original article

Diabetes, Obesity and Metabolism 16: 410–417, 2014.

© 2013 John Wiley & Sons Ltd

Early combination therapy for the treatment of type 2

diabetes mellitus: systematic review and meta-analysis
original
article

O. J. Phung1 , D. M. Sobieraj2 , S. S. Engel3 & S. N. Rajpathak3

1 College of Pharmacy, Western University of Health Sciences, Pomona, CA, USA
2 School of Pharmacy, University of Connecticut, Storrs, CT, USA
3 Merck & Co., Inc., Whitehouse Station, NJ, USA

Aims: Guidelines for type 2 diabetes recommend add-on agents when metformin alone fails to provide adequate glycaemic control.
However, early combination therapy may benefit health outcomes. We conducted a systematic review and meta-analysis to investigate this
question.
Methods: We searched MEDLINE and Cochrane CENTRAL (up to July 2012) without language restrictions. We sought randomized controlled
trials (RCTs) evaluating initial combination therapy with metformin versus metformin monotherapy in patients with untreated type 2 diabetes.
Weighted mean differences (WMDs) for changes from baseline and relative risks (RRs) [with 95% confidence intervals (CIs)] were calculated
using random-effects model.
Results: In 15 RCTs (N = 6693), the mean age range was 48.4–62.7 years; mean baseline glycosylated haemoglobin (A1c) was 7.2–9.9%
and mean diabetes duration was 1.6–4.1 years, with median follow-up of 6 months and with 13 comparisons for A1c change, 14 comparisons
for A1c goal attainment of <7% and 13 comparisons for change in fasting plasma glucose (FPG). Drugs combined with metformin included
thiazolidinediones (TZDs), insulin secretagogues, dipeptidyl peptidase-4 (DPP-4) inhibitors or sodium glucose transporterase (SGLT-2) inhibitors.
Compared to metformin alone, combination therapy with metformin provided statistically significant reductions in A1c (WMD −0.43%, 95% CI
−0.56, −0.30), increases in attainment of A1c goal of less than 7% (RR 1.40, 95% CI 1.33–1.48) and reductions in FPG (WMD −14.30 mg/dl,
95% CI −16.09, −12.51).
Conclusions: These results suggest a potential benefit of initial combination therapy on glycaemic outcomes in diabetes compared to
metformin monotherapy across a wide range of baseline A1c levels. Further research should explore if early combination treatment may also
affect longer term health outcomes in diabetes.
Keywords: antidiabetic drug, diabetes mellitus, medicines management, meta-analysis, type 2 diabetes

Date submitted 9 September 2013; date of first decision 10 October 2013; date of final acceptance 2 November 2013

