The Minster Practice, Lichfield

Chapter 14

This chapter has built up over time and has not yet been checked for inconsistencies in the presentation of the evidence at the time of display.

Statistics

Obesity is defined as BMI >30kg/m². Between 1980 and 1995 in the UK, the percentage of individuals with BMI>30 grew from 8% to 15%. There is a mismatch between the genes of mankind and the modern environment but how to influence the situation is complicated[1]. BMI >30 is associated with IHD, hypertension, CVA, DM, osteoarthritis, obstructive sleep apnoea, and gallstones. 

Central obesity is an even more significant risk factor than BMI (see below). Weight gain after age 18-20 predicts increased risk with a gain over 10kg or 1kg/yr being high risk. A sedentary lifestyle increases mortality from all causes. 

BMI relative risk follows a curve similar in shape (though about half the value) to both hypertension and cholesterol. Hypertension increases renal failure, heart failure and stroke. Hypercholesterolaemia increases atherosclerosis and coronary and cerebrovascular occlusion. Overweight increases heart failure, diabetes, gallbladder disease and some cancers.

 The cost of diseases associated with overweight is about 3-7% of total health care costs[2] plus social security payments for incapacity and pensions. Intentional weight loss reduces risk factors other than obesity[3] as BP reduces, lipid patterns improve and risk of diabetes falls though no study has shown a reduction in mortality.

 Whilst treatments for obesity may work by producing weight loss, the condition is not “curable” [4] as weight is regained when treatment stops; analogous to treatment of hypertension and hyperlipidaemia. Though in the case of obesity, as weight loss on treatment is a modest 10-15%, there is a school of thought that suggests that just treating any resultant diseases like DM, hypertension and dyslipidaemia is more cost effective.

 But it is interesting to note GPs comments like “does the weight loss continue in the next 3 months on the drug?” as it suggests a different approach to say an oral hypoglycaemic i.e. should it be expected to reduce blood sugar over consecutive time periods? 

Diet

No single dietary factor has precedence in the development of CHD; the whole diet is important. A wide range of dietary factors are implicated in CHD via links with physiological factors which in turn are associated with the pathological events leading up to MI. [5]  The latest report on cardiovascular disease by the Committee on Medical Aspects of food policy (COMA, Nov 1994 [6] ) reassesses dietary research and advice.

Salt intake does have a direct effect on blood pressure and thereby a potential indirect effect on atherosclerosis. This is discussed in chapter 8 (Physical activity, diet, stress and relaxation). Salt substitutes should be used with care if there is renal impairment. But potassium intake is associated with a lower stroke risk in men[7]. Men in the top fifth of potassium intake (supplements as well as diet) were 38% less likely to have a CVA compared to those in the bottom fifth.

 The Dietary Approaches to Stop Hypertension (DASH) study[8] looked at diet in 459 adults with SBP<160 and DBP 80 to 95. A diet rich in fruits, vegetables and low fat dairy foods with reduced saturated and total fat reduced BP by 11.4/5.5 in those with initial BP>140/90 (p<0.001) and 3.5/2.1 in those without hypertension (p=0.003). 

For obesity to develop there must be a period of imbalance between energy consumed and the amount used up in daily life. There are two sides to this equation which is responsible for a doubling of clinical obesity in Britain in the last ten years. The subject was reviewed by Prentice & Jebb[9] and greed encouraged by a highly palatable, heavily advertised range of foods may be the less dominant factor. Low levels of physical activity were more significant in a study of Finns[10] than any features of the diet. Inactivity must be addressed in public health strategies aimed at reversing the increasing trends in obesity.

Body image is important. People who dislike their body the most are the least likely to achieve weight-loss success. Researchers at Stanford University School of Medicine looked at 177 men and women who were mildly to moderately overweight[11]. One group dieted; the other dieted and exercised. Those who did both were more successful. But the researchers also noticed that those who started out more satisfied with their body were more than twice as likely to succeed as their deeply dissatisfied counterparts (55 percent compared to 26 percent).

