Download CLI PS - Samford University

SAMFORD UNIVERSITY GLOBAL DRUG INFORMATION SERVICE’S
C L I PS
CURRENT LITERATURE AND INFORMATION FOR PHARMACISTS®
http://pharmacy.samford.edu/msop_dic.aspx
Volume 15 (Issue 25)
July 11, 2011
EFFECT OF ADDING A THIRD AGENT IN UNCONTROLLED TYPE 2 DIABETES
In many patients with Type 2 diabetes mellitus (T2DM), long-term glucose control is not achieved or maintained
through lifestyle modifications or combination therapy with metformin and sulfonylurea. A third agent, such as insulin, αglucosidase inhibitors (acarbose, miglitol), thiazolidinediones (pioglitazone, rosiglitazone), glucagon-like peptide-1
agonists (exenatide, liraglutide),or dipeptidyl peptidase-4 inhibitors (sitagliptin, saxagliptin, linagliptin) are often added in
an effort to achieve long-term glucose control. This issue of CLIPs briefly summarizes a meta-analysis that sought to
determine if any of these drug classes offer greater benefit as a third agent with regard to changes in hemoglobin A1c
(HgA1c) levels, weight or frequency of severe hypoglycemic episodes in patients with uncontrolled T2DM. If you need
further information, please contact the Samford University Drug Information Service at (205) 726-2659.
Gross JL, Kramer CK, Leitão CB, et al. Effect of antihyperglycemic agents added to metformin and a
sulfonylurea on glycemic control and weight gain in type 2 diabetes: a network meta-analysis. Ann Intern Med.
2011 May 17;154:672-679.
Methods
 Analysis included 18 randomized, controlled trials (n=4535) that evaluated the effect on glucose control with
addition of a third antihyperglycemic agent to metformin and sulfonylurea in patients with uncontrolled T2DM.
 Patients ≥18 year or older with HbA1c level greater than 7.0% on stable therapy with metformin (≥1000
mg/day) and a sulfonylurea (≥50% of max dose) for at least 3 months.
 Endpoints evaluated included mean change in HbA1c level, weight, and frequency of severe hypoglycemic
episodes (blood glucose ≤35 mg/dL).
Results
 A decrease in HbA1c was seen with each class of antihyperglycemics (see Table)
 Compared to placebo, noninsulin agents reduced HbA1c a mean of 0.96% (95% CI, -1.11 to -0.81). Compared
to insulin, noninsulin antihyperglycemic agents, as a whole, led to a mean increase of 0.29% (95% CI, 0.06 to
0.51) in HbA1c level in comparison to insulin.
Noninsulin Antihyperglycemic Agents or Insulins vs. Placebo
Difference in HbA1c level, %
Intervention (# studies)
Weighted Mean (95% CI)
All agents (9)
-0.96 (-1.11 to -0.81)
Insulin (2)
-0.71 (-0.95 to -0.47)
Thiazolidinediones (3)
-1.15 (-1.35 to -0.95)
Acarbose (1)
-0.60 (-1.16 to -0.04)
Glucagon-like peptide-1 [GLP-1] agonists (2)
-1.04 (-1.24 to -0.85)
Dipeptidyl peptidase-4 [DPP-4] inhibitors (1)
-0.89 (-1.11 to -0.67)
Noninsulin Antihyperglycemic Agents vs. Insulins
All agents (10)
0.29 (0.06 to 0.51)
Thiazolidinediones (6)
0.22 (0.07 to 0.37)
Acarbose (1)
0.20 (-0.60 to 1.00)
GLP-1 agonists (3)
0.10 (-0.28 to 0.42)
CI=confidence interval
CONTINUED NEXT PAGE
Results (continued)
 Changes in HgA1c levels were not associated with baseline HgA1c levels, duration of diabetes or baseline
body mass index (BMI).
 Changes in weight varied among drug classes.
o Compared to placebo, insulin caused a significant increase in weight (2.31 kg [95% CI, 0.13 to 4.48 kg]) and
acarbose caused a significant decrease in weight (-0.96 kg [95% CI -1.80 to -0.12]).
o Compared to insulin, thiazolidinediones were associated with a weight increase (1.67 kg [95% CI, 0.98 to
2.36 kg]) and GLP-1 agonists with a weight decrease (-4.99 kg [95% CI, -5.80 to-4.18 kg]). Data on changes
in weight were not available for the DPP-4 inhibitors.

The frequency of hypoglycemic episodes could not be analyzed because many studies did not report this
information.
o Compared to placebo, severe hypoglycemic episodes were reported in two patients taking insulin (2/335), in
one taking acarbose (1/41) and five patients taking GLP-1 agonists (5/466).
o Overall, severe hypoglycemic episodes occurred at twice the frequency in patients taking insulin compared
to patients taking noninsulin antihyperglycemics (2.7% [15/566] vs. 1.1% [6/553], respectively). Increased
frequency was also noted with the GLP-1 agonists (4.1% [6/145] vs. 2.2% [3/138], respectively) and the
thiazolidinediones (2.1% [9/421] vs. 0.07% [3/415], respectively). No data was available for acarbose or the
DPP-4 inhibitors compared with insulin.
Discussion
 Direct meta-analysis compared all agents against placebo and noninsulin agents against insulin. Network
meta-analysis compared all agents against each other. Only results of the direct meta-analysis are presented.
 Results suggest that adding a third agent is beneficial, but does not distinguish which drug class is superior for
reducing HbA1c.
 Studies suggest that patients taking insulin are at greater risk of weight gain than patients taking any of the
other noninsulin antihyperglycemics. Among the noninsulin agents, weight gain was noted with the
thiazolidinediones and weight loss was noted with acarbose and the GLP-1 agonists. The other noninsulin
antihyperglycemic agents did not have a significant effect on weight gain or loss.
 Differences in the occurrence of severe hypoglycemia were found between the drug classes. Insulin caused
the most risk of severe hypoglycemia followed by the GLP-1 agonists and the thiazolidinediones.
 This analysis is limited by short-term trials (<1 year) with varied quality and indirect comparisons which
increased the uncertainty of the results and conclusions.
Summary
 No apparent difference in benefit between drug classes (insulin, α-glucosidase inhibitors, thiazolidinediones,
GLP-1 agonists or DPP-4 inhibitors) exist when choosing a third agent for the treatment of patients with
uncontrolled T2DM who are already taking metformin and a sulfonylurea.
 Selection of a third drug should include consideration of the patient’s clinical needs, such as importance of
weight changes and potential risk of hypoglycemia.
2
Prepared by: Rhonda Hamilton, Pharm.D. Candidate
Reviewed by: Rachel Slaton, Pharm.D., BCPS
Effect of adding a third agent in uncontrolled type 2 diabetes. CLIPs- Current Literature and Information for
Pharmacists. 2011 July 11;15(25):1-2.