Introduction patients are unlikely to achieve target A1c with metformin

The commonly recommended guidelines for management
of hyperglycaemia in diabetes, including those of the
American Diabetes Association (ADA) and the European
Association for the Study of Diabetes (EASD), suggest the
initial use of metformin monotherapy and adding a second
antihyperglycaemic agent only if metformin alone is not
adequate to achieve glycaemic targets. Using this approach
may lead to a delay in optimal glycaemic treatment because
of various causes such as clinical inertia or patients not
accessing care in a timely manner [1]. Previous studies have
shown that adding a second agent to metformin can decrease
glycosylated haemoglobin (A1c) by 0.64–0.97% [2]. The
latest position statement from the ADA/EASD recommends
initiating a combination of two non-insulin agents when the
patients have a high baseline A1c (≥9.0%) because these
Correspondence to : Olivia J. Phung, PharmD, College of Pharmacy, Western University of
Health Sciences, 309 E. Second St., Pomona, CA 91766, USA.
E-mail: ophung@westernu.edu
monotherapy [3]. Similarly, the American Association of
Clinical Endocrinologists (AACE) treatment algorithm also
recommends the use of early combination therapy based on
initial glycaemic severity, recommending that patients with
elevated A1c greater than 7.5% receive combination therapy
[4]. However, these guidelines are based on our understanding
of the ability to reach glycaemic targets, rather than approaches
to modify disease progression [5]. It has been hypothesized
[6] that combining metformin and an agent from another
class with a different mechanism of action may help to
preserve β-cell function and thereby maintain a long-term
glycaemic efficacy or ‘durability’ as opposed to a stepwise
treatment approach as recommended above. To date, there
has not been a systematic review to evaluate the use of early
combination therapy and its effect on glycaemic targets. Hence,
we conducted a systematic review and meta-analysis to evaluate
the effect of early combination pharmacotherapy in patients
with diagnosed type 2 diabetes, compared to metformin
monotherapy.
DIABETES, OBESITY AND METABOLISM
Materials and Methods
Literature Search
The recommendations of the Cochrane Handbook of
Systematic Reviews, a set of guidance for conducting a
high-quality systematic review, were followed [7]. Two
independent investigators conducted a systematic literature
search of MEDLINE, Embase and Cochrane Central Register
of Controlled Trials from the earliest possible date through
July 2012, combining Medical Subject Headings and keyword
terms for type 2 diabetes, metformin and combination therapy
without language restrictions. A hand search of relevant
references from previous systematic reviews was planned, but
no prior systematic reviews were identified. A complete search
strategy is given in Appendix.
Study Selection
Studies were included in the meta-analysis if they met the
following inclusion criteria:
1 randomized controlled trials (RCTs) of parallel design with
at least 3 months of treatment duration;
2 in patients with newly diagnosed (within 3 months) or
treatment-naı̈ve type 2 diabetes;
3 comparing a combination regimen that includes metformin
to metformin monotherapy and
4 reported any of the following outcomes: A1c, fasting
plasma glucose (FPG), hypoglycaemia, measures of insulin
sensitivity or measures of pancreatic β-cell function.
Two independent investigators evaluated all citations
independently to determine inclusion; discrepancies were
resolved by discussion.
Data Extraction
Data were collected independently by two investigators using
a standardized data extraction form, with disagreements
resolved by discussion. Investigators collected the following
data from each study and reported the results in tables of
trial characteristics: study design characteristics, sample size,
inclusion and exclusion criteria, duration of patient follow-up,
baseline population characteristics, patient demographics and
co-morbidities, drugs and dosage utilized and use of concurrent
lifestyle modification. Endpoints collected included: A1c, body
weight, hypoglycaemia, measures of insulin sensitivity and
measures of pancreatic β-cell function. In cases in which
there was more than one published report on the same
population or group of patients, the article reporting data from
the prespecified primary timepoint was selected for analysis,
although related articles were reviewed to supplement missing
data where applicable.
Validity Assessment
Validity assessment was conducted for each included study by
two investigators independently, with disagreements resolved
by discussion. RCTs were assessed using the Cochrane Risk of
Bias tool [8]. The Risk of Bias tool evaluates six domains of bias:
selection bias, performance bias, detection bias, attrition bias,
Volume 16 No. 5 May 2014
original article
reporting bias and other bias. Each item on the tool is assessed
and given a judgment as low, unclear or high risk of bias.
Statistical Analysis
When more than one trial provided results on the
outcomes of interest, outcomes were meta-analysed using a
DerSimonian–Laird random-effects model [9]. Continuous
outcomes were pooled to find weighted mean differences
(WMDs) and accompanying 95% confidence intervals (CIs);
categorical outcomes were pooled to find relative risks (RRs)
and accompanying 95% CIs. Each endpoint was analysed
separately. In cases where one study provided multiple
combination therapy arms compared to monotherapy, each
combination therapy was analysed separately, with the
monotherapy data divided evenly among the comparisons;
therefore, one trial may contribute more than one comparison
to an analysis [7]. Statistical heterogeneity was assessed using
the I 2 statistic, with results ranging from 0 to 100% and
values of 25, 50 and 75% representing low, moderate and high
levels of heterogeneity, respectively [10]. Publication bias was
assessed using visual inspection of funnel plots and Egger’s
weighted regression statistics, where asymmetrical funnel plot
and Egger’s p-value <0.05 indicate potential publication bias
[11]. Statistical analysis will be performed using StatsDirect
statistical software, version 2.7.8.
Results
Study Selection and Characteristics
Upon literature search and manual review for pertinent
references, 724 citations were retrieved and evaluated for
inclusion at the title and abstract review stage (Figure 1).
From these, 44 full-text articles were evaluated for inclusion.
Twenty-seven articles were excluded because they were not
RCTs, did not include patients who were newly diagnosed
or treatment-naı̈ve, were not evaluating combination therapy
compared with monotherapy, did not report endpoints, did
not report data in a meta-analysable format or reported on
the same population as an already included paper. A total of
15 RCTs were included in the overall analysis [12–25] .One
paper was analysed as two separate trials because results were
reported as ‘Study 1’ and ‘Study 2’ within that publication [25].
The total sample size of all the studies combined is
6693 patients, with a median follow-up of 6 months. The
mean age of patients ranged from 48.4 to 62.7 years, mean
baseline A1c ranged from 7.2 to 9.9% and mean duration of
diabetes ranged from 1.6 to 4.1 years. The definition of newly
diagnosed or treatment-naı̈ve also varied by study (Table S1,
Supporting Information), where nine of the trials allowed
patients into the trial as long as there was not any recent
use of antidiabetic drugs (typically within 8–12 weeks of the
screening visit), whereas other trials excluded patients who had
used any antidiabetic drug in the past. The use of concomitant
medications by patients in the trials was not consistently
reported. The RCTs included evaluated various classes of
antidiabetic agents combined with metformin, with five
trials evaluating thiazolidinediones (TZDs) [15,16,18,21,22],
doi:10.1111/dom.12233 411
original article DIABETES, OBESITY AND METABOLISM

