We searched Medline, PubMed, the Cochrane library, and Google Scholar, for mainly original research articles published between January, 1973, and November, 2013, and focused on the dual treatment of obesity and type 2 diabetes. The main search terms used were “obesity”, “type 2 diabetes”, “glucose-lowering”, “antidiabetic”, “anti-obesity”, and “weight loss”. We identified full-text papers without imposing any language restrictions. Reference lists of original studies, narrative reviews, and
ReviewCombating the dual burden: therapeutic targeting of common pathways in obesity and type 2 diabetes
Introduction
The dramatic rise of the dual epidemics of type 2 diabetes and obesity is associated with increased mortality and morbidity and represents one of the most important public health challenges worldwide.1 Type 2 diabetes is a complex disease in which genetic and epigenetic factors interact with a toxic environment that promotes the development of obesity.2 Environmental risk factors include the consumption of high-calorie and high-fat foods, inadequate physical activity, and recently proposed alternative mechanisms (panel), to create a chronic energy imbalance.3 Abdominal adiposity in particular is associated with a substantially increased risk for type 2 diabetes, and overall 80% of people with type 2 diabetes are overweight or obese. Striking parallel increases in the prevalence of obesity and type 2 diabetes support the importance of body fatness as a contributing factor to the occurrence of diabetes and its complications.4 Furthermore, adipose tissue is an active endocrine and immune organ whose dysfunction (adiposopathy or so-called sick fat) is promoted by excessive caloric balance. Thus, targeting of adiposopathy and not only excess bodyweight should be viewed as a main objective in the management of obese patients with type 2 diabetes.5
Both obesity and type 2 diabetes are associated with many medical complications, especially cardiovascular disease,6 which substantially increase global health-care costs.1 Aggressive treatment, especially prevention of weight gain and ideally facilitation of weight reduction, can minimise and reduce diabetes-associated complications.7 However, weight loss and maintenance are challenging in obese people without diabetes, and even more so in obese people with type 2 diabetes.8
The close link between type 2 diabetes and excess bodyweight emphasises the need to consider the weight effects of different treatment regimens, besides their effects on glucose homoeostasis.9 A shift from a glucocentric to a weight-centric management of type 2 diabetes can be proposed, which emphasises the urgent need for new treatment strategies.10, 11 Some glucose-lowering drugs cause weight loss and some (albeit fewer) anti-obesity drugs improve glucose tolerance; thus, in this Review, we explore the overlapping pathophysiology of obesity and type 2 diabetes and also how the various treatments can, alone or in combination, combat the dual burden of these diseases. We will focus on lifestyle and drug therapy; the notable success of bariatric or metabolic surgery in combating obesity and type 2 diabetes has been covered elsewhere.12
Section snippets
Effect of weight changes on type 2 diabetes
The excess risk for diabetes with even modest weight gain is substantial and absolute weight gain during adulthood is a significant independent risk factor for type 2 diabetes.7 Intentional weight loss is associated with reduced insulin resistance and a subsequent reduction in glucolipotoxicity, which improves overall glucose homoeostasis.4, 13 In both the Finnish and US diabetes prevention programmes, weight loss gradually reduced the risk of type 2 diabetes, and even modest weight loss
Diet alone
Obesity is usually caused by excess calorie intake in relation to energy expenditure,3 so its treatment should mainly focus on healthy diet and increased physical activity, especially in the presence of type 2 diabetes (figure 2).39 However, implementation and maintenance of the lifestyle changes associated with weight loss can be challenging for many patients.24 Various weight loss strategies with follow-up for at least 6 months have been assessed in people with type 2 diabetes, with varying
Anti-obesity drugs with positive effects on diabetes
Although the obesity epidemic is continually expanding, at very high costs for health-care systems, very few options are available for the pharmacotherapy of obesity because most anti-obesity drugs developed so far have poor efficacy and safety profiles.48 However, several such drugs have shown potential in the prevention and management of type 2 diabetes,49 although the long-term health benefits remain unclear.
Most drugs used as anti-obesity agents have been withdrawn because of safety issues.
Pramlintide
Pramlintide is an analogue of the pancreatic hormone amylin, which is deficient in patients with type 2 diabetes.36 Through mechanisms similar to those of amylin, pramlintide (120–240 μg three times daily) improves overall glycaemic control and reduces bodyweight in patients with type 2 diabetes (figure 3, appendix p 5). In addition to reducing postprandial glucose concentrations, pramlintide treatment is also associated with improvements in markers of oxidative stress and cardiovascular risk.
The future for pharmacology of type 2 diabetes and obesity
Novel pharmacological treatments are under investigation as potential treatments for obesity and type 2 diabetes.48, 50 There are two main avenues of investigation: the first targets the CNS to reduce food intake (with drugs including naltrexone plus bupropion, tesofensine, and zonisamide), but again with the risk of frequent adverse events;95 the second is more innovative and targets complex interrelated hormonal pathways (brain, gut, and adipose tissue) involved in weight regulation and
Conclusions
The management of the obese patient with diabetes remains challenging, but, in any case, weight reduction should be regarded as a key objective. Lifestyle interventions for weight loss are recommended for most patients with type 2 diabetes to improve glycaemic control and reduce associated risk factors for complications. Even modest weight loss can significantly improve glucose homoeostasis and reduce cardiometabolic risk factors, although achievement and especially maintenance of 5–10%
Search strategy and selection criteria
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