Unfortunately, reduction in weight is accompanied by compensatory changes in energy expenditure which work to return the weight to the usual weight. Other factors beside overeating and lack of exercise are involved. It is becoming increasingly apparent that the system for regulating fat stores and energy balance is very complex.[12]

 The adrenergic system plays a major role in the control of energy expenditure. Catecholamines mobilise lipids by stimulating lipolysis in fat cells and thermogenesis in brown adipose tissue and skeletal muscle. The b₃-adrenergic receptor is the principal mediator in catecholamine stimulated thermogenesis in brown adipose tissue which is scattered about the major vessels in the thorax and abdomen. Brown adipose tissue oxidises lipids to produce heat and rid the body of excess fat.

 White adipose tissue which includes subcutaneous and visceral adipose tissue is the more abundant. This stores fat which can be converted to free fatty acids for use by other tissues. The b₃-adrenergic receptor is also important in mediating the stimulation of this lipolysis by catecholamines.

 Low b₃-adrenergic receptor could promote obesity via both routes. The more important is reduced thermogenesis in brown adipose tissue, but slowing of lipolysis in white tissue could lead to retention of lipids in fat cells. As b₃-adrenergic receptor activity is more prominent in visceral adipose tissue, this could be important in contributing to truncal obesity which is the most dangerous form of regional fat accumulation as mentioned in the next section.

Besides b₃-adrenergic receptors, the function of b₂-adrenergic receptors are impaired in subcutaneous  adipose tissue of obese subjects with insulin resistance syndrome.[13]

 The discussion about antioxidant vitamins can be found in chapter 8 on diet. 

Overweight

There is a progressive risk of SCD with increased weight. The risk is more than doubled in those weighing 120% or more of their ideal weight compared with those weighing less than 110%[14]. 13% of men and 16% of women are obese (defined as BMI > 30).[15] Increased ventricular ectopy has been reported in cardiopathy of obesity.[16] Truncal obesity is more closely related to SCD[17]. Waist to hip ratio is an independent risk factor for CHD, NIDDM, and CVA.[18] The health effects of obesity vary according to race and sex.[19]

Weight gain since age 18 of >10kg is associated with higher mortality in women, [20] and the increase in mortality is evident at gains above 5kg.[21] BMI was less strongly associated with mortality in the Honolulu Heart Program (Japanese American men)[22]. The BMI in middle aged British men associated with the lowest all cause mortality was in the range 20 to 23.9[23]. Looking at BMI and mortality across various age groups of non-smokers, between ages 30 and 74 BMI correlated with both overall and cardiovascular mortality[24]. However, the *relative* risk for death conferred by BMI weakened with advancing age for both men and women. For example, for 30- to 44-year-old men, the RR for cardiovascular death increased by about 10 percent for every one-unit increment of BMI above 21. But for 65- to 74-year-old men, RR increased by only about 3 percent per unit increment of BMI. The absolute number of deaths associated with obesity was greater in the older group, since that group has a much higher baseline death rate. Above age 74, there was little correlation between BMI and mortality.

 Women with a high BMI at entry to the Nurses Health Study in 1976 benefited most from weight loss preventing onset of hypertension. Over 16 years of follow-up[25], 16,395 women of the original 82,743 aged 30 to 55 at entry were diagnosed with hypertension. Long-term (12 to 50 years) weight change since age 18 was a significant predictor of hypertension in multivariate analyses adjusted for age, body mass index at age 18, height, parity, family history of myocardial infarction, hormone use, menopause, and smoking. Compared with weight changes of 2 kg or less, the relative risks for hypertension were 0.85 for a loss of 5 to 9.9 kg, 0.74 for a loss of 10 or more kg, 1.29 for a gain of 2.1 to 4.9 kg, and 2.70 for a gain of 10 to 19.9 kg. Similar results were found for medium-term (2 to 14 years) weight changes occurring after age 30.

 Important factors contributing to obesity related hypertension include enhanced sympathetic nervous activity, insulin resistance and hyperinsulinaemia[26]. The sympathetic nervous system is involved in adaptive thermogenesis either in response to exposure to cold or to changes in dietary intake[27]. Insulin is the link between the sympathetic nervous system’s energy control and dietary energy intake. Increase in insulin stimulates the sympathetic nervous system to increase thermogenesis to restore energy balance but the heart blood vessels and kidneys are also stimulated[28]. Obesity related hypertension may therefore result from efforts to restore energy balance and stabilise body weight. Hyperinsulinaemia is common in hypertension. [29] [30] and it is a risk factor for CHD. [31] The finding of impaired insulin action in essential hypertension before treatment [32] has led to suggestions that insulin resistance is an underlying metabolic defect in essential hypertension. Not only would this contribute to the rise in BP but it would also account for the range of observed abnormalities in carbohydrate, lipid and lipoprotein metabolism prevalent in hypertensive subjects. [33] Patients with essential hypertension have significant peripheral insulin resistance but hepatic insulin sensitivity seems to largely preserved.[34] (also see below)

