Postgrad Med. 2014 May_126(3)_pp111-25

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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

Postgraduate Medicine, Volume 126, Issue 3, May 2014, ISSN 0032-5481, e-ISSN 1941-9260 111ResearchSHARE: www.research-share.com Permissions: [email protected] Reprints: [email protected]

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Inuence of Baseline Glycemia on OutcomesWith Insulin Glargine Use in Patients Uncontrolled

on Oral Agents

Mary Ann Banerji, MD1

Michelle A. Baron, MD2

Ling Gao, ME2

Lawrence Blonde, MD3

1Professor of Medicine andEndocrinology, Division Chief,Endocrinology at SUNY, SUNYDownstate Medical Center, Brooklyn,NY; 2Sanofi Inc., Bridgewater, NJ;3Director, Ochsner Diabete s ClinicalResearch Unit, Department ofEndocrinology, Ochsner MedicalCenter, New Orleans, LA

Correspondence: Mary Ann Banerji, MD,Professor of Medicine,Director, Diabetes Treatment Center,State University of New York DownstateMedical Center,450 Clarkson AvenueBrooklyn, NY 11203.Tel: 718-270-1542Fax: 718-270-1534E-mail: [email protected]

DOI:10.3810/pgm.2014.05.2761

AbstractPurpose: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 man-

agement of patients with T2DM. Our study aim was to provide comparative data on efcacy 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]-4 inhibitors or sodium-glucose linked transporter [SGLT]-2 inhibi-

tors) in insulin-naive patients with T2DM who remained uncontrolled with OADs. Methods:

Patient-level data were pooled from 9 randomized controlled trials of24 weeks duration with

comparable patient populations. The effect of adding glargine was compared with intensication

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 HbA1clevel

7.0% with glargine treatment than with pooledcomparators, intensication 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 intensication of lifestyle interventions or OADs. When stratied by baseline HbA1c

level,

efcacy/target attainment with glargine use was better than for pooled comparators across all

HbA1c

strata; OAD intensication, when baseline HbA1c

level was8.0%; 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 intensication 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 benetrisk balance supports initiating insulin rather than intensication ofOAD therapy when baseline HbA

1clevel is 8.0%.

Keywords: type 2 diabetes mellitus; insulin; insulin glargine; glycemic control;

hypoglycemia

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

The evidence is clear for patients with microvascular complications,13 and meta-

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Effect of Baseline Glycemia on Outcomes With Glargine Use



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

X2test or 2-tailed ttest, 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 dened as 7.0%; the

frequencies of goal attainment, as well as the frequency of

HbA1clevel decrease of1.0% were calculated by treatment

group, using Cochran-Mantel-Haenszel test, stratied by study.

Odds ratios (ORs) and 95% condence 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 conrmatory SMBG was per-

formed. 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 hypo-

glycemia, including severe, daytime, and nocturnal), total

reported nocturnal hypoglycemia, and severe hypogly-

cemia (dened 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 stratied by study. Event

rates were compared with rank ANOVA, using treatment

group and study as factors.

Efcacy and safety also were compared between treat-

Figure 1. Flow chart for selection of studies.

Abbreviations:Glargine, insulin glargine; NPH, neutral protamine Hagedorn; OAD, oral antidiabetic drug; RCT, randomized controlled trials.


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Banerji et al

114 Postgraduate Medicine , Volume 126, Issue 3, May 2014, ISSN 0032-5481, e-ISSN 1941-9260ResearchSHARE: www.research-share.com Permissions: [email protected] Reprints: [email protected]


ment groups, stratied by patient baseline HbA1clevel (8.0%, 8.0% to 9.0%, 9.0% to 10.0%, and 10.0%).

ResultsPatient Demographics and BaselineCharacteristicsA 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 (Table 2).

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

stratied by treatment and baseline HbA1c

level (Table 3

for glargine vs pooled comparators; Table 4 for glargine vs

individual comparators). There were no major differences

between patients in the treatment groups in terms of demo-graphics or baseline characteristics.