Records identified through Additional records identified

Identification
database searching through other sources
MEDLINE (n = 431) (n = 0)
EMBASE (n = 425)
CENTRAL (n = 164)

Records after duplicates removed

Screening (n = 724)

Records excluded (n = 680)

Records screened Not an RCT (n = 542)
(n = 724) Not in patients with T2DM (n = 1)
Not in patients who are treatment
naïve (n = 35)
Not evaluating combination therapy
compared with monotherapy (n =
102)
Full-text articles assessed
Eligibility

for eligibility
(n = 44) Full-text articles excluded (n = 20)
Not an RCT (n = 2)
Not in patients who are treatment
naïve (n = 6)
Not evaluating combination therapy
Studies included in
compared with monotherapy (n = 6)
qualitative synthesis Did not report endpoints (n = 6)
(n = 15) Data not in meta-analyzeableform (n
= 2)
Reported on the same population as
Included

another paper (n = 7)

Studies included in
quantitative synthesis
(meta-analysis)
(n = 15)

Figure 1. PRISMA flow diagram of study inclusion and exclusion.

four trials evaluating insulin secretagogues [12–14, 20], four
trials evaluating dipeptidyl peptidase-4 (DPP-4) inhibitors
[17,19,23,24] and two trials evaluating sodium glucose
transporterase-2 (SGLT-2) inhibitors [25] (Tables S1 and S2,
Figure 2). Although trials evaluating α-glucosidase inhibitors
and glucagon-like peptide-1 analogues were sought, none of
the RCTs meeting inclusion criteria evaluated these drugs.
Changes in A1c
A total of 13 comparisons were included in the analysis of
change in A1c. The majority of comparisons included a DPP-4
inhibitor (7 of 13), whereas others included a SGLT-2 inhibitor,
TZD or sulphonylurea (SU). Trial duration ranged from 16
to 76 weeks. Combination therapy significantly reduced A1c
compared to metformin monotherapy [WMD −0.43% (−0.56
to −0.30)] (Figure 3). Heterogeneity was moderate as indicated
by the I 2 value of 72%. No publication bias was detected (Egger’s
p-value = 0.21).
A1c Goal Attainment
Fourteen comparisons were included in the analysis of A1c goal
attainment less than 7%. The most common therapies evaluated
were the DPP-4 inhibitors (five comparisons) although other
classes including TZDs, SGLT-2 inhibitors and SU were also
included. Trials ranged from 16 to 80 weeks. Combination
therapy significantly increased the attainment of goal A1c
compared to metformin monotherapy [RR 1.40 (1.33–1.48)]
(Figure 3). Neither heterogeneity (I 2 = 0%) nor publication
bias (Egger’s p-value = 0.23) was detected.
Fasting Plasma Glucose
Thirteen comparisons were included in the analysis of change
in FPG. The majority of comparisons evaluated a DPP-4
inhibitor (7 of 13). Trial duration ranged from 16 to 76 weeks.
Combination therapy significantly reduced FPG compared
to metformin monotherapy [WMD −14.30 mg/dl (−16.09
to −12.51)] (Figure 3). A high level of heterogeneity was
found (I 2 = 76.3%) although publication bias was not detected
(Egger’s p-value = 0.70).
Hypoglycaemia
In the analysis of hypoglycaemia, 17 comparisons were
included. The most common therapy included was the DPP-4
inhibitors, while TZDs, SU and SGLT-2 inhibitors were also
represented. Trials ranged from 16 to 80 weeks in duration and a
similar number of trials allowed rescue therapy or did not report
if rescue therapy was used (seven each). A significant increase
in the risk of hypoglycaemia was found with combination

