Postgrad Med. 2014 May - 126 (3) - pp111-25

All rights reserved: reproduction in whole or part not permitted.
All permission requests to reproduce or adapt published

material must be directed to the journal office in Conshohocken, PA, no othe rpersons of offices are authorized to act on our behalf.
Reprints:
reprints@postgradmed.com -- permissions@postgradmed.com
C L I N I C A L F O C U S : D I A B E T E S A N D C O N C O M I TA N T D I S O R D E R S
Influence of Baseline Glycemia on Outcomes

With Insulin Glargine Use in Patients Uncontrolled
on Oral Agents
DOI: 10.3810/pgm.2014.05.2761
Mary Ann Banerji, MD 1

Michelle A. Baron, MD 2
Ling Gao, ME 2
Lawrence Blonde, MD 3
1
Professor of Medicine and
Endocrinology, Division Chief,
Endocrinology at SUNY, SUNY
Downstate Medical Center, Brooklyn,
NY; 2Sanofi Inc., Bridgewater, NJ;
3
Director, Ochsner Diabetes Clinical
Research Unit, Department of
Endocrinology, Ochsner Medical
Center, New Orleans, LA
Correspondence: Mary Ann Banerji, MD,

Professor of Medicine,
Director, Diabetes Treatment Center,
State University of New York Downstate
Medical Center,
450 Clarkson Avenue
Brooklyn, NY 11203.
Tel: 718-270-1542
Fax: 718-270-1534
E-mail: MaryAnn.Banerji@downstate.edu
Abstract
Purpose: Optimizing glycemic control in patients with type 2 diabetes mellitus (T2DM) not
controlled with $1 oral antidiabetes drugs (OADs) is challenging. Many therapeutic options
exist; however, data comparing the effectiveness of different strategies are lacking for the management of patients with T2DM. Our study aim was to provide comparative data on efficacy and
hypoglycemia when initiating insulin glargine (glargine) versus alternative treatment options
(not including the newest antidiabetes agents, glucagon-like peptide [GLP]-1 receptor agonists,
dipeptidyl peptidase [DPP]-4inhibitors or sodium-glucose linked transporter [SGLT]-2inhibitors) in insulin-naive patients with T2DM who remained uncontrolled with OADs. Methods:
Patient-level data were pooled from 9 randomized controlled trials of $24 weeks duration with
comparable patient populations. The effect of adding glargine was compared with intensification
of lifestyle interventions or OADs, addition of neutral protamine Hagedorn (NPH) insulin, insulin
lispro, premixed insulin, or all comparators pooled, on patient glycated hemoglobin (HbA1c)
level, fasting plasma glucose level, weight, and hypoglycemia. Results: A greater proportion
of patients achieved a target HbA1c level # 7.0% with glargine treatment than with pooled
comparators, intensification of OADs, or lifestyle interventions; there was no difference when
compared with NPH, premixed, or insulin lispro use. The rate for reported hypoglycemic events
was lower for glargine use than for pooled comparators or other insulins, but higher compared
with intensification of lifestyle interventions or OADs. When stratified by baseline HbA1c level,
efficacy/target attainment with glargine use was better than for pooled comparators across all
HbA1c strata; OAD intensification, when baseline HbA1c level was $8.0%; and premixed insulin
if baseline HbA1c level was,8.0%; but similar to other insulins for all other categories. The
incidence of reported hypoglycemia was less frequent with glargine use than other insulins,
but more frequent than intensification of lifestyle interventions or OADs. Conclusion: When
adequate glycemic control is not achieved using OADs in patients with T2DM, initiating insulin
glargine is generally less likely to elicit hypoglycemia than initiating NPH, premixed, or prandial
insulins, and the benefitrisk balance supports initiating insulin rather than intensification of
OAD therapy when baseline HbA1c level is $8.0%.
Keywords: type 2 diabetes mellitus; insulin; insulin glargine; glycemic control;
hypoglycemia
Introduction
Long-term complications of diabetes decrease with improvement of glycemic control.

The evidence is clear for patients with microvascular complications,13 and meta-
Postgraduate Medicine, Volume 126, Issue 3, May 2014, ISSN 0032-5481, e-ISSN 1941-9260 111
ResearchSHARE: www.research-share.com Permissions: permissions@postgradmed.com Reprints: reprints@postgradmed.com
Warning: No duplication rights exist for this journal. Only JTE Multimedia, LLC holds rights to this publication. Please contact the publisher directly with any queries.
Banerji etal
analyses suggest it is also true for some cases of macrovascular complications48; however, optimizing glycemic control
in patients for whom adequate control has not been achieved
using $1 oral antidiabetes drug (OAD) is challenging, and
the target glycated hemoglobin (HbA1c) levelalong with
the method of attaining the goalshould be individualized.9
Although many therapeutic options exist, data comparing
the effectiveness of different strategies among comparable
groups of patients treated in a consistent manner are lacking
for type 2 diabetes mellitus (T2DM).10 There is interest at
the federal level for such comparative information to inform
clinical decision-making for both clinicians and payors; this is
especially true when treatment with OADs does not achieve
or maintain adequate glycemic goals in individual patients.
As T2DM is a progressive disorder,11 failure to achieve
glycemic targets is expected to be a growing problem, both
because of the increasing incidence of T2DM in the population and the longer duration of the disease process.
Our analysis pooled data on patients who were naive to
insulin therapy and receiving a stable regimen of $1 OAD(s)
but experiencing suboptimal glycemic control (defined as an
HbA1c level.7.0%). The effect of adding the basal insulin,
insulin glargine (glargine), to ongoing OAD treatment was
compared with alternative therapeutic options, including
intensification of lifestyle interventions or OAD therapy, and
the addition of neutral protamine Hagedorn (NPH) insulin,
premixed insulin, or a prandial insulin (insulin lispro). We did
not include the newest antidiabetes agents, such as glucagonlike peptide (GLP)-1 receptor agonists, dipeptidyl peptidase
(DPP)-4inhibitors or sodium-glucose linked transporter
(SGLT)-2inhibitors. We compared achievement of glycemic
goals, risk of hypoglycemia, and frequency of hypoglycemic
events between the treatment groups and according to baseline HbA1c level category. The results from our study may
aid health care providers by offering comparative evidence
regarding the intensification of treatment in patients with
suboptimal glycemic control using $1 OAD(s).
Methods
Data Sources
The data source for our analysis was the database of clinical
trials of insulin glargine in patients with T2DM conducted
by Sanofi between 1997 and 2007.
Study Selection Criteria
A total of 63 randomized controlled trials (RCTs) utilizing

glargine, performed between 1997 and 2007, were assessed
for inclusion eligibility in our pooled analysis. As illustrated
112
in Figure1, eligibility required that studies were prospective RCTs with a duration of $24 weeks, which enrolled
insulin-naive adult patients with T2DM who had suboptimal
glycemic control while being treated with a stable regimen
of $1 OAD(s) or lifestyle management. Glargine was given
once daily with no prandial or bolus insulin administration,
and taken according to predefined titration algorithms with
frequent insulin dose adjustment (at least every week) to
achieve fasting plasma glucose (FPG) levels # 100mg/dL
(# 5.6mmol/L).
Nine studies 1220 met the eligibility criteriatheir
patient populations were considered homogeneous and
appropriate for pooling. The 24-week patient-level data
from the 9studies were pooled according to treatment. All
studies were conducted according to Good Clinical Practice and in accordance with the Declaration of Helsinki.
All patients from the 9selected clinical trials who were
a) randomized and treated with glargine or a comparator;
and b) had both a baseline and $1 post-baseline measurements of HbA1c level were included in our analysis.
The patient group was termed the modified intention-totreat population. Within the pooled patients, treatment
groups, glargine (n=1462) versus pooled comparators
(n=1476), were: glargine versus intensification of lifestyle interventions: 1 study12; glargine versus OAD intensification: 3 studies14,16,18; glargine versus NPH insulin:
2studies17,19 (glargine and NPH insulin were both titrated
weekly to achieve a fasting glucose level # 100mg/dL
[# 5.6mmol/L]); glargine versus insulin lispro: 1 study13
(insulin lispro was titrated weekly to achieve a preprandial
glucose of,100mg/dL [, 5.5mmol/L] and a postprandial glucose [immediately before the next meal] # 135mg/
dL [# 7.5 mmol/L]); glargine versus premixed insulin:
2studies15,20 (premixed insulin [70% NPH/30% regular
human insulin, or 75% insulin lispro protamine suspension/25% insulin lispro] was titrated to achieve fasting
and pre-dinner capillary blood glucose levels # 100mg/
dL [# 5.6mmol/L]). All comparator insulins were titrated
appropriately according to the type of insulin, and further
details regarding the studies included in our analysis can
be found in Table1 and in original publications.1220
Data Extraction, Synthesis, and Analysis
The primary outcomes of our analysis were the percentage

