A large, multicentre, randomized, double-blind, placebo-controlled study determined the effects of orlistat 120 mg t.i.d. in obese type 2 diabetic patients treated with sulfonylurea hypoglycemic agents [29]. After 1 year of treatment, a mean difference of 2.4 kg greater weight loss was observed in the orlistat group vs. the placebo group, which was associated with significant reductions in fasting blood glucose and HbA1c levels. Furthermore, a significant reduction in the dose of oral hypoglycemic agents was seen in the orlistat group. A 1-year, multicentre, randomized, double-blind, placebo-controlled trial demonstrated that orlistat is a useful adjunct treatment for producing weight loss and improving glycemic control in obese patients with type 2 diabetes who are being treated with metformin [32]. Finally, in overweight or obese patients with type 2 diabetes who had suboptimal metabolic control with insulin therapy, 1 year of orlistat treatment, compared with placebo, produced significantly greater decreases in body weight, HbA1c levels, fasting serum glucose concentrations, and the required doses of insulin and other diabetic medications [33]. A post hoc analysis of the results of these three large-scale studies suggests that lowering of HbA1c levels with orlistat in obese type 2 diabetic patients may be partially independent of weight loss as some improvement of blood glucose control was also observed in the absence of weight reduction.
A significant improvement of lipid profile was observed with orlistat compared with placebo in the three 1-year clinical trials performed in obese diabetic patients treated with sulfonylureas [29–31], metformin [31, 32] or insulin [33].
This improvement of lipid profile may be partially explained by the somewhat greater weight reduction but also by the specific mode of action of orlistat on fat intestinal absorption. In particular, greater reductions in total cholesterol, LDL cholesterol and LDL/HDL ratio were observed with diet plus orlistat compared with diet plus placebo, confirming the results observed in obese non-diabetic subjects [39]. In addition, a mild reduction in blood pressure has also been reported in obese diabetic patients [32] as in non-diabetic obese individuals [40]. This might be attributed to weight loss and improvement of insulin sensitivity [41]. All together, orlistat significantly improves the cardiovascular profile of obese patients with type 2 diabetes as has already been demonstrated in the obese non-diabetic population [42, 43]. Whether these changes in risk profile will be able to improve the poor cardiovascular prognosis of obese type 2 diabetic patients remains to be demonstrated in long-term clinical studies evaluating hard outcomes such as cardiovascular morbidity and mortality. A Markov health economic model was developed to predict, over a 10-year period, the complication rates and mortality with and without 2 years of orlistat treatment, assuming a 5-year catch-up period after treatment [44]. The results suggest that orlistat is cost-effective in the management of obese type 2 diabetic patients, especially in those with hypercholesterolemia and/or hypertension. However, evidence of longer term benefits of orlistat (>2 years) will be important for future decision-making.
To test the hypothesis that orlistat combined with dietary intervention improves glucose tolerance status and prevents worsening of diabetes
status more effectively than placebo, an analysis of pooled data from three randomized, double-blind, placebo-controlled, multicentre clinical trials was performed [45]. Weight reduction was greater with orlistat (n = 359) than with placebo (n = 316): 6.72 vs. 3.79 kg (p < 0.001). The comparison of oral glucose tolerance tests before and after 104 weeks of treatment showed that a smaller percentage of subjects with IGT at baseline progressed to diabetic status in the orlistat group (3.0% vs. 7.6% in the placebo group). Conversely, among subjects with IGT at baseline, glucose levels normalized in more subjects after orlistat treatment (71.6% vs. 49.1% after placebo). Thus, the addition of orlistat to a conventional weight loss regimen significantly improves oral glucose tolerance and diminishes the rate of progression to the development of IGT and type 2 diabetes [27, 45].
