Weight effect of current and experimental drugs for diabetes mellitus: from promotion to alleviation of obesity.
Two landmark intervention studies, the Diabetes Control and Complications Trial (DCCT) in patients with type 1 diabetes mellitus and the United Kingdom Prospective Diabetes Study (UKPDS) in patients with type 2 diabetes mellitus, have unequivocally demonstrated that intensive diabetes therapy reduces the risk of long-term diabetic complications. As a result, the commonly accepted treatment goal for most patients with diabetes is the achievement and maintenance of glycemic control that is as close to the normal range as safely possible. Important adverse effects of intensive diabetes therapy, particularly when the treatment includes insulin or several of the oral antihyperglycemic agents, are an increased risk of hypoglycemia and undesired weight gain. Improvement of glycemic control with insulin, insulin secretagogues (sulfonylureas, meglitinides), and insulin sensitizers (thiazolidinediones) is often accompanied by weight gain. The etiology of this weight gain is likely multifaceted, including a reduction of glucosuria, increased caloric intake to prevent hypoglycemia, and anabolic effects on adipose tissue. Biguanides and alpha-glucosidase inhibitors have a neutral or even positive effect (decrease) on weight, which may partly be attributable to their non-insulinotropic mechanism of action, a modest effect on satiety, and to their gastrointestinal adverse effect profile. Several antihyperglycemic agents that are currently in clinical development may improve glycemic control in conjunction with weight reduction. These include an analog of the pancreatic beta-cell hormone amylin (pramlintide), as well as glucagon-like peptide-1 (GLP-1) and exendin, and their analogs. Pharmacological agents with antihyperglycemic and positive weight effects have the potential to become important additions to our therapeutic armamentarium, in that they may help to achieve glycemic targets while addressing the long-standing clinical problem of weight gain as an adverse effect of intensive diabetes therapy.
Purnell
Jonathan Q
JQ
Division of Endocrinology, Diabetes, and Clinical Nutrition, Oregon Health & Science University, Portland, Oregon 97201, USA. purnellj@ohsu.edu
Weyer
Christian
C
D000682:Amyloid / Q000627:therapeutic use; D001549:Benzamides / Q000627:therapeutic use; D001645:Biguanides / Q000627:therapeutic use; D001835:Body Weight / Q000187:drug effects*; D003920:Diabetes Mellitus / Q000188:drug therapy*; D003922:Diabetes Mellitus, Type 1 / Q000188:drug therapy; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy; D005934:Glucagon / Q000627:therapeutic use; D052216:Glucagon-Like Peptide 1; D065089:Glycoside Hydrolase Inhibitors; D006801:Humans; D007004:Hypoglycemic Agents / Q000009:adverse effects*; D007328:Insulin / Q000009:adverse effects; D058228:Islet Amyloid Polypeptide; D009765:Obesity / Q000139:chemically induced* / Q000188:drug therapy*; D010446:Peptide Fragments / Q000627:therapeutic use; D011498:Protein Precursors / Q000627:therapeutic use; D013453:Sulfonylurea Compounds / Q000009:adverse effects; D045162:Thiazolidinediones / Q000627:therapeutic use; D015430:Weight Gain / Q000187:drug effects
D000682:Amyloid; D001549:Benzamides; D001645:Biguanides; D065089:Glycoside Hydrolase Inhibitors; D007004:Hypoglycemic Agents; D007328:Insulin; D058228:Islet Amyloid Polypeptide; D010446:Peptide Fragments; D011498:Protein Precursors; D013453:Sulfonylurea Compounds; D045162:Thiazolidinediones; D052216:Glucagon-Like Peptide 1; C030516:meglitinide; D005934:Glucagon