of patients achieving HbA1c levels # 7.0% at the Week
24 endpoint; change in HbA1c level and FPG from baseline to endpoint; and total reported, nocturnal, and severe
hypoglycemia incidence and event rates during the 24-week
Postgraduate Medicine, Volume 126, Issue 3, May 2014, ISSN 0032-5481, e-ISSN 1941-9260
Effect of Baseline Glycemia on Outcomes With Glargine Use

Figure1. Flow chart for selection of studies.
Abbreviations: Glargine, insulin glargine; NPH, neutral protamine Hagedorn; OAD, oral antidiabetic drug; RCT, randomized controlled trials.
treatment period.
Demographic and patient characteristics (body weight,
body mass index [BMI], duration of known diabetes, HbA1c
level, and FPG) were assessed at baseline and compared by
X2 test or 2-tailed t test, where appropriate, to verify balance
between treatment groups.
Patient body weight, HbA1c level, FPG, and BMI were
assessed at week 24; changes in these parameters from baseline
were compared between treatment groups with an ANCOVA
model, using treatment and study as factors, and baseline value
as a covariate. Target HbA1c level was defined as # 7.0%; the
frequencies of goal attainment, as well as the frequency of
HbA1c level decrease of $1.0% were calculated by treatment
group, using Cochran-Mantel-Haenszel test, stratified by study.
Odds ratios (ORs) and 95% confidence intervals (CIs) were
estimated by logistical regression, using treatment and study
as factors, and HbA1c level at baseline as a covariate.
In all studies included in our analysis, patients received
glucose-monitoring devices and supplies, and were
instructed to perform self-monitoring of blood glucose
(SMBG) every morning in the fasting state and during

any suspected hypoglycemic episode. All symptomatic
episodes consistent with hypoglycemia were recorded,
irrespective of whether a confirmatory SMBG was performed. This permitted pooling and standardization of
hypoglycemia outcomes. The incidence and event rate
(events per patient-years of exposure [PYE]) of total
reported hypoglycemia (all reported symptomatic hypoglycemia, including severe, daytime, and nocturnal), total
reported nocturnal hypoglycemia, and severe hypoglycemia (defined as that requiring assistance, with either
a plasma glucose level , 36 mg/dL [, 2.0 mmol/L],
or prompt recovery after oral carbohydrate, intravenous
glucose, or glucagon administration) were calculated and
compared between treatment groups. Odds ratios and 95%
CIs for incidence of hypoglycemia were calculated using
Cochran-Mantel-Haenszel test stratified by study. Event
rates were compared with rank ANOVA, using treatment
group and study as factors.
Efficacy and safety also were compared between treat-
Banerji etal
Table 1. Description of Pooled Studies

Reference
Study
Entry Criteria
Duration, Pool
Wks
1 (4042)
Blickl et al12
40
Glargine vs lifestyle intensification
2 (3502)
Gerstein et al14
HbA1c level 7.0-8.0% on $ 2 OADs

(SU + metformin at MTD)
HbA1c level 7.5%-11.0% on 0,a 1, or 2 OADs
($ 1 at # 50% MTD)
26
3 (4014)
Rosenstock et al18
24
4 (4020)
Meneghini et al16
5 (4002)
Riddle et al17
6 (6001)
Yki-Jrvinen et al19
7 (4040)
Bretzel et al13
8 (4021)
NCT0133675120
9 (4027)
Janka et al15
HbA1c level 7.5-11.0% on stable regimen of

$ 50% maximally labeled dose of SU and $ 1 g/d
metformin; metformin titrated to MTD during
run-in stabilization period
HbA1c level $ 8.0 to # 12.0% on stable regimen
of either $ 50% maximally labeled dose of SU or
metformin 1-2.5 g/d
HbA1c level 7.5-10.0% on stable regimen of
1 or 2 OADs (SU, metformin, pioglitazone, or
rosiglitazone)
HbA1c level $ 8.0% on stable SU regimen and
metformin $ 1.5 g/d
HbA1c level 7.5-0.5% on stable regimen OADs,
excluding -glucosidase inhibitors
HbA1c level 8.0-11.0% on stable regimen 50%
maximally labeled SU dose and 1-2.5 g/d
metformin
HbA1c level 7.5-10.5% on stable SU regimen
+ metformin $ 850 mg/d (all SUs switched to
glimepiride 3 or 4 mg/d during run-in)
Glargine vs OAD (glargine vs conventional

management, ie, avoidance of insulin and
intensification of OAD)
Glargine vs OAD (glargine vs rosiglitazone
add-on to OAD)
24
Glargine vs OAD (glargine vs pioglitazone

add-on to OAD)
28
Glargine vs NPH insulin
36
Glargine vs NPH insulin
44
Glargine vs insulin lispro (glargine vs insulin

lispro TID)
Glargine vs premixed insulin (glargine
once daily vs 75% lispro protamine
suspension/25% lispro injection once daily)
Glargine vs premixed insulin (glargine once
daily vs 30% regular/70% NPH insulin BID)
24
28
a
Approximately 17% of participants were drug-naive.
Abbreviations: BID, twice daily; HbA1c, glycated hemoglobin; MTD, maximum tolerated dose; NPH, neutral protamine Hagedorn; OAD, oral antidiabetic drug; SU,
sulfonylurea; TID, three times daily.
ment groups, stratified by patient baseline HbA1c level (,

8.0%, 8.0% to,9.0%, 9.0% to,10.0%, and $10.0%).
between patients in the treatment groups in terms of demographics or baseline characteristics.
Results
Patient Demographics and Baseline
Characteristics
Efficacy and Safety With Glargine

Compared with Pooled Comparators
A total of 1462 patients received glargine, and 1476 patients

were included in the pooled comparators group. Age, sex, race,
duration of known diabetes, HbA1c level, FPG level, body
weight, and BMI at baseline were comparable between pooled
glargine and pooled comparators patient groups (Table2).
Overall, patients had a mean age of 57 years, 56% were men,
84% were white, with a mean duration of known diabetes of 8.6
years, and a mean HbA1c level of 8.7%. The majority of patients
(72.5%) were receiving a stable regimen of 2 or 3 OADs.
Patient demographics and baseline characteristics were
stratified by treatment and baseline HbA1c level (Table 3
for glargine vs pooled comparators; Table4 for glargine vs
individual comparators). There were no major differences
114
Addition of glargine was associated with a larger mean

decrease in HbA1c level than pooled comparators (adjusted
mean change [AM], 1.7 0.02% vs 1.5 0.02%;
P ,0.001). A higher percentage of patients achieved a
target HbA1c level # 7.0% with glargine than with pooled
comparators (Figure2A), and a higher percentage of patients
experienced $1.0% decrease in HbA1c level with glargine
treatment compared with pooled comparators (Figure2B).
Compared with pooled comparators, event rates
with glargine were significantly lower for total reported
hypoglycemia, and numerically lower for total reported nocturnal and severe hypoglycemia (Table5). Incidences were
also slightly numerically lower with glargine for total
reported hypoglycemia (Figure2C), total reported noc-
Table 2. Patient Demographic and Baseline Characteristics

