GLP-1 Agonists: Increasing Effective Insulin Release

Our understanding of this progressive disease has moved from a "dual defect" to an "ominous octet" description. This multi-factor concept may explain the difficulty in achieving and maintaining glycemic goals with traditional therapies. Glucagon-like peptide-1 (GLP-1) agonists, which improve insulin secretion, decrease glucagon secretion, increase satiety (and therefore decrease food intake), and may have beneficial effects on beta-cell function, represent an important addition to treatment options. Their glucose-dependent mechanism limits the risk for hypoglycemia, and they are associated with weight loss. GLP-1 agonists may be used alone in patients intolerant of metformin or in combination with metformin, thiazolidinediones, and sulfonylureas (or in any combination thereof). Concomitant use of dipeptidyl-peptidase-4 inhibitors (DPP-4) is not recommended because they have a similar basis of action.

Incretins are peptide hormones secreted by entero-endocrine cells in the gastrointestinal tract. Incretins modulate pancreatic islet secretions as part of the "entero-insular axis," and their primary function is to regulate postprandial nutrient utilization and storage. There are several incretin hormones, but GLP-1 appears to be the major player in type 2 diabetes and is best understood. The primary actions are to regulate insulin and glucagon secretion only when plasma glucose exceeds normal fasting levels. Thus, a deficiency of GLP-1 is now considered as part of the pathophysiology of type 2 diabetes¹.

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The pharmacologic effects of GLP-1 are noted in the next figure. The importance of GLP-1 is demonstrated in experiments showing that it accounts for up to 60% of postprandial insulin secretion in healthy individuals.

Strategies to correct the incretin defects in patients with type 2 diabetes include replacement of GLP-1 with a long-acting analog that resists degradation and development of drugs that inhibit the enzyme DPP-4, which breaks down GLP-1.

The first strategy, exenatide was the first GLP-1 analog introduced for the treatment of patients with type 2 diabetes. Liraglutide then became available, and several other GLP-1 analogs are in development. The administration of pharmacologic quantities of GLP-1 analogs result in plasma activities that are 5- to 7-fold higher than physiologic levels. At these levels, the effects on gastric emptying, satiety, and decrease in food intake are seen. Glucagon-like peptide-1 receptor agonists induce glucose-dependent insulin secretion, beta-cell protection, and other extraglycemic benefits such as weight loss and improvement in markers of cardiovascular risk. The half-life of exenatide necessitates twice-daily dosing, while the longer half-life of liraglutide allows once-daily dosing. Longer-acting GLP-1 analogs that can be administered once each month are currently in clinical trials.

Glucagon is synthesized and released from pancreatic alpha cells and from intestinal L cells of the ileum and colon. Pancreatic glucagon is a 29–amino acid peptide that regulates glucose homeostasis via gluconeogenesis, glycogenolysis, and lipolysis and is counter regulatory to insulin. The gene for glucagon encodes not only preproglucagon but also glucagon-like peptides (GLPs). This precursor peptide consists of a signal peptide, a glucagon-related polypeptide, glucagon, and GLP-1 and GLP-2. Tissue-specific peptide processing occurs through prohormone convertases that produce glucagon in the pancreas and GLP-1 and GLP-2 in the intestine².

Glucagon and GLP-1 regulate glucose homeostasis. Glucagon is released from the endocrine pancreas in response to a meal and binds to G protein-coupled receptors on skeletal muscle and the liver to exert its glucoregulatory effects. GLP-1 stimulates insulin secretion and augments the insulin-releasing effects of glucose on the pancreatic beta cell. GLP-1 analogs have been developed for the treatment of type II diabetes mellitus. A human GLP-1 analog improves beta cell function and can lower body weight in patients with type II diabetes².

The enthusiasm for potential therapeutic use of GLP-1 derives from studies demonstrating that unlike GIP, the glucose-lowering actions of GLP-1 are preserved in patients with type 2 diabetes. Similarly, the actions of GLP-1 on inhibition of gastric emptying are also preserved in subjects with poorly controlled type 2 diabetes. Although the actions of GLP-1 on the beta-cell are preserved yet modestly diminished in T2DM, the diabetic alpha-cell retains near normal responsivity to low dose GLP-1 infusion, with inhibition of glucagon secretion seen to a similar extent in diabetic vs. non-diabetic subjects. Hence, modestly diminished GLP-1 action in diabetic subjects does not likely contribute to the defective glucose-stimulated glucagon suppression that remains a characteristic of diabetic subjects³.

Native GLP-1 has been infused by the subcutaneous route (4.8 pmol/kg/min) using a portable insulin pump in a non-randomized study of subjects with type 2 diabetes over the age of 40 (mean age 55) with mean initial HbA1c of about 9%, and mean fasting glucose ~14 mM. Oral antidiabetic medication was discontinued 3 weeks prior to the study. In GLP-1-infused subjects, plasma levels of GLP-1 rose from ~ 19 pM to 197 pM by week 1, and 282 pM at week 6. Six weeks of GLP-1 infusion resulted in significant improvements in fasting (decrease of 4.3 mM glucose) and 8 h mean glucose (decrease of 5.5 mM), fasting and mean 8h free fatty acids, a reduction in HbA1c from 9.2% to 7.9%, a decrease in fructosamine from 349 uM to 282 uM, and a reduction in gastric emptying^3,4.

In one study⁵ where they assessed the efficacy of eight classes of diabetes medications used in current clinical practice [metformin, sulphonylureas, alpha-glucosidase inhibitors, thiazolidinediones, glinides, dipeptidyl peptidase-4 inhibitors, glucagon-like peptide-1 (GLP-1) analogues and insulin analogues] to reach the HbA1c target <7% in type 2 diabetes. The results were a total of 218 RCTs (339 arms and 77 950 patients) met the inclusion criteria. The proportion of patients who achieved the HbA1c goal ranged from 25.9% (95% CI 18.5–34.9) with alpha-glucosidase inhibitors to 63.2% (54.1–71.5) with the long-acting GLP-1 analogue. There was a progressive decrease of the proportion of patients at target for each 0.5% increase in baseline HbA1c, ranging from 57.8% for HbA1c ≤7.5% to 20.8% for HbA1c ≥10% (p for trend 9.0% with no further decrease, whereas for non-insulin drugs the relationship was continuous without any evidence of plateau⁵.

It is obvious from the information above that the use of GLP-1 analogs can make a great difference in diabetes management and that the effective lowering of postprandial glucose is directly related to the ability of these analogs to increase glucose dependent insulin secretion.

Written by Wael Diab, RPh, PharmD Candidate University of Colorado College of Pharmacy

Copyright © 2012 Diabetes In Control, Inc.