412 Phung et al. Volume 16 No. 5 May 2014

DIABETES, OBESITY AND METABOLISM
Figure 2. Risk of bias assessment of studies.
therapy in comparison to metformin monotherapy [RR 1.56
(1.08–2.26)] (Figure 3). A moderate level of heterogeneity was
found (I 2 = 52.7%) although publication bias was not detected
(Egger’s p-value = 0.55). In a sensitivity analysis whereby SUs
and glinides were excluded (13 comparisons analysed), the risk
of hypoglycaemia was no longer significantly increased in the
combination group compared to metformin monotherapy [RR
1.20 (0.91–1.56)].
Discussion
The results of this meta-analysis suggest that the use of
combination therapy versus metformin monotherapy upon
initiation of pharmacologic therapy in type 2 diabetes is
beneficial in improving glycaemic outcomes.
In the treatment approach recommended by the ADA/EASD,
metformin monotherapy is the preferred initial drug therapy
[3]. In cases where patients have a high baseline A1c, defined
by the ADA/EASD as ≥9%, initiating drug therapy with an
additional agent may be warranted, as monotherapy is unlikely
to achieve glycaemic targets [3]. In contrast, the AACE provides
a treatment algorithm that stratifies initial pharmacologic
treatment approach by the current A1c level of the patient [4]. In
this set of recommendations, combination therapy is warranted
when the patient’s A1c is between 7.6 and 9.0%, and those
with A1c >9.0% warranting triple therapy [4]. In both sets of
guidelines, the rationale for initiating with combination therapy
is that patients would be unlikely to reach glycaemic target with
monotherapy. Our meta-analysis confirms this reasoning, as
combination therapy was significantly associated with a greater
likelihood of attaining A1c goal less than 7%. Prior analyses
that have evaluated patients within a baseline range of A1c from
Volume 16 No. 5 May 2014
original article
7.5 to 9% have also shown that initial combination therapy
yields a greater proportion of patients achieving A1c versus
monotherapy, also supporting the recommendation that initial
combination therapy should be used in these patients [5].
In patients with type 2 diabetes, the initiation of
monotherapy often fails to reach glycaemic targets across a wide
range of baseline A1c levels [26]. This is most likely because
monotherapy fails to address the multiple pathophysiological
causes of diabetes, whereas combination treatment can address
multiple mechanisms. The patients in the trials included
in this meta-analysis varied in baseline A1c, and greater
efficacy of combination treatment was demonstrated in all
trials. This suggests that initial combination therapy may be
a reasonable treatment option across a wide range of A1c
levels, including those with lower A1c levels, as our analysis
included trials with mean baseline A1c ranging from 7.2 to
9.9%. Although a greater likelihood of hypoglycaemia was seen
with combination therapy versus metformin monotherapy,
it is not surprising that this effect was not significant
when the trials of combination of metformin with SUs or
glinides were excluded. Initial combination therapy may also
potentially decrease some adverse drug reactions over time
by optimizing glycaemic control early on with lower doses of
the component medications, thus potentially decreasing the
need for dose intensification. Additionally, while it has been
shown that patients receiving monotherapy are more likely to
be adherent to their regimens than those receiving multiple
medications [27], the availability of fixed-dose combinations
of antihyperglycaemic agents may address this concern [28].
The evidence available on initial combination therapy most
often reports data on glycaemic outcomes, with limited data on
insulin sensitivity. A few trials included in this meta-analysis
doi:10.1111/dom.12233 413
original article DIABETES, OBESITY AND METABOLISM