(Overall mITT Population)
Pooled Studies mITT Population
Parameter
Age, y
Sex, Men
Race
White
Black
Hispanic
Asian
Multiracial
Other
Duration of Diabetes, y
HbA1c level, %
HbA1c level category
HbA1c , 8.0%
8.0% # HbA1c , 9.0%
9.0% # HbA1c , 10.0%
HbA1c $ 10.0%
FPG, mmol/Lb
Body weight, kg
BMI, kg/m2
Pooled
Glarginea
Mean [SD] or n (%) Comparators
(n = 1462)
Mean [SD] or n (%)
(n = 1476)
57.2 [9.9]
57.1 [9.8]
818 (56.0)
833 (56.4)
1078 (83.1)
117 (9.0)
57 (4.4)
34 (2.6)
7 (0.5)
4 (0.3)
8.6 [6.1]
8.7 [1.0]
1126 (83.9)
114 (8.5)
63 (4.7)
31 (2.3)
5 (0.4)
3 (0.2)
8.6 [6.0]
8.7 [1.0]
373 (25.5)
509 (34.8)
391 (26.7)
189 (12.9)
10.9 [2.9]
91.0 [18.0]
31.6 [5.2]
384 (26.0)
551 (37.3)
355 (24.1)
186 (12.6)
10.8 [2.9]
91.2 [18.6]
31.6 [5.2]
a
Not statistically significant between-treatment differences in any demographic or
baseline characteristic.
b
To convert mmol/L to mg/dL, multiply by 18.
Abbreviations: BMI, body mass index; FPG, fasting plasma glucose; HbA1c, glycated
hemoglobin; mITT, modified intention to treat; SD, standard deviation.
turnal hypoglycemia (OR, 0.96; 95% CI, 0.7981.165;

P=0.707), and total severe hypoglycemia (OR, 0.68; 95%
CI, 0.3731.224; P=0.156).
Efficacy and Safety With Glargine Versus

Individual Comparators
Relative to specific comparators, glargine was significantly

more likely to result in a target HbA1c level # 7.0% than
was intensification of lifestyle interventions or OAD therapy
(Figure2A); there were no significant differences between
glargine and the other insulins. A similar pattern was seen for
achieving an HbA1c level decrease of $1.0% (Figure2B).
Compared with intensification of lifestyle interventions or
OAD therapy, the incidence and event rates of total reported
hypoglycemia were significantly higher with glargine use
(Figure2C; Table5). There was no statistically significant
increase in the event rate for severe hypoglycemia with
glargine compared with intensification of either lifestyle
interventions or OAD therapy (Table 5). Compared with
other insulins, the risk of total reported hypoglycemia events
with glargine use was slightly, but not significantly, less
than with NPH or premixed insulin, and significantly lower
than with insulin lispro (Figure2C). The event rates for total
reported hypoglycemia were significantly lower with glargine
use than with NPH insulin, insulin lispro, or premixed insulin
use (Table6). Event rates for nocturnal hypoglycemia also
were significantly lower with glargine than with NPH insulin
(3.9 vs 5.8 events/PYE, respectively; P=0.005) or premixed
insulin (1.1 vs 2.0 events/PYE, respectively; P,0.001). The
only significant difference in event rates for severe hypoglycemia was seen between premixed insulin and glargine (0.08
vs 0.02 events/PYE; P=0.022).
Table 3. Demographic and Patient Baseline Characteristics Stratified by Treatment and Baseline HbA1c Level
Overall mITT Population
Mean [SD] or n (%)
Glargine
Pooled Comparators
HbA1c Level Stratum, %
, 8.0
8.0 - , 9.0
9.0 - , 10.0 $ 10.0
, 8.0
8.0 - , 9.0
9.0 - , 10.0 $ 10.0
N
Age, y
Sex, Men
Race
White
Black
Hispanic
Asian
Multiracial
Other
Duration of diabetes, y
HbA1c level, %
FPG, mmol/Lb
Body weight, kg
BMI, kg/m2
373
58.4 [9.3]
222 (59.5)
509
57.9 [9.5]
279 (54.8)
391
56.4 [10.1]
224 (57.3)
189
54.4 [10.6]
93 (49.2)
384
58.9 [9.4]
227 (59.1)
551
57.3 [9.7]
314 (57.0)
355
56.2 [10.0]
191 (53.8)
186
54.9 10.2]
101 (54.3)
244 (87.8)
23 (8.3)
4 (1.4)
6 (2.2)
1 (0.4)
0 (0.0)
8.7 [5.9]
7.6 [0.3]
9.1 [1.8]
89.5 [15.5]
30.9 [4.7]
411 (86.5)
32 (6.7)
16 (3.4)
13 (2.7)
2 (0.4)
1 (0.2)
8.6 [6.4]
8.4 [0.3]a
10.3 [2.4]
90.8 [17.5]
31.6 [4.8]
307 (83.0)
27 (7.3)
20 (5.4)
9 (2.4)
4 (1.1)
2 (0.5)
9.0 [6.2]
9.4 [0.3]
12.0 [2.7]
92.3 [19.7]
32.1 [5.6]
116 (65.5)
35 (19.8)
17 (9.6)
6 (3.4)
0 (0.0)
1 (0.6)
8.1 [5.7]
10.6 [0.6]
13.9 [3.2]
91.5 [19.9]
31.9 [6.2]
271 (86.6)
24 (7.7)
7 (2.2)
6 (1.9)
2 (0.6)
3 (1.0)
8.5 [6.1]
7.5 [0.3]
9.0 [1.9]
89.5 [17.5]
31.0 [4.8]
442 (85.3)
42 (8.1)
19 (3.7)
13 (2.5)
2 (0.4)
0 (0.0)
8.6 [6.2]
8.5 [0.3]
10.5 [2.3]
91.2 [17.5]
31.6 [5.1]
281 (82.4)
26 (7.6)
23 (6.7)
9 (2.6)
0 (0.0)
0 (0.0)
9.2 [6.0]
9.4 [0.3]
11.7 [2.6]
91.5 [19.3]
31.7 [5.2]
132 (76.7)
22 (12.8)
14 (8.1)
3 (1.7)
1 (0.6)
0 (0.0)
7.4 [4.7]
10.6 [0.7]
14.0 [3.2]
94.3 [22.0]
32.6 [6.5]
P , 0.05 versus comparator.

