[acb-diabetics] GLP 1

Sun May 27 14:01:25 EDT 2012

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 

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