The Efficacy of Vildagliptin

in Korean Patients with Type 2 Diabetes

영남의대 내과학교실

원 규 장

제 26차 대한당뇨병학회 춘계학술대회

2

2

5

Powerful Efficacy Vildagliptin

Intent-to-treat population; *P ≤0.001 vs placebo; #P =0.005 vs placebo (placebo= -1.4 kg)

Pi-Sunyer FX et al. Diabetes Res Clin Pract 2007;76:132–8

Vildagliptin 50 mg twice daily

Mean change from baseline

vs placebo (%)

*

Vildagliptin monotherapy

Weight change vs baseline: -0.02 kg (baseline=90.4 kg)#

No patients reported hypoglycemia

**

HbA1c

(baseline mean 8.4%)

Mean change from baseline

vs placebo (mmol/L)

Duration: 24 weeks

*

n=79 n=79

• Adverse events (AEs) occurred with similar frequency in each group: 59.3% and 57.6% of patients receiving

vildagliptin 50 mg bid or placebo, respectively.

FPG

(baseline mean 10.9 mmol/L)

Vildagliptin plus metformin: powerful 1.1% reduction

in HbA1c at 24 weeks

HbA1c=haemoglobin A1c.

Primary intention-to-treat population.

Only data using the marketed regimen of vildagliptin are shown.

Bosi E, et al. Diabetes Care. 2007; 30: 890–895.

Add-on treatment to metformin (2.1 g mean daily)

Reduction in HbA1c

Placebo + metformin (n=130)

Vildagliptin 50 mg twice daily + metformin (n=143)

7.2

7.4

7.6

7.8

8.0

8.2

8.4

8.6

−4 0 4 8 12 16 20 24

Time (weeks)

Mean HbA1c (%)

*

-1.1%

difference

P <0.001

8

Mechanism of Powerful Efficacy

Tight binding

Longer duration

DPP-4 inhibition

High GLP-1 level

99

Vildagliptin

• Extends the meal induced increase in GLP-1 levels into the

inter-meal and overnight periods by blocking GLP-1 inactivation by

DPP-4, leading to increased glucose-sensitive insulin secretion and

decreased glucagon levels during meals resulting in

‒ reduced PPG

‒ reduced FPG (secondary to reduced PPG)

• Increased glucose-sensitive insulin secretion and decreased

glucagon levels during the overnight period results in

‒ reduced FPG (secondary to reduced overnight HGP)

• Vildagliptin 50 mg twice daily: blocks GLP-1 inactivation over

24 hours, providing an additional reduction in FPG due to a direct

effect on overnight HGP

DDP-4=dipeptidyl peptidase-4; FPG=fasting plasma glucose ;GLP-1=glucagon-like peptide-1; HGP=hepatic glucose production;

PPG=postprandial blood glucose

Ahrén B et al. Diabetes Obes Metab 2011;13:775–83

Tight substrate-like blocker binding of vildagliptin

Natural

substrate:(GLP-1)

GLP-1

+

DPP-4

K-1

K1

GLP-1: DPP-4

complex

K2

Fast(~1 sec)

DPP-4Inactive

GLP-1

+

DPP-4=dipeptidyl peptidase-4; GLP-1=glucagon-like peptide-1.

Burkey BF, et al. Poster 0788 presented at EASD 2006; Deacon CF, Holst JJ. Adv Ther. 2009; 26: 488–499;

Miller SA, St Onge EL. Ann Pharmacother. 2006; 40: 1336–1343; Neumiller JJ. J Am Pharm Assoc. 2009; 49: S16–S29;

Potashman MH & Duggan ME. J Med Chem 2009; 52: 1231-1246. White JR. Clin Diabetes. 2008; 26: 53–57.10

Substrate

acting as

inhibitor:(vildagliptin)

Substrate-like

enzyme blocker

+

DPP-4

K-1

K1

Substrate-like

enzyme blocker:

DPP-4 complex

K2

Slow

(~ 1 h)

DPP-4Inactive

substrate-like

enzyme blocker

+Slow dissociation

Inhibitor

+

DPP-4

K-1

K1

Inhibitor: DPP-4

complex

Competitive

inhibitor:(sitagliptin)

Fast dissociation

Tight substrate-like blocker binding of vildagliptin

leads to longer DPP-4 inhibition

DPP-4=dipeptidyl peptidase-4; GLP-1=glucagon-like peptide-1.

