There is incontrovertible evidence to show that early pharmaceutical intervention achieves better glycaemic control and reduces macrovascular and microvascular outcomes for Type 2 diabetic subjects (82). However, the conflict for obese diabetic patients between the need to achieve glycaemic control whilst minimising weight gain poses a challenging dilemma, as weight gain is an unfortunate consequence of several diabetic medications, a summary of which is provided in Table 8.2 (83).
Despite the undoubted ability of insulin to influence glycaemic control and microvascular outcomes, the mean weight gain by insulin-treated Type 2 obese subjects after 6 years is 10.4 kg. Sulphonylureas have a similar, but less pronounced effect, with a mean gain of 4.9 kg (84). For this reason, there is a general reluctance to use insulin in particular with the obese, although there is
Table 8.2 Anti-diabetic agents and their impact on body weight
Sulphonylureas (e.g. gliclazide) Biguanides (e.g. metformin) a-Glucosidase inhibitors (e.g. acarbose) Thiazolidinediones (e.g. pioglitazone, rosiglitazone) Insulin
Source: Adapted from Hauner (83).
some evidence that the use of basal insulin as opposed to meal-time insulin will lessen the weight gain effect (85). Newer agents such as the thiozolidinedione insulin sensitisers remain controversial, as the impact of undesirable subcutaneous weight gain, despite reductions in the more harmful visceral fat, continues to be debated (8).
a-Glucosidase inhibitors such as acarbose, although generally less effective hypoglycaemic agents, may have some value in the management of the obese Type 2 diabetic patient. Although they generally have a neutral effect on weight, some studies suggest they cause modest weight loss and are thought to act by reducing the energy available from carbohydrates by delaying fermentation in the gut (86).
Biguanides such as metformin, on the other hand, have a weak anorectic action, and were shown by the UKPDS to be the treatment of choice for the obese Type 2 diabetic patient, causing no weight gain relative to conventional policy and demonstrating a cardio-protective effect by reducing the rates of mortality and myocardial infarction (87).
Furthermore, there is some evidence that the combination of metformin with intensive insulin therapy can negate the weight gain caused by insulin (88). However the effects of metformin on microvascular outcomes are less favourable than insulin, and for many patients its side-effects and contraindications mean that it is not a viable option.
Clearly there is no easy way for an individual with diabetes who is obese to improve glycaemic control, reduce microvascular and macrovascular complications and lose weight at the same time. A more rational approach may be to address the problem of obesity first, using agents that cause weight loss as a primary effect and achieve reductions in hyperglycaemia as a desirable consequence. One such agent is orlistat, an intestinal lipase inhibitor, which acts enterically to inhibit the absorption of approximately 30% of dietary fat (89). Orlistat is recommended for use in those aged 18-75 years with a BMI 28-30kg/m2, in the presence of significant co-morbidities and in those with a BMI>30kg/m2 with no associated co-morbidities. Patients are required to demonstrate a weight loss of at least 2.5 kg in the month prior to the drug being prescribed. The NICE (90) guidelines in the UK have also recently recommended that continuation of this therapy beyond three months should be supported by evidence of a loss of at least a further 5% of body weight, and beyond six months by evidence of at least 10% weight loss. Several clinical trials have been conducted to examine the efficacy of this drug treatment in obese diabetic and non-diabetic patients (89,91). While over a one-year period, Type 2 diabetic subjects taking sulphonylureas and orlistat lost less weight than non-diabetic subjects taking orlistat (mean 6.2 kg vs 9.5 kg), the subsequent improvements in HbA1c reduced the need for diabetic medication and had favourable effects on lipid profiles and hypertension. In addition, improvements in the insulin resistance index of obese non-diabetic subjects, proportional to the degree of weight lost, suggest that orlistat may have a valuable role in the delay of onset or perhaps the prevention of Type 2 diabetes in the obese (92).
Sibutramine is a selective serotonin and noradrenaline reuptake inhibitor, which promotes weight loss. The blocking of serotonin reuptake has a satiety enhancing effect and inhibition of noradrenaline uptake promotes thermogen-esis. Sibutramine has only recently been licensed in the UK, the drug having been available on prescription in the USA for considerably longer. The results of the clinical trials show that obese non-diabetic patients are more able to achieve a 5-10% weight loss with sibutramine than with placebo, although the positive effects are dose-related. A 10 mg dose results in a mean weight loss of 5.5% and a 15mg dose a loss of 7.2% (93). For the Type 2 diabetic patient who loses weight with sibutramine, the ensuing improvements in all modifiable risk factors are proportional to the degree of weight lost, with significant improvements, specifically a reduction in HbA1c of 0.4%, seen in those who lost >5% of body weight (94). As a word of caution, slight increases in pulse and blood pressure (2-3 mmHg) are associated with sibutramine, but in the long term, weight loss results in a net decrease in blood pressure.
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