Liraglutide

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Liraglutide is a glucagon-like peptide-1 (GLP-1) analog that is being developed by Novo Nordisk for the treatment of type 2 diabetes.

Liraglutide (NN2211) – Enters Phase 2 Clinical Trials

Currently in phase 2 clinical trials, liraglutide is based on a naturally occurring hormone called Glucagon-Like Peptide-1 (GLP-1). Studies to date suggest liraglutide improves control of blood glucose (glycemic control) and may have advantages over current therapies:

• • It acts in a glucose-dependent manner, meaning that it will stimulate insulin secretion only when blood glucose levels are higher than normal

• • It has the potential for beta cell regeneration (seen in animal studies)

• • It shows negligible risk of hypoglycemia, and only mild and transient side effects

• • It decreases appetite and maintains body weight

• • It is suitable for once-daily administration

Glucagon-Like Peptide-1 Liraglutide is a long-acting derivative of GLP-1, a naturally occurring peptide hormone discovered in the early nineteen eighties. Physiologically, GLP-1 is released from the GI tract upon ingestion of food. GLP-1 has four main mechanisms of action which all work in a glucose-dependent manner:

• • It promotes the synthesis and release of insulin from the pancreas

• • It lowers blood levels of glucagon, a hormone that normally stimulates glucose production and release from the liver

• • It promotes feelings of satiety by slowing gastric emptying, which attenuates blood glucose surges following meals and decreases food intake

• • It inhibits death of insulin-producing pancreatic beta cells as well as stimulating growth, proliferation and neogenesis

• • The glucose-dependent activity (affecting both types 1 and 2) is important because it results in GLP-1 being more active when blood glucose is elevated, but being less active when blood glucose is normal or low. Thus, GLP-1 does not cause serious hypoglycaemia even at high doses.

Liraglutide (NN2211)

Liraglutide is the first once-daily GLP-1 derivative in development for the treatment of type 2 diabetes. GLP-1, in its natural form, is short-lived in the body (the half-life after subcutaneous injection is approximately 1 hour), so it is not very useful as a therapeutic agent. However, liraglutide is a ‘timed release’ form of GLP-1 with prolonged activity; the half-life after subcutaneous injection is 11–15 hours, making it suitable for once-daily dosing. ,

The prolonged action of liraglutide is achieved by attaching a fatty acid molecule at one position of the GLP-1 molecule, enabling it to bind to albumin within the subcutaneous tissue and bloodstream. The active GLP-1 is then released from albumin at a slow, consistent rate. Binding with albumin also results in slower degradation and reduced elimination of liraglutide from the circulation by the kidneys compared to GLP-1 in its natural form.

To date, liraglutide has been studied in animals and in humans, and is currently in phase 2 clinical trials. Some of the key findings include:

In men with type 2 diabetes, liraglutide effectively reduced fasting as well as meal-related glycaemia (12 hours after liraglutide administration) by increasing insulin secretion, delaying gastric emptying, and suppressing prandial glucagon secretion. In a study of 190 people with type 2 diabetes, those who took liraglutide maintained weight, whereas those who took the insulin secretagogue glimepiride gained weight as expected. The main side effects were gastrointestinal, and mild and transient; the risk of hypoglycaemia was very low

Liraglutide has also been shown to reduce food intake and promote weight loss in obese monkeys and other diabetic and/or obese animal models. , , , It has also been shown to reduce blood triglyceride levels in normal, obese and prediabetic rats12, Studies in diabetic rats and mice show that liraglutide increases beta cell mass13, , and reduces the death of beta cells (apoptosis or programmed cell death) ,

Liraglutide is a promising GLP-1 derivative in development for treatment of type 2 diabetes. Its multiple modes of action offer potential advantages over many current therapies. Studies in humans show it can improve glycaemic control, decrease appetite and maintain body weight, with minimal side effects. Its glucose-dependent stimulation of insulin secretion and inhibition of glucagon appear to improve glycaemic control while minimising the risk of hypoglycaemia. Studies in animals further suggest that liraglutide can inhibit beta cell death and stimulate their growth as well as lower blood triglyceride levels. It is anticipated that this new drug could be brought to market in 2006.

v • d • e Oral antidiabetic drugs and Insulin analogs (A10) Biguanides Metformin Sulfonylureas Carbutamide, Chlorpropamide, Glibenclamide (Glyburide), Gliclazide, Glimepiride, Glipizide, Gliquidone, Tolazamide, Tolbutamide Alpha-glucosidase inhibitors Acarbose, Miglitol, Voglibose Thiazolidinediones (TZD) Pioglitazone, Rivoglitazone†, Rosiglitazone, Troglitazone‡ Meglitinides Nateglinide, Repaglinide, Mitiglinide Dipeptidyl peptidase-4 (DPP-4) inhibitors Alogliptin†, Saxagliptin†, Sitagliptin, Vildagliptin Glucagon-like peptide-1 analog Exenatide, Liraglutide†, Albiglutide† Amylin analog Pramlintide Insulin analogs fast acting (Insulin lispro, Insulin aspart, Insulin glulisine), long acting (Insulin glargine, Insulin detemir), Inhalable insulin (Exubera) Dual PPAR agonists Aleglitazar†, Muraglitazar§, Tesaglitazar§ SGLT2 inhibitor Dapagliflozin†, Remogliflozin† †Undergoing clinical trials. ‡ Withdrawn from market. §Development halted.