Dr John Wright

Gastroenterologist
MbChB MRCP(UK) PhD

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Obesity: A Modern Plague
Medical therapy

Dr John P Wright
Updated: 8 September 2005

Obesity is a worldwide phenomenon which is likened to a pandemic. This high incidence of obesity has serious health implications. In a very large survey of over a million subjects followed for 14 years it was concluded that “The risk of death from all causes (including), cardiovascular disease, cancer, or other diseases increases throughout the range of moderate and severe overweight for both men and women in all age groups.”(1).

Obesity is best quantified with the body mass index (BMI) which is defined as the weight in kilograms divided by height in meters squared. Overweight is defined as a BMI of 25 to 29.9 kg/m2 while obesity is a BMI > 30 kg/m2. Morbid obesity is a BMI = 40 kg/m2.

In the USA the prevalence of obesity was 30.5% in 1999-2000 compared with 22.9% in 1988 to 1994; P<.001). The number of overweight people also increased during this period from 55.9% to 64.5% of the population (P<.001). Morbid obesity also increased significantly in the population, from 2.9% to 4.7% (P =.002)(2).

Most of our population follows a sedentary lifestyle which is associated with a low calorie requirement. Our instincts, however, are based on tough prehistoric times which lead us to over consume food. Many obese subjects spend a lifetime trying to control what their genes are telling them to do, namely stock up for the lean times ahead which never materialize.

Behavior modification, diet, and exercise are the mainstays of treatment for obesity but the drive for a convenient medicinal approach without the need for calorie reduction is sought by many devotees of “the quick fix”.

Anti-obesity drugs, may be indicated for subjects who have had limited success with traditional calorie reduction or who are at high risk for the medical complications of obesity. They should not be given to subjects who have not shown compliance to the more traditional techniques. This is because the relapse rate after stopping medication in such subjects negates the gains made with the assistance of these drugs. These drugs should only be used as part of a program of diet and exercise in subjects with a BMI of greater than 30 kg/m2. Subjects at particularly high risk such as those with sleep apnoea may also warrant a trial of therapy. Anti-obesity drugs do not cure obesity. Subjects need to realize that once medication is stopped weight gain will again commence unless dietary and other measures are in place.

Achieving and maintaining weight loss is made difficult by the reduction in energy expenditure that is induced by weight loss. The converse also appears to be true that a gain in body weight induces increased energy consumption which limits the weight gain. These two effects probably account for the relative weight stability enjoyed equally by the fat and thin. A gain or loss of 10 percent of body weight was associated with an 8 kcal/kg increase or reduction in total energy expenditure in obese subjects(3).

The decision to initiate drug therapy in overweight subjects should be made only after a careful evaluation of risks and benefits. This evaluation should include determination of the body mass index (BMI), the distribution of fat based on the waist circumference or the waist-to-hip circumference ratio (WHR), and investigations for related conditions such as diabetes mellitus, dyslipidaemia, hypertension, and heart disease.

Before starting therapy the goal of the program needs to be quantified. The goal needs to be realistic both from the initial weight loss figure and the sustainable weight in the long term. Overoptimistic goals frustrate the dieter and lead to capitulation to the drives of the appetite. The hope to return to normal body weight is unrealistic. In obese patients a weight loss of more than 5 percent below baseline by three to six months which remains at this level would be considered effective. Weight loss of 10 to 15 percent is considered a good response and loss exceeding 15 percent is considered an excellent response. This degree of weight loss will have substantial benefits, including lowering blood pressure and serum lipid concentrations, increasing insulin sensitivity, and reducing hyperglycemia.

The medication available includes sympathomimetic agents, drugs that alter fat metabolism, experimental molecules that effect appetite and various herbal products.

Sympathomimetic drugs are commonly used for weight reduction. They stimulate the release of norepinephrine from synaptic granules. They reduce food intake either by suppressing appetite or by causing early satiety.

Ephedrine is such a drug with a prolonged duration of action that is used as a nasal vasoconstrictor. When used alone it is of limited effect but when combined with caffeine appears to have a greater effect than when used alone.(4). In South Africa Redupon® contains both ephedrine and caffeine but then also has phenolphthalein, a laxative with known toxicity. Nor-pseudoephedrine (Nobese No. 1® and many others), Phenylpropanolamine (Restaslim®), Phentermine (Duromine®) and diethyopropion (Tenuate Dospan® ) have similar sympathomimetic actions and are approved for use in weight reduction...

The side-effect profile of the noradrenergic sympathomimetic drugs is similar. They cause insomnia, dry mouth, asthenia, and constipation. They may increase the blood pressure and should be used with caution in subjects with known cardiovascular disease. The dangers attributable these drugs reduce their value in long term weight reduction programs.

Sibutramine (Reductil®) which has similar actions to the sympathomimetic agents causes early satiety and increases thermogenesis by blocking norepinephrine and serotonic reuptake. Studies have shown that a 10 or 15 mg dose will lead to a 7% weight loss compared to a 1.2% weight loss for those on placebo over a 24 weeks dosing period (5). Once therapy is stopped weight gain is inevitable unless there have been eating and lifestyle changes. The drug is metabolized by the cytochrome P450 enzyme system (isoenzyme CYP3A4) and may interfere with the metabolism of erythromycin and ketoconazole.

