Download file (Appropriate Selection of a 2nd Generation

Nick Wytiaz
University of Pittsburgh
APPE – Care to the Underserved
August 18, 2011
[email protected]
Drug Information Question
Appropriate Selection of a Second Generation Sulfonylurea
Sulfonylureas are the oldest class of oral agents used for the treatment of type 2 diabetes. They work by
stimulating the release of insulin from pancreatic beta cells, thereby increasing both basal and
postprandial insulin secretion and generally lower blood glucose concentrations by approximately 20%
and A1C levels by 1-2%.1 The sulfonylureas can be divided into two categories: first generation
(acetohexamide, chlorpropamide, tolazamide, and tolbutamide) and second generation (glimepiride,
glipizide, and glyburide). First generation agents are no longer recommended by current diabetes
treatment guidelines (ADA [American Diabetes Association] and AACE [American Association of
Clinical Endocrinologists) due to their increased side effect profile, primarily hypoglycemia, and
increased frequency of dosing. The ADA currently considers second generation sulfonylureas the
preferred 2nd line treatment option after metformin and lifestyle changes.2 The AACE considers these for
add-on therapy to metformin in patients with elevated fasting plasma glucose and A1C 6.5- 9% or as part
of a multi-drug regimen with metformin, in drug-naïve, asymptomatic patients with A1C > 9%.3 All
sulfonylureas share the same mechanism of action, are equally effective when administered in equipotent
doses, and have similar drug-drug interactions and adverse event profiles.1 Sulfonylureas do differ in their
pharmacokinetic properties. The differences may be a factor when selecting a specific agent for a patient.
Table 1. Parameters of Second Generation Sulfonylureas 4-7
Medication
Onset
Duration
Metabolism
Renal
Active
Half-life
(hours) (hours)
Excretion
Metabolite (hours)
Glimepiride
2-3
24
Hepatic
60%
Yes
9
Glipizide
1-3
10-24
Hepatic
80-85%
No
2-4
Glipizide SR
2-3
24
Hepatic
80%
No
2-5
Glyburide
2-4
16-24
Hepatic
50%
Yes
10
Glyburide, micronized
1
12-24
Hepatic
50%
Yes
4
Another main difference among the sulfonylureas is their propensity to cause hypoglycemia, the hallmark
adverse effect of the class given their mechanism of action. Glyburide has been associated with the
greatest risk for hypoglycemia, relative to other second generation agents. One study suggests that the risk
for hypoglycemia with glyburide is almost 40% higher than glipizide.8 A meta-analysis also supported
this finding, reporting a higher risk for hypoglycemia with glyburide compared to other sulfonylureas.8
However, the difference was not statistically significant. Still, the concern for hypoglycemia seems to be
clinically significant as reflected by the ADA Consensus Guidelines, which recommend against the use of
glyburide when initiating a sulfonylurea as add-on therapy.
The potential risk for increased hypoglycemia with glyburide is most likely linked to its pharmacokinetic
profile. Glyburide has a longer duration of binding to the pancreatic sulfonylurea receptor than other
sulfonylureas, resulting in a relative higher degree of fasting hyperinsulinemia. In addition, the longer
half-life and active metabolite may contribute to the hypoglycemic activity.
Since multiple studies have demonstrated comparable clinical effectiveness and glycemic control for all
the second generation sulfonyureas and cost is not an issue (all sulfonyureas are generically available), the
selection of a specific agent comes down to the characteristics of the individual patient and the risk of
hypoglycemia.1 Given the pharmacokinetic properties of the drugs and studies comparing the rate of
hypoglycemia, initial treatment with glyburide is not recommended. For older patients and those with
renal or hepatic dysfunction, sulfonyureas with shorter half-lives, such as glipizide, should be
recommended and extended-release products (i.e. glipizide SR) should be avoided. Regardless of the
agent chosen, initial treatment should start at a lower dose and then be titrated up slowly as tolerated by
the patient.
References:
1
McColloch DK. Sulfonylureas and meglitinides in the treatment of diabetes mellitus. In: Rose BD,
editor. UpToDate; 2007. Available from: http://www.utdol.com/utd/index.do .
American Diabetes Association. Standards of medical care in diabetes – 2011. Diabetes Care.
2011;34(Suppl. 1): S11–S61.
2
3
AACE Diabetes Mellitus Clinical Practice Guidelines Task Force. American Association of Clinical
Endocrinologists Medical Guidelines for Clinical Practice for Developing a Diabetes Mellitus
Comprehensive Care Plan. Endocr Pract. 2011;17(Suppl 2):1-53.
4
Amaryl® [package insert]. New York, NY: Sanofi-Aventis US; 2006 Feb.
5
Glucotrol® [package insert]. New York, NY: Pfizer; 2006 Sep.
6
Micronase® [package insert]. Kalamazoo, MI: Pharmacia & Upjohn Co; 2002 Mar.
7
Glynase PresTab® [package insert]. Kalamazoo, MI: Pharmacia & Upjohn Co; 2006 May.
8
Selecting a sulfonylurea. Pharmacist’s Letter/Prescriber’s Letter. 2009;25(4): 250411.