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International Journal of (1999) 23, Suppl 7, S2±S4 ß 1999 Stockton Press All rights reserved 0307±0565/99 $12.00 http://www.stockton-press.co.uk/ijo Obesity and type 2 : a con¯ict of interests?

G Williams

Department of Medicine, University of Liverpool, University Aintree, UK

Obesity is a major risk factor for the development of and is an important obstacle to the management of this . The increasing incidence of both obesity and type 2 diabetes makes management of these related conditions particularly important. Conventional approaches to the management of type 2 diabetes that focus primarily on improving glycaemic controlÐnotably or sulphonylurea treatmentÐoften lead to , which is particularly detrimental to patients with type 2 diabetes. By contrast, reducing body weight in such patients improves glycaemic control and other cardiovascular risk factors associated with the . This suggests that weight reduction is a rational option in the management of obese patients with type 2 diabetes. While reductions in body weight of approximately 10% have been achieved in some studies, this is dif®cult to achieve in real life, especially for patients with type 2 diabetes. agents such as sibutramine and , used as part of an integrated programme of , physical activity and behavioural therapy, are thus an attractive early option for the management of type 2 diabetes in obese patients.

Keywords: obesity; type 2 diabetes; management; weight management agents

Introduction and hence improve the quality of life and ultimately the of these patients.