Burkey BF, et al. Poster 0788 presented at EASD 2006; Deacon CF, Holst JJ. Adv Ther. 2009; 26: 488–499;

Miller SA, St Onge EL. Ann Pharmacother. 2006; 40: 1336–1343; Neumiller JJ. J Am Pharm Assoc. 2009; 49: S16–S29;

Davis JA, et al. Indian J Pharmacol 2010; 42: 229-233.

Fast dissociation Slow dissociation

GLP-1

GLP-1

GLP-1

DPP-4

Competitive

inhibitor*

GLP-1

GLP-1

GLP-1DPP-4

Substrate-

like

blocker**

Duration of sitagliptin binding: <30 seconds Duration of vildagliptin binding: 55 minutes

**Vildagliptin or saxagliptin*Sitagliptin or alogliptin

Pharmacodynamics of DPP-4 inhibitorsVildagliptin leads to greater increases in active GLP-1 than linagliptin

with usual dose

Drugs 2011; 71 (11): 1441-1467

13

Efficacy ComparisonVildagliptin vs SU

1414

Vildagliptin: similar efficacy to glimepiride when added to metformin

at 52 weeks – no weight gain and low incidence of hypoglycemia

6.5

6.7

6.9

7.1

7.3

7.5

87.5

88.0

88.5

89.0

89.5

90.0

90.5

91.0

Time (weeks)

Mean HbA1c(%

)

HbA1c and body weight data from the per protocol population

Hypoglycemia data from the safety population

CI=confidence interval; hypo=hypoglycemia; NI=non-inferiority

Ferrannini E et al. Diabetes Obes Metab 2009;11:157–66; Data on file, Novartis Pharmaceuticals

NI: 97.5%

CI (0.02, 0.16)

–0.5%

–0.4%

Vildagliptin 50 mg twice daily + metformin

Glimepiride up to 6 mg once daily + metformin

Number of hypoglycemic

Events

Severe events(grade 2 and

suspected grade 2)

Patients with≥1 hypos (%)

1.7

16.2

0

4

8

12

16

20

1,389

39

554

0

100

200

300

400

500

600

0

10

0

2

4

6

8

10

12

1,383 1,389 1,383 1,389 1,383n =

Incidence (%)

No. of events

No. of events

Time (weeks)

−1.8 kg

differenceBody weight (kg)

Duration: 52 weeks

Add-on to metformin: vildagliptin vs glimepiride

Add-on treatment to metformin (~1.9 g mean daily)

–8 –4 0 4 8 12 16 20 24 28 32 36 40 44 48 52 56

–8 –2 12 22 32 42 52

• Overall incidence of AEs was 74.5% and 81.1%

in patients receiving vildagliptin and

glimepiride, respectively

15

Efficacy ComparisonVildagliptin vs Sitagliptin

Glucose fluctuation & DPP-4 inhibitor - 1

Large MAGE decrements in

the vildagliptin compared

with the sitagliptin.

A marked increase in GLP-1

occurred during interprandial

period in vildagliptin toward

sitagliptin

Marfella R, et al. J Diabetes Complications. 2010; 24:79- 83

Effects of vildagliptin vs. sitagliptin on glucose fluctuationsMAGE decreased significantly along with vildagliptin group

MAGE=mean amplitude of glycemic excursions

Marfella R, et al. J Diabetes Complications. 2010; 24:79-83

0

Vildagliptin n = 18 Sitagliptin n = 20

20

40

60

80

100

70 ± 22

34 ± 7

* P <0.01

MAGE (m

g/dl)

0

20

40

60

80

100 69 ± 18

59 ± 16

At baseline At baseline After 3 monthAfter 3 month

MAGE (m

g/dl)

� Patients were prior inadequately controlled by metformin max dose (3000 mg/d) and randomized to treat with either Vildagliptin

50 mg bid or Sitagliptin 100 OD on to metformin over a period of 3 months

� CSGM shows large MAGE decrements in the vildagliptin group compared with Sitagliptin group

P =ns

Glucose fluctuation & DPP-4 inhibitor - 2

MAGE reduction is associated

with reduction of oxidative

stress and markers of

systemic inflammation in

type 2 diabetic patients.