A. Change from Baseline in A1c (%) B. Attainment of A1c Goal <7%

Henry, 2012a (SGLT2) Henry, 2012a (SGLT2)

Henry, 2012b (SGLT2) Henry, 2012b (SGLT2)
Kadaglou, 2011 (TZD) Borges, 2011 (TZD)
Olansky, 2011 (DPP4)
Olansky, 2011 (DPP4)
Pfutzner, 2011a (DPP4) Pfutzner, 2011a (DPP4)
Pfutzner, 2011b (DPP4) Pfutzner, 2011b (DPP4)
Chen, 2010 (SU) Bosi, 2009a (DPP4)

Bosi, 2009a (DPP4) Bosi, 2009b (DPP4)

Bosi, 2009b (DPP4) Perez, 2009 (TZD)
Williams-Herman, 2009a (DPP4) Rosenstock, 2006 (TZD)
Williams-Herman, 2009b (DPP4) Horton, 2004 (Glinide)

Stewart, 2006 (TZD) Garber, 2003 (SU)

Horton, 2004 (Glinide) Garber, 2002a (SU)
Combined Garber, 2002b (SU)
Combined
-3 -2 -1 0 1 2 3
1 2
Weighted Mean Difference -0.43 (95% Confidence Interval -0.56,-0.30)
Relative Risk 1.40 (95% Confidence Interval 1.33,1.48)

C. Change from Baseline in Fasting Plasma Glucose (mg/dl) D. Hypoglycaemia

Henry, 2012a(SGLT2) Henry, 2012a (SGLT2)

Henry, 2012b (SGLT2) Henry, 2012b (SGLT2)
Borges, 2011 (TZD)
Kadaglou, 2011 (TZD)
Olansky, 2011 (DPP4)
Olansky, 2011 (DPP4)
Pfutzner, 2011a (DPP4)
Pfutzner, 2011a (DPP4
Pfutzner, 2011b (DPP4
Pfutzner, 2011b (DPP4)
Bosi, 2009a (DPP4)
Chen, 2010 (SU)
Bosi, 2009b (DPP4)
Bosi, 2009a (DPP4) Perez, 2009 (TZD)
Bosi, 2009b (DPP4) Williams-Herman, 2009a (DPP4)
Williams-Herman, 2009a (DPP4) Williams-Herman, 2009b (DPP4)
Williams-Herman, 2009b (DPP4) Rosenstock, 2006 (TZD)
Stewart, 2006 (TZD) Stewart, 2006 (TZD)
Horton, 2004 (Glinide) Horton, 2004 (Glinide)
Combined Garber, 2003 (SU)
Garber, 2002a (SU)
-100 -50 0 50 100 Garber, 2002b (SU)
Weighted Mean Difference -14.30 (95% Confidence Interval -16.09,-12.51) Combined

0.001 0.01 0.10.2 0.5 1 2 5 10 100 1000 1.00E+05

Relative Risk 1.56 (95% Confidence Interval 1.08,2.26)

Figure 3. Results of meta-analysis of studies comparing early combination therapy with metformin to metformin monotherapy on change from baseline
in glycosylated haemoglobin (A1c) (A), attainment of A1c goal <7% (B), change from baseline in fasting plasma glucose (C) and hypoglycaemia (D).
Notes: Henry, 2012a and b [25] were two separate trials published within the same article. Other notations of a and b refer to different dosing arms of
the combination therapy. Abbreviations: DPP-4, dipeptidyl peptidase-4 inhibitor; SGLT-2, sodium glucose transporterase-2 inhibitor; SU, sulphonylurea;
TZD, thiazolidinedione.

