A 44-year-old man comes to the office for follow-up of type 2 diabetes mellitus. He was diagnosed with diabetes 4 years ago and has been taking metformin since then. Six months ago, a new antidiabetic agent was added due to suboptimal glycemic control. Today, the patient is happy because he has lost 7 kg (15.4 lb) without any changes in diet or activity since the new therapy was started. His only symptoms are occasional nausea, vomiting, and a prolonged sensation of fullness after eating. Vital signs are within normal limits with no orthostatic changes. BMI is 34 kg/m². Physical examination shows normal heart and lung sounds, a nontender abdomen, and normal deep tendon reflexes and sensory examination. Laboratory testing reveals normal renal function studies and hemoglobin A1c of 7.2%. If this patient's weight loss is due to the new medication, which of the following agents is most likely responsible?

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11ec160b_3bb2_136c_9249_5d98ac6cc93d_MD0001_00 This patient with uncontrolled diabetes on metformin therapy was started on a second medication to improve his glycemic control. The new agent was associated with significant weight loss, a side effect that is characteristic of glucagon-like peptide-1 (GLP-1) agonists (eg, exenatide, liraglutide). GLP-1 is secreted by intestinal L cells in response to food intake and regulates glucose by slowing gastric emptying, suppressing glucagon secretion, and increasing glucose-dependent insulin release. It acts through cell surface receptors that are coupled with a G protein-adenylyl cyclase system. Native GLP-1 is degraded by dipeptidyl peptidase-4 (DPP-4), but synthetic GLP-1 agonists are resistant to degradation, allowing for a prolonged therapeutic effect. Although insulin secretion is increased by GLP-1 agonists, most patients lose weight due to enhanced satiety and a prolonged feeling of fullness following meals; this effect is also seen in patients who do not have diabetes. GLP-1 agonists are administered parenterally. Adverse effects include nausea and vomiting (due to delayed gastric emptying) and pancreatitis, but the risk of hypoglycemia is low because insulin secretion is not stimulated when circulating glucose levels are normal. (Choice A) Basal-bolus insulin therapy is effective in patients with even the most poorly controlled diabetes (eg, hemoglobin A1c >10%). It has few side effects but is typically associated with significant weight gain. (Choice B) DPP-4 inhibitors (eg, sitagliptin) are oral agents that block degradation of endogenous GLP-1. They share several side effects with GLP-1 agonists (eg, nausea), but are generally less potent and typically do not induce noticeable weight loss. (Choice D) Sulfonylureas directly stimulate pancreatic insulin secretion independent of circulating glucose levels. They typically cause weight gain and carry a risk of hypoglycemia. (Choice E) Thiazolidinediones (eg, pioglitazone) are peroxisome proliferator-activated receptor-gamma agonists that increase transcription of certain insulin-responsive genes and decrease insulin resistance. Because they do not promote insulin release, they do not cause hypoglycemia, but common side effects include fluid retention and weight gain. Educational objective: Glucagon-like peptide-1 (GLP-1) is secreted by intestinal L cells in response to food intake and regulates glucose levels by slowing gastric emptying, suppressing glucagon secretion, and increasing glucose-dependent insulin release. GLP-1 agonists are parenteral antidiabetic agents that can improve glycemic control with low risk of hypoglycemia. They are also associated with significant weight loss unlike many other antidiabetic agents. __________ References: GLP-1 receptor agonists: nonglycemic clinical effects in weight loss and beyond. (http://www.ncbi.nlm.nih.gov/pubmed/25959380)

A 44-Year-Old Man Comes to the Office for Follow-Up of Type