To definitely confirm this hypothesis, a large-scale, randomized, double-blind, placebo-controlled, prospective, multicentre trial has recently been performed in Sweden, the Xenical in the Prevention of Diabetes in Obese Subjects (XENDOS) trial. The XENDOS trial investigated whether orlistat 120 mg t.i.d. combined with a hypocaloric diet and moderate physical exercise could reduce the incidence of type 2 diabetes in obese subjects over a period of 4 years [46]. The study also evaluated a number of secondary parameters such as weight loss, risk factors, safety and tolerability. This study enrolled 3304 obese patients (BMI ³30 kg/m2), ranging in age between 30 and 60 years. In contrast to previous studies [7, 8], subjects were not specifically selected because they had IGT at baseline (only 21% of enrolled subjects). Weight loss was greater in the orlistat group (-6.9 kg; n = 1640) than in the placebo group (-4.1 kg; n = 1637; p < 0.001). Such a difference in weight reduction was sufficient to significantly reduce the cumulative incidence of type 2 diabetes (6.2% vs. 9.0%; p = 0.0032; relative risk reduction 37.3%). The difference was especially remarkable in obese patients with IGT, with a reduction of conversion to diabetes from 28.8% in the placebo group to 18.8% in the orlistat group (p < 0.005); the number needed to treat to avoid one event was only 11. Significant and sustained reductions in cardiovascular risk factors such as arterial blood pressure and lipid levels were also observed in the orlistat group compared with the placebo group. XENDOS is thus the first study to demonstrate that an antiobesity agent like orlistat is able to reduce the progression to diabetes in obese subjects compared with lifestyle changes alone [47].

Clinical trials with sibutramine
Sibutramine, a new norepinephrine and serotonin reuptake inhibitor, has been shown to produce dose-related weight loss in obese subjects at optimal daily doses of 10–15 mg up to a maximal dose of 20 mg [48] (Table I). The multicentre prospective Sibutramine Trial of Obesity Reduction and Maintenance (STORM) clinical study showed that almost all patients who persisted with the management scheme combining restricted diet and sibutramine 15 mg could achieve at least a 5% weight loss, and over half lost more than 10% of their body weight within 6 months [49]. Furthermore, sustained weight loss was maintained in most patients continuing therapy with sibutramine for 2 years, whereas weight regain was noticed in most patients randomized to placebo, thus demonstrating that sibutramine favours weight maintenance in the long term.
Owing to the close relationship between obesity and abnormal glucose metabolism, sibutramine may be useful in the treatment of obese diabetic patients [50]. Favourable results were reported with sibutramine in three 6-month [35–37] and two 1-year [34, 38] randomized clinical trials (Table II). All studies demonstrated that, when compared with placebo, an average 3–5 kg further weight loss resulting from the prescription of sibutramine at a daily dose of 15–20 mg is sufficient to improve fasting plasma glucose and HbA1c levels. Post hoc analysis demonstrated a close relationship between the degree of weight loss and the reduction in HbA1c in obese diabetic patients receiving sibutramine; the most impressive HbA1c reduction (around 1%) was observed in patients losing ³10% of their baseline body weight. The observation that similar diminutions of HbA1c levels were reported in placebo-treated and sibutramine-treated patients losing the same amount of body weight suggests that sibutramine has no intrinsic favourable effect on glucose metabolism beyond its effect on weight loss, a finding which appears to be different to what has previously been described with the purely serotoninergic agents such as fenfluramine, dexfenfluramine and fluoxetine [19, 20].
Interestingly, these changes in body weight were associated with improvements of other metabolic vascular risk factors, such as lipid parameters, confirming the results observed in obese non-diabetic subjects reported in the STORM trial [49]. For instance, in the largest study ever published with sibutramine in obese type 2 diabetic patients [38], plasma triglycerides fell with both 15 and 20 mg/day, especially in subjects with weight loss of ³10% of their initial body weight (decrease of 29%; p < 0.01), while HDL cholesterol increased slightly (+0.1 mmol/l). Total cholesterol-to-HDL cholesterol ratio showed modest but significant falls of 8% and 16% with a daily dosage of 15 and 20 mg sibutramine, respectively.