 Short term studies have shown that control of obesity will correct hypertension, hyperlipidaemia, and diabetes in some cases and lead to reduced requirement for drug therapy in others. A 5% reduction from initial body weight leads to improvement in cardiovascular risk factors and co-existing disorders[35]. However, there is no evidence that weight reduction reduces mortality. Indeed, those with fluctuating weight have a greater incidence of CHD than those with stable weight. [36] It is therefore much easier to justify prevention of further weight gain than weight loss.

 With a deficit of 500 - 1000 calories, loss of adipose tissue will be 1 - 2 pounds per week. As energy requirements are reduced by weight reduction, life long behavioural changes are required to reduce energy balance so that weight is maintained at the new level. Use of very low calorie diets may be useful in some patients but do not correct the underlying eating disorder. In any case they should be limited to 4 weeks duration.

As waist circumference relates closely to BMI, reflects intra-abdominal fat, and is the best indicator of change in intra-abdominal fat during weight loss, it has been suggested as a measurement to use in health promotion programmes to identify those needing to reduce weight. Circumference above or equal to 102 cm in males and 88 cm in females indicates need to reduce weight. 94 cm and 80 cm respectively indicate the level at which no further weight gain should be allowed.[37] This approach was validated in Holland, using data gathered in the ongoing monitoring project on risk factors for chronic diseases (MORGEN project). Waist circumference >80cm in women and >94cm in men correctly identified people with BMI>25 and waist:hip ratio >0.95 in men and >0.8 in women, with a sensitivity and specificity >96%. Identification of individuals with at least one cardiovascular risk factor were identified with a sensitivity of 57%-67% and specificity of 62%-72%.[38]

Glucocorticoids regulate adipose tissue differentiation. Omental fat can generate active cortisol from inactive cortisone through the expression of 11ß-HSD1 (type 1 isoform of 11ß-hydroxysteroid dehydrogenase) and activity is increased after exposure to cortisol and insulin. This has been termed “Cushing’s disease of the omentum”[39]. Adipose cells from subcutaneous fat do not generate cortisol.

 Administration of testosterone undecanoate over 3 months decreased waist/hip ratio, without change in body fat mass, increased muscle strength, and increased fractional velocity of glycogen synthase.[40] This is more effective than dihydrotestosterone, which is the major predictor of sexual behaviour in healthy young men.[41]

 Appetite Suppressant Drugs

Long term treatment with appetite suppressant drugs[42] has been associated with addiction, tolerance, systemic hypertension and increased risk of primary pulmonary hypertension and valvular heart disease. Sibutramine (see below) was not associated with any echocardiogram changes at the time of FDA approval (November 1997). 

Valvular Heart Disease[43] and Pulmonary Hypertension

24 women with no prior history of heart disease who took fenfluramine and phentermine in combination for an average of 1 year presented with cardiovascular symptoms and new murmurs of mitral aortic and/or tricuspid incompetence; 8 had newly documented pulmonary hypertension. The appearance of the valves was similar to carcinoid induced valvular disease and the authors speculate that the effect is via an alteration in serotonin metabolism. The frequency of the association is unclear. 

The diet drugs fenfluramine and dexfenfluramine were withdrawn from the market in 1997 because of reports of cardiac valvular abnormalities in patients taking them. Since then, three controlled studies suggest that the concern was warranted. 

One study[44] compared echocardiographic findings in 233 patients who took the drugs for an average of 20 months in open-label trials and 233 controls matched for sex, age, and body-mass index. The prevalence of significant valvular regurgitation (i.e. at least mild aortic or moderate mitral insufficiency) was significantly higher among diet drug users than among controls (22.7 percent vs. 1.3 percent).  

Another study compared echocardiograms of 718 dexfenfluramine recipients and 354 placebo recipients from a randomized trial[45]. The drug-treated group had a significantly higher prevalence of any degree of aortic regurgitation (17 percent vs. 12 percent) and mitral regurgitation (61 percent vs. 54 percent) than the placebo group. However, there was no statistically significant excess of significant valvular regurgitation, based on the definition in the previous paragraph. The average duration of treatment was only 71 days.  

