MONOTHERAPY WITH LIRAGLUTIDE, A ONCE-DAILY HUMAN GLP-1 ANALOG, PROVIDES SUSTAINED REDUCTIONS IN A_1C, FPG, AND WEIGHT COMPARED WITH GLIMEPIRIDE IN TYPE 2 DIABETES: LEAD-3 MONO 2-YEAR RESULTS [162-OR]

Garber AJ, Henry R, Ratner R, Hale P, Chang CT, Bode B; Houston, TX; San Diego, CA; Hyattsville, MD; Princeton, NJ; Atlanta, GA

Weight gain, hypoglycemia, and other adverse effects of diabetes therapy can be difficult for patients to tolerate, contribute to poor treatment adherence, and may lead clinicians to avoid intensifying treatment despite inadequate control of blood glucose.¹ The incretins are a family of hormones that are abnormally regulated in patients with type 2 diabetes, and that have emerged as significant therapeutic targets in the treatment of these patients. The incretins glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) increase insulin secretion and decrease glucagon secretion in response to intestinal absorption of glucose, and they also promote pancreatic ß-cell survival and proliferation.^1,2 Drugs that act on the incretin system include analogues of GLP-1 and inhibitors of the enzyme dipeptidyl peptidase-4 (DPP-4), an incretin inactivator.

Liraglutide is a GLP-1 analogue that has recently been developed for the once-daily treatment of type 2 diabetes. Liraglutide stimulates insulin release only when blood glucose levels are high, and therefore has a low risk of hypoglycemia.³ It may also promote satiety by slowing gastric emptying and by acting at GLP-1 receptors of the central nervous system.^3,4 Liraglutide has been evaluated in a series of clinical studies in a variety of combination regimens that have included metformin, glimepiride, and rosiglitazone.¹ Monotherapy with liraglutide was directly compared to glimepiride monotherapy in the recent LEAD-3 clinical trial. After 52 weeks, glycosylated hemoglobin (A_1c) decreased by an average of 0.51% with glimepiride, 0.84% with liraglutide 1.2 mg (P = .0014), and 1.14% with liraglutide 1.8 mg (P <.0001).⁵

At the 2009 American Diabetes Association 69th Scientific Sessions, the LEAD-3 investigators presented their results from a 1-year open-label extension phase of this clinical trial. After a total of 2 years, patients who received glimepiride exhibited a mean decrease in A_1c values from baseline of 0.6%, compared to 0.9% with liraglutide 1.2 mg (P = .037) and 1.1% with liraglutide 1.8 mg (P = .0016). A target A_1c value of less than 7% was achieved by 37% of patients receiving glimepiride, 44% with liraglutide 1.2 mg (P = .0269), and 58% with liraglutide 1.8 mg (P = .0054). The incidence of minor hypoglycemic events (defined as a plasma glucose concentration <56 mg/dL) was approximately 6-fold greater with glimepiride than with liraglutide (mean of 1.76 events per patient per year with glimepiride vs 0.21 and 0.23 events for patients in the liraglutide 1.8- and 1.2-mg groups, respectively; P ≤.0001).

Many patients with diabetes are overweight, and the risk of weight gain with therapy is a significant concern. In this study, the mean body mass index of patients at the beginning of treatment was approximately 33 kg/m². Patients in the glimepiride group gained an average of 1.1 kg over the course of the 2-year study, compared to an average weight loss of 2.7 kg for patients in the liraglutide 1.8-mg group and 2.1 kg for the liraglutide 1.2-mg group. The most common adverse events with liraglutide included transient nausea and vomiting.

Liraglutide is not approved in the United States. It has been approved in Europe and Japan, and approval by the US Food and Drug Administration is expected soon.⁶

References
1. Rossi MC, Nicolucci A. Liraglutide in type 2 diabetes: from pharmacological development to clinical pracctice. Acta Biomed. 2009;80:93-101.
2. Drucker DJ. The biology of incretin hormones. Cell Metab. 2006;3:153-165.
3. Gallwitz B. Therapies for the treatment of type 2 diabetes mellitus based on incretin action. Minerva Endocrinol. 2006;31:133-147.
4. Barnett AH. New treatments in type 2 diabetes: a focus on the incretin-based therapies. Clin Endocrinol. 2009;70:343-353.
5. Garber A, Henry R, Ratner R, et al. Liraglutide versus glimepiride monotherapy for type 2 diabetes (LEAD-3 Mono): a randomised, 52-week, phase III, double-blind, parallel-treatment trial. Lancet. 2009;373:473-481.
6. Kerr M. GLP-1 analog outperforms sulfonylurea in type 2 diabetes. Available at: http://www.theheart.org/article/979165.do. Accessed September 24, 2009.