The steadily increasing incidence of type 2 diabetes in many countries is likely to make this one of the major Obesity predisposes to type 2 of the next millennium. It is estimated that the incidence will increase by 50% over the next 7 ± diabetes 8 y, bringing the total number of people worldwide with the disease to 150 million. In the face of an Obesity is one of the biggest obstacles to the manage- epidemic of this magnitude, it is clearly important to ment of type 2 diabetes and yet is frequently ignored establish effective strategies for the management of by the medical profession, who often believe that they type 2 diabetes in parallel with attempts to develop can do little to help their obese patients. This is approaches that can reverse this worrying trend. Since particularly detrimental to such patients, since obesity obesity is a major risk factor for the development of is one of the most in¯uential risk factors for type 2 type 2 diabetes, effective is a 1 diabetes. Although obesity does not necessarily lead logical and important goal. to the development of type 2 diabetes, epidemiologi- There is a commonly held myth amongst physicians cal studies2 have shown that the risk of type 2 diabetes that type 2 diabetes is a relatively mild disease which increases exponentially with (BMI) is easily managed (Table 1). The fact that type 2 over 28 kg=m2. For example, the risk is 80-fold diabetes usually becomes manifest in older patients greater in an individual with morbid obesity (BMI has led to complacency about how strictly it should be > 40 kg=m2) compared with an individual with a BMI managed and how hard one should aim to prevent of < 22 kg=m2. The life-time risk of acquiring type 2 associated complications. However, the fact that com- diabetes is approximately 50% in subjects with plications such as obesity, , morbid obesity. Central obesity is particularly diabe- and dyslipidaemia arise frequently is togenic, as is demonstrated by the very strong syner- an unambiguous warning that type 2 diabetes is a gistic interaction between BMI and a high waist:hip serious illness which is all too often dif®cult to ratio. manage. Type 2 diabetes thus warrants rigorous inter- There is evidence for a causal link between obesity vention to minimise the development of complications and type 2 diabetes. Obesity worsens insulin resis- tance, one of the fundamental causes of type 2 diabetes, although the pathophysiological mechanisms remain uncertain.3 There are particularly strong links Correspondence: Professor Gareth Williams, MD, FRCP, with visceral ; high levels of free fatty acids Department of Medicine, University Hospital Aintree, Longmoor Lane, Liverpool L97AL, UK. generated by intra-abdominal fat depots may act E-mail: [email protected] directly on the to interfere with handling, Obesity and type 2 diabetes G Williams S3 Table 1 Common myths about type 2 diabetes are considered separately. The side-effects and meta- bolic effects of drugs used to manage type 2 diabetes,  `Mild' diabetes  Easier to treat than hypertension, dyslipidaemia and obesity frequently  Treatment targets less rigorous than type 1 diabetes (older exacerbate the other complications. For example, if patients) the physician focuses on achieving control of blood  Complications either won't happen (older patients) or are inevitable (may be present at diagnosis) glucose levels with insulin or sulphonylurea therapy,  Obesity is best ignored (can't do anything about it) this can lead to weight gain which in turn may worsen and other aspects of the metabolic syndrome. Exacerbation of hypertension and dyslipi- insulin clearance and other vital homeostatic meta- daemia may then arise. On the other hand, treating bolic processes. In addition to obesity, other factorsÐ hypertension with the conventional combination of b- including a genetic predisposition, physical activity, blockers and can exacerbate hyperglycaemia and diabetogenic drugsÐmay also contri- and worsen dyslipidaemia. bute to the risks of type 2 diabetes. In contrast to these approaches, recent studies have Obesity makes a signi®cant contribution to the shown that addressing the problem of obesity ®rst can morbidity and mortality associated with type 2 dia- lead to an improvement in blood glucose control betes, largely through its contribution to cardiovascu- which can be accompanied by a decrease in blood lar disease. In non-diabetic subjects, obesity is pressure, an increase in insulin sensitivity and favour- commonly associated with hypertension, dyslipidae- able changes in blood pro®les. Swedish and mia and ultimately with atherogenesis and premature American studies of patients undergoing bariatric death from cardiovascular disease. These risks appear gastric surgery found that of the 50% of patients to be accentuated in diabetic subjects. For example, who had type 2 diabetes or were glucose intolerant the risk of premature death is 10-fold greater in 2 before surgery, most patients developed normal glu- a diabetic person with a BMI > 36 kg=m , compared cose tolerance within 5 ± 6 y of surgery.4 Thus, the with a non-obese diabetic patient. successful loss of a substantial amount of weight As with the prevalence of type 2 diabetes, the improved glucose tolerance dramatically. prevalence of obesity is increasing rapidly. At present Other studies have shown that a loss of 5 ± 10% of in the UK, the incidence of obesity appears to be body weight can produce statistically signi®cant ben- doubling each decade. This means that, by the year e®ts. Several studies, notably those of Wing,5 have 2010, one-third of adults are likely to have clinically reported that patients achieving a loss of body weight signi®cant obesity. Similar trends are being observed of 5% or greater achieved a small but signi®cant in other Westernised countries. Based on the experi- decrease in HbA levels, and that clinically mean- ence of the Pima Indians, it seems likely that this 1c ingful improvements in HbA1c can be obtained with a obesity epidemic will be followed by an epidemic of  10% decrease in body weight. This is comparable, type 2 diabetes. for example, to the improvement in glycaemic control anticipated following the addition of a second oral Managing type 2 diabetes and antidiabetic agent. obesity How to achieve and maintain Managing a patient with type 2 diabetes and obesity can be seen as a con¯ict of interests, because the most effective treatments for type 2 diabetes, that is insulin Weight loss in obese patients with type 2 diabetes can and sulphonylureas, frequently lead to weight gain therefore signi®cantly improve their clinical condition. (Figure 1). This is one of the dangers of the conven- As already emphasised, the multiple bene®cial effects tional approach to the management of type 2 diabetes of weight loss on several features of the metabolic in which the disease and its associated complications syndrome (that is insulin resistance, hyperglycaemia, hypertension and dyslipidaemia) that contribute to atheroma mean that weight reduction is a rational and conceptually attractive option in the management of type 2 diabetes. IndeedÐin theory, at leastÐit could be preferable to using several different drugs to treat the individual disorders of this syndrome. The target of 10% weight loss is very dif®cult for patients to achieve and maintain in real life, when relying on dietary and lifestyle modi®cation alone. This is especially the case for patients with type 2 Figure 1 Type 2 diabetes: a therapeutic `merry-go-round'. (SUs: diabetes who seem to ®nd it more dif®cult than non- sulphonylureas; TZLDs: .) diabetic patients to reduce weight. Only a few per cent Obesity and type 2 diabetes G Williams S4 of patients with newly diagnosed type 2 diabetes will weight loss have been unconvincing or buried in an be able to reduce their weight enough with standard unfashionable corner of the medical literature. Now dietetic and lifestyle advice to maintain acceptable that its importance is appreciated, and now that glycaemic control without oral hypoglycaemic effective antiobesity drugs are becoming available, agents.6 diabetes physicians can at last begin to take seriously The introduction of the new anti-obesity drugs, their obligations to their obese diabetic patients. sibutramine and orlistat, therefore constitutes an important development in the management of type 2 diabetes. Clinical trials suggest the use of either References agentÐas part of an integrated programme of diet, 1 Wilding J, Williams G. Diabetes and obesity. In: Kopelman P, physical activity and behavioural therapyÐcould Stock MJ (eds). Clinical Obesity. Oxford: Blackwell Science, 1998, pp 308 ± 349. allow approximately one-third of patients with type 2 Colditz GA, Willett WC, Rotnitzky A, Manson JF. Weight 2 diabetes to achieve weight loss of at least 10% of gain as a risk factor for clinical diabetes mellitus in women. their body weight. In most patients, this would lead to Ann Intern Med 1995; 122: 481 ± 486. 3 DeFronzo RA, Bonadonna RC, Ferrannini E. Pathogenesis of a reduction in HbA1c of up to 1%, a reduction in blood glucose levels of 1 ± 3 mmol=l and favourable changes NIDDM. A balanced overview. Diabetes Care 1992; 15: 318 ± 368. in other aspects of the metabolic disorder of this 4 Pories WJ, Swanson MS, MacDonald KG. Who would have syndrome. Improvements in quality of life and life thought it ± an operation proves to be the most effective expectancy would be expected to accompany these therapy for adult-onset diabetes mellitus. Ann Surg 1995; changes.7, 8 222: 339 ± 352. 5 Wing RR, Koeske R, Epstein LH, Norwalk MP, Gooding W, Becker D. Long term effects of modest weight loss in type 2 diabetic subjects. Arch Int Med 1987; 147: 1749 ± 1753. 6 Han T, Lean MEJ. Diet and lifestyle modi®cation in the Conclusions management of non-insulin dependent diabetes mellitus. In: Textbook of Diabetes. Pickup JC, Williams G (eds). Oxford: Blackwell Science, 1997, Ch 37. Obesity is widely regarded as a `Cinderella' problem 7 Lean MEJ, Powrie JK, Anderson AS, Garthwaite PH. Obesity, that falls somewhere between a true disease and a weight loss and prognosis in type 2 diabetes. Diabet Med cosmetic inconvenience. Diabetes is one area in which 1990; 7: 228 ± 233. its potentially serious and ultimately lethal in¯uence is 8 UKPDS Group. United Kingdom Prospective Diabetes Study. Relative ef®cacy of randomly allocated diet, sulphonylurea, particularly obvious. Diabetologists have long ignored insulin, or in patients with newly diagnosed non- obesity, mainly because they have lacked the means to insulin dependent diabetes followed for three years. Br Med J tackle it and because evidence of the bene®ts of 1995; 310: 83 ± 88.