Abbreviations: BMI, body mass index; FPG, fasting plasma glucose; HbA1c, glycated hemoglobin; mITT, modified intention to treat; SD, standard deviation.
a
116
n
Age, y
Sex, Men
Race
HbA1c level, %
FPG, mmol/La
Body weight, kg
BMI, kg/m2
83 (89.2)
8 (8.6)
1 (1.1)
1 (1.1)
0 (0.0)
0 (0.0)
7.0 [4.4]
7.6 [0.3]
9.1 [1.7]
92.7 [16.6]
32.3 [5.7]
n
Age, y
Sex, Men
Race
White
Black
Hispanic
Asian
Multiracial
Other
HbA1c level, %
FPG, mmol/La
Body weight, kg
BMI, kg/m2
, 8.0
102
57.2 [9.5]
56 (54.9)
n
Age, y
Sex, Men
Glargine
158
55.7 [9.5]
93 (58.9)
8.0 to , 9.0
121 (77.1)
16 (10.2)
9 (5.7)
10 (6.4)
0 (0.0)
1 (0.6)
7.6 [6.3]
8.4 [0.3]b
10.1 [2.7]b
92.2 [18.2]
32.5 [5.2]
93
57.6 [9.6]
55 (59.1)
Glargine Versus NPH Insulin mITT Population
157
56.7 [9.8]
90 (57.3)
Glargine
, 8.0
Mean [SD] or n (%)

8.0 to , 9.0
88
60 [8]
48 (54.5)
NA
9.4 [6.1]
7.5 [0.3]
9.4 [1.9]
86.1 [12.4]
30.4 [3.6]
Glargine Versus OAD mITT Population
Glargine
, 8.0
Mean [SD] or n (%)
Glargine Versus Lifestyle Intensification Population
116
54.3 [9.3]
67 (57.8)
9.0 to , 10.0
96 (73.3)
14 (10.7)
13 (9.9)
5 (3.8)
0 (0.0)
2 (1.5)
7.6 [4.9]
9.4 [0.3]
12.2 [2.7]
95.0 [19.9]
33.3 [6.7]
131
54.9 [10.2]
78 (59.5)
9.0 to , 10.0
13
65 [6]
8 (61.5)
NA
13.2 [7.1]
8.2 [0.1]
10.3 [1.6]b
80.0 [10.6]
28.6 [3.1]
8.0 to , 9.0
40
53.2 [8.7]
20 (50.0)
$ 10.0
40 (50.6)
23 (29.1)
11 (13.9)
3 (3.8)
0 (0.0)
1 (1.3)
7.4 [5.7]
10.8 [0.7]
14.3 [3.4]
94.0 [22.6]
33.0 [7.8]
79
51.7 [11.0]
38 (48.1)
$ 10.0
Table 4. Demographic and Patient Baseline Characteristics Stratified by Treatment and Baseline HbA1c Level
111
57.3 [8.7]
64 (57.7)
, 8.0
NPH Insulin
90 (81.8)
8 (7.3)
5 (4.6)
3 (2.7)
1 (0.9)
3 (2.7)
7.7 [6.0]
7.6 [0.3]
8.9 [1.9]
90.8 [20.1]
31.7 [5.4]
110
57.9 [10.1]
65 (59.1)
, 8.0
OAD
66
61 [8]
38 (57.6)
NA
10.7 [7.1]
7.4 [0.3]
9.2 [1.4]
83.0 [13.1]
29.4 [3.4]
, 8.0
168
56.5 [8.8]
98 (58.3)
8.0 to , 9.0
149 (81.9)
16 (8.8)
11 (6.0)
6 (3.3)
0 (0.0)
0 (0.0)
7.6 [5.9]
8.5 [0.3]
10.7 [2.4]
94.7 [19.7]
32.9 [5.7]
182
56.3 [10.5]
106 (58.2)
8.0 to , 9.0
Lifestyle Intensification
115
55.8 [8.7]
61 (53.0)
9.0 to , 10.0
72 (69.9)
12 (11.7)
14 (13.6)
4 (3.9)
0 (0.0)
0 (0.0)
7.5 [5.5]
9.5 [0.3]
12.1 [2.7]
95.4 [19.0]
33.1 [5.8]
103
53.0 [10.6]
56 (54.4)
9.0 to , 10.0
17
61 [8]
9 (52.9)
NA
11.0 [7.2]
8.1 [0.1]
8.9 [1.2]
82.2 [15.6]
29.5 [3.6]
8.0 to , 9.0
35
54.5 [9.4]
21 (60.0)
$ 10.0
59 (67.8)
15 (17.2)
11 (12.6)
2 (2.3)
0 (0.0)
0 (0.0)
6.3 [4.0]
10.8 [0.8]
14.4 [3.2]
98.4 23.8]
33.8 [7.6]
87
52.4 [10.3]
50 (57.5)
$ 10.0
Banerji etal
76 (80.0)
15 (15.8)
3 (3.2)
1 (1.1)
9.1 [5.9]
7.6 [0.4]
9.4 [1.9]
92.5 [16.5]
31.6 [4.8]
75 (98.7)
0 (0.0)
1 (1.3)
0 (0.0)
9.1 [6.7]
8.4 [0.3]b
10.3 [2.2]
83.3 [14.9]
29.2 [3.8]
44
59.8 [9.5]
29 (65.9)
43 (97.7)
0 (0.0)
1 (2.3)
0 (0.0)
9.2 [6.6]
7.6 [0.3]
8.7 [1.8]
85.3 [15.2]
29.1 [3.9]
n
Age, y
Sex, Men
Race
White
Black
Asian
Multiracial
HbA1c level, %
FPG, mmol/La
Body weight, kg
BMI, kg/m2
94 (89.5)
4 (3.8)
7 (6.7)
0 (0.0)
0 (0.0)
, 8.0
46
58.0 [10.3]
34 (73.9)
42 (91.3)
0 (0.0)
3 (6.5)
1 (2.2)
0 (0.0)
n
Age, y
Sex, Men
Race
White
Black
Hispanic
Asian
Multiracial
8.0 to , 9.0
105
60.2 [9.3]
51 (48.6)
Glargine
Mean [SD] or n (%)
Glargine Versus Premixed Insulin mITT Population
76
60.9 [7.9]
37 (48.7)
Glargine
, 8.0

8.0 to , 9.0
121 (88.3)
12 (8.8)
2 (1.5)
2 (1.5)
8.3 [5.6]
8.4 [0.3]
10.7 [2.3]
95.4 [17.0]
32.4 [4.6]
Mean [SD] or n (%)
Glargine Versus Insulin Lispro Population
Race
White
Black
Asian
Multiracial
HbA1c level, %
FPG, mmol/La
Body weight, kg
BMI, kg/m2
74 (85.1)
5 (5.8)
7 (8.1)
0 (0.0)
1 (1.2)
87
58.0 [10.6]
47 (54.0)
9.0 to , 10.0
55 (96.5)
0 (0.0)
1 (1.8)
1 (1.8)
9.0 [7.9]
9.3 [0.3]
11.2 [2.3]
84.9 [15.9]
29.5 [3.7]
57
61.4 [9.0]
32 (56.1)
9.0 to , 10.0
82 (86.3)
8 (8.4)
3 (3.2)
2 (2.1)
8.6 [4.9]
9.4 [0.3]
12.6 [2.6]
95.7 [20.9]
32.6 [5.0]
36 (73.5)
6 (12.2)
6 (12.2)
0 (0.0)
0 (0.0)
49
58.1 [9.8]
28 (57.1)
$ 10.0
21 (100)
0 (0.0)
0 (0.0)
0 (0.0)
8.6 [4.8]
10.6 [0.5]
12.8 [2.6]
81.0 [8.0]
28.8 [2.4]
21
57.9 [11.5]
7 (33.3)
$ 10.0
19 (67.9)
6 (21.4)
3 (10.7)
0 (0.0)
7.6 [4.2]
10.5 [0.5]
14.1 [2.6]
95.1 [19.0]
32.4 [4.9]
37 (90.2)
2 (4.9)
2 (4.9)
0 (0.0)
0 (0.0)
41
59.8 [10.6]
24 (58.5)
, 8.0
Premixed insulin
53 (94.6)
1 (1.8)
2 (3.6)
0 (0.0)
8.8 [5.9]
7.6 [0.4]
8.8 [1.9]
85.1 [14.6]
29.4 [3.5]
56
60.9 [9.4]
36 (64.3)
, 8.0
Insulin Lispro
91 (85.8)
13 (12.3)
1 (0.9)
1 (0.9)
8.0 [5.5]
7.5 [0.3]
9.2 [2.0]
94.8 [16.6]
32.3 [4.8]
95 (87.2)
6 (5.5)
8 (7.3)
0 (0.0)
0 (0.0)
109
57.8 [9.5]
60 (55.0)
8.0 to , 9.0
73 (97.3)
0 (0.0)
2 (2.7)
0 (0.0)
8.2 [6.7]
8.5 [0.3]
10.3 [2.8]
83.8 [14.4]
29.5 [3.7]
75
59.9 [9.5]
41 (54.7)
8.0 to , 9.0
125 (82.2)
20 (13.2)
5 (3.3)
2 (1.3)
9.1 [5.7]
8.5 [0.3]
10.7 [2.2]
93.9 [15.9]
32.0 [4.8]
75 (86.2)
1 (1.2)
9 (10.3)
1 (1.2)
0 (0.0)
87
57.9 [10.7]
44 (50.6)
9.0 to , 10.0
50 (100)
0 (0.0)
0 (0.0)
0 (0.0)
9.4 [6.1]
9.4 [0.3]
10.5 [2.6]
82.2 [15.9]
28.5 [3.6]
50
60.9 [7.8]
30 (60.0)
9.0 to , 10.0
84 (83.2)
13 (12.9)
4 (4.0)
0 (0.0)
9.7 [5.4]
9.4 [0.3]
12.2 [2.2]
94.6 [17.8]
32.3 [4.8]
(Continued)
34 (82.9)
3 (7.3)
3 (7.3)
1 (2.4)
0 (0.0)
41
58.5 [10.0]
18 (43.9)
$ 10.0
23(100)
0 (0.0)
0 (0.0)
0 (0.0)
7.5 [4.6]
10.5 [0.6]
12.3 [3.7]
86.4 [14.8]
30.2 [3.0]
23
58.2 [9.2]
12 (52.2)
$ 10.0
16 (76.2)
4 (19.0)
0 (0.0)
1 (4.8)
8.3 [4.9]
10.5 [0.6]
14.2 [2.2]
94.8 [19.4]
32.2 [5.6]
118

