Dietary intervention is fundamental to the control of glucose and weight in obese individuals with type 2 diabetes. Understanding how specific dietary interventions and anti-obesity agents affect an individual’s dietary composition and energy intake should enable us to target these interventions more effectively. In the present study we investigated the effects of a dietary intervention involving the use of the anti-obesity agent, rimonabant on blood glucose, energy intake and dietary composition in obese adults with type 2 diabetes.
The main findings of the present study were that an individualised diet based on healthy eating and portion control, in combination with rimonabant therapy led to significant weight loss over a 6 month period with a majority of patients losing in excess of 5% of their body weight. The reduction in body weight was accompanied by a reduction in weight circumference and favourable changes to the lipid profile and blood glucose control. These beneficial effects on body weight and metabolic parameters occurred in association with a significant reduction in energy intake, together with reductions in the intake of the principal macronutrients, carbohydrate, fat and protein. The levels of these macronutrients were reduced to a similar degree such that the overall dietary composition remained unchanged.
As well as conventional lifestyle intervention, pharmacological therapies are increasingly used to combat obesity. Rimonabant is a cannabinoid-1 receptor blocker that induces weight loss and improves the cardiovascular risk profile, glycemia and insulin sensitivity in diabetic subjects
. The endocannabinoid system, consisting of cannabinoid type 1 (CB1) receptors and endogenous ligands is expressed widely, not only in the central nervous system but also in peripheral organs including visceral adipose tissue
. The effects of CB1 receptor blockers on weight, energy expenditure and calorific intake have been studied in detail in rodent models. In these studies CB1-receptor antagonism at the hypothalamic level resulted not only in reduced food intake but also a change in the composition of the diet
[8, 9, 19]. In particular, Mathes et al. using a novel dessert protocol in female rats demonstrated a lowered calorific consumption with reduced intake of palatable food (sugar fat whip) following rimonabant treatment
. In addition, rimonabant has been shown in a rodent model to enhance lipolysis in adipose tissue leading to increased energy expenditure through oxidation of fatty acids and this effect was considered an important determinant of weight loss independent of food intake
Inferences from these animal studies include the contention that the endocannabinoid system is an important modulator of the rewarding properties of foods by acting through specific mesolimbic areas in the brain and that CB1 receptor antagonists may have the potential in humans to reduce the intake of hedonistic type foods in favour of less energy-dense and healthier alternatives
[4, 20]. To date these observations remain unproven in human studies and indeed, results from our present study are at variance with these animal studies in that our patients’ dietary composition following rimonabant therapy was unchanged, with no evidence of a shift towards a healthier, less palatable diet. Instead, individuals appeared to simply reduce calorie intake by globally reducing intake of most macronutrients and several micronutrients in addition. ‘Surrogate markers’ of a healthier diet such as an increased intake of potassium or dietary fibre were not observed and in fact levels of both these nutrients fell following rimonabant therapy.
In the present study we observed a strong relationship between carbohydrate intake and blood glucose levels, with reduction in carbohydrate intake during the study being closely correlated with reduction in glycated haemoglobin independent of body weight change or total energy intake. In contrast, changes in body weight appeared to be more closely related to fat intake rather than carbohydrate intake. These data are in keeping with the growing body of evidence in favour of carbohydrate restriction as a key intervention to optimise glucose control in individuals with type 2 diabetes
Micronutrient intake was also assessed in the present study. Of note, levels of several micronutrients fell following dietary and rimonabant therapy, paralleling the changes observed in macronutrients. Indeed, there appeared to be a trend for an increasing number of subjects failing to meet the Reference Nutrient Intake (RNI) for several important micronutrients following the intervention. This observation appears to suggest that some patients could be at risk of adopting a poorer quality diet following this type of dietary intervention and is an area of major concern.
Study limitations and recommendations
This study was intended to mimic that of a clinical situation as much as possible to give an insight into how CB1 receptor antagonists impact patient’s diets and to ascertain whether further research on CB1 receptor antagonists and indeed other anti-obesity medication on dietary composition is worthwhile. There are certainly limitations to this study, namely the relatively small sample size, open design and lack of a control group. Ideally a randomised, placebo-controlled trial would have been the preferred study design but this was not feasible within the resources available to us. Another alternative would have been to study a parallel group of similar patients who lost weight through dietary intervention alone, without anti-obesity medication. This latter type of study design would have significantly enhanced the quality of this study and indeed was originally intended. Unfortunately, it was not possible to achieve meaningful weight loss through our dietary intervention alone in our intended control group of type 2 diabetic patients. Since no valid comparisons in terms of dietary changes between rimonabant-treated patients and controls are possible without comparable weight loss achieved in each group, it was decided that the rimonabant-treated patients alone would be included in the final analysis.
Detailed dietary analysis can be a difficult method to employ in clinical research but it is hoped that future research including larger controlled trials will be possible to examine dietary changes induced by both centrally acting anti-obesity drugs and other potential anti-obesity agents such as glucagon-like-peptide-1 (GLP-1) agonists. This is certainly an area worthy of further study given the potential widespread application of such agents and the knowledge gleaned from the present study suggesting significant change in dietary composition associated with CB-1 receptor antagonism. In particular, our observations that levels of some important micronutrients may fall below recommended levels of intake following anti-obesity medication is an area of special concern. We would suggest that detailed dietetic input is warranted in this situation to ensure that dietary intake of essential micronutrients is not compromised during this type of weight loss intervention.