These effects were greater in

the vildagliptin group than in

the sitagliptin group

Rizzo et al. Diabetes Care 35:2076-82, 2012

19

OPTIMA study

Vildagliptin induced better

circadian glycemic control

than sitagliptin with a

significant decrease on

overall hyperglycemia,

mainly driven by reduction

on basal hyperglycemia

Guerci, et. al. Diabetes & Metabolism (2012) 38(4):359-66

20

Efficacy Comparison Vildagliptin vs other DPP-4 Inhibitors

After adjusting for baseline

differences among trials of

vildagliptin and sitagliptin in

Japanese patients with type 2

diabetes, vildagliptin 50mg

twice daily was associated

with significantly greater

HbA1c reduction than

sitagliptin 50mg or 100mg

once daily

Signorovitch et al. Clin Drug Investig 2011; 31 (9): 665-674

22

The data of the present

retrospective database study

suggest that vildagliptin in

combination with

metformin/sulfonylureas is a

safe and effective treatment

for type 2 diabetes patients

in real-life clinical practice and

support previous observation

from randomized clinical trials

Perfusion 2011; 24:206-211

Vildagliptin vs. other DPP-4 Is in real-life clinical practiceThe greatest reductions in median HbA1c differences were observed

in the vildagliptin groups (–1.1 %)

Perfusion 2011; 24:206-211

p = 0.0071

� Retrospective analysis of patient data in Germany (used the IMS® Disease Analyzer)

� Population: T2DM patients who received a DPP-4I or GLP-1 mimetic in combination with Met

or SUs for the first time in the study period (4/2007~10/2010)

� The present data are in agreement with data from randomized clinical trials & support the

efficacy of incretin-based therapies in HbA1c lowering in T2DM patients under real-life

conditions

Greater reductions in HbA1c

and FPG were found with

vildagliptin compared with the

other DPP-4 inhibitors.

Clin Ther. 2012 Jun;34(6):1247-1258

Efficacy of DPP-4 Is: Meta-Analysis and Systematic ReviewGreater reductions in HbA1c and FPG were found with vildagliptin

compared with the other DPP-4 inhibitors

� Trial databases were searched for relevant literature published between January 1, 1990,

and June 30, 2011

� 80 randomized trials of 12-52 weeks’ durationClin Ther. 2012 Jun;34(6):1247-1258

Efficacy of DPP4 inhibitors as Add-on to Metformin

%

Sitagliptin + Metformin(100 + > 1500 mg OD)Baseline HbA1c – 8.01

Saxagliptin + Metformin(5 + 1500-2000 mg OD)Baseline HbA1c – 8.0

Vildagliptin + Metformin(Low dose : (50 + 500) BD

High dose : (50 + 1000) BD)Baseline HbA1c – 8.7

Adapted from –

Raz etal, Current Medical Research and Opinion, Vol. 24, No. 2, 2008, 537–550

Charbonnel etal, Diabetes Care, 2006, , 29(12), 2638-44

Defronzo etal, Diabetes, 2009, 52 (suppl 1): S296

Bosi etal, Diabetes, Obesity and Metabolism, 11, 2009, 506–515

Package Insert – Tradjenta ( Liagliptin)

Note = Data has been compiled from different studies.

Head-on comparisons from single study is not currently available

22

4744

55.4

65.4

28.3

0

10

20

30

40

50

60

70

Raz etal 2008 Charbonnel2006

Defronzo 2009 Bosi etal 2009(Low-dose met)

Bosi etal 2009(high-dose met)

LinagliptinPakage Insert

Patients with % HbA1c < 7%

Linagliptin + Metformin(5 + > 1500 mg OD)Baseline HbA1c – 8.1

27

Efficacy

Various Populations

28

Vildagliptin plus metformin: a 1.1% reduction in HbA1c in

the very elderly with no hypoglycaemia or weight change

-1.1-1.2

-1.0

-0.8

-0.6

-0.4

-0.2

0.0

Change in HbA1c (%)

from baseline

n=

BL (%)=

25

8.5

*

Pooled analysis (24 weeks) of 3 add-on therapy studies, patients ≥75 years

HbA1c1

-0.2

-0.5

-0.4

-0.3

-0.2

-0.1

0.0

n=

BL (kg)=

Change in weight (kg)

from baseline

25

82.8

Body weight1

n 31

Any events,

n (%)0 (0.0%)

Severe

events, n (%)0 (0.0%)

Hypoglycaemia2

Overall AEs, drug-related AEs and SAEs were all reported with a lower frequency in elderly patients receiving vildagliptin (133.9, 14.5 and 8.8 events per

100 SYE, respectively) than in elderly patients receiving comparators (200.6, 21.8 and 16.5 events per 100 SYE, respectively), and the incidence of

discontinuations due to AEs was similar in the 2 treatment groups (7.2 vs 7.5 events per 100 SYE, respectively). The incidences of AEs, drug-related AEs,

SAEs and discontinuations due to AEs were overall comparable between younger and older patients. The most notable difference was a higher incidence

of SAEs in the comparator group in patients ≥75 years vs <75 years.1Efficacy pool: all randomised, double-blind, controlled, parallel-group studies with duration ≥24 weeks and with patients ≥75 years. Only includes studies

with the approved dose of 50 mg twice daily. 2Safety pool: a pool of 38 Phase II and III studies (monotherapy and add-on therapy).