suggested greater improvement in insulin resistance among
patients on initial combination therapy compared to those
on metformin alone [12,13,15,18,19,21]. However, most, if
not all, of such effect may be attributable to the individual
drugs used in combination with metformin. Only one study
reported β-cell function as measured by homeostatic model
assessment (HOMA)-β, and showed that combination therapy
with sitaglipin and metformin improves β-cell functioning
at week 18 compared with metformin monotherapy [19].
Whether improved glycaemic effects related to combination
treatment may also mediate some of the benefit on insulin
sensitivity, for example, through reversal of glucose toxicity,
remains to be explored.
The current meta-analysis has several limitations that require
consideration when interpreting the results. The studies that
were included in the analysis had an inconsistent definition
of treatment-naı̈ve, with some studies allowing patients to
be included even if they had use of antidiabetic drugs in
the distant past. Although the patients were not recently using
antidiabetic drugs, it is possible that these patients may respond
to combination therapy differently than those who have never
used antidiabetic drugs. Additionally, the small number of
studies included in this analysis did not allow the comparison of
the effect of combination therapy between classes of antidiabetic
drugs combined with metformin. As there were only a few
studies from each class, these quantitative comparisons were
not made. Although body weight was collected and reported
in Table S2, it was not sufficiently reported to allow for meta-
analysis. Also, major safety outcomes such as liver or kidney
damage were not consistently reported by the included RCTs.
The duration of the studies included was relatively short,
with most studies around 24 weeks, and only three studies
reporting outcomes beyond 1 year. Additional studies may be
needed to determine if the benefits of combination therapy
initiated at the time of pharmacological therapy initiation are
sustained over time. It is possible that observational cohort
studies may provide insight on how patient outcomes would be
affected. Heterogeneity was found to be moderate to high for the
evaluation of change in A1c, change in FPG and hypoglycaemia.
Some potential sources of heterogeneity include the diversity

414 Phung et al. Volume 16 No. 5 May 2014

 Table 1. Outcomes of studies evaluating early combination therapy in type 2 diabetes.

Change in Achieved Change in Change in Hypoglycaemia

Follow-up A1c (%), A1c goal FPG (mg/dl), weight (kg), overall
Study name, year, reference (weeks) Group mean ± SD N* <7% (n/N) mean ± SD N* mean ± SD N* (n/N)

Garber et al., 2002 [12], N = 484 20 Glyburide and metformin 5/2000 mg/day −1.48† 158 104/119 −42† 158 1.4† 158 8/158
Glyburide and metformin 10/2000 mg/day −1.53† 165 119/165 −40† 165 1.9† 165 26/165
Metformin 2000 mg/day −1.03† 161 81/161 −21† 161 −0.6† 161 0/161

Volume 16 No. 5 May 2014

Garber et al., 2003 [13], N = 335 16 Glyburide and metformin 5/1000 mg/day −2.27† 171 135/171 −62.4† 171 1.1† 171 98/171
Metformin 2000 mg/day −1.53† 164 102/164 −43.8† 164 −1.6† 164 29/164
Horton et al., 2004 [14] , N = 193 24 Nateglinide and metformin 360/1500 mg/day −1.6 ± 0.94 89 62/89 −41.4 ± 50.94 89 NR 26/89
Metformin 1500 mg/day −0.8 ± 1.02 104 43/104 −21.6 ± 55.08 104 NR 11/104
Rosenstock et al., 2006 [15] , N = 309 32 Rosiglitazone and metformin 8/2000 mg/day −2.3† 152 117/152 −73.8† 152 NR 19/155
Metformin 2000 mg/day −1.8† 150 86/150 −50.4† 150 NR 14/154
DIABETES, OBESITY AND METABOLISM

