This systematic review and meta-analysis compared the safety and efficacy of dipeptidyl peptidase-4 (DPP-4) inhibitors versus sulfonylureas as second-line adjunctive therapy for type 2 diabetes patients inadequately controlled with metformin. The analysis found no significant difference in efficacy (HbA1c change) between the two classes, but patients on DPP-4 inhibitors experienced significantly fewer hypoglycemic events. Future research should focus on the economic implications of DPP-4 inhibitors compared to sulfonylureas in this patient population.

1. Clinical efficacy and safety of metformin-based combination therapy with dipeptidyl
peptidase - 4 inhibitors versus sulfonylurea in type 2 diabetes mellitus
Foroutan N1,2, Muratov S1,2, Levine M1,2
1PATH Research Institute, St. Joseph’s Healthcare Hamilton, Hamilton, Ontario;
2Department of Clinical Epidemiology & Biostatistics, Faculty of Health Sciences, McMaster University, Hamilton, Ontario
R E S U LT S
BAC KG RO U N D
To compare the safety and efficacy of DPP-4 inhibitors versus sulfonylurea as second-
line adjunctive therapy in patients with type 2 diabetes mellitus inadequately controlled
with metformin mono-therapy.
• Metformin is the most commonly prescribed first-line oral hyperglycemic agent (OHA) in
patients with type 2 diabetes with a low potency of development of hypoglycaemia.
However, metformin fails to maintain glycemic control for a long period of time and thus
additional therapies as second-line medications are required.
• Sulfonylureas (SUs) are the most common adjunctive second-line therapeutic drugs
particularly in patients failing to achieve or maintain glycaemic control on metformin mono-
therapy but can cause adverse events such as hypoglycaemia and weight gain.
• Over the last decade clinical studies have shown that “Dipeptidyl peptidases (DPP)-4
inhibitors” as an alternative to SU may have a better safety and efficacy profile as a
second-line adjunctive therapy added to metformin.
O B J E C T I V E
Methodological quality and risk of bias
The included studies (Fig 1.) were found to
be of “low to moderate” quality.
The body of evidence in general was
judged to be at low risk of bias
Quality of evidence per outcome were
reported as “moderate” based upon the
quality of evidence for critical outcome
(hypoglycemia)
C O N C LU S I O N S
M E T H O D S
• A systematic review of published randomised controlled trials (RCTs) in humans, in any
language, was performed in MEDLINE, MEDLINE In-Process & Other Non-Indexed
Citations, EMBASE, PubMed and the Cochrane Central Register of Controlled Trials
from 1980 to June 2015.
• Study inclusion criteria based upon the following PICOS description:
 Population: adults with type 2 diabetes mellitus requiring an OHA added to metformin because
of inadequate glycemic control (HbA1c > 6.5%, fasting plasma glucose >7 mmol/L
or 2-hour postprandial glucose > 10 mmol/L)
 Intervention: any DPP-4 inhibitor (alogliptin, linagliptin, saxagliptin, sitagliptin, and
vildagliptin), in the treatment of type 2 diabetes (as second-line therapy)
 Comparator(s): any Sulfonylurea compound
 Outcome(s): HbA1c (%) (mean change from baseline) and Hypoglycemic event
(proportion of patients who experienced at least one hypoglycemic event defined as
a finger-stick glucose value ≤50 mg/dl with associated symptoms)
 Study type(s): RCTs in humans, published in any language, with at least 12 weeks
follow-up duration.
• Study selection and quality assessment: Two review authors independently selected
the studies and assessed risk of bias for the included RCTs using the “Cochrane
Collaboration’s Risk of Bias tool” and abstracted data using a study-specific data
extraction form.
• Statistical analysis: A direct comparison meta-analysis using a random effect model
was conducted to calculate mean differences in treatment effects and risk ratio (RR) -
with 95% confidence interval- between DPP-4 inhibitors and sulfonylurea.
Figure 2: Efficacy results
Figure 3: Safety results
Records identified through database
searching
(n =3561)
Records after duplicates removed
(n = 3081)
Records excluded not
meeting inclusion criteria
(n =3047)
Full-text articles assessed
for eligibility
(n = 34)
Full-text articles excluded,
with reasons (n =24)
- Non-RCTs (n=9)
- Conference proceedings &
unpublished trials (n=3)
- Trials do not meet inclusion
(PICOS) criteria (n=6)
- Same study with multiple
articles (n=3)
- Post-hoc analyses (n=2)
- <12 week follow-up (n=1)
Studies included in
qualitative synthesis
(n =10)
Studies included in
quantitative synthesis
(meta-analysis)
(n = 10)
Records passed title &
abstract screening
(n = 34)
Figure 1 : PRISMA flow diagram
Efficacy Assessment (HbA1c% change
score) : As illustrated in figure 2, the meta-
analysis results showed a non-significant
difference between the test and the control
groups (MD=0.06, 95% CI -0.00- 0.13,
P=0.07) from the 10 studies evaluating
HbA1c% (difference from baseline) in
10,139 subjects. Following a sensitivity
analysis that was performed to test the
robustness of the results, stratifying into
high risk of bias (for missing data >20%)
and low risk studies, the results changed to
a significant difference in favor of SUs and
heterogeneity (I2) decreased from 73% to
less than 48% in the low risk subgroup.
Safety assessment (hypoglycemic event rate): Figure 3 shows the results of the meta-
analysis of eight RCTs involving 10,616 diabetic patients, with at least one hypoglycemic
event during the follow-up period. Patients on metformin plus DPP-4inhibitors were found to
experience significantly fewer hypoglycemic events compared to the metformin plus
sulfonylurea group (RR= 0.15; 95% CI, 0.11-0.22; P<0.00001). There was substantial
heterogeneity (I2=77%), but by removing two outliers and one high risk of bias study, the
heterogeneity (I2) equaled zero for the remaining 5 studies. The result from these five
studies was similar to the 8 study analysis for hypoglycemic event rates (RR= 0.12; 95% CI,
0.1-0.15; P<0.00001).
• The present study is the first systematic-review/ meta-analysis comparing safety and
efficacy of all DPP-4 inhibitors as a group (alogliptin, linagliptin, saxagliptin, sitagliptin,
and vildagliptin) with sulfonylureas as adjunctive second-line therapy added to metformin
monotherapy in patients with type 2 diabetes mellitus.
• With respect to efficacy, the review shows no significant difference between DPP4-
inhibitors and sulfonylurea when either is added to metformin mono-therapy. In contrast,
the safety assessment analysis showed a significant decrease in the risk of
hypoglycemic events in patients using DPP4-inhibitors. Future research activities should
include an economic and financial analysis of DPP-4 inhibitors compared with SUs, as
the medication added to metformin mono-therapy in type 2 diabetic patients with
inadequate glycemic control. That would inform policy makers and clinicians with a
comprehensive efficacy, safety and economic-financial impact of each treatment.
Softwares: Cochrane Collaboration’s Review Manager (RevMan®) Analysis Version 5.3
statistical software was applied for meta-analysis.
GRADEprofiler® (GRADE Working Group) was used to assess the quality of evidence per
outcome and ultimately to create the summary of findings table and evidence profile.
M E T H O D S ( C O N T. )