*P <0.05 vs baseline (within group). AEs=adverse events; bid=twice daily; BL=baseline; HbA1c=haemoglobin A1c; SAEs=serious adverse events.

Schweizer A, et al. Diabetes Obes Metab. 2011; 13: 55–64.

29

Glucose-dependent effect of incretins makes them

a good alternative option for elderly patients

• In the “Warnings and precautions” section of the labelling

information, vildagliptin is the only incretin with no restrictions in

very elderly patients1

Labelling Information on Elderly in the EU

Vildagliptin: No dose adjustments are necessary in elderly patients1

Sitagliptin: No dose adjustment is necessary based on age. Limited safety data are available in

patients ≥75 years of age and care should be exercised2

Saxagliptin: Experience in patients aged 75 years and older is very limited and caution should be

exercised when treating this population3

Liraglutide: Elderly (>65 years old): No dose adjustment is required based on age. Therapeutic

experience in patients ≥75 years of age is limited4

Exenatide: Should be used with caution and dose escalation from 5 µg to 10 µg should proceed

conservatively in patients >70 years. The clinical experience in patients >75 years is very limited5

1Galvus® (vildagliptin) Summary of Product Characteristics, Feb 2011; 2Januvia® (sitagliptin) Summary of Product Characteristics, Jan 2011; 3Onglyza® (saxagliptin) Summary of Product Characteristics, Feb 2011; 4Victoza® (liraglutide [rDNA origin] injection), Dec 2010; 5Byetta® (exenatide) injection Summary of Product Characteristics, Jan 2011.

30Novartis data on file – study LAF237A23137

Moderate RI

N 157 128

Ad

juste

d M

ean

ch

an

ge

fro

m b

ase

line in

Hb

A1

c (

%)

*

BL

Severe RI

N 122 95

Ad

juste

d M

ea

n c

ha

nge

fro

m b

ase

line in

Hb

A1

c (

%)

BL7.86 7.79

Mean change

from baseline to

endpoint

-0.74

-0.21

-1

-0.9

-0.8

-0.7

-0.6

-0.5

-0.4

-0.3

-0.2

-0.1

07.69 7.65

-0.88

-0.32

-0.56-0.53*

Vildagliptin provided robust reduction in HbA1c in T2DM

patients with moderate or severe RI

Source: PT-Table 14.2-1.1b

* p<0.0001 vs. placebo; BL=Baseline

Full analysis set

Between treatment

difference vs.

placebo

-0.8

-0.7

-0.6

-0.5

-0.4

-0.3

-0.2

-0.1

0

Mean change

from baseline to

endpoint

Between treatment

difference vs.

placebo

Vilda 50mg qd

Placebo

3131

Changes in HbA1c levels in patients with T2DM fasting

during Ramadan (VECTOR study)

• No AEs or SAEs were reported in the vildagliptin cohort compared with 18 patients

treated with SU reporting at least one AE (mainly driven by hypoglycemia)

NS=not significant; SAE=severe adverse event

Hassanein M et al. Curr Med Res Opin 2011;27:1367–74

Vildagliptin lowered HbA1c vs SU pre- to post-Ramadan;

between-group difference −0.5% (P=0.0262)Mean change in HbA1c

pre to post Ramadan

n=23 n=36

NS

NS

P=0.0262

–0.5

–0.4

0.2

0.1

0.0

–0.1

–0.2

–0.3

–0.4

–0.5

–0.6

0.1

Vildagliptin SU cohort Between-group

difference

Observational study

Duration: up to 16 weeks

Add-on to metformin:

vildagliptin vs SU

32

Efficacy

in Korean Patients with T2DM

Vildagliptin-metformin

treatment provided blood

glucose control efficacy

comparable to that of

glimepiride-metformin

treatment and resulted in

better adverse event profiles

with lower risks of

hypoglycemia and weight gain

Diabetes Metab J 2011;35:529-535

N=51 – Glime 2mg bid + Met 500mg bid

N* = 102

N=51 - Vilda 50mg bid + Met 500mg bid

32 weeks2 weeks

Objective: the efficacy and safety of vildagliptin-metformin treatment

compared to those of glimepiride-metformin treatment

Target Population: Drug naïve or low dose glimepiride(2-4mg) or low

dose metformin (500-1000mg) T2DM; HbA1c 7.5%–12%

Vildagliptin-Met vs Glimepiride-Met in Korean patients

Decrement of HbA1c on the week 32 end-point

-1.5

-1

-0.5

0

Vildagliptin Glimepiride

Change from baseline in

HbA1c (%)

-0.94% -1.00%

Body weight change

0

0.5

1

1.5

2

2.5

3

vildagliptin glimepiride

(kg)

Vildagliptin( n = 51 )

Glimepiride( n = 51 )

One or more AE 5 10SAEs 0 1Discontinuations due to AE 3 1

Hypoglycemia (patient number) 1 10 Overall gastrointestinal AE 4 0Selected gastrointestinal AEAbdominal pain 0 0Nausea 1 0Vomiting 2 0Diarrhea 1 0

Safety summary

AE : adverse event

SAE : serious adverse event, which means to need medical assistance

The patients who discontinued medication due to AE were not contained in final analysis.

Vildagliptin was efficacious for

glycemic control,

especially for lowering FPG

and HbA1c levels, in drug

naive diabetes subjects where

it was combined with

metformin treatment, where

it was added to existing

metformin or sulfonylurea

treatment, and where it

replaced sulfonylureas.

Diabetes Metab J 2013;37:72-80

3939

Subject profiles

4040

Glycemic Efficacy of Vildagliptin Treatment in Korean

Subjects with Type 2 Diabetes

� Group1: Drug naive� Met+Vilda

� Group2: Met mono � Met+Vilda

� Group3: Met+SU � Met+SU+Vilda

� Group4: Met+SU � Met+Vilda

� Group5: Met+Glinide � Met+Vilda

Diabetes Metab J 2013;37:72-80

41

Mean changes from baseline in HbA1c, FPG according to

baseline HbA1c subgroup were significant

42

New Label

Triple & Insulin

Vildagliptin + Metformin + Glimepiride

Objective: To assess the efficacy and safety of vildagliptin 50 mg bid compared with placebo as add-on therapy in patients with type 2 diabetes inadequately controlled with dual therapy of metformin and glimepiride.

*Metformin ≥1500 mg daily at stable dose, to be maintained throughout the study. ^Glimepiride ≥4 mg daily, to be maintained throughout the stabilization

period. After randomization visit, glimepiride could be adjusted downward to a maximum tolerated dose at the investigators discretion.

After the screening visit, eligible patients on metformin ≥1500 mg + glimepiride ≥4 mg for ≥12 weeks proceeded directly to the start of the double-blind

treatment phase.

Eligible patients on dual therapy of metformin (≥1500 mg) + more than ½ max daily dose of SU labeled for the region (or glimepiride ≥2 to <4 mg)

proceeded to start of the stabilization phase and were switched to glimepiride 4 mg. Eligible patients on dual therapy of metformin (≥1500 mg) + less than

½ max daily dose of SU labeled for the region or + <2 mg glimepiride or + TZD/glinide were switched to glimepiride 2 mg at start of titration phase, up-

titrated to 4 mg at start of stabilization phase provided FPG >7 mmol/L and then continued into the stabilization phase. Eligible patients on metformin

monotherapy (≥1500 mg) followed the same titration and stabilization phases. Patients who did not up-titrate were discontinued.

All patients with HbA1c 7.5-11% at the visit one week before the randomization visit were eligible for randomization.

FPG, fasting plasma glucose; HbA1c, glycosylated hemoglobin A1c; SU, sulphonylurea; TZD, thiazolidinedione.

Study 23152, Novartis Data on file, CSR Section 9.1 and Figure 9-1.43

Screening Titration Stabilization

Placebo + Metformin + Glimepiride n = 160

Double-blind Treatment Period

Vildagliptin 50 mg bid + Metformin + Glimepiride n = 158

Metformin* Metformin* + Glimepiride^

2 weeks 2 weeks 10 weeks 24 weeks

Vildagliptin as Add-on Therapy to Dual Combination of Metformin and