The third study identified 9,765 patients who received diet & drugs and 9,281 weight-matched controls from the VAMP database in the UK[46]. During an average follow-up of 4 years, there were 11 newly diagnosed cases of idiopathic valvular disorders among patients using dexfenfluramine or fenfluramine, but no cases among controls. Valvular disorders were more likely among patients using the drugs at least 4 months.  

Criteria for approval of anti-obesity drugs

The European Medicines Evaluation Agency uses a 10% weight loss from baseline with a drug effect significantly greater than placebo as one criteria for approval. [47].

The FDA requires that a benefit greater than diet, exercise and behaviour modification alone is demonstrated and that there is a fixed difference between drug and placebo at 1 year of 5% extra weight loss. As drugs for the treatment of obesity will be sought for cosmetic as well as medical reasons, they must improve associated conditions and quality of life and be very safe given the projected duration of use. Comparing response of anti obesity medication with hypoglycaemic medication for diabetics shows a similar graph for response through the range of effect of taking medication to the sequelae of stopping medication.[48]. 

Orlistat: gastrointestinal lipase inhibitor

This is the first approved treatment for obesity that is not an appetite suppressant. By powerfully blocking gastric and pancreatic lipase, orlistat reduces absorption of dietary fat by an average of 30% on a dose of 120mg tds. The unabsorbed fat is excreted in the faeces[49] and the lost calories thereby promote weight loss providing there is no compensatory change in dietary intake of fat. Any such increased intake in fat can be expected to increase the side effects mentioned below.

 A 2 year double blind randomised placebo controlled trial[50] with parallel group design (both active and placebo groups reassigned at 1 year to assess weight regain; continuing current therapy or switching to the other therapy) recruited 743 (688 randomised) European men and women over age 18 with BMI 28-47 (average weight 100kg). They all followed a hypocaloric diet (600 kcal/day deficit; 30% fat) for the first year and a weight maintenance diet for the second year (estimated BMR x 1.3). At the end of year 1, weight loss on orlistat was 10.2% (10.3kg) and on placebo 6.1% (6.1kg); 68% greater loss on orlistat and most loss occurring in the first 6 months. After 2 years of continuous orlistat treatment, 57.1% maintained a weight loss greater than 5% compared to 37.4% on continuous placebo. Average weight gain during the second year was 2kg in those continuing orlistat for the second year and 4.6kg in those switched to placebo. Total cholesterol, LDL, LDL/HDL ratio, glucose and insulin levels decreased more in the orlistat group than placebo. 

Half of the weight loss in the trial was accounted for by the hypocaloric diet. It has been calculated that the calories lost as a result of reduced fat absorption due to orlistat amount to 156 kcal/day[51]. As this is only a slight added calorie deficit it raises the possibility that funds spent on orlistat might be better transferred to stricter supervision of dieting particularly over the long term prescriptions implied by the results. 

Decreased absorption of fat soluble vitamins may be a problem as the orlistat group registered significant differences in absolute levels of ß-carotene, vitamin D and vitamin E. Gastrointestinal side effects were particularly prominent in year 1: fatty stool 31% (placebo 5%), increased defecation 20% (7%), oily spotting 18% (1%), soft stool 15% (9%), flatulence 7% (3%), faecal incontinence 7% (0%). 

In an American study of 322 obese patients with type 2 DM receiving orlistat[52] weight loss was greater than placebo on a hypocaloric diet. (orlistat 6.2kg, placebo 4.3kg). There was also a modest but significant improvement in fasting glucose and glycated haemoglobin levels.  

Although gastrointestinal side effects were common in both trials, only 4% of patients withdrew because of the severity. 

Sibutramine: noradrenaline and serotonin reuptake inhibitor[53] [54] [55] [56]

This drug started out as a potential antidepressant in the late 80s but besides acting on areas controlling mood it also appeared to have an appetite suppressant effect. Its main mode of action is via noradrenaline and serotonin but it also has an effect on dopamine metabolism. In September 1996, an FDA advisory committee concluded that sibutramine should not be approved because patients' BP tended to rise during clinical trials. In November 1997, the FDA approved sibutramine providing there were “appropriate warnings and labelling”.

