Exenatide - A Lizard Hormone For Treating Diabetes
By - 12/09/2005
Mrs. Lakshmi Sivasubramaniam
Diabetes: Overview
Diabetes is a chronic metabolic disease characterized by high glucose (sugar) levels in the blood. Insulin, a hormone produced by the pancreas, regulates the amount of glucose in the blood.
In patients with diabetes, the body either does not produce enough insulin,
or does not adequately respond to the insulin it is producing. This causes blood
sugar levels to be higher than normal. Diabetes can be associated with serious
complications such as heart disease, blindness, kidney failure, stroke and lower-limb
amputations, but steps can be taken to control the disease and lower the risk
of complications.
Diabetes affects an estimated 194 million adults worldwide1 and more than 18 million in the United States. Approximately 90-95 percent of those affected have type 2 diabetes, a disease in which the body does not produce enough insulin and the cells in the body do not respond normally to the insulin.
Diabetes is of two types namely;
· Type 1 diabetes: Previously called insulin-dependent diabetes
mellitus (IDDM) or juvenile-onset diabetes) develops when the body’s immune
system destroys pancreatic beta cells which make insulin.
Type 1 diabetes usually occurs in children and young adults, who must have insulin delivered by injections or a pump in order to survive. Type 1 diabetes may account for 5% to 10% of all diagnosed cases of diabetes. Risk factors include autoimmune, genetic, and environmental factors.
Type 2 diabetes: Previously known as non insulin-dependent diabetes mellitus
(NIDDM) or adult-onset diabetes) develops gradually, and is usually caused by
a combination of impaired secretion of insulin and reduced sensitivity of the
body’s cells to insulin (insulin resistance). As a result, blood glucose levels
become elevated.
Type 2 diabetes usually occurs in adults, however it is increasingly being diagnosed in people at a younger age, even in childhood and adolescence. Type 2 diabetes may account for about 90% to 95% of all diagnosed cases of diabetes, and the prevalence is rising at an alarming rate throughout the world. This is believed to be due to increases in longevity, sedentary lifestyles and a dramatic upsurge in obesity.
Type 2 diabetes can be controlled. Therapeutic lifestyle management such as
following a careful diet and exercise program, and losing excess weight may
help, though oral medications are often necessary. Risk factors include older
age, obesity, a family history of diabetes, prior history of gestational diabetes,
impaired glucose tolerance, physical inactivity, and race/ethnicity. African
Americans, Hispanic/Latino Americans, American Indians, and some Asian Americans
and Pacific Islanders are at particularly high risk for type 2 diabetes.
Other types:
- Impaired Glucose Tolerance (IGT): Impaired Glucose Tolerance is an intermediate state between normal blood glucose control and type 2 diabetes. IGT is an early sign that a person’s carbohydrate metabolism is impaired. It carries a high risk of progressing to type 2 diabetes. IGT (and type 2 diabetes) result from a combination of impaired secretion of insulin and reduced sensitivity of the body’s cells to insulin (insulin resistance).
- Gestational diabetes: Gestational diabetes is a form of glucose intolerance diagnosed in some women during pregnancy, but usually disappears after the mother gives birth. Treatment is required to normalize blood glucose levels to avoid complications in the infant. Gestational diabetes occurs more frequently among African Americans, Hispanic/Latin Americans, and Native Americans. It is also more common among obese women and women with a family history of diabetes.
- Secondary diabetes: Secondary diabetes can result from other conditions such as specific genetic syndromes, surgery, drugs, malnutrition, infections, and other damage to or diseases of the pancreas.
Risk factors complications
How is diabetes diagnosed?
Type 1: Patients with type 1 diabetes usually develop symptoms over a short period of time, and the condition is often diagnosed in an emergency setting. Urinalysis of an acutely ill type 1 diabetic patient will detect high glucose levels, and high levels of ketones. Ketones are produced by the breakdown of fat and muscle, and they are toxic at high levels. Ketones in the blood cause a condition called "acidosis" (low blood pH). Blood glucose levels are also high.
Type 2: Patients with type 2 diabetes develop symptoms over a longer period of time. Type 2 diabetes is diagnosed when:
· The blood glucose is 126 milligrams per deciliter (mg/dl) or higher on two occasions after fasting (abstaining from food) for 8 or more hours; or
· The blood glucose level is 200 mg/dl or higher at any time between meals with symptoms of diabetes, such as increased thirst, urination, and fatigue; or
· A blood glucose level drawn two hours after drinking a 75-gram glucose solution is 200 mg/dl or higher.
There are many ways of treating diabetes by pharmacotherapy, yoga or homeopathy but what is new in the market is that a lizard hormone is now being tested for its use against Diabetes.
Exenatide (synthetic exendin-4)
Exenatide, also known as synthetic exendin-4, is a new agent for the treatment of type 2 diabetes. Clinical trials suggest that exenatide treatment decreases blood glucose toward target levels and is associated with weight loss.
Exenatide is a first-in-class drug candidate for the treatment of
type 2 diabetes. Exenatide is initially being developed to improve glucose control
in patients with type 2 diabetes who are not using insulin and are not achieving
target levels with diet and oral medications. In September 2002 Amylin announced
a global agreement with Eli Lilly and Company to collaborate on the development
and commercialization of exenatide.
If Exenatide is approved for clinical use it may enable type 2 diabetics
to effectively control their blood-glucose levels while reducing or eliminating
the risk of hypoglycaemia and weight gain.
Scientific Overview
Exendin-4, is a peptide made up of 39 amino acids. It is a powerful stimulator of a receptor known as GLP-1 (Glucagon Like Peptide – 1). Exendin-4, therefore has similar properties to GLP-1. It is also more potent than GLP-1. It regulates gastric emptying, insulin secretion, food intake, and glucagon secretion.
Although exendin-4 was originally found to stimulate amylase secretion from pancreatic acinar cells, subsequent experiments demonstrated that exendin-4 was a potent agonist for the mammalian GLP-1 receptor, consistent with the ~53% amino acid identity that exendin-4 shares with GLP-1.
Exendin-4 displays similar functional properties to native GLP-1, and regulates gastric emptying, insulin secretion, food intake, and glucagon secretion. Exendin-4 lowers blood glucose in normal rodents and in both mice and rats with experimental diabetes. Although the lizard exendin gene is distinct from the lizard proglucagon, a separate mammalian exendin gene has not been identified.
The available evidence suggests that exendin-4 exerts the majority of its glucose-lowering effects through the GLP-1 receptor. No convincing evidence to date supports the existence of a separate functional exendin receptor coupled to glucose homeostasis, although non-classical effects of GLP-1 and exendin have been observed in some experimental systems that lack the known GLP-1 receptor.
Exendin-4 is much more potent than native GLP-1, largely due to its improved PK profile as a result of resistance to DPP-IV-mediated inactivation. In contrast to GLP-1 which contains an alanine at position 2, exendin-4 has a glycine at position 2, hence it is not a substrate for DP IV and has a much longer t1/2 in vivo. The potent glucose-lowering properties of exendin-4, taken together with its comparatively prolonged duration of action, prompted studies employing exendin-4 for the treatment of patients with Type 2 diabetes.
A truncated version of exendin-4, exendin (9-39) binds to but does not activate the GLP-1 receptor, and functions as a GLP-1 receptor. Exendin (9-39) has been employed as a GLP-1R antagonists in multiple preclinical studies and in human experiments to probe the consequences of disrupting GLP-1R activation.
A long-acting form of exendin-4, designated Exenatide-LAR has been studied in single dose studies in 9 week old ZDF rats. In the absence of Exenatide, HbA1c increased rapidly over the 28 day study period. In contrast, a single injection of Exenatide LAR (a poly-lactide-glycolide microsphere suspension (3% peptide) containing 0, 1, 10, 100, 1,000, 3,000 or 9,000 ug Exenatide ) significantly reduced the rate of deterioration in glycemic control, together with an increased b cell responsivity to glucose, and an increase in insulin sensitivity
Source of Exenatide
The lizard Heloderma species, including H. horridum
and H. suspectum are native to several American states and are
poisonous. Lizard venom contains a number of highly bioactive peptides
including the peptides exendin-3 and exendin-4. These peptides
were named exendins by Eng and Raufman in that they were isolated from
an exocrine gland and were subsequently shown to have endocrine actions. Exendin-4
was initially isolated from the venom found in the saliva of a poisonous
lizard found in South America, known as the Gila monster. This lizard eats four
times a year. When it eats, exendin-4 secreted in the saliva causes it’s pancreas
to ‘switch on’.
Mechanism of Action
Exenatide is a potent 39-amino acid peptide that exhibits several anti-diabetic, or glucose lowering, actions. The effects on glucose control seen with exenatide treatment are thought to be due to several properties that are similar to those of the naturally occurring incretin hormone GLP-1. These actions include stimulating the insulin response in response to glucose and preventing glucagon (a hormone which raises blood sugar) release after meals. It is the first member of a new class of therapeutic medications known as incretin mimetic agents. Exenatide (synthetic exendin-4) is being investigated for its potential to address important unmet medical needs of many people with type 2 diabetes. Clinical trials suggest that exenatide treatment decreases blood glucose toward target levels and is associated with weight loss. The effects on glucose control seen with exenatide treatment are likely due to several actions that are similar to those of the naturally occurring incretin hormone GLP-1. These actions include stimulating the body’s ability to produce insulin in response to elevated levels of blood glucose, inhibiting the release of glucagon following meals and slowing the rate at which nutrients are absorbed into the bloodstream. In animal studies exenatide administration resulted in preservation and formation of new beta cells, the insulin-producing cells in the pancreas, which fail as type 2 diabetes progresses.
Animal studies have shown that exenatide helped preserve and form new beta
cells, the insulin-producing cells in the pancreas, which fail as type 2 diabetes
progresses.
How effective is it?
Unlike most other oral hypoglycaemic drugs which work by a single mechanism, exendin-4 works by several mechanisms: it stimulates insulin secretion, slows emptying of the stomach and inhibits production of glucose by the liver. It also appears to suppress appetite and helps weight loss. This would be a particular advantage with type 2 diabetes.
Drawback
The main drawback is that it has to be injected.
Scientific Evidence
Early studies in small numbers of people with type 2 diabetes has shown that taking this drug results in lower blood sugar levels after meals. It was also found to reduce triglyceride concentrations after meals.
Side effects
In these clinical trials, exenatide was well tolerated. Most of the reported side effects were mild or moderate. Nausea was the most common reported effect.
Use
People with type 2 diabetes who are not well controlled on diet and oral agents i.e. those not achieving target HbA1c levels on sulphonylureas, metformin or thiazolidenediones.
Formulations available after trial
· Exenatide – given subcutaneously twice a day at breakfast and dinner.
· Exenatide LAR (Long Acting Release). Work is currently underway to develop this preparation which may allow once-a-week to once-a-month administration of exenatide for the treatment of type 2 diabetes.
Prodcut available in market
GENERIC NAME: exenatide BRAND NAME: Byetta
DRUG CLASS AND MECHANISM: Exenatide is an injectable drug that reduces the level of sugar in the blood. It is used for treating type 2 diabetes. Exenatide belongs in a class of drugs called incretin mimetics because these drugs mimic the effects of incretins. Incretins, such as human-glucagon-like peptide-1 (GLP-1), are hormones that are produced and released into the blood by the intestine in response to food. GLP-1 increases the secretion of insulin from the pancreas, slows absorption of glucose from the gut, and reduces the action of glucagon (Glucagon is a hormone that increases glucose production by the liver.) All three of these actions reduce levels of glucose in the blood. In addition, GLP-1 reduces appetite. Exenatide is a synthetic (man-made) hormone that resembles and acts like GLP-1. In studies, exenatide-treated patients achieved lower blood glucose levels and experienced weight loss. Exenatide was approved by the FDA in May, 2005.
PRESCRIPTION: Yes. GENERIC AVAILABLE: No.
PREPARATIONS: Multiple dose pre-filled pen: 1.2 mL, 5 mcg per
dose (60 doses) or 2.4 mL, 10 mcg per dose (60 doses)
STORAGE: Exenatide should be refrigerated between 2-8°C (36-46°F)
and protected from light. It should not be frozen or used if frozen. The pen
should be discarded 30 days after its first use.
PRESCRIBED FOR: Exenatide is used in combination with other drugs
for reducing blood glucose in patients with type 2 diabetes who have not achieved
adequate blood glucose reduction while taking metformin
(Glucophage) or a combination of metformin (Glucophage) and a sulfonylurea.
Exenatide should not be used in patients with type 1 diabetes or as a substitute
for insulin in patients who require insulin. .
DOSING: The initial dose of exenatide is 5 mcg injected under
the skin (subcutaneously) twice daily, 60 minutes before breakfast or dinner.
Exenatide should not be administered after a meal. Each dose should be injected
in the thigh, abdomen or upper arm. The dose can be increased to 10 mcg twice
daily after 1 month of therapy.
DRUG INTERACTIONS: Exenatide slows down transit of food and drugs
through the intestine and, therefore, can reduce the absorption of drugs that
are taken orally. To avoid this interaction, administer oral medications one
hour before exenatide is administered. Orally administered drugs that need to
be administered with food should be given with a light meal or snack when exenatide
is not administered.
Pregnancy: There are no adequate studies of exenatide in pregnant
women. Most experts agree that insulin is the drug of choice in pregnant women
with diabetes.
NURSING MOTHERS: There are no adequate studies of exenatide in
nursing mothers, and it is not known whether exenatide is excreted in human
breast milk.
SIDE EFFECTS: The most common side effect of exenatide is nausea.
Nausea from exenatide is more common with the higher doses and decreases over
time. Other common side effects include hypoglycemia (excessively low blood
glucose), vomiting, diarrhoea, headache, nervousness and stomach discomfort.
Patients may also experience decreased appetite, acid reflux and increased sweating.
Exenatide Injection Byetta™
FDA Approval: | April 30, 2005 |
Indication: | Type 2 diabetes, as an adjunct to metformin and/or a sulfonylurea |
Pharmacology: | Incretin (glucagon-like peptide) mimetic |
Usual Dose: | 5 mcg SQ twice daily within 60 minutes of the morning and evening meal |
Contraindications: | Hypersensitivity to ingredients |
Warnings: |
Not indicated for treatment of type 1 diabetes or ketoacidosis
Not a substitute for insulin
Not recommended for patients with ESRD or CrCl<30 mL/min
Not recommended for patients with severe GI disease, including gastroparesis
Increased risk of hypoglycemia with sulfonylureas
Safety and effectiveness not established in pediatric patients
Pregnancy Category:
C
Side Effects:
nausea, vomiting, diarrhea, dyspepsia
jittery feeling, dizziness, headache
hypoglycemia
Drug Interactions:
sulfonylureas
oral contraceptives
oral antibiotics
Difference of exenatide from existing therapy
Exenatide is unique among currently marketed drugs in its broad effects to normalize postprandial physiology. In some ways, it can be thought of as having some of the same benefits of a secretagogue plus a biguanide plus an alpha-glucosidase inhibitor, without the baggage of hypoglycemia, lactic acidosis, or flatulence. Exenatide will fundamentally transform our thinking of how to approach the patient failing one or more oral agents and broaden the options beyond adding another pill or insulin to include an option that is associated with weight loss and sustained efficacy.
Advantages and disadvantages of exenatide compared with other drugs
The major disadvantage to exenatide is that it is injected twice daily. That said, it is critical to recognize the many ways in which this form of injected therapy is more convenient than insulin. First, the volumes administered are tiny and injection site pain is uncommon. Second, there is no need to fumble with bottles and syringes; exenatide will only be provided in pen form for administration. Finally, there is no need for dose adjustments in response to the size of meals or activity. Mild to moderate nausea which tends to diminish with continued exposure is fairly common with the initiation of exenatide therapy; it is similar in intensity and duration to that associated with metformin.
The major advantage of exenatide over sulfonylurea and insulin is a lack of hypoglycemia as an adverse effect. Versus metformin and glitazones, there is no need for clinical or laboratory assessments of vital organ (kidney, liver, or heart) function before initiating therapy or in monitoring therapy. Versus all antidiabetic agents, it is the first glucose-lowering drug to demonstrate substantial and sustained weight loss.
Clinical trials
A small Phase 2 clinical trial of exenatide completed in 1999 in people with type 2 diabetes showed statistically significant reductions in post-meal glucose concentrations, post-meal increases in glucagon concentrations and reductions in the rate of nutrient release from the stomach. Patients also reported sensations of fullness and satiety following exenatide administration. In another Phase 2 clinical trial completed in 1999, the blood glucose concentration during the first five hours following a standardized meal was reduced on average by 34% in participants that were treated with exenatide (compared to participants that were treated with placebo). In addition to lowering post-meal glucose concentrations, exenatide has also been shown to suppress post-meal elevations in serum triglyceride concentrations in people with type 2 diabetes. Elevations in post-meal triglycerides appear to be an independent risk factor for cardiovascular mortality.
In June 2001, Amylin announced the results of a Phase 2 clinical trial designed
to examine the effect of exenatide on glucose control in over 100 subjects with
type 2 diabetes who were not achieving adequate blood glucose control with their
current oral medications. In this 28-day trial, patients treated with exenatide,
together with their current oral medications, experienced statistically significant
lowering of A1C levels by 0.7% to 1.1%, compared to the average reductions experienced
by patients treated with their current oral medications and placebo of 0.3%.
Moreover, 90% of patients treated with exenatide together with their current
oral medications experienced reductions in A1C levels of greater than or equal
to 0.5%, compared to 33% of patients treated with their current oral medications
and placebo. It is important to note that this was a 28 day study and that A1C
measures average blood glucose concentrations over a 3-4 month period.
In these clinical trials, exenatide was well tolerated. The majority of reported adverse events in the trials were judged to be mild or moderate in intensity. These events included nausea, which was the most common adverse event, and to a much lesser extent, vomiting. To better understand how to minimize nausea, Amylin performed a Phase 2 dose-escalation trial in which patients achieved a target dose either gradually or suddenly. The data indicated that patients who gradually increased their dose of exenatide had a clinically meaningful reduction in the incidence of nausea over patients who did not receive a gradual dose increase.
In September 2001, Amylin announced that another Phase 2 clinical trial indicated that exenatide stimulated insulin secretion and lowered the elevated fasting blood glucose concentrations in people with type 2 diabetes after an overnight fast.
Amylin commenced a Phase 3 program for exenatide in December 2001. The Phase
3 program includes three pivotal trials.
In all three studies, patients are randomized into three groups, two on exenatide
and one on placebo. Those on active drugs receive an introductory 5 microgram
dose for one month, given by subcutaneous injection twice a day at breakfast
and dinner, followed by six-months of exposure to doses of either 5 micrograms
or 10 micrograms given twice a day.
The first pivotal study was designed to evaluate the effects of exenatide in
people with type 2 diabetes not achieving target blood glucose concentrations
using metformin alone prior to entering the study. Metformin is one of several
available oral therapies for the treatment of type 2 diabetes. The second pivotal
trial is evaluating the effects of exenatide on patients not achieving target
blood glucose concentrations using sulfonylureas alone. Sulfonylureas are another
form of oral therapy for the treatment of type 2 diabetes. The third of the
three Phase 3 pivotal trials is evaluating the effects of exenatide on patients
who are currently not achieving target blood glucose concentrations using a
combination of metformin and sulfonylureas. All of the treatment groups in each
of the three Phase 3 clinical trials are continuing to use their current therapies
of oral medications.
In August 2002, Amylin commenced an open-label clinical study using a similar
protocol to the Phase 3 pivotal trials. This study includes patients not achieving
target blood glucose concentrations using metformin, sulfonylureas or both metformin
and sulfonylureas. In August 2003, 105 patients in this ongoing open-label study
showed mean reductions in A1C of 1.3% at the end of six months. At the end of
six months, 44% of these participants had lowered their A1C to the treatment
goal of less than or equal to 7% set by the American Diabetes Association. In
this trial, the effect of exenatide on A1C appears unaltered by the formation
of antibodies. The most common adverse event reported was mild to moderate nausea,
consistent with previous exenatide clinical studies. Participants maintain their
current diabetes treatment regimens for the duration of the trial. Subjects
received an introductory 5-microgram dose for four weeks by subcutaneous injection
twice a day at breakfast and dinner. After four weeks, the dose was increased
to 10 micrograms twice a day.
In November 2003, Amylin reported positive results from the final Phase3 pivotal
study of exenatide (synthetic exendin-4), marking the conclusion of the long-term
human clinical trials required for regulatory submission to the FDA. All three
pivotal studies met the primary glucose control endpoint as measured by hemoglobin
A1c (A1C). The average reduction in A1C across the Phase 3 program in patients
completing the studies on the highest dose of exenatide (10 micrograms twice
daily) was approximately one percent. Additionally, approximately 40 percent
of these patients achieved A1C measurements of 7 percent or less. On average,
subjects in the Phase 3 program on the highest dose of exenatide also showed
statistically significant reductions in body weight of approximately two kilograms.
The most common adverse event was mild to moderate, transient nausea.
Results from clinical trials reported to date suggest Exenatide is
well tolerated.
Regulatory Status
Amylin filed an Investigational New Drug Application, or IND, for exenatide in January 1999 prior to the initiation of clinical trials. The successful completion of exenatide's phase 3 pivotal studies was announced in November 2003. A New Drug Application (NDA) is planned for submission to the FDA mid-2004.
Target Market
The initial patient focus for exenatide is patients with type 2 diabetes who are not using insulin and are not achieving target blood glucose concentrations with diet plus metformin and/or sulfonylureas. The current therapeutic steps available to this patient population are additional oral medications, the addition of insulin to the oral agent regimen or insulin therapy alone. These approaches are often not very successful and are usually associated with inconvenience and side effects, particularly weight gain. Amylin estimates this population of people with diabetes who were using oral medications as of 2001 to be 11.9 million in the United States, France, Germany, Italy, Japan, Spain and the United Kingdom, which comprise the seven largest pharmaceutical markets worldwide, of which an estimated 5.9 million people are in the United States. Amylin currently plans to market exenatide in an injectable pen/cartridge delivery system, subject to receiving the necessary regulatory approvals.
A reference article for the Pharmaceutical news shows the study done on this
hormone.
Amylin Pharmaceuticals, Inc., and
Eli Lilly and Company have presented
detailed 30-week data from two of the three pivotal Phase 3 studies of exenatide
during a late-breaking session at the American Diabetes Association's (ADA)
64th Scientific Sessions in Orlando, Florida. Exenatide is the first potential
therapy in a new class of drugs under investigation for the treatment of type
2 diabetes known as incretin mimetics. The studies showed that exenatide significantly
lowered average glucose (blood sugar) levels, measured by A1C, in patients who
were unable to achieve adequate glucose control on common oral regimens. In
addition, exenatide treatment resulted in reductions in body weight. 52-week
data from open-label extension studies of these pivotal trials were also released,
demonstrating sustained reductions in A1C of one percent or more with associated
weight loss.
"The reduction in blood sugar and the associated weight loss seen with exenatide
is an important combination of effects. With other therapies, improved blood
sugar control is often accompanied by weight gain -- and this weight gain can
be a significant frustration for people working to achieve better control of
their diabetes," said Dr. David Kendall, International Diabetes Center in Minneapolis,
Minnesota.
Study Design/Protocol
Approximately 1,000 patients unable to achieve adequate control with commonly
prescribed oral therapies were involved in the two 30-week, triple- blind, placebo-controlled
pivotal phase 3 studies of exenatide. In both studies, patients continued their
pre-study oral therapies and were randomized to one of three arms in which they
received either 10 micrograms of exenatide, 5 micrograms of exenatide, or placebo
via subcutaneous injection at breakfast and dinner. At the conclusion of the
30-week studies, participants in all three treatment arms were offered the option
to continue in open-label extension studies in which all subjects received 10
micrograms exenatide.
Key Study Findings
The first 30-week study examined the effects of exenatide or placebo when added
to the regimens of 336 patients (average disease duration six years) who were
unable to achieve glycemic control with metformin alone. Of patients completing
the study, 46 percent in the 10 microgram arm achieved an A1C of seven percent
or less. A1C is a measure that reflects a person's average glucose levels over
the prior three to four months. The ADA's recommended target for A1C is less
than seven percent. At the study's outset, the average A1C of all subjects was
8.2 percent. At the end of the study, the average A1C for the 10 microgram group
was reduced by 0.9 percent (difference from placebo). These reductions in A1C
were accompanied by average reductions in weight of 5.5 pounds or 2.5 kilograms
(difference from placebo).
In the second 30-week study, researchers evaluated 733 patients (average disease
duration nine years) who were unable to achieve glycemic control using a combination
of metformin and sulfonylureas. In order to assess the effect of sulfonylureas
on the incidence of hypoglycemia, each of the three arms of this study were
further divided into two groups taking either maximally effective or minimum
recommended doses of sulfonylurea. At the study's outset, the average A1C of
all subjects was 8.5 percent. Of patients completing the study, 34 percent taking
10 micrograms of exenatide achieved an A1C of seven percent or less. The average
reduction in A1C in the 10 microgram arm was one percent (difference from placebo).
The average reduction in weight for the 10 microgram group was 1.5 pounds or
0.7 kilograms (difference from placebo).
In both studies, exenatide was generally well tolerated and the most common
adverse event reported was mild to moderate nausea, which occurred most frequently
early in the study.
In the 30-week metformin-only study, 45 percent of patients taking 10 micrograms
reported nausea, compared to 23 percent for placebo. The dropout rate due to
nausea was three percent for 10 micrograms and zero percent for placebo. Hypoglycemia
rates were consistent with exenatide's glucose- dependent action, with no difference
between the placebo and drug arms (five percent for each group).
In the metformin-sulfonylurea combination study, 49 percent of patients taking
10 micrograms reported nausea compared to 21 percent for placebo. The dropout
rate due to nausea was four percent for 10 micrograms and less than one percent
for placebo. As expected, some patients taking exenatide in combination with
sulfonylurea and metformin experienced mild-to-moderate hypoglycemia, with those
taking the minimally effective doses of sulfonylureas reporting a lower incidence
than those taking maximally effective doses. The incidence of mild-to-moderate
hypoglycemia was 28 percent in the 10 microgram group and 13 percent in the
placebo group. One incident of severe hypoglycemia was reported in the 5 microgram
arm of this study. No participants withdrew from the study because of hypoglycemia.
One-Year Data Shows Sustained Effect
To evaluate the durability of exenatide's effect at the highest dose tested,
the group of patients who had received 10 micrograms of exenatide for 52 weeks
were examined. In the 51 patients who completed 52 weeks on 10 micrograms of
exenatide in combination with metformin, the average reduction in A1C from baseline
was 1.1 percent with average reductions in body weight of 9.9 pounds (4.5 kilograms).
In the 77 patients who had completed 52 weeks on 10 micrograms of exenatide
and a metformin-sulfonylurea combination, the average reduction in A1C from
baseline was 1.0 percent with average reductions in body weight of 7.3 pounds
(3.3 kilograms).
References:
1. Glucagon-like peptide 1 and its derivatives in the treatment of diabetes,
Michael A. Nauck and Juris J. Meier, Pubmed [MEDLINE]
2. http://www.news-medical.net/
4. Canadian Pharmacy Online Pharmaceutical News
19. www.glucagon.com
21. www.diabetes.org
23. www.drugdevelopment-technology.com
About Authors
Madhumathi Seshadrib, Neha Shahc and Mrs. Lakshmi
Sivasubramaniam a, *
* a Lecturer, Department of Pharmaceutical Analysis, College of
Pharmacy, SRM Institute of Science and Technology.
*,a Author for Correspondence: Lakshmi Sivasubramaniam,
Lecturer, Department of Pharmaceutical Analysis, College of Pharmacy, SRM Institute
of Science and Technology, Deemed University, Katangulathur, Chennai, India.
E-mail: laxmisiva@rediffmail.com.
b Department of Chemistry, Pharmaceutical Chemistry unit,
Vellore Institute of Technology, Vellore-632 014, India.
c Bio medical Genetics, Department of Bio sciences,
Vellore Institute of Technology, Vellore-632 014, India.