Efcacy and Safety With GlargineCompared with Pooled ComparatorsAddition 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 (Figure 2A), and a higher percentage of patients

experienced 1.0% decrease in HbA1clevel with glarginetreatment compared with pooled comparators (Figure 2B).

Compared with pooled comparators, event rates

with glargine were signicantly lower for total reported

hypoglycemia, and numerically lower for total reported noc-

turnal and severe hypoglycemia (Table 5). Incidences were

also slightly numerically lower with glargine for total

reported hypoglycemia (Figure 2C), total reported noc-

Table 1. Description of Pooled Studies

Reference Study Entry Criteria Duration,

Wks

Pool

1 (4042) Blickl et al12 HbA1clevel 7.08.0% on 2 OADs

(SU +metformin at MTD)

40 Glargine vs lifestyle intensication

2 (3502) Gerstein et al14 HbA1clevel 7.5%11.0% on 0,a1, or 2 OADs

(1 at 50% MTD)

26 Glargine vs OAD (glargine vs conventional

management, ie, avoidance of insulin and

intensication of OAD)

3 (4014) Rosenstock et al18

HbA1clevel 7.511.0% on stable regimen of50% maximally labeled dose of SU and 1 g/d

metformin; metformin titrated to MTD during

run-in stabilization period

24 Glargine vs OAD (glargine vs rosiglitazoneadd-on to OAD)

4 (4020) Meneghini et al16 HbA1clevel 8.0 to 12.0% on stable regimen

of either 50% maximally labeled dose of SU or

metformin 12.5 g/d

24 Glargine vs OAD (glargine vs pioglitazone

add-on to OAD)

5 (4002) Riddle et al17 HbA1clevel 7.510.0% on stable regimen of

1 or 2 OADs (SU, metformin, pioglitazone, or

rosiglitazone)

28 Glargine vs NPH insulin

6 (6001) Yki-Jrvinen et al19 HbA1clevel 8.0% on stable SU regimen and

metformin 1.5 g/d

36 Glargine vs NPH insulin

7 (4040) Bretzel et al13 HbA1clevel 7.50.5% on stable regimen OADs,

excluding -glucosidase inhibitors

44 Glargine vs insulin lispro (glargine vs insulin

lispro TID)

8 (4021) NCT0133675120 HbA1clevel 8.011.0% on stable regimen 50%

maximally labeled SU dose and 12.5 g/d

metformin

24 Glargine vs premixed insulin (glargineonce daily vs 75% lispro protamine

suspension/25% lispro injection once daily)

9 (4027) Janka et al15 HbA1clevel 7.510.5% on stable SU regimen

+metformin 850 mg/d (all SUs switched to

glimepiride 3 or 4 mg/d during run-in)

28 Glargine vs premixed insulin (glargine once

daily vs 30% regular/70% NPH insulin BID)

aApproximately 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.


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Banerji et al



Table4.

DemographicandP

atientBaselineCharacteristicsStratiedb

yTreatmentandBaselineHbA

1cLevel

GlargineVersusLifestyleInte

nsicationPopulation

Mean[SD]orn(%)

Glargine

LifestyleIntensication

HbA1c

LevelStratum,%

8.0

8.0to9.0

8.0

8.0

to9.0

n

88

13

66

17

Age,y

60[8]

65[6]

61[8]

61[8]

Sex,

Men

48(54.5)

8(61.5)

38(57.6)

9(5

2.9)

Race

NA

NA

NA

NA

Durationofdiabetes,y

9.4[6

.1]

13.2

[7.1

]

10.7

[7.1

]

11.0[7

.2]

HbA

1clevel,%

7.5[0

.3]

8.2[0

.1]

7.4[0

.3]

8.1

[0.1

]

FPG,mmol/La

9.4[1

.9]

10.3

[1.6

]b

9.2[1

.4]

8.9

[1.2

]

Bodyweight,kg

86.1

[12.4]

80.0

[10.6]

83.0

[13.1]

82.2[15.6]

BMI,kg/m2

30.4

[3.6

]

28.6

[3.1

]

29.4

[3.4

]

29.5[3

.6]

GlargineVersusOADmITTPopulation

Mean[SD]orn(%)

