GLP 1

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GLP-1 Agonists: Increasing Effective Insulin Release

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

The pathophysiology of type 2 diabetes mellitus is complex, consisting of

far more physiologic defects than simple insulin resistance and beta-cell

dysfunction....

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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.

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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.

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.

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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 emptying3,4.

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.

References:

1. J Am Osteopath Assoc February 1, 2011 vol. 111 no. 2.

www.jaoa.org/content/111/2_suppl_1/eS10.full. Accessed May 24,2012