P , 0.05 versus comparator.
Abbreviations: BMI, body mass index; FPG, fasting plasma glucose; HbA1c, glycated hemoglobin; mITT, modified intention to treat; NA, not applicable; NPH, neutral protamine Hagedorn; OAD, oral antidiabetes drug; SD, standard
deviation.
8.8 [5.4]
10.4 [0.4]
13.9 [3.3]
89.5 [22.0]
31.7 [5.8]
Efficacy and Safety Stratified by Baseline

HbA1c Level
Treatment with glargine resulted in greater reductions in

HbA1c level and target HbA1c level attainment than pooled
comparators across the HbA1c level continuum (Figure3A,
Figure 4A). Reductions in HbA1c level were similar with
glargine and OADs if baseline HbA1c level was,8.0%, but
greater with glargine if HbA1c level was $8.0% (Figure3B);
goal attainment tended to be greater with glargine compared
with OADs across the HbA1c level continuum (Figure4B).
Reductions in HbA1c level and goal attainment were generally similar between glargine and other insulins across all
categories (Figure 3, Figure 4); there was a significantly
greater reduction in HbA1c level with glargine than with
premixed insulin use if baseline HbA1c level was,8.0%
(Figure3E).
The total reported hypoglycemia risk for patients was
similar between glargine and pooled comparators, but significantly higher than intensification of lifestyle interventions,
and significantly lower than insulin lispro across all baseline
HbA1c level strata (Figure5); hypoglycemia risk was also
significantly higher than intensification of OAD therapy,
and significantly lower than premixed insulin when patient
baseline HbA1c level was $9.0% but,10% (Figure5). The
rates of severe hypoglycemia were very low overall (0.00 to
0.19 events/PYE), and no trends related to baseline HbA1c
level stratum were apparent.
FPG and Body Weight
Overall, glargine elicited significantly greater reductions in

FPG than the pooled comparators, having a similar effect on
body weight (2.0kg vs 1.9kg; Table6). There was slight
patient weight gain with glargine use, and greater weight
loss with intensification of lifestyle interventions, resulting
in a statistically significant difference. There was similar
patient weight gain with glargine and NPH insulin, and a
trend toward modestly greater weight gain with insulin
lispro and premixed insulin relative to glargine (Table6).
Weight gain was not significantly different between
glargine and intensification of OAD therapy; however, in
individual studies, glargine was associated with greater
weight gain than intensification of OADs when choice
was unspecified,14 and less weight gain than the addition
of thiazolidinediones.16,18
9.0 to , 10.0
10.3 [7.1]
9.4 [0.3]
11.3 [2.8]
88.4 [21.2]
31.0 [5.2]
9.8 [6.6]
8.4 [0.3]
10.1 [2.1]
87.5 [15.8]
30.7 [4.6]
8.0 to , 9.0
9.4 [6.7]
10.5 [0.4]
13.6 [3.4]
89.1 [18.1]
31.1 [4.6]
11.6 [7.6]
9.4 [0.3]
11.4 [3.0]
88.9 [18.7]
31.3 [5.1]
9.4 [7.1]
7.6 [0.3]
8.5 [1.8]
86.7 [14.2]
29.5 [4.3]
HbA1c level, %
FPG, mmol/La
Body weight, kg
BMI, kg/m2
9.4 [6.8]
8.5 [0.3]
10.0 [2.4]
88.6 [17.1]
31.4 [4.6]
Premixed insulin
, 8.0
$ 10.0
9.0 to , 10.0
8.0 to , 9.0
Glargine
, 8.0
Mean [SD] or n (%)
Glargine Versus Premixed Insulin mITT Population
Table 4. (Continued)
8.0 [5.5]
7.7 [0.3]
8.8 [1.8]
88.4 [18.2]
29.9 [4.9]
$ 10.0
Banerji etal

Figure2. A) Odds ratio for achievement of Week-24 endpoint HbA1c level # 7.0%; B) For experiencing a decrease in HbA1c level $1.0% from baseline to Week 24; and
C) For experiencing $1 hypoglycemic event(s) with glargine versus comparators.
P,0.001.
P,0.01.
Abbreviations: glargine, insulin glargine; HbA1c, glycated hemoglobin; NPH, neutral protamine Hagedorn; OAD, oral antidiabetic drug.
a
FPG and Body Weight Stratified by

Baseline HbA1c Level
Treatment with glargine led to significantly greater reductions
in patient FPG level compared with pooled comparators,

OAD therapy, and intensification of lifestyle, regardless of
HbA1c level category at baseline. Treatment with glargine
Banerji etal
led to significantly greater reductions in FPG level compared

with insulin lispro and premixed insulin when baseline HbA1c
level was,10%.
There were no significant differences in weight gain
between glargine and pooled comparators, or any individual
treatment group across the HbA1c level continuum, except
for the intensification of lifestyle interventions group, which
had negative weight gain. There was a trend for patients with
higher baseline HbA1c levels to have greater reductions in
HbA1c (Figure3) and FPG levels, and greater changes in body
weight, regardless of any treatment intervention.
Discussion
Deterioration of glycemic control in patients with T2DM,

despite treatment with OADs, represents a significant therapeutic crossroads for patients and health care professionals
alike. While there is a consensus that treatment should
be intensified to achieve HbA1c levels,7.0%,9 or even
# 6.5%,21 many factors may influence the decision regarding how best to improve a patients glycemic control, and
all therapeutic decisions must balance efficacy and safety.
It is generally acknowledged that therapeutic interventions and treatment goals should be individualized, but there
are few data available to inform decisions and guide this individualization.10 The decision to initiate insulin therapy can
be particularly challenging.2224 In our analysis, we compared
the efficacy and hypoglycemic potential of the basal insulin
preparation, insulin glargine, with several other options avail-
able for intensification of therapy in patients with suboptimal

