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Weight Management in Type 2 Diabetes: Current and Emerging Approaches to Treatment

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Weight Management in Type 2 Diabetes: Current and Emerging Approaches to Treatment Diabetes Care Volume 38, June 2015 1161 Weight Management in Type 2 Luc Van Gaal1 and Andre´ Scheen2 Diabetes: Current and Emerging Approaches to Treatment Diabetes Care 2015;38:1161–1172 | DOI: 10.2337/dc14-1630 Diabetes is a growing global health concern, as is obesity. Diabetes and obesity are intrinsically linked: obesity increases the risk of diabetes and also contributes to disease progression and cardiovascular disease. Although the benefits of weight loss in the prevention of diabetes and as a critical component of managing the condition are well established, weight reduction remains challenging for individuals with type 2 diabetes due to a host of metabolic and psychological factors. For many patients, lifestyle intervention is not enough to achieve weight loss, and alternative options, such as pharmacotherapy, need to be considered. However, many traditional glucose-lowering medications may lead to weight gain. This article focuses on the potential of currently available pharmacological strategies and on emerging approaches in development to support the glycemic and weight-loss goals of individuals with type 2 diabetes. Two pharmacotherapy REVIEW types are considered: those developed primarily for blood glucose control that have a favorable effect on body weight and those developed primarily to induce weight loss that have a favorable effect on blood glucose control. Finally, the potential of combination therapies for the management of obese patients with type 2 diabetes is discussed. Obesity and diabetes are intimately linked (1). Obesitydin particular abdominal obesitydis a major driver in the development of diabetes and cardiovascular dis- ease (2), with the increasing prevalence of obesity mirrored by the rising prevalence of diabetes (3). In addition, obesity and overweight are associated with multiple comorbidities (4). Weight reduction, therefore, is a key therapeutic goal in both the prevention and management of type 2 diabetes (5). Weight reduction with intensive lifestyle intervention (ILI) has been shown to reduce the incidence of diabetes by 58% (6). For individuals with diabetes, studies (Look AHEAD [Action for Health in Diabetes], N = 5,145) have shown that a loss of 1 – fi Department of Endocrinology, Diabetology 5 10% of body weight can improve tness, reduce HbA1c levels, improve cardio- and Metabolism, Antwerp University Hospital, vascular disease (CVD) risk factors, and decrease use of diabetes, hypertension, and Antwerp, Belgium lipid-lowering medications (7,8). Additional benefits of weight loss include reduction 2Department of Diabetes, Nutrition and Meta- of depression symptoms and remission or reduced severity of obstructive sleep apnea bolic Disorders and Clinical Pharmacology Unit, (9,10). Greater clinical improvements are observed with greater weight loss (8). University of Liege,` Liege,` Belgium Guidelines recommend lifestyle modifications as the foundation of weight loss. Corresponding author: Luc Van Gaal, luc.van [email protected]. Although ILI produces clinically beneficial weight loss for many patients, the reality is that ILI is difficult to achieve and maintain over the long-term for most patients. Even in Received 3 July 2014 and accepted 22 February 2015. an optimal clinical trial setting, such as Look AHEAD, one-third of all patients were © 2015 by the American Diabetes Association. unable to achieve at least 5% weight loss after 1 year (11). Most individuals with Readers may use this article as long as the work diabetes tend to lose weight over a period of 4–6months,andlose4–10% of their is properly cited, the use is educational and not baseline weight before experiencing a plateau in weight loss, generally followed by a for profit, and the work is not altered. 1162 Weight Management in Type 2 Diabetes Diabetes Care Volume 38, June 2015 weight regain (12). In Look AHEAD, half of the emotional and cognitive control re- (13,14). The resultant decrease in blood all patients who lost 5% of their body lated to food intake (22). These factors glucose levels corresponds with a weight after 1 year of ILI regained some mean that sustained weight loss can be decrease in glycosuria, a major con- or all of their initial weight loss by year 8 even more difficult to achieve for over- tributing factor to the weight gain (11). Long-term weight loss is still difficult weight and obese people with diabetes. observed in patients treated with con- to achieve for many patients, and alter- Although improvement of glucose con- ventional antihyperglycemic agents. native options, such as pharmacotherapy, trol remains the primary goal in pharma- Treatment with certain classes of ther- should