Stewart et al., 2006 [16] , N = 526 32 Rosiglitazone and metformin up to 8/2000 mg/day −0.51 ± 0.72 246 52/246 −27.18 ± 48.06 246 NR 17/254
Metformin up to 3000 mg/day −0.38 ± 0.79 263 44/263 −16.02 ± 49.68 263 NR 10/272
Bosi et al., 2009 [17] , N = 879 24 Vildagliptin and metformin 100/2000 mg/day −1.8 ± 1.01 285 185/283 −47.34 ± 39.42 285 −1.19 ± 3.71 285 0/295
Vildagliptin and metformin 100/1000 mg/day −1.6 ± 1.0 277 149/269 −39.78 ± 38.88 277 −1.17 ± 3.83 277 0/290
Metformin 2000 mg/day −1.4 ± 1.01 285 123/283 −34.45 ± 285 285 −1.62 ± 3.71 285 1/294
Perez et al., 2009 [18] , N = 411 24 Pioglitazone and metformin 30/1700 mg/day −1.83† 201 128/201 −39.90† 201 NR 2/201
Metformin 1700 mg/day −0.99† 210 81/210 −24.80† 210 NR 3/210
Williams-Herman et al., 2009 [19] , N = 554 54 Sitagliptin and metformin 100/1000 mg/day −1.4 ± 0.93 147 48%‡ −42.5 ± 37.91 146 NR 4/190
Sitagliptin and metformin 100/2000 mg/day −1.8 ± 0.95 153 67%‡ −55.6 ± 37.86 153 NR 5/182
Metformin 2000 mg/day −1.3 ± 0.89 134 44%‡ −39.6 ± 37.8 134 NR 2/182
Chen et al., 2010 [20] , N = 47 16 Gliclazide and metformin up to 60/1000 mg/day −1.60 ± 4.18 23 NR −41.4 ± 137.88 23 NR NR
Metformin up to 2500 mg/day −1.5 ± 4.24 24 NR −14.4 ± 130.32 24 NR NR
Borges et al., 2011 [21] , N = 697 80 Rosiglitazone and metformin up to 8/2000 mg/day NR 239/344 NR NR 20/344
Metformin up to 2000 mg/day NR 174/334 NR NR 10/334
Kadoglou et al., 2011 [22] , N = 140 24 Rosiglitazone and metformin 4/500 mg/day −0.98 ± 0.95 67 NR −32 ± 39.59 67 NR NR
Metformin 1700 mg/day −0.69 ± 0.98 69 NR −36 ± 23.07 69 NR NR
Olansky et al., 2011 [23] , N = 1246 44 Sitagliptin and metformin 100/2000 mg/day −2.3 ± 1.81 560 258/560 −65 ± 60.36 560 NR 19/625
Metformin 2000 mg/day −1.8 ± 1.82 569 173/569 −53.4 ± 60.14 567 NR 23/621
Pfutzner et al., 2011 [24] , N = 971 76 Saxagliptin and metformin 5/2000 mg/day −2.31 ± 1.22 303 157/307 −54 ± 46.14 315 −1.2† NR 15/320
Saxagliptin and metformin 10/2000 mg/day −2.33 ± 1.24 313 160/315 −55 ± 46.29 317 −0.7† NR 22/323
Metformin 2000 mg/d −1.79 ± 1.23 308 109/314 −40 ± 50.09 320 −1† NR 20/308
Henry et al., 2012 [25] , N = 395 (Study 1) 24 Dapagliflozin and metformin 5/2000 mg/day −2.05 ± 1.21 185 96/185 −61.02 ± 38.16 192 −2.66 ± 3.36 192 5/194
Metformin 2000 mg/day −1.35 ± 1.25 195 68/195 −33.48 ± 38.34 200 −1.29 ± 3.40 201 0/201
Henry et al., 2012 [25] , N = 419 (Study 2) 24 Dapagliflozin and metformin 10/2000 mg/day −1.98 ± 1.11 211 92/201 −60.3 ± 36.54 209 −3.33 ± 3.4 201 7/211
Metformin 2000 mg/day −1.44 ± 1.09 203 72/203 −34.74 ± 37.08 207 −1.36 ± 3.45 208 6/208