Drugs that alter fat metabolism are currently fashionable. Orlistat (Xenical®) alters fat metabolism by inhibiting pancreatic lipases. As a result, ingested fat is not completely hydrolyzed to its constituent fatty acids and glycerol, and fecal fat excretion is increased. Up to approximately 30 percent of ingested fat may not be digested which is then responsible for the unpleasant side effects of steatorrhoea. Orlistat does not alter the pharmacokinetics of digoxin, phenytoin, oral contraceptives, alcohol, atenolol or captopril. However, absorption of fat-soluble vitamins may be decreased by orlistat.(6) Patients on warfarin should have their INR’s checked.

In a double blind placebo controlled trial a combination of orlistat and a diet with a deficit of 600 kcal/day resulted in a 10.3KG loss as compared to a 6.1KG loss for the placebo group in the first year. During the second year calorie intake returned to normal and those on orlistat regained less than those on placebo. The use of Orlistat was also associated with an improvement in serum lipid composition.(7)

Orlistat is generally well-tolerated. Side effects related to fat malabsorption such as intestinal borborygmi, cramps, flatus, fecal incontinence, oily spotting,and flatus are common but tend to improve with time.

Molecules that effect food intake such as leptin have been studied. Leptin is an intriguing new agent that may still come to market. It is a protein hormone which is important to the homeostatic regulation of body weight. It is produced in adipose tissue. It has the physiological effect of decreasing food intake and causing weight loss. The decrease in weight was due mostly to loss of fat.(8) Whether the weight loss can be sustained is not clear. It has been suggested that leptin therapy prevents weight gain after significant weight loss, by preventing the weight loss-associated decrease in energy expenditure.(9)

Several herbal preparations are purported to cause weight loss. These include ephedra (ma huang) which has sympathomimetic effects but with a number of dangerous side effects. There are many preparations available in South Africa including Phedra-Cut®. Apple cider vinegar been given in capsules. Garcinia cambogia, a source of hydroxycitric acid, HCA, which failed to cause more weight loss than placebo in a controlled clinical trial.(10)

Guar gum preparations increase the viscosity of gastric contents, leading to a feeling of postprandial fullness. They are also purported to block absorption of sugar but this is unproven. The benefits of guar gum in weight loss remain to be proven.(11)

In a similar vein chitosan is being sold as a “fat trapper”. Studies have in fact been done on this agent which does indeed hold on to fat in milligram amounts. This is insignificant in a diet with grams of fat.

The list of herbal agents is almost endless but the reader is urged to visit www.quackwatch.com and www.weight.com/gimmick.html for more detailed critiques of the alternative wonder drugs.

It is clear from all the data available that the use of therapeutic drugs without serious calorie reduction does not contribute to long term weight reduction. In the end the truism “You are what you eat” prevails.

  1. Body-mass index and mortality in a prospective cohort of U.S. adults. Calle EE; Thun MJ; Petrelli JM; Rodriguez C; Heath CW Jr. N Engl J Med 1999;3411097-105.
  2. The spread of the obesity epidemic in the United States, 1991-1998. Mokdad AH; Serdula MK; Dietz WH; Bowman BA; Marks JS; Koplan JP JAMA 1999 Oct 27;282(16):1519-22.
  3. Changes in energy expenditure resulting from altered body weight. Leibel RL; Rosenbaum M; Hirsch J N Engl J Med 1995 Mar 9;332(10):621-8.
  4. The effect and safety of an ephedrine/caffeine compound compared to ephedrine, caffeine and placebo in obese subjects on an energy restricted diet. A double blind trial. Astrup A; Breum L; Toubro S; Hein P; Quaade F Int J Obes Relat Metab Disord 1992 Apr;16(4):269-77.
  5. Sibutramine produces dose-related weight loss. Bray GA; Blackburn GL; Ferguson JM; Greenway FL; Jain AK; Mendel CM; Mendels J; Ryan DH; Schwartz SL; Scheinbaum ML; Seaton TB Obes Res 1999 Mar;7(2):189-98.
  6. Mode of action of orlistat. Guerciolini R Int J Obes Relat Metab Disord 1997 Jun;21 Suppl 3:S12-23.
  7. Randomised placebo-controlled trial of orlistat for weight loss and prevention of weight regain in obese patients. European Multicentre Orlistat Study Group. Sjostrom L; Rissanen A; Andersen T; Boldrin M; Golay A; Koppeschaar HP; Krempf M Lancet 1998 Jul 18;352(9123):167-72.
  8. Recombinant leptin for weight loss in obese and lean adults: a randomized, controlled, dose-escalation trial. Heymsfield SB; Greenberg AS; Fujioka K; Dixon RM; Kushner R; Hunt T; Lubina JA; Patane J; Self B; Hunt P; McCamish M JAMA 1999;282: 1568-75.
  9. Low dose leptin administration reverses effects of sustained weight-reduction on energy expenditure and circulating concentrations of thyroid hormones. Rosenbaum M; Murphy EM; Heymsfield SB; Matthews DE; Leibel RL J Clin Endocrinol Metab 2002;87:2391-4.
  10. Garcinia cambogia (hydroxycitric acid) as a potential antiobesity agent: a randomized controlled trial. Heymsfield SB; Allison DB; Vasselli JR; Pietrobelli A; Greenfield D; Nunez C JAMA 1998;280:1596-600.
  11. Guar gum for body weight reduction: meta-analysis of randomized trials. Pittler MH; Ernst E Am J Med 2001;110:724-30.