Glucagon-Like Peptide 1 Drugs as Second-Line Therapy for Type 2 Diabetes

Opinion EDITORIAL LESS IS MORE Glucagon-Like Peptide 1 Drugs as Second-Line Therapy for Type 2 Diabetes Peter C. Butler, MD Two relatively new classes of therapeutics, dipeptidyl peptidase-4 (DPP-4) inhibitors and glucagon-like peptide 1 (GLP-1) agonists (Table 1 and Table 2), have been widely adopted in practice for diabetes management based on clinical trial evidence dem- onstrating effective glycos- Related articles ylated hemoglobin control, benefits for weight manage- ment, and low risk of hypoglycemia. It has been suggested that these agents may also reduce risk for cardiovascular outcomes among patients with diabetes. This benefit has recently been reported in a placebo control randomized clinical trial (RCT) for the GLP-1 agonist Liraglutide (Victoza) (A). GLP-1 agonists amplify glucose-mediated insulin secre- tion, whereas DPP-4 inhibitors enhance and prolong the action of endogenously secreted GLP-1. While the first drug of choice in type 2 diabetes is metfor- min, many patients require additional therapy to adequately manage blood glucose levels, and the choice of second-line therapies is best tailored to individual patients. For example, relatively lean individuals with diabetes not controlled by met- formin are good candidates for a sulfonylurea or, if neces- sary, insulin. In contrast, there is clearly a need an alternative to simply escalating the dose of insulin in obese patients with diabetes who are unable to sustainably alter their lifestyle to achieve weight reduction. Escalating insulin doses in such in- dividuals is often ineffective, may exacerbate weight gain, and has been postulated to contribute to the increased risks of car- diovascular disease and cancer in obese patients with type 2 diabetes. 1 Gastric bypass surgery is increasingly advocated for these patients, but is available only to a minority and may be associated with significant complications. 2 Recently, Vanderheiden and colleagues 3 reported a small 6-month trial among patients with morbid obesity (body mass index [calculated as weight in kilograms divided by height in meters squared], 41) and poorly controlled type 2 diabetes pre- scribed high-dose insulin who were randomized to the addi- tion of the GLP-1 mimetic liraglutide or placebo. The addition of liraglutide improved glycemic control without weight gain and reduced insulin dosage, breaking the cycle of escalating insulin doses and progressive weight gain. Approximately a third of patients receiving liraglutide had gastrointestinal tract adverse effects, such as nausea, in the first weeks of therapy, but in most these resolved. There was also an increase in pan- creatic lipase levels, reproducing findings observed in larger RCTs, and raising the issue of potential adverse effects of GLP-1 drugs on the exocrine pancreas, addressed by Azoulay and colleagues 4 in this issue of JAMA Internal Medicine. This impressively large study combined retrospective ob- servational data from 7 consortiums and found no increased risk of pancreatitis in users of GLP-1–based drugs (DPP-4 in- hibitors or GLP-1 mimetics) compared with users of 2 or more other oral antidiabetic drugs. The same group also recently found no increased risk of pancreatic cancer with GLP-1– based therapy in the same study population. 5 The possibility of GLP-1–induced pancreatitis first came up as a signal in the Table 1. GLP-1 Receptor Agonists Characteristic Albiglutide Dulaglutide Exenatide Exenatide ER Liraglutide Trade name Tanzeum Trulicity Byetta Bydureon Victoza, Saxenda Initial adult dose 30 mg subcutaneously once weekly 0.75 mg subcutaneously once weekly 5 μg subcutaneously twice daily 2 mg subcutaneously once weekly 0.6 mg subcutaneously once daily Maintenance adult dose 30 to 50 mg subcutaneously once weekly 0.75 to 1.5 mg subcutaneously once weekly 10 μg subcutaneously twice daily 2 mg subcutaneously once weekly 1.2 to 1.8 mg (Victoza); 3 mg (Saxenda) subcutaneously once daily Abbreviation: GLP, glucagon-like peptide. Table 2. DPP-4 Inhibitors Characteristic Alogliptin Linagliptin Saxagliptin Trade name Nesina Tradjenta Onglyza Januvia Usual dosage 25 mg once daily 5 mg once daily 2.5 or 5 mg once daily 100 mg once daily jamainternalmedicine.com Sitagliptin Abbreviation: DPP-4, dipeptidyl peptidase-4. (Reprinted) JAMA Internal Medicine Published online August 1, 2016 Copyright 2016 American Medical Association. All rights reserved. Downloaded From: http://archinte.jamanetwork.com/ by a University of California - Los Angeles User on 08/19/2016 E1