Glargine

OAD

HbA1c

LevelStratum,%

8.0

8.0to9.0

9.0to1

0.0

1

0.0

8.0

8.0to9.0

9.0

to1

0.0

1

0.0

n

93

157

131

79

110

182

103

87

Age,y

57.6

[9.6

]

56.7

[9.8

]

54.9

[10.2]

51.7

[11.0]

57.9

[10.1]

56.3

[10.5]

53.0[10.6]

52.4

[10.3]

Sex,

Men

55(59.1)

90(57.3)

78(59.5)

38(48.1)

65(59.1)

106(58.2)

56(54.4)

50(57.5)

Race

White

Black

Hispanic

Asian

Multiracial

Other

83(89.2)

8(8

.6)

1(1

.1)

1(1

.1)

0(0

.0)

0(0

.0)

121(77.1)

16(10.2)

9(5

.7)

10(6

.4)

0(0

.0)

1(0

.6)

96(73.3)

14(10.7)

13(9

.9)

5(3

.8)

0(0

.0)

2(1

.5)

40(50.6)

23(29.1)

11(13.9)

3(3

.8)

0(0

.0)

1(1

.3)

90(81.8)

8(7

.3)

5(4

.6)

3(2

.7)

1(0

.9)

3(2

.7)

149(81.9)

16(8

.8)

11(6

.0)

6(3

.3)

0(0

.0)

0(0

.0)

72(69.9)

12(11.7)

14(13.6)

4(3

.9)

0(0

.0)

0(0

.0)

59(67.8)

15(17.2)

11(12.6)

2(2

.3)

0(0

.0)

0(0

.0)


7.0[4

.4]

7.6[6

.3]

7.6[4

.9]

7.4[5

.7]

7.7[6

.0]

7.6[5

.9]

7.5

[5.5

]

6.3[4

.0]

HbA

1clevel,%

7.6[0

.3]

8.4[0

.3]b

9.4[0

.3]

10.8

[0.7

]

7.6[0

.3]

8.5[0

.3]

9.5

[0.3

]

10.8

[0.8

]

FPG,mmol/La

9.1[1

.7]

10.1

[2.7

]b

12.2

[2.7

]

14.3

[3.4

]

8.9[1

.9]

10.7

[2.4

]

12.1[2

.7]

14.4

[3.2

]

Bodyweight,kg

92.7

[16.6]

92.2

[18.2]

95.0

[19.9]

94.0

[22.6]

90.8

[20.1]

94.7

[19.7]

95.4[19.0]

98.4

23.8

]

BMI,kg/m2

32.3

[5.7

]

32.5

[5.2

]

33.3

[6.7

]

33.0

[7.8

]

31.7

[5.4

]

32.9

[5.7

]

33.1[5

.8]

33.8

[7.6

]

GlargineVersusNPHInsulin

mITTPopulation

Glargine

NPHInsulin

HbA1c

LevelStratum,%

8.0

8.0to9.0

9.0to1

0.0

1

0.0

8.0

8.0to9.0

9.0

to1

0.0

1

0.0

n

102

158

116

40

111

168

115

35

Age,y

57.2

[9.5

]

55.7

[9.5

]

54.3

[9.3

]

53.2

[8.7

]

57.3

[8.7

]

56.5

[8.8

]

55.8[8

.7]

54.5

[9.4

]

Sex,

Men

56(54.9)

93(58.9)

67(57.8)

20(50.0)

64(57.7)

98(58.3)

61(53.0)

21(60.0)


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Banerji et al



Table4.

(Continued)

GlargineVersusPremixedInsulinmITTPopulation

Mean[SD]orn(%)

Glargine

Premixedinsulin

HbA1c

LevelStratum,%

8.0

8.0to9.0

9.0to1

0.0

1

0.0

8.0

8.0to9.0

9.0

to1

0.0

1

0.0


9.4[7

.1]

9.4[6

.8]

11.6

[7.6

]

9.4[6

.7]

8.0[5

.5]

9.8[6

.6]

10.3[7

.1]

8.8[5

.4]

HbA

1clevel,%

7.6[0

.3]

8.5[0

.3]

9.4[0

.3]

10.5

[

0.4]

7.7[0

.3]

8.4[0

.3]

9.4

[0.3

]

10.4

[0.4

]

FPG,mmol/La

8.5[1

.8]

10.0

[2.4

]

11.4

[3.0

]

13.6

[3.4

]

8.8[1

.8]

10.1

[2.1

]

11.3[2

.8]

13.9

[3.3

]

Bodyweight,kg

86.7

[14.2]

88.6

[17.1]

88.9

[18.7]

89.1

[18.1]

88.4

[18.2]

87.5

[15.8]

88.4[21.2]

89.5

[22.0]

BMI,kg/m2

29.5

[4.3

]

31.4

[4.6

]

31.3

[5.1

]

31.1

[4.6

]

29.9

[4.9

]

30.7

[4.6

]

31.0[5

.2]

31.7

[5.8

]

aToconvertmmol/Ltomg/dL,multiplyby18.

bP0.0

5versuscomparator.

Abbreviations:BMI,bodymassinde

x;FPG,

fastingplasmaglucose;HbA

1c,g

lycatedhemoglobin;mITT,modiedintentiontotreat;NA,notapplicable;NPH,neutralprotamineHagedorn;OAD,oralant

idiabetesdrug;SD,standard

deviation.

Efcacy and Safety Stratied by BaselineHbA

1cLevel

Treatment with glargine resulted in greater reductions in

HbA1c

level and target HbA1c

level attainment than pooled

comparators across the HbA1c

level continuum (Figure 3A,

Figure 4A). Reductions in HbA1c

level were similar with

glargine and OADs if baseline HbA1c

level was8.0%, but

greater with glargine if HbA1c

level was8.0% (Figure 3B);

goal attainment tended to be greater with glargine compared

with OADs across the HbA1c

level continuum (Figure 4B).

Reductions in HbA1c

level and goal attainment were gener-

ally similar between glargine and other insulins across all

categories (Figure 3, Figure 4); there was a signicantly

greater reduction in HbA1c

level with glargine than with

premixed insulin use if baseline HbA1c

level was 8.0%

(Figure 3E).

The total reported hypoglycemia risk for patients was

similar between glargine and pooled comparators, but signi-

cantly higher than intensication of lifestyle interventions,

and signicantly lower than insulin lispro across all baseline

HbA1c

level strata (Figure 5); hypoglycemia risk was also

signicantly higher than intensication of OAD therapy,

and signicantly lower than premixed insulin when patient

baseline HbA1c

level was9.0% but10% (Figure 5). 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 WeightOverall, glargine elicited signicantly greater reductions in

FPG than the pooled comparators, having a similar effect on

body weight (2.0 kg vs 1.9 kg; Table 6). There was slight

patient weight gain with glargine use, and greater weight

loss with intensication of lifestyle interventions, resulting

in a statistically signicant 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 (Table 6).

Weight gain was not significantly different between

glargine and intensication of OAD therapy; however, in

individual studies, glargine was associated with greater

weight gain than intensication of OADs when choice

was unspecied,14and less weight gain than the addition

of thiazolidinediones.16,18


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FPG and Body Weight Stratied byBaseline HbA

1cLevel

Treatment with glargine led to signicantly greater reductions

in patient FPG level compared with pooled comparators,

OAD therapy, and intensication of lifestyle, regardless of

HbA1c

level category at baseline. Treatment with glargine

Figure 2. 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.

aP0.001.bP0.01.

Abbreviations:glargine, insulin glargine; HbA1c

, glycated hemoglobin; NPH, neutral protamine Hagedorn; OAD, oral antidiabetic drug.


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Banerji et al



led to signicantly greater reductions in FPG level compared

with insulin lispro and premixed insulin when baseline HbA1c

level was 10%.

There were no signicant differences in weight gain

between glargine and pooled comparators, or any individual

treatment group across the HbA1c

level continuum, except

for the intensication of lifestyle interventions group, which

had negative weight gain. There was a trend for patients withhigher baseline HbA

1clevels to have greater reductions in

HbA1c

(Figure 3) and FPG levels, and greater changes in body

weight, regardless of any treatment intervention.

DiscussionDeterioration of glycemic control in patients with T2DM,

despite treatment with OADs, represents a signicant thera-

peutic crossroads for patients and health care professionals

alike. While there is a consensus that treatment should

be intensied to achieve HbA1c

levels 7.0%,9 or even

6.5%,21many factors may inuence the decision regard-ing how best to improve a patients glycemic control, and

all therapeutic decisions must balance efcacy and safety.

It is generally acknowledged that therapeutic interven-

tions and treatment goals should be individualized, but there

are few data available to inform decisions and guide this indi-

vidualization.10The decision to initiate insulin therapy can

be particularly challenging.2224In our analysis, we compared

the efcacy and hypoglycemic potential of the basal insulin

preparation, insulin glargine, with several other options avail-

able for intensication of therapy in patients with suboptimal

glycemic control while treated with1 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 benetrisk prole would favor anyother 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

experiencing1.0% decrease in HbA1c

, without increased

risk of hypoglycemia or weight gain. When stratied by

baseline HbA1c

level, glargine had greater efcacy than

pooled comparators across the HbA1c

level spectrum, without

increased patient risk of hypoglycemia.

Addition of glargine was more likely to result in a targetHbA

1clevel7.0% than intensication of lifestyle interven-

tions 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

level7.0%, 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

intensication of OAD therapy, when baseline HbA1c

level

Table 5. Hypoglycemia Event Rates per PYE

Total Reported Hypoglycemia,

Events/PYE

Total Nocturnal Hypoglycemia,

Events/PYE

Total Severe Hypoglycemia,

Events/PYE

Glargine (n =1462) 6.85 1.51 0.04

Pooled Comparators (n =1476) 9.69 2.11 0.05

PValue 0.001 0.293 0.160

Glargine (n =101) 4.72 0.68 0.06

Lifestyle Intensication (n =83) 2.96 0.50 0.00

PValue 0.001 0.034 0.199

Glargine (n =460) 4.34 0.65 0.04

OAD Intensication (n =482) 2.92 0.35 0.05

PValue 0.001 0.001 0.706

Glargine (n =416) 11.79 3.86 0.07

NPH Insulin (n =429) 14.78 5.80 0.04

PValue 0.033 0.005 0.870

Glargine (n =198) 4.23 0.47 0.02

Insulin Lispro (n =204) 15.33 0.35 0.04

PValue 0.001 0.218 0.267

Glargine (n =287) 6.53 1.10 0.02

Premixed Insulin (n =278) 10.45 1.97 0.08

PValue 0.004 0.001 0.022

Abbreviations:NPH, neutral protamine Hagedorn; OAD, oral antidiabetes drug; PYE, patient-years of exposure.


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was8.0%; however, glargine therapy was associated with

an increase in frequency of reported hypoglycemic events.

When considering goal attainment and hypoglycemic poten-

tial, 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 homoge-

neous 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 reected in the statisti-

cal 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.

Figure 3. Adjusted mean changes in HbA1clevel, from baseline to Week-24 endpoint, stratied by baseline HbA

1Clevel. A)Glargine versus pooled comparators;

B)Glargine versus OAD intensication; C)Glargine versus NPH insulin; D)Glargine versus insulin lispro; and E)Glargine versus premixed insulin.

aP0.05.bP0.01.cP0.001.Abbreviations:glargine, insulin glargine; HbA

1c, glycated hemoglobin; NPH, neutral protamine Hagedorn; OAD, oral antidiabetes drug.

An obvious limitation of our study is that data were derived

from only the rst 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)-4 inhibitors, included. Although head-to-head com-

parisons of glargine with insulin detemir,25liraglutide,26and

exenatide27in 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,


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Banerji et al



it was found that the efcacy of the comparator was either

non-inferior25,27or slightly superior26to glargine; there were

no signicant differences in hypoglycemia event rates. In

the Liraglutide Effect and Action in Diabetes 5 (LEAD-5)

study,26rates of major, minor, and symptomatic hypoglyce-

mia 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 Help-

ing Evaluate Exenatide in overweight patients with diabetes

compared with Long-Acting insulin (HEELA) study,27there

were no signicant differences between exenatide and insulin

glargine use in patient incidence of symptomatic hypogly-

cemia or glucose-conrmed hypoglycemia (62 mg/dL

[3.4 mmol/L]; P= 0.139 and P= 0.369, respectively);

however, the incidence of nocturnal hypoglycemia was sig-

nicantly 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

ConclusionResults of our analysis support the recommendation to initiate

insulin therapy with a basal insulin,9and are consistent with

earlier reports that glargine is associated with less hypoglyce-

mia than NPH, prandial, or premixed insulins.28,29The 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 3 months.30In our study, we found addition of glargine

Figure 4. Percentage of patients achieving Week 24 endpoint HbA1clevel 7.0%, stratied by baseline HbA

1clevel. A)Glargine versus pooled comparators; B)Glargine

versus OAD intensication; C)Glargine versus NPH insulin; D) Glargine versus insulin lispro; and E)Glargine versus premixed insulin.

aP

0.05.bP0.01.cP0.001.

Abbreviations:glargine, insulin glargine; HbA1c

, glycated hemoglobin; NPH, neutral protomine Hagedorn; OAD, oral antidiabetes drug.


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Table 7. Adjusted Mean Changes in Patient Body Weight and FPG

AM[SE] Glargine Pooled Comparators PValue

n 1462 1476

Body weight, kg 2.0 [0.1] 1.9 [0.1] 0.5998

FPG, mmol/La 4.2 [0.2] 3.2 [0.2] 0.001

Glargine Lifestyle Intensication PValue

n 101 83

Body weight, kg 0.6 [0.3] 2.0 [0.3] 0.001

FPG, mmol/L NA NA NAGlargine OAD PValue

n 460 482

Body weight, kg 2.1 [0.2] 1.9 [0.2] 0.463

FPG, mmol/L 4.5 [0.1] 2.9 [0.1] 0.001

Glargine NPH Insulin PValue

n 416 429

Body weight, kg 2.7 [0.2] 2.5 [0.2] 0.523

FPG, mmol/L 4.8 [0.1] 4.6 [0.1] 0.295

Glargine Insulin Lispro Pvalue

n 198 204

Body weight, kg 2.4 [0.3] 3.1 [0.3] 0.081

FPG, mmol/L 4.1 [0.2] 2.1 [0.2] 0.001

Glargine Premixed Insulin Pvalue

n 287 278

Body weight, kg 2.0 [0.2] 2.5 [0.2] 0.083

FPG, mmol/L 3.8 [0.1] 3.1 [0.2] 0.001

aTo 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.

Figure 5. Odds ratio for experiencing 1 hypoglycemic event stratied by

baseline HbA1clevel.

aP0.05.bP0.01.cP0.001.

Abbreviations:glargine, insulin glargine; NPH, neutral protamine Hagedorn; OAD,

oral antidiabetes drug.

had greater efcacy than intensication 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 intensication in these patients.

AcknowledgmentsStudy funding was provided by Sano 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 Sano US Inc.

Conict of Interest StatementMary Ann Banerji, MD, has received research support

from Bristol-Myers Squibb Company, Boehringer Ingel-

heim, 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 Sano US Inc.

Michelle Baron, MD, was an employee and shared stock

holder of Sano US Inc. Ling Gao, ME, is a senior statisti-

cal consultant for Sano US Inc. Lawrence Blonde, MD,

has received grant/research and investigator support from

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

level8.0%, glargine


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Banerji et al



Amgen Inc., Boehringer Ingelheim Pharmaceuticals, Inc.,

Eli Lilly and Company, Merck & Co., Inc., Novo Nordisk,

Roche, and sano-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 Pharma-

ceuticals, Inc., AstraZeneca, Boehringer Ingelheim Phar-

maceuticals, 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 Pzer Inc.

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Postgraduate Medicine, Volume 126, Issue 3, May 2014, ISSN 0032-5481, e-ISSN 1941-9260 125R hSHARE h h P i i i i @ t d d R i t i t @ t d d

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