Antidepressant SSRIs are known to cause weight loss but at doses much higher than required to treat depression[57]. Also continued use of even high dose fluoxetine did not maintain the initial weight loss[58]. 

Sibutramine induces thermogenesis in rats resulting in increased oxygen consumption by the activation of efferent sympathetic activity involving activation of β₃ adrenergic receptors but there is no evidence of a similar effect in humans. 

Sibutramine helps reduce food intake via β₁ and 5HT_2A/2C receptors. It is indicated for weight loss and maintenance of weight loss when used in conjunction with a reduced calorie diet. It is indicated for people whose initial BMI is at least 30. Patients with other risk factors, such as hypertension or diabetes, can be treated with the drug if their BMI is over 27. Its usage must be combined with a low calorie diet, exercise, and behavioural modification to achieve optimum results. 

In clinical trials, patients treated with sibutramine while on a reduced-calorie diet, showed a significant weight loss during the first six months of treatment, and significant weight loss was maintained for one year. In one 12-month study, the average weight loss in patients taking sibutramine, 10 mg daily, was about 10 lbs., and in those taking 15 mg daily was about 14 lbs[59]. The average weight loss in persons on only a reduced calorie diet was 3.5 lbs. The recommended starting dose of sibutramine is 10 mg once daily. It may be taken with or without food. If there is inadequate weight loss, the dose may be titrated after four weeks to a total of 15 mg once daily. The 5 mg dose should be reserved for patients who do not tolerate the 10 mg dose. Doses above 15 mg daily are not recommended due to increased adverse effects with no increase in efficacy. 

The most common side effects associated with sibutramine include dry mouth, headache, constipation, agitation and insomnia. The drug causes a small increase in average blood pressure though can cause a higher increase in some patients. FDA recommends patients taking sibutramine have regular medical follow up including BP checks. People with uncontrolled high blood pressure should not take sibutramine and those already on antihypertensives should be very closely monitored. Unlike dexfenfluramine, there is no stimulation of serotonin release from neurones.

 It must not be taken with monoamine oxidase inhibitors including selegiline or SSRI antidepressants. It should not be taken with OTC drugs that may raise BP or heart rate such as decongestants and cough, cold and allergy medications containing phenylpropanolamine, ephedrine or pseudoephedrine. Other drugs that should be used with caution include ketoconazole, erythromycin, cimetidine, alcohol, warfarin, phenytoin, lithium, sumatriptan (and similar agents) or tryptophan.

 Sibutramine therapy also results in decreased triglycerides and LDL and total cholesterol, as well as increased HDL cholesterol.

Thermogenic drugs

A successful maintenance of weight loss programme requires increased exercise and activity[60]. But obesity itself can make it difficult to increase activity even if complications like CHD have not arisen. Thermogenic drugs, which raise BMR and dissipate energy as heat, are therefore being sought.

Thyroxine and tri-iodothyronine are thermogenic but the side effects include dysrhythmias and protein loss is accelerated.

Caffeine[61] raises BMR by about 4% for 100mg (about 2 cups of coffee) but the effect is short lived and is followed by a period of reduced energy expenditure. The combination of caffeine with ephedrine is available in Denmark[62].

Ephedrine increases BMR but also has a marked anorectic effect which may account for up to 80% of the weight loss[63]. The action is via noradrenaline which may act via β₃ receptors on brown adipose tissue, β₂ receptors stimulating protein synthesis and increasing lean body mass, and ά receptors involved in conversion of thyroxine to tri-iodothyronine[64]. The effects of long term treatment have not been studied.

 The identification of β₃ receptors which mediate thermogenesis opened up a new area for targeted drugs[65].

However testing of new drugs stimulating β₃ receptors has been disappointing. Unlike rats where these agents act via β₃ receptors on brown adipocytes, the mode of action in man is in skeletal muscle. The skeletal  muscle tremor caused by some β₃ receptor agonists may be responsible for the thermogenesis[66]. The human β₃ receptor is now known to be different form the rat receptor so more specific compounds may be identified in the future.

References for Chapter 14

Send mail to webmaster @minster.org.uk with questions or comments about our website. N.B. Website is for practice patients ONLY.
Copyright © 1997-2007 Dr Michael Causer Click here for full copyright notice & site warning.
Homepage last modified: August 25, 2008.