A1c, glycosylated haemoglobin; FPG, fasting plasma glucose; N, sample size; NR, not reported; SD, standard deviation; SE, standard error.
*May not add up to total sample size due to attrition.
†Reported without measures of variance; could not be meta-analysed.
‡Difference between groups (referent given), given as mean and standard error.
original article

doi:10.1111/dom.12233 415
original article
of pharmacologic classes evaluated, the duration of trials that
ranged from 16 to 80 weeks and the use of rescue antidiabetic
medications. However, the patient populations were similar
with respect to demographics such as baseline glucose level
(Table 1).
Although the current evidence has its limitations, these
results suggest a potential benefit of initial combination therapy
on glycaemic outcomes in diabetes compared to metformin
monotherapy across a wide range of baseline A1c levels. Further
research should explore if early combination treatment may
also affect long-term health outcomes in diabetes.
Conflict of Interest
O. J. P. and S. N. R. designed the study. O. J. P. and D. M.
S. performed the data collection and analysed the data. O. J.
P., D. M. S., S. S. E. and S. N. R. were involved in writing the
manuscript. O. J. P. and D. M. S. have received grant funding
from Merck & Co, Inc. S. S. E. and S. N. R. are employees of
Merck & Co, Inc.
Supporting Information
Additional Supporting Information may be found in the online
version of this article:
Table S1. Characteristics of studies evaluating early combi-
nation therapy in type 2 diabetes.
Table S2. Baseline characteristics of patients in studies
evaluating early combination therapy in type 2 diabetes.
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Appendix: PubMed Search Strategy
(randomized controlled trial[pt] OR controlled clinical
trial[pt] OR randomized[tiab] OR placebo[tiab] OR ”drug
therapy”[Subheading] OR randomly[tiab] OR trial[tiab]
OR groups[tiab]) NOT (”animals”[MeSH Terms] NOT
”humans”[MeSH Terms])
AND
(”diabetes mellitus, type 2”[MeSH Terms] OR ”type 2
diabetes mellitus”[All Fields] OR ”type 2 diabetes”[All Fields]
OR ”type ii diabetes”[All Fields] OR ”diabetes type 2”[All
Fields] OR ”diabetes type ii”[All Fields] OR ”niddm”[All
Fields] OR ”noninsulin dependent diabetes”[All Fields] OR
”t2dm”[All Fields])
AND
(treatment-naive[All Fields] OR ”newly diagnosed”[All
Fields] OR ”untreated”[All Fields] OR ((initial or initiation
Volume 16 No. 5 May 2014
original article
or starting)AND(therapy or treatment or drug or pharma-
cotherapy)) or drug-naive or early combination)
AND
(”metformin”[MeSH Terms] OR ”metformin”[All Fields])
AND
(‘‘Sulfonylurea Compounds’’[MeSH] OR sulfonylurea[tiab]
OR Acetohexamide[MeSH] OR acetohexamide[tiab] OR
carbutamide[MeSH] OR carbutamide[tiab] OR Chlor-
propamide[MeSH] OR chlorpropamide[tiab] OR Gli-
clazide[MeSH] OR gliclazide[tiab] OR Glipizide[MeSH] OR
glipizide[tiab] OR Glyburide[MeSH] OR glyburide[tiab]
OR glimepiride[tiab] OR Tolazamide[MeSH] OR tolaza-
mide[tiab] OR Tolbutamide[MeSH] OR tolbutamide[tiab]
OR Thiazolidinediones[MeSH] OR thiazolidinedione[tiab]
OR TZD[tiab] OR glitazone[tiab] OR glitazones[tiab] OR
thiazolidinediones[tiab] OR rosiglitazone[tiab] OR piogli-
tazone[tiab] OR troglitazone[tiab] OR ‘‘alpha-glucosidase
inhibitors’’[tiab] OR ‘‘a-glucosidase inhibitors’’[tiab] OR Acar-
bose[MeSH] OR acarbose[tiab] OR miglitol[tiab] OR vogli-
bose[tiab] OR nateglinide[tiab] OR repaglinide[tiab] OR
Linagliptin[tiab] OR Saxagliptin[tiab] OR Sitagliptin[tiab]
OR ‘‘Dipeptidyl-peptidase IV inhibitors’’[MeSH] OR Exe-
natide[tiab] OR Liraglutide[tiab] OR Dapagliflozin[tiab]
OR Remogliflozin[tiab] OR ‘‘Sodium-glucose transporter
2’’[MeSH]).
doi:10.1111/dom.12233 417