be considered for patients who cological treatment of type 2 diabetes, apies and several baseline patient char- cannot lose weight with lifestyle modifi- avoidance of pharmacologically induced acteristics are predictive of weight gain cation alone. weight gain should also be considered (Table 2) (24). Many conventional glucose-lowering as a clinically important goal (23). Guide- Substantial increases in weight have agents commonly result in weight gain lines recommend lowering HbA1c to been observed in patients treated with (13,14). In addition to antihyperglyce- #6.5% (48 mmol/mol) or #7.0% (53 insulin (24). The mechanisms responsi- mic agents, some antipsychotic medica- mmol/mol), which often necessitates in- ble for insulin-induced weight gain are tions used to treat comorbid psychiatric sulin escalation or use of combination varied, complex, and partially unknown. disorders and antiepileptic drug deriva- therapies to achieve this goal (5). When Subcutaneous administration bypasses tives used to treat diabetic neuropathy considering combination therapies, clini- hepatic insulin sensors and leads to may lead to weight gain (15,16). Meta- cians should remain aware of the weight physiologically abnormal levels of insu- bolic, psychological, and behavioral fac- gain that is often associated with diabetes lin exposure at peripheral tissues, which tors also affect the ability of people with medications. may disrupt the homeostatic regulation diabetes to lose weight (17,18). In addi- The focus of this review article is to discuss of body weight (25). A comparative tion, homeostatic control of body weight the potential for pharmacotherapiesd study showed that subcutaneous deliv- is regulated by a complex neurohor- those currently available and those in ei- ery of insulin leads to more weight gain d monal system that involves a feedback ther late- or early-stage development to than intraperitoneal delivery (26). Pre- loop between the brain and peripheral support the glycemic and weight loss goals clinical research has shown that insulin tissues, and perturbations to this system of people with diabetes. Although we rec- has a role in the central nervous system, affect weight (19). Diet-induced weight ognize that bariatric surgery may offer a where it regulates satiety signals and loss increases the orexigenic hormones potential treatment solution for some pa- suppresses appetite, and it is suggested ghrelin and gastric inhibitory/glucose- tients (1), this topic will not be considered thatthesefunctionsmaybeimpaired dependent insulinotropic polypeptide in the present review. in type 2 diabetes (27). Insulin-induced (GIP) and decreases anorexigenic hor- hypoglycemia is a further factor; mild mones leptin, peptide YY (PYY), cholecys- WEIGHT GAIN WITH hypoglycemia in rats stimulates appe- tokinin (CCK), amylin, and glucagon-like CONVENTIONAL THERAPIES tite and leads to the increased consump- peptide 1 (GLP-1) (20,21). Improved Many pharmacological agents used tion of calories (28). Some patients glycemic control decreases glycosuria, in the treatment of diabetes directly participate in compensatory overeating which may impair weight loss. Functional contribute to weight gain through their because of their fear of hypoglycemia changes within the brain also affect glucose-lowering mechanisms (Table 1) (29). Preclinical data indicate that Table 1—Antidiabetes therapies associated with weight gain Drug class Mechanism of action How mechanism of action leads to weight gain Insulin* (25,27,28,30,32) c Regulates glucose metabolism c Causes hypoglycemia, a potent stimulus to feed c Lowers blood glucose by facilitating peripheral c Perceived risk of hypoglycemia may lead to glucose uptake, primarily by skeletal compensatory overeating muscle and fat c Glycemic control reverses the negative energy balance c Inhibits hepatic glucose production from glycosuria c Inhibits lipolysis c Insulin is an anabolic hormone and may lead to changes c Inhibits proteolysis in metabolism that encourage weight gain c Enhances protein synthesis Sulfonylurea (24,32) c Stimulates release of insulin from pancreatic c Glycemic control reverses the negative energy balance b-cells from glycosuria c May also have mild extrapancreatic effects c Causes hypoglycemia, a potent stimulus to feed such as increasing the sensitivity of peripheral tissues to insulin TZD (32–35) c Decreases insulin resistance in the periphery and c Increases adipocyte differentiation in the liver c Improves glycemic control c Redistributes fat (less visceral, more subcutaneous) c Increases plasma volume *Most insulins are associated with weight gain; however, insulin detemir has been shown to have a reduced weight-gain effect compared with other insulins (111). care.diabetesjournals.org Van Gaal and Scheen 1163 Table 2—Predictors of weight gain* through the activation of peroxisome – Baseline patient
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