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Copyright 2009 by Therapeutic Research Center

Pharmacists Letter / Prescribers Letter ~P.O. Box 8190, Stockton, CA 95208 ~Phone: 209-472-2240 ~Fax: 209-472-2249
www.pharmacistsletter.com ~www.prescribersletter.com


Detail-Document #250411
This Detail-Document accompanies the related article published in
PHARMACISTS LETTER / PRESCRIBERS LETTER
April 2009 ~Volume 25 ~Number 250411


Selecting a Sulfonylurea

Background
Sulfonylureas have been used to treat type 2
diabetes for around 50 years. Their major
mechanism of action is stimulation of insulin
secretion from beta cells in the pancreas.
Sulfonylureas are a second-line therapy choice
after metformin.
1,2,3
They reduce A1c on average
by around 1.5%. Glyburide (Diabeta) has been
available for more than twenty years and is one of
the most widely used sulfonylureas. But starting
patients on glyburide, or the older and rarely
prescribed chlorpropamide (Diabinese), isnt
recommended because of the relatively higher risk
for hypoglycemia.
1-3
This document discusses the
sulfonylureas and how they differ.

Hypoglycemia with Sulfonylureas
One of the main differences among
sulfonylureas is their ability to cause
hypoglycemia. Reported rates of hypoglycemia in
type 2 diabetes patients vary widely, depending on
drug therapies, A1c targets, and duration of
disease. The estimate for episodes of severe
hypoglycemia (requiring assistance of another
person) in patients with type 2 diabetes is as high
as 70 per 100 patient-years.
4
Insulin and
sulfonylureas are the main causes of
hypoglycemia.
5
Hypoglycemia is associated with
reduced cognition, and about one in five patients
with hypoglycemia experiences unconsciousness.
5

Hypoglycemia with sulfonylureas is
particularly difficult to reverse. Sulfonylureas, to
varying degrees, raise insulin levels independent
of blood glucose. Plus, they have relatively long
half-lives.
6
Hypoglycemia with sulfonylureas
sometimes requires hospitalization and can last for
a few days.
6

An annual rate of severe hypoglycemia as high
as 7% has been reported for patients taking a
sulfonylurea.
6
Theres data to suggest that the risk
for hypoglycemia with glyburide is about 40%
higher than with glipizide (Glucotrol, U.S. only).
6

The risk for hypoglycemia with glyburide might
be even more profound in elderly patients with
renal dysfunction.
6
However, this is controversial
as there is also data to the contrary.
6

One meta-analysis suggested a higher risk for
hypoglycemia with glyburide compared to other
sulfonylureas, but the difference was not
statistically significant.
7
Another meta-analysis
showed that the relative risk for hypoglycemia
with glyburide is 1.52 (95% confidence interval
[CI], 1.21-1.92) compared to other secretagogues,
including repaglinide (Prandin, U.S. only). A
criticism of this data is that the result was swayed
by just two trials out of twelve where glyburide
caused more hypoglycemia than the respective
comparator drug (gliclazide [Diamicron, Canada
only], and chlorpropamide). In this same meta-
analysis, there was no difference in the risk for
hypoglycemia between glyburide and insulin.
8


Mechanisms for Hypoglycemia
The potentially higher risk for hypoglycemia
with glyburide might be due to its time-activity
profile.
6
This refers to the fact that glyburide has
a longer duration of binding to the sulfonylurea
receptor in the pancreas than other drugs in its
class. The result is a higher degree of fasting
hyperinsulinemia than with other sulfonylureas.
Glimepiride (Amaryl) and glipizide are thought to
be more glucose-sensitive in their stimulation of
insulin secretion.
5

Pharmacokinetics also play a role, with a
longer half-life increasing the risk for
hypoglycemia. Glyburide has a half-life of about
ten hours.
9
So does gliclazide.
10
Chlorpropamide
has an even longer half-life of about 36 hours.
11

Glipizide and tolbutamide (Orinase) have the
shortest half-lives, at four to five hours.
12,13

In addition, glyburides metabolites have some
hypoglycemic activity. About 50% of these
metabolites are excreted by the kidneys.
9

Chlorpropamide is excreted exclusively by the
kidneys, to some extent as unchanged drug.
11
The
metabolites of gliclazide, glimepiride, glipizide,
(Detail-Document #250411: Page 2 of 3)
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Copyright 2009 by Therapeutic Research Center
Pharmacists Letter / Prescribers Letter ~P.O. Box 8190, Stockton, CA 95208 ~Phone: 209-472-2240 ~Fax: 209-472-2249
www.pharmacistsletter.com ~www.prescribersletter.com
tolazamide (Tolinase, U.S. only), and tolbutamide
are mostly inactive and excreted in the urine.
12-15


Other Considerations
Initiating treatment with chlorpropamide or
glyburide isnt recommended by the ADA.
1,3,16
In
addition, chlorpropamide is not recommended for
use in the elderly by the American Geriatric
Society.
17
Canadian guidelines note the higher
risk of hypoglycemia with glyburide compared to
gliclazide or glimepiride.
3
Some experts recommend continuing therapy
with glyburide in stable patients who are using it
without problems. They say theres no reason to
switch.
All of the recommended sulfonylureas are
metabolized by the liver and excreted mostly by
the kidneys. For older patients and for patients
with either kidney or liver dysfunction, regardless
of the drug used, the recommendation is to start
low and titrate up slowly.
1,9-15
Sulfonylureas with
shorter half-lives, such as glipizide and
tolbutamide, are recommended for the elderly.
2
It is worth noting that glimepiride and glipizide
appear to cause less weight gain than other
sulfonylureas.
5

Since glimepiride is now available as a
generic, the prices of the sulfonylureas are very
similar. In the U.S., a one-month supply of any
sulfonylurea will generally cost a patient around
$20 or less. All sulfonylureas are available as
generics in Canada as well.