Sibutramine may have contrasting effects on the cardiovascular risk profile, as it promotes weight loss, improves blood glucose control and lipid parameters but tends to slightly increase heart rate and arterial blood pressure, two independent cardiovascular risk factors [48]. Such a mild rise in heart rate and blood pressure is attributed to a sibutramine-induced sympathetic drive, an effect that may also somewhat hinder the improvement of insulin sensitivity resulting from weight loss. Slight increases in heart rate and blood pressure have also been observed in obese patients with type 2 diabetes, although the effect on blood pressure was less evident in subjects who had a weight loss of ³10% of their initial body weight [38]. A large-scale, prospective, randomized, controlled trial, the Sibutramine Cardiovascular and Diabetes Outcome Study, is currently underway to examine the long-term health benefits of weight management with sibutramine plus lifestyle interventions (diet and exercise). This multinational study will recruit more than 10,000 overweight/obese patients at high cardiovascular risk. Patients will be males or females, ³55 years old, with a BMI ³27 kg/m2 or a BMI ³25 kg/m2 plus an increased waist circumference (>102 cm in males and >88 cm in females). High cardiovascular risk will be assessed by the presence of coronary, cerebral and/or peripheral arteriopathy as well as by the presence of IGT or type 2 diabetes plus at least one other classical vascular risk factor. Patients with uncontrolled arterial hypertension will be excluded from the trial. It has been planned that half of the patients entering the study will have type 2 diabetes mellitus, i.e. more than 5000 diabetic individuals. Lifestyle interventions and sibutramine or placebo will be given for an average of 4 years. Primary outcomes will be cardiovascular morbidity/mortality and progression to type 2 diabetes. This landmark study will combine the principles and practices of large cardiovascular outcome studies with those of obesity studies. It will attempt to answer the three fundamental questions of whether long-term weight loss and weight maintenance result in health benefits, whether adding sibutramine to lifestyle intervention is able to delay or prevent type 2 diabetes and whether sibutramine can improve cardiovascular prognosis of obese type 2 diabetic patients.

Conclusions
Control of body weight appears to be crucial for both the prevention and treatment of type 2 diabetes. Weight loss is a major target in treating obese patients with type 2 diabetes as it allows improvement of both glycemic control and various associated vascular risk factors. Lifestyle modifications should be used first in all cases. Recently available antiobesity drugs, such as sibutramine and orlistat, can be used as adjunct therapy to diet since the additional weight loss, though generally modest, is able to improve blood glucose control and some other risk factors. Beneficial effects essentially appear in individuals considered to be good responders, i.e. those achieving a weight loss of ³10% of their initial body weight with diet plus active drug, as compared with placebo. Although the available data suggest that orlistat may produce a greater, more reproducible and partially weight loss-independent reduction in HbA1c level compared with sibutramine, the effects of orlistat vs. sibutramine should be verified in direct comparative clinical trials in obese type 2 diabetic patients. In addition, it would be interesting to assess the efficacy of a combined therapy with sibutramine and orlistat in a well-designed, long-term clinical trial, as the percentage of obese diabetic patients who succeed in achieving a 10% weight reduction remains rather low with either monotherapy. Finally, these two drugs may help to delay the progression from IGT to type 2 diabetes in obese individuals, especially orlistat, as recently demonstrated in the XENDOS trial. However, even if targeting weight excess rather than hyperglycemia per se may be a valuable alternative in selected obese diabetic patients, long-term prospective studies are required to more precisely determine the place of each strategy in the overall management of patients with both obesity and type 2 diabetes. The results of the ongoing Sibutramine Cardiovascular and Diabetes Outcome Study will certainly provide crucial information on the potential role of pharmacologically induced weight reduction with long-term treatment by sibutramine on the cardiovascular prognosis of obese type 2 diabetic patients.

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