glycemic control while treated with $1 OAD(s). Additional
subanalyses of goal attainment and hypoglycemic potential
were performed according to baseline HbA1c level stratum.
This is an important factor because initiation of insulin
therapy is often postponed until patient HbA1c level is very
high, due to the assumption that in patients with HbA1c levels
approaching target, the benefitrisk profile would favor any
other choice than insulin.
Our analysis revealed that, compared with pooled
comparators, glargine therapy was associated with greater
decreases in patient HbA1c and FPG levels, and an increased
probability of achieving target HbA1c level #7.0% and of
experiencing $1.0% decrease in HbA1c, without increased
risk of hypoglycemia or weight gain. When stratified by
baseline HbA1c level, glargine had greater efficacy than
pooled comparators across the HbA1c level spectrum, without
increased patient risk of hypoglycemia.
Addition of glargine was more likely to result in a target
HbA1c level # 7.0% than intensification of lifestyle interventions or OAD therapy, but with an increased risk of reported
hypoglycemic events. Compared with the other insulins,
treatment with glargine was no more likely to achieve a target
HbA1c level # 7.0%, but did present a lower risk of reported
hypoglycemic events. When examined by baseline HbA1c
level category, glargine use resulted in greater reductions in
HbA1c level and improved goal attainment compared with
intensification of OAD therapy, when baseline HbA1c level
Table 5. Hypoglycemia Event Rates per PYE
Glargine (n = 1462)
Pooled Comparators (n = 1476)
P Value
Glargine (n = 101)
Lifestyle Intensification (n = 83)
P Value
Glargine (n = 460)
OAD Intensification (n = 482)
P Value
Glargine (n = 416)
NPH Insulin (n = 429)
P Value
Glargine (n = 198)
Insulin Lispro (n = 204)
P Value
Glargine (n = 287)
Premixed Insulin (n = 278)
P Value
Total Reported Hypoglycemia,

Events/PYE
Total Nocturnal Hypoglycemia,

Events/PYE
Total Severe Hypoglycemia,

Events/PYE
6.85
9.69
0.001
4.72
2.96
1.51
2.11
0.293
0.68
0.50
0.034
0.65
0.35
0.001
3.86
5.80
0.005
0.47
0.35
0.218
1.10
1.97
0.04
0.05
0.160
0.06
0.00
0.199
0.04
0.05
0.706
0.07
0.04
0.870
0.02
0.04
0.267
0.02
0.08
0.022
, 0.001
4.34
2.92
, 0.001
11.79
14.78
0.033
4.23
15.33
, 0.001
6.53
10.45
0.004
, 0.001
Abbreviations: NPH, neutral protamine Hagedorn; OAD, oral antidiabetes drug; PYE, patient-years of exposure.
120

Figure3. Adjusted mean changes in HbA1c level, from baseline to Week-24 endpoint, stratified by baseline HbA1C level. A) Glargine versus pooled comparators;
B) Glargine versus OAD intensification; C) Glargine versus NPH insulin; D) Glargine versus insulin lispro; and E) Glargine versus premixed insulin.
P,0.05.
P,0.01.
c
P,0.001.
Abbreviations: glargine, insulin glargine; HbA1c, glycated hemoglobin; NPH, neutral protamine Hagedorn; OAD, oral antidiabetes drug.
a
was $8.0%; however, glargine therapy was associated with

an increase in frequency of reported hypoglycemic events.
When considering goal attainment and hypoglycemic potential, glargine was generally similar to, or more effective than,
each individual comparator across all HbA1c level strata.
A major strength of our study was the ability to pool a
large sample of patient-level data from a relatively homogeneous population with adjustments for potential differences
built into the statistical model. The pooled analysis and
meta-analysis shared many common features, although the
meta-analysis generally made use of summary data from the
published studies (mean, SD, standard error [SE], etc) and
the effect size from each study was reflected in the statistical analysis. The pooled analysis also considered the study
effect, but utilized the original data for individual patients,
making it ideal to conduct regression or predictor analyses.
An obvious limitation of our study is that data were derived

from only the first 24-week treatment period in the studies
included; thus, they can only highlight short-term differences
that are important at the time of initiating add-on therapy in
patients who have not attained glycemic targets with OAD
treatment. Another limitation is that the available data pool
included no comparisons with basal insulin preparations
other than glargine (eg, insulin detemir), nor were studies
of the newest antidiabetes agents, such as glucagon-like
peptide (GLP)-1 receptor agonists and dipeptidyl peptidase
(DPP)-4inhibitors, included. Although head-to-head comparisons of glargine with insulin detemir,25 liraglutide,26 and
exenatide27 in patients with T2DM who have not achieved/
maintained optimal glycemic control using OADs have been
performed, patient-level data were not available for inclusion
in our pooled analysis. In studies including the newer agents,
Banerji etal
Figure4. Percentage of patients achieving Week 24 endpoint HbA1c level # 7.0%, stratified by baseline HbA1c level. A) Glargine versus pooled comparators; B) Glargine
versus OAD intensification; C) Glargine versus NPH insulin; D) Glargine versus insulin lispro; and E) Glargine versus premixed insulin.
P,0.05.
P,0.01.
c
P,0.001.
Abbreviations: glargine, insulin glargine; HbA1c, glycated hemoglobin; NPH, neutral protomine Hagedorn; OAD, oral antidiabetes drug.
a
it was found that the efficacy of the comparator was either

non-inferior25,27 or slightly superior26 to glargine; there were
no significant differences in hypoglycemia event rates. In
the Liraglutide Effect and Action in Diabetes 5 (LEAD-5)
study,26 rates of major, minor, and symptomatic hypoglycemia were 0.06, 1.2, and 1.0 events/PYE, respectively, in the
liraglutide treatment group compared with 0, 1.3, 1.8 events/
PYE, respectively, in the insulin glargine group. In the Helping Evaluate Exenatide in overweight patients with diabetes
compared with Long-Acting insulin (HEELA) study,27 there
were no significant differences between exenatide and insulin
glargine use in patient incidence of symptomatic hypoglycemia or glucose-confirmed hypoglycemia (, 62 mg/dL
[3.4 mmol/L]; P = 0.139 and P = 0.369, respectively);
however, the incidence of nocturnal hypoglycemia was sig122
nificantly lower in the exenatide-treated group (P=0.001).

Use of GLP-1 receptor agonists were associated with less
patient weight gain relative to glargine, but with a higher
number of treatment-related adverse events.26,27
Conclusion
Results of our analysis support the recommendation to initiate

insulin therapy with a basal insulin,9 and are consistent with
earlier reports that glargine is associated with less hypoglycemia than NPH, prandial, or premixed insulins.28,29 The current
American Diabetes Association/European Association for
the Study of Diabetes consensus report also highlights the
importance of achieving a target HbA1c level # 7.0% and
reviewing treatment choices when targets are not reached
within 3months.30 In our study, we found addition of glargine

Figure5. Odds ratio for experiencing $1 hypoglycemic event stratified by
baseline HbA1c level.
Table 7. Adjusted Mean Changes in Patient Body Weight and FPG

AM [SE]
Glargine
Pooled Comparators
n
Body weight, kg
FPG, mmol/La
1462
2.0 [0.1]
-4.2 [0.2]
Glargine
101
0.6 [0.3]
NA
Glargine
460
2.1 [0.2]
-4.5 [0.1]
Glargine
416
2.7 [0.2]
-4.8 [0.1]
Glargine
198
2.4 [0.3]
-4.1 [0.2]
Glargine
287
2.0 [0.2]
-3.8 [0.1]
1476
1.9 [0.1]
-3.2 [0.2]
Lifestyle Intensification
83
-2.0 [0.3]
NA
OAD
482
1.9 [0.2]
-2.9 [0.1]
NPH Insulin
429
2.5 [0.2]
-4.6 [0.1]
Insulin Lispro
204
3.1 [0.3]
-2.1 [0.2]
Premixed Insulin
278
2.5 [0.2]
-3.1 [0.2]
n
Body weight, kg
FPG, mmol/L
n
Body weight, kg
FPG, mmol/L
n
Body weight, kg
FPG, mmol/L
n
Body weight, kg
FPG, mmol/L
n
Body weight, kg
FPG, mmol/L
P Value
0.5998
, 0.001
P Value
, 0.001
NA
P Value
0.463
, 0.001
P Value
0.523
0.295
P value
0.081
, 0.001
P value
0.083
, 0.001
a
To convert from mmol/L to mg/dL, multiply by 18.
Abbreviations: AM, adjusted mean change; FPG, fasting plasma glucose; NA, not
applicable; NPH, neutral protamine Hagedorn; OAD, oral antidiabetes drug.
had greater efficacy than intensification of OAD therapy, with

only a modest increase in frequency of hypoglycemic events,
indicating that the addition of glargine may be a better choice
than OAD intensification in these patients.
Acknowledgments
Study funding was provided by Sanofi US Inc. Editorial

support was provided by Beth Dunning Lower, PhD, of
Embryon, LLC, A Division of Advanced Health Media,
LLC, and Nicola Truss, PhD, of Excerpta Medica; and was
funded by Sanofi US Inc.
Conflict of Interest Statement

P,0.05.
P,0.01.
c
P,0.001.
Abbreviations: glargine, insulin glargine; NPH, neutral protamine Hagedorn; OAD,
oral antidiabetes drug.
a
to be an effective approach to achieving target HbA1c levels

# 7.0% across all baseline HbA1c level strata in patients with
T2DM who achieved only suboptimal glycemic control using
OADs; and, for patients with an HbA1c level $8.0%, glargine
Mary Ann Banerji, MD, has received research support

from Bristol-Myers Squibb Company, Boehringer Ingelheim, Merck & Co. Inc., Takeda, Roche, and Amylin
Pharmaceuticals, Inc. She has also received honoraria
from Novartis Pharmaceuticals Corporation and Sanofi
US Inc. Dr Banerji also served on the advisory board for
Novartis Pharmaceuticals Corporation and Sanofi US Inc.
Michelle Baron, MD, was an employee and shared stock
holder of Sanofi US Inc. Ling Gao, ME, is a senior statistical consultant for Sanofi US Inc. Lawrence Blonde, MD,
has received grant/research and investigator support from
Banerji etal
Amgen Inc., Boehringer Ingelheim Pharmaceuticals, Inc.,

Eli Lilly and Company, Merck & Co., Inc., Novo Nordisk,
Roche, and sanofi-aventis. He has received speaker honoraria
from AstraZeneca, Bristol-Myers Squibb, Daiichi Sankyo,
LifeScan, Merck & Co., and Novo Nordisk. Dr Blonde has
also received consultant honoraria from Amylin Pharmaceuticals, Inc., AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Bristol-Myers Squibb, Daiichi Sankyo,
GlaxoSmithKline, Halozyme, Johnson & Johnson, Mannkind
Corporation, Merck & Co, Inc., Novo Nordisk, Orexigen
Therapeutics, Roche, sanofi-aventis, and VeroScience.
Dr Blondes late spouses estate contains shares of Amylin
Pharmaceuticals and Pfizer Inc.
References
1. Effect of intensive blood-glucose control with metformin on complications in overweight patients with type 2 diabetes (UKPDS
34). UK Prospective Diabetes Study (UKPDS) Group. Lancet.
1998;352(9131):854865.
2. Intensive blood-glucose control with sulphonylureas or insulin compared
with conventional treatment and risk of complications in patients with
type 2 diabetes (UKPDS 33). UK Prospective Diabetes Study (UKPDS)
Group. Lancet. 1998;352(9178):837853.
3. The effect of intensive treatment of diabetes on the development and
progression of long-term complications in insulin-dependent diabetes
mellitus. The Diabetes Control and Complications Trial Research Group.
N Engl J Med. 1993;329(14):977986.
4. Action to Control Cardiovascular Risk in Diabetes Study Group, Gerstein
HC, Miller ME, Byington RP etal. Effects of intensive glucose lowering
in type 2 diabetes. N Engl J Med. 2008;358(24):25452559.
5. ADVANCE Collaborative Group, Patel A, MacMahon S, Chalmers J,
etal. Intensive blood glucose control and vascular outcomes in patients
with type 2 diabetes. N Engl J Med. 2008;358(24):25602572.
6. Dormandy JA, Charbonnel B, Eckland DJ, etal; PROactive Investigators. Secondary prevention of macrovascular events in patients with type
2 diabetes in the PROactive Study (PROspective pioglitAzone Clinical
Trial In macroVascular Events): a randomised controlled trial. Lancet.
2005;366(9493):12791289.
7. Skyler JS, Bergenstal R, Bonow RO, etal; American Diabetes Association; American College of Cardiology Foundation; American
Heart Association. Intensive glycemic control and the prevention of
cardiovascular events: implications of the ACCORD, ADVANCE,
and VA diabetes trials: a position statement of the American Diabetes
Association and a scientific statement of the American College of
Cardiology Foundation and the American Heart Association. Diabetes
Care. 2009;32(1):187192.
8. Ray KK, Seshasai SR, Wijesuriya S, etal. Effect of intensive control
of glucose on cardiovascular outcomes and death in patients with diabetes mellitus: a meta-analysis of randomised controlled trials. Lancet.
2009;373(9677):17651772.
9. Nathan DM, Buse JB, Davidson MB, etal; American Diabetes Association; European Association for the Study of Diabetes. Medical management of hyperglycemia in type 2 diabetes: a consensus algorithm for
the initiation and adjustment of therapy: a consensus statement of the
American Diabetes Association and the European Association for the
Study of Diabetes. Diabetes Care. 2009;32(1):193203.
10. Bennett WL, Maruthur NM, Singh S, etal. Comparative effectiveness
and safety of medications for type 2 diabetes: an update including
124
new drugs and 2-drug combinations. Ann Intern Med. 2011;154(9):

602613.
11. Turner RC, Cull CA, Frighi V, Holman RR. Glycemic control with
diet, sulfonylurea, metformin, or insulin in patients with type 2 diabetes mellitus: progressive requirement for multiple therapies (UKPDS
49). UK Prospective Diabetes Study (UKPDS) Group. JAMA. 1999;
281(21):20052012.
12. Blickl JF, Hancu N, Piletic M, etal. Insulin glargine provides greater
improvements in glycaemic control vs. intensifying lifestyle management for people with type 2 diabetes treated with OADs and 78%
A1c levels. The TULIP study. Diabetes Obes Metab.2009;11(4):
379386.
13. Bretzel RG, Nuber U, Landgraf W, Owens DR, Bradley C, Linn T.
Once-daily basal insulin glargine versus thrice-daily prandial insulin
lispro in people with type 2 diabetes on oral hypoglycaemic agents
(APOLLO): an open randomised controlled trial. Lancet. 2008;
371(9618):10731084.
14. Gerstein HC, Yale JF, Harris SB, Issa M, Stewart JA, Dempsey E.
A randomized trial of adding insulin glargine vs. avoidance of insulin
in people with Type 2 diabetes on either no oral glucose-lowering
agents or submaximal doses of metformin and/or sulphonylureas.
The Canadian INSIGHT (Implementing New Strategies with Insulin Glargine for Hyperglycaemia Treatment) Study. Diabet Med.
2006;23(7):736742.
15. Janka HU, Plewe G, Riddle MC, Kliebe-Frisch C, Schweitzer MA,
Yki-Jrvinen H. Comparison of basal insulin added to oral agents
versus twice-daily premixed insulin as initial insulin therapy for type
2 diabetes. Diabetes Care. 2005;28(2):254259.
16. Meneghini LF, Taylor L, Schwartz S. Improved glycemic control with
insulin glargine vs pioglitazone as add-on therapy to sulfonylurea or
metformin in patients with uncontrolled type 2 diabetes. Endocrine
Practice. 2010;16(4):588599.
17. Riddle MC, Rosenstock J, Gerich J, Insulin Glargine 4002 Study Investigators. The treat-to-target trial: randomized addition of glargine or
human NPH insulin to oral therapy of type 2 diabetic patients. Diabetes
Care. 2003;26(11):30803086.
18. Rosenstock J, Sugimoto D, Strange P, Stewart JA, Soltes-Rak E, Dailey G.
Triple therapy in type 2 diabetes: insulin glargine or rosiglitazone added
to combination therapy of sulfonylurea plus metformin in insulin-naive
patients. Diabetes Care. 2006;29(3):554559.
19. Yki-Jrvinen H, Kauppinen-Mkelin R, Tiikkainen M, et al. Insulin
glargine or NPH combined with metformin in type 2 diabetes: the
LANMET study. Diabetologia. 2006;49(3):442451.
20. US National Institutes of Health. Lantus Versus Humalog Mix as
add-on Therapy in Type 2 Diabetes Patients Failing Sulfonylurea and
Metformin Combination Treatment. http://clinicaltrials.gov/ct2/show/
NCT01336751. Accessed January 28, 2014.
21. Rodbard HW, Jellinger PS, Bloomgarden ZT, etal. Statement by an
American Association of Clinical Endocrinologists/American College of
Endocrinolgy consensus panel on type 2 diabetes mellitus: an algorithm
for glycemic control. Endocr Pract. 2009;15(6):541559.
22. Korytkowski M. When oral agents fail: practical barriers to starting insulin. Int J Obes Relat Metab Disord. 2002;26(Suppl 3):
S18S24.
23. Brunton SA, Davis SN, Renda SM. Overcoming psychological barriers to insulin use in type 2 diabetes. Clin Cornerstone. 2006;8(Suppl
2):S19S26.
24. Hayes RP, Fitzgerald JT, Jacober SJ. Primary care physician beliefs
about insulin initiation in patients with type 2 diabetes. Int J Clin Pract.
2008;62(6):860868.
25. Rosenstock J, Davies M, Home PD, Larsen J, Koenen C, Schernthaner G.
A randomised, 52-week, treat-to-target trial comparing insulin detemir
with insulin glargine when administered as add-on to glucose-lowering
drugs in insulin-naive people with type 2 diabetes. Diabetologia.
2008;51(8):408416.

26. Russell-Jones D, Vaag A, Schmitz O, etal; Liraglutide Effect and Action
in Diabetes 5 (LEAD-5) met+SU Study Group. Liraglutide vs insulin
glargine and placebo in combination with metformin and sulfonylurea
therapy in type 2 diabetes mellitus (LEAD-5met+SU): a randomised
controlled trial. Diabetologia. 2009;52(10):20462055.
27. Davies MJ, Donnelly R, Barnett AH, Jones S, Nicolay C, Kilcoyne A.
Exenatide compared with long-acting insulin to achieve glycaemic
control with minimal weight gain in patients with type 2 diabetes:
results of the Helping Evaluate Exenatide in patients with diabetes
compared with Long-Acting insulin (HEELA) study. Diabetes Obes
Metab.2009;11(12):11531162.
28. Holman RR, Thorne KI, Farmer AJ, etal; 4-T Study Group. Addition
of biphasic, prandial, or basal insulin to oral therapy in type 2 diabetes.
N Engl J Med. 2007;357(17):17161730.
29. Horvath K, Jeitler K, Berghold A, etal. Long-acting insulin analogues

versus NPH insulin (human isophane insulin) for type 2 diabetes mellitus. Cochrane Database Syst Rev. 2007;(2):CD005613.
30. Inzucchi SE, Bergenstal RM, Buse JB, etal; American Diabetes Association (ADA); European Association for the Study of Diabetes (EASD).
Management of hyperglycemia in type 2 diabetes: a patient-centered
approach: position statement of the American Diabetes Association
(ADA) and the European Association for the Study of Diabetes (EASD).
Diabetes Care. 2012;35(6):13641379.

Postgrad Med. 2014 May - 126 (3) - pp111-25

Transféré par

Informations du document

Titre original

Copyright

Formats disponibles

Partager ce document

Partager ou intégrer le document

Options de partage

Avez-vous trouvé ce document utile ?

Ce contenu est-il inapproprié ?

Droits d'auteur :

Formats disponibles

Postgrad Med. 2014 May - 126 (3) - pp111-25

Transféré par

Droits d'auteur :

Formats disponibles

All rights reserved: reproduction in whole or part not permitted.

All permission requests to reproduce or adapt published

Influence of Baseline Glycemia on Outcomes

Mary Ann Banerji, MD 1

Correspondence: Mary Ann Banerji, MD,

Long-term complications of diabetes decrease with improvement of glycemic control.

Study Selection Criteria

A total of 63 randomized controlled trials (RCTs) utilizing

Data Extraction, Synthesis, and Analysis

The primary outcomes of our analysis were the percentage

Effect of Baseline Glycemia on Outcomes With Glargine Use

(SMBG) every morning in the fasting state and during

Table 1. Description of Pooled Studies

Glargine vs lifestyle intensification

HbA1c level 7.0-8.0% on $ 2 OADs

HbA1c level 7.5-11.0% on stable regimen of

Glargine vs OAD (glargine vs conventional

Glargine vs OAD (glargine vs pioglitazone

Glargine vs NPH insulin

Glargine vs NPH insulin

Glargine vs insulin lispro (glargine vs insulin

ment groups, stratified by patient baseline HbA1c level (,

between patients in the treatment groups in terms of demographics or baseline characteristics.

Efficacy and Safety With Glargine

A total of 1462 patients received glargine, and 1476 patients

Addition of glargine was associated with a larger mean

Effect of Baseline Glycemia on Outcomes With Glargine Use

Table 2. Patient Demographic and Baseline Characteristics

turnal hypoglycemia (OR, 0.96; 95% CI, 0.7981.165;

Efficacy and Safety With Glargine Versus

Relative to specific comparators, glargine was significantly

HbA1c Level Stratum, %

9.0 - , 10.0 $ 10.0

9.0 - , 10.0 $ 10.0

P , 0.05 versus comparator.

HbA1c Level Stratum, %

HbA1c Level Stratum, %

Glargine Versus NPH Insulin mITT Population

Mean [SD] or n (%)

HbA1c Level Stratum, %

Glargine Versus OAD mITT Population

Mean [SD] or n (%)

Glargine Versus Lifestyle Intensification Population

HbA1c Level Stratum, %

Mean [SD] or n (%)

Glargine Versus Premixed Insulin mITT Population

HbA1c Level Stratum, %

Mean [SD] or n (%)

Glargine Versus Insulin Lispro Population

Effect of Baseline Glycemia on Outcomes With Glargine Use

To convert mmol/L to mg/dL, multiply by 18.

Efficacy and Safety Stratified by Baseline

Treatment with glargine resulted in greater reductions in

FPG and Body Weight

Overall, glargine elicited significantly greater reductions in

Mean [SD] or n (%)

Glargine Versus Premixed Insulin mITT Population

Effect of Baseline Glycemia on Outcomes With Glargine Use

FPG and Body Weight Stratified by

Treatment with glargine led to significantly greater reductions

in patient FPG level compared with pooled comparators,

led to significantly greater reductions in FPG level compared

Deterioration of glycemic control in patients with T2DM,