Conclusion
Initiating treatment with chlorpropamide or
glyburide is generally not recommended
[Evidence level C; consensus].
1,3
Glyburide
appears to cause a higher incidence of
hypoglycemia than other sulfonylureas [Evidence
level A; high-quality meta-analysis].
8

To help patients avoid hypoglycemia with any
of the sulfonylureas, remind them to avoid
skipping meals, to consume carbohydrates before
planned exercise, and to be aware that
consumption of alcohol can lower blood glucose.
4



Users of this document are cautioned to use their own
professional judgment and consult any other necessary
or appropriate sources prior to making clinical
judgments based on the content of this document. Our
editors have researched the information with input
from experts, government agencies, and national
organizations. Information and Internet links in this
article were current as of the date of publication.

Levels of Evidence
In accordance with the trend towards Evidence-Based
Medicine, we are citing the LEVEL OF EVIDENCE
for the statements we publish.
Level Definition
A High-quality randomized controlled trial (RCT)
High-quality meta-analysis (quantitative
systematic review)
B Nonrandomized clinical trial
Nonquantitative systematic review
Lower quality RCT
Clinical cohort study
Case-control study
Historical control
Epidemiologic study
C Consensus
Expert opinion
D Anecdotal evidence
In vitro or animal study
Adapted from Siwek J , et al. How to write an evidence-based
clinical review article. Am Fam Physician 2002;65:251-8.

Project Leader in preparation of this Detail-
Document: Stacy A. Hester, R.Ph., BCPS,
Assistant Editor


References
1. Nathan DM, Buse J B, Davidson MB, et al. Medical
management of hyperglycemia in type 2 diabetes:
a consensus algorithm for the initiation and
adjustment of therapy: a consensus of the
American Diabetes Association and the European
Association for the Study of Diabetes. Diabetes
Care 2009;32:193-203.
2. Mizuno CS, Chittiboyina AG, Kurtz TW, et al. Type
2 diabetes and oral antihyperglycemic drugs. Curr
Med Chem 2008;15:61-74.
3. Canadian Diabetes Association Clinical Practice
Guidelines Expert Committee. Canadian Diabetes
Association 2008 clinical practice guidelines for the
prevention and management of diabetes in
Canada. Can J Diabetes 2008;32:S1-S201.
4. Cryer PE, Axelrod L, Grossman AB, et al.
Evaluation and management of adult hypoglycemic
disorders: an Endocrine Society Clinical Practice
Guideline. J Clin Endocrinol Metab 2009;94:709-
28.
5. Cefalu WT, Waldman S, Ryder S.
Pharmacotherapy for the treatment of patients with
type 2 diabetes mellitus: rationale and specific
agents. Clin Pharmacol Ther 2007;81:636-49.
6. Amiel SA, Dixon T, Mann R, J ameson K.
Hypoglycaemia in type 2 diabetes. Diabet Med
2008;25:245-54.
(Detail-Document #250411: Page 3 of 3)

7. Bolen S, Feldman L, Vassy J , et al. Systematic
review: comparative effectiveness and safety of
oral medications for type 2 diabetes mellitus. Ann
Intern Med 2007;147:386-99.
8. Gangji AS, Cukierman T, Gerstein HC, et al. A
systematic review and meta-analysis of
hypoglycemia and cardiovascular events: a
comparison of glyburide with other secretagogues
and with insulin. Diabetes Care 2007;30:389-94.
9. Product information for Diabeta. Sanofi-Aventis.
Bridgewater, NJ 08807. March 2007.
10. Product monograph for Diamicron. Servier
Canada. Laval, Quebec H7V4A7. J anuary 2009.
11. Product information for Diabinese. Pfizer. New
York, NY 10017. February 2009.
12. Product information for Glucotrol. Pfizer. New
York, NY 10017. February 2009.
13. Product information for tolbutamide. Mylan.
Morgantown, WV 26505. J anuary 2006.
14. Product information for Amaryl. Sanofi-Aventis.
Bridgewater, NJ 08807. September 2008.
15. Product information for Tolinase. Pfizer. New
York, NY 10017.
16. American Diabetes Association. Standards of
medical care in diabetes-2008. Diabetes Care
2008;31:S12-54.
17. California Healthcare Foundation/American
Geriatrics Society Panel on Improving Care for
Elders with Diabetes. Guidelines for improving the
care of the older person with diabetes mellitus. J
Am Geriatr Soc 2003;51:S265-80.



Cite this Detail-Document as follows: Selecting a sulfonylurea. Pharmacists Letter/Prescribers Letter
2009;25(4):250411.


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