stimulate NPY/AgRP axis and conversely decrease POMC/CART axis, thus leading to an increase in feeding and decrease in energy expenditure therefore promoting weight gain.
However, further development of NPY antagonists decreased after several studies carried out in knockout mice. Studies showed neither the elimination of NPY nor that of its important receptor subtypes, NPY 1 or NPY 5, resulted in a lean phenotype.17 These observations concluded NPY antagonists as an ineffective therapeutic approach to obesity.
Studies and clinical trials showed that melanocortin system plays an important role in the regulation of energy balance. Interruption of melanocortin system in genetically modified mice either by eliminating the endogenous agonist a-MSH, by over expressing its endogenous antagonist AgRP, or by knocking out the MC-4 receptor, resulted in obesity.18 Mutation of the MC-4 receptor in humans led to the most frequent form of obesity which was accounted for up to 5% of all severe cases.19 Besides its effect in reduction of food intake, MC-4 receptor agonists also increased blood pressure and heart rate, and these effects cannot be separated from that of appetite reduction.20 Recent studies have shown that signalling pathways appear to diverge downstream of the MC-4 receptor, therefore these pathways could be attractive target for selective pharmacological effects.
2.Central targets/ Gut Hormones.
I. Peptide YY ( PYY )
PYY decreases food intake which is thought to act at NPY Y2 receptors in the brain. Unlike leptin, PYY levels are lower in obese patients ( i.e. no resistance ) hence could be an attractive target. PYY-36 which is release in response to a meal in the large intestine, is considered to be the main circulating form of PYY.21 This hormone cannot be administered orally because of its proteinaceousnature. Currently, Phase II trials have been carried out at Nastech to test its suitability for intranasal delivery, however its appetite-lowering efficacy in patients is still doubted.
Ghrelin is produced in the stomach, intestine, pituitary and possibly hypothalamus and may activate the growth hormone secretagogue receptor. Ghrelin secretion increased during 'starvation' increases food intake. Antagonists or inverse agonists of ghrelin receptors can be important targets to reduce the frequency of meals.22 Ghrelin antagonist GHS- R1a is currently in development and is orally available. Clinical trials are being carried out to show whether it causes weight loss.
III. GLP -1
GLP-1 is known to increase insulin secretion while decreasing glucagon secretion. It also delays gastric emptying and reduces food intake resulting in an improvement in diabetic patient's blood glucose levels. Thus GLP -1 analogue like exenatide is another useful agent for patients with obesity.
However GLP-1 is rapidly inactivated by the enzyme dipeptidyl peptidase IV ( DPP IV ) hence inhibitors of DPP IV like vildagliptin may be use in overweight patients, however the extent to which weight loss is achieved with DPP-IV remains unclear compared to GLP -1 injectable analogues. 23
3.Peripheral targets/ Energy Expenditure.
Increasing energy expenditure through physical activity or by decreasing energy intake is important in achieving weight reduction in obese patients. ?3 - Adrenergic agonists may increase heat production by increasing the expression of uncoupling protein 1 ( UCP 1 ) through effects on fat cell mitochondria and thus reducing body fat.24
Early clinical trials have suggested poor selectivity of ß3 receptor agonists hence stimulating other ß receptors including ß1 receptors in the heart resulting in increased heart rate. No drug so far has progressed beyond phase II trials, however studies are still being carried on to search for selective agents that can increase fatty acid oxidation in adipose tissue while avoiding cardiovascular side effects.24
With a high increasing number of clinical trials carried out, the limited compounds in the market shows that the search for antiobesity agent is very difficult. Currently most of the research concentrates on the development of drugs which reduce energy intake by targeting appetite suppression or decreasing intestinal lipid absorption. As the effort to increase energy expenditure does not seem to be effective, the next possible aim is to decrease energy storage by directly targeting adipose tissue. Currently, long term weight reduction can only be achieved by lifestyle changes as well as increase physical activity and dietary measures. Although it is very difficult for patients to maintain it, it is the best way in the long run as it reduces risk of morbidity and mortality from obesity related diseases. 25
If you are the original writer of this essay and no longer wish to have the essay published on the UK Essays website then please click on the link below to request removal:
More from UK Essays
- Free Essays Index - Return to the FREE Essays Index
- More Sciences Essays - More Free Sciences Essays (submitted by students)
- Sciences Essay Writing Service -find out more about how we can help you
- Example Sciences Essays - See examples of Sciences Essays (written by our in-house experts)
Need help with your essay?
We offer a bespoke essay writing service and can produce an essay to your exact requirements, written by one of our expert academic writing team. Simply click on the button below to order your essay, you will see an instant price based on your specific needs before the order is processed: