exenatide for type 2 diabetes

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ה
P H A R x M A
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מ ר א פ
הביטאון לענייני
תרופות ותראפיה
ISRAEL DRUG BULLETIN
כרך 14, ביטאון מס'‏ 81
לשימוש רציונאלי בתרופות
אמינה ובלתי ובלתי-תלויה
סקירה
תשרי-חשוון תשס"ח,‏ אוקטובר-נובמבר 2007
עוד בביטאון:‏ Sitagliptin for Type 2 Diabetes
חדש בביטאון:‏ בדיקת מחירי תרופות חדשות בארץ ובחו"ל
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EXENATIDE FOR TYPE 2 DIABETES
אקסנטיד,‏ הראשונה בקבוצת תרופות חדשה,‏ מאושרת לטיפול בסוכרת סוג בשילוב עם מטפורמין ו/או
סולפונילאוריאה בחולים ללא שליטה גליקמית הולמת במינון המירבי הנסבל של תרופות פומיות אלה.‏
הוספת זריקות אקסנטיד לטיפול הפומי יכולה לשפר את השליטה הגליקמית בצום ולאחר ארוחות,‏ וללא עלייה
במשקל.‏ עם זאת,‏ יעילותה ובטיחותה בטווח הארוך אינן ידועות.‏
בחילה היא תופעת לוואי שכיחה;‏ היפוגליקמיה עשויה לקרות,‏ במיוחד בחולים הנוטלים גם סולפונילאוריאה.‏
במחקרים השוואתיים לא סמויים,‏ טיפול באקסנטיד,‏ אינסולין גלרגין או אינסולין דו-פאסי אספארט השיגו
שיפורים דומים בשליטה הגליקמית;‏ מינוני האינסולין במחקרים אלה היו נמוכים.‏
• האם העדר עלייה במשקל הינו סיבה טובה דייה לנסות אקסנטיד לפני שמתחילים טיפול באינסולין דורש הבהרה.‏
In response to food, several peptide hormones
(incretins) are released from cells in the gastrointestinal
tract. Glucagon-like peptide-1 (GLP-1) is one of these; it
acts on pancreatic beta-cells to potentiate insulin
secretion stimulated by glucose. 1 Exenatide, a
synthetic peptide, is a GLP-1 agonist and the first of a
new class known as incretin mimetics. It potentiates
insulin secretion, inhibits secretion of glucagon, slows
gastric emptying and reduces food intake due to
decreased appetite and increased satiety. Animal
studies have shown increased growth of pancreatic
beta-cells in response to treatment with exenatide;
whether this occurs in patients with diabetes remains to
be determined. 2
Exenatide injection (Byetta; Eli Lilly) has been
approved by the Israel Ministry of Health for the
treatment of type 2 diabetes mellitus in combination
with metformin and/or sulphonylureas in patients who
have not achieved adequate glycaemic control on
maximally tolerated doses of these oral therapies.
EVIDENCE OF CLINICAL EFFICACY
The efficacy of exenatide has been assessed in
placebo-controlled trials and open-label comparator
studies. Six such trials enrolled patients with type 2
diabetes with HbA 1c levels of 7.1% to 11%; only
patients with a BMI >25kg/m 2 were included. The
studies investigated the efficacy of the addition of
exenatide 5 or 10mcg twice daily to existing oral
hypoglycaemic therapy in adults with type 2 diabetes
uncontrolled by maximally effective doses of metformin
2
(>1500mg daily) and/or a sulphonylurea. Oral therapy
was continued at the baseline dose, though the dose of
sulphonylureas could be adjusted if hypoglycaemia
occurred. In all studies the primary endpoint was the
change from baseline in % glycated haemoglobin
(HbA 1c) in an intention-to-treat cohort. Secondary
endpoints included the proportion of patients with HbA 1c
>7% at baseline who achieved HbA 1c

A total of 974 patients who had completed one of
the above studies enrolled in an open-label extension
study during which all patients received exenatide
10mcg twice daily. 6 Of the patients who completed two
years of exenatide treatment, the reduction in HbA 1c
was maintained and weight loss continued. However,
the withdrawal rate was high and only 283 patients
completed two years of exenatide treatment.
In two of the above trials exenatide was added to
oral monotherapy. 3,4 However, it is more likely that in
clinical practice exenatide will be added to treatment
once combination therapy with two (and possibly three)
oral hypoglycaemics has failed.
A 16-week placebo-controlled RCT in 233 patients
with type 2 diabetes on glitazone treatment with or
without metformin found exenatide 10mcg twice daily
reduced HbA 1c levels to a greater extent than placebo (-
0.9% vs +0.1%; p25kg/m 2 and were on
combination therapy with metformin and a
sulphonylurea.
The change in HbA 1c in the exenatide group was
found to be non-inferior to that in the insulin glargine
group (both -1.1%) and the biphasic insulin aspart
group (-1.0% vs. -0.9%). In order to prove clinical noninferiority
to insulin, it must be proven that insulin
treated subjects had maximally tolerated doses of
insulin. 10 This is doubtful and that, based on the nonblinded
nature of these studies, a potential bias towards
lower doses of insulin cannot be fully excluded, even
though an attempt to minimise this bias was made. The
proportion of patients achieving the target HbA 1c was
46% for exenatide compared with 48% for insulin
glargine, and 32% for exenatide and 24% with biphasic
insulin aspart. Patients treated with exenatide lost
bodyweight (2.3 to 2.5kg) whereas patients treated with
insulin glargine or biphasic insulin aspart gained
bodyweight.
ADVERSE EFFECTS
The main adverse effects of exenatide are nausea,
vomiting, diarrhoea, and hypoglycaemia. In comparator
studies, the incidence of nausea ranged from 33% to
57% in exenatide groups compared with 0.4% to 9% in
patients treated with insulin analogues; for vomiting the
equivalent rates were 9% to 17% and 2.4% to 4%
respectively. Most episodes of nausea were mild to
moderate, dose-related, and decreased in frequency
with continued treatment. There have been reports of
pancreatitis in postmarketing surveillance data. 10,11
The incidence of hypoglycaemia with exenatide
increased when used in combination with a
sulphonylurea, but not metformin. A reduction in the
sulphonylurea dose should be considered when giving
in combination with exenatide and blood glucose
monitoring may become necessary. In comparator
studies, the incidence of hypoglycaemia was
comparable in exenatide– and insulin-treated groups.
Some patients developed anti-exenatide antibodies,
which did not increase the incidence of any adverse
effects, but in a few patients appeared to attenuate the
anti-hyperglycaemic effect of the drug.
More exenatide-treated patients withdrew from the
studies because of adverse events compared with
patients treated with insulin glargine 9 (10% vs 1%) or
biphasic insulin aspart (8% vs 0%). 8 In pregnant
animals, exenatide at 3 times the human dose had
adverse effects on the foetus, including reduced growth,
skeletal abnormalities and teratogenic effects. It should
not be used during pregnancy.
Drug interactions: Because the drug slows gastric
emptying, exenatide may reduce the extent and rate of
absorption of some oral medicines. Patients receiving
oral medicines with a narrow therapeutic range or those
requiring careful monitoring should be followed closely.
Oral medicines dependent on threshold concentrations,
e.g. contraceptives or antibiotics, should be taken at
least one hour before exenatide. Increased INR has
been reported during concomitant use with warfarin.
DOSAGE AND COSTS
Therapy should be initiated at 5mcg twice daily for
at least one month to improve tolerability, then
increased to 10mcg twice daily to further improve
glycaemic control. Doses should be administered
subcutaneously in the thigh, abdomen or upper arm at
any time within one hour before the morning and
evening meals (or two main meals approximately 6
hours or more apart) and should not be administered
after a meal. Exenatide is not recommended for
patients with severe renal impairment (CrCl

Cost of Exenatide and Insulins
Drug Dose 1 Cost (NIS) 2
Exenatide (Byetta) 5-10mcg twice 805
daily
Isophane insulin 25-50U daily 112-223
(Humulin 30/70 /
Insulatard)
Biphasic insulin aspart 25-50U daily 156-312
(Novomix 30)
Insulin glargine (Lantus) 25-50U daily 217-434
Insulin detemir (Levemir) 25-50U daily 223-447
1
Doses are for general comparison only and do not imply therapeutic
equivalence.
2
30 days; cartridge costs at retail price.
International cost comparison (monthly cost at.
price to retail pharmacy): Israel NIS 593; UK NIS 560
(₤1 = NIS 8.2), for both strengths. In the USA: NIS 588
(1.2ml pen), NIS 690 (2.4ml pen) (USD = NIS 4.0).
Comparing prices in Israel with drug prices in the UK
and USA is instructive, as prices in these countries are
usually higher than elsewhere. Furthermore, the UK
and USA are much higher income countries than Israel,
meaning they are better able to fund the cost of new
drugs.
CONCLUSION
Adding twice daily injections of exenatide to oral
therapy was seen to reduce HbA 1c levels to a greater
extent than placebo. Non-blinded comparator studies
found exenatide to be non-inferior to insulin glargine or
biphasic insulin aspart in reducing HbA 1c levels;
however, insulin doses in these studies were low.
Nausea is common, and hypoglycaemia can occur,
particularly in patients also taking a sulphonylurea.
There are no data on the effects of exenatide on
mortality or morbidity outcomes. Further long-term data
are needed to establish safety and if short-term
improvements in HbA 1c are sustained. Weight loss with
exenatide, which appears to be directly proportional to
baseline BMI is an important advantage over insulin in
overweight patients. Whether the absence of weight
gain is reason enough to try it before starting insulin
remains to be seen. It has no advantage over insulin in
terms of the number of daily injections required.
The dose of exenatide does not need to be adjusted
on a day to day basis. However, blood glucose
monitoring may still be necessary to adjust the dose of
sulphonylureas.
References
1. Davidson M et al, Nature Reviews Drug Discovery 4:713,
2005.
2. Joy S et al, Ann Pharmacother 39:110, 2005.
3. De Fronzo R et al, Diabetes Care 28:1092, 2005.
4. Buse J et al, Diabetes Care 27:2628, 2004.
5. Kendall D et al, Diabetes Care 28:1083, 2005.
6. Buse J et al, Clin Ther 29:139, 2007.
7. Zinman B et al, Ann Intern Med 146:477, 2007
8. Nauck M et al, Diabetologia 50:259, 2007.
9. Heine R et al, Ann Intern Med 143:559, 2005.
10. European public assessment report (Byetta), December
2006.
11. www.fda.gov/cder/drug/Inforsheets/HCP/exenatideHCP,
16.10.07.
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SITAGLIPTIN FOR TYPE 2 DIABETES
נראה שסיטאגליפטין,‏ הראשונה בקבוצת תרופות חדשה לטיפול בסוכרת סוג הינה בעלת יעילות בינונית הן
בטיפול יחיד והן בשילוב עם תרופות אנטי סוכרתיות אחרות.‏
עד היום לא נצפה קשר לעלייה במשקל או להיפוגליקמיה.‏ ואולם,‏ הניסיון הקליני עם סיטגליפטין מוגבל ובטיחותה
ארוכת הטווח אינה ידועה.‏
יעילותה של סיטאגליפטין בהשוואה לתרופות ותיקות יותר עדיין דורשת ביסוס.‏ נראה כי מטפורמין
וסולפונילאוריאה יעילות יותר בהורדת רמות HbA 1c בטווח הקצר והן זולות בהרבה.‏
סיטאגליפטון נמצאת בהליכי רישום במשרד הבריאות.‏
,2
•
•
•
•
Sitagliptin (Januvia; MSD) is the first of a new class
of oral antidiabetic agents known as dipeptidyl
peptidase type 4 (DPP-4) inhibitors. They enhance the
levels of active incretin hormones (including glucagonlike
peptide-1 [GLP-1]), which are released by the
intestine steadily throughout the day and are increased
in response to a meal. Incretin hormones enhance
insulin secretion, reduce glucagon secretion, and so
reduce blood glucose levels. However, they are rapidly
inactivated by the DPP-4 enzyme. DPP-4 inhibitors help
to prevent this inactivation. 1
Sitagliptin has been approved in the EU and USA in
combination with metformin or thiazolidinediones, such
as rosiglitazone, when monotherapy with these agents
does not provide adequate glycaemic control. In the
USA it is also licensed for use in combination with
sulphonylurea or as part of a triple therapy regimen. It
has also been approved as monotherapy in the USA.
Here we assess sitagliptin's efficacy as monotherapy
and as part of combination therapy.
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81 ,14 אוקטובר-נובמבר 2007
3
פארמה,‏ כרך
ביטאון מס'‏

Pharmacokinetics: Sitagliptin is rapidly absorbed;
plasma concentrations reach a peak 1-4 hours after
ingestion. A single 100mg dose inhibits DPP-4 activity
over a 24-hour period and increases glucose- or mealstimulated
plasma GLP-1 and glucose-dependent
insulinotropic polypeptide (GIP) levels about 2- to 3-
fold. 2
EVIDENCE OF CLINICAL EFFICACY
Monotherapy
In two double-blind, placebo-controlled studies of 18
weeks' (n=521) and 24 weeks' (n=741) duration in
patients with type 2 diabetes not controlled by diet and
exercise, sitagliptin 100mg once daily was associated
with reductions in HbA 1c of 0.48% and 0.61% from
baseline, compared to an increase of 0.12% and 0.18%
with placebo. 3,4 These decreases in HbA 1c are less than
those generally expected with metformin (1.5%),
sulfonylureas (1.5%) or thiazolidinediones (0.5%-
1.4%). 5 Significantly (p

ADVERSE EFFECTS
Adverse events reported in the trials included
nasopharyngitis, urinary tract infection, abdominal pain
and headache. 6-9 One concern is that many other peptides
besides the incretin hormones, including neuropeptides,
cytokines and chemokines, are metabolised by the
relatively nonspecific DPP-4 enzyme. 11 Whether inhibiting
this activity could have untoward effects is unknown. 12
There are no published safety data beyond 52 weeks for
sitagliptin.
Safety data for sitagliptin used in combination therapy
suggest that the overall incidence of gastrointestinal
adverse events was similar to placebo 6 and glipizide 8
when added to ongoing metformin, but higher than
placebo (13.7% vs 6.2%) when added to ongoing
pioglitazone. 9 The addition of sitagliptin to metformin or
pioglitazone did not significantly increase the incidence of
hypoglycaemia vs placebo, 6,9 and fewer patients reported
hypoglycaemic episodes (of any severity) with sitagliptin
(4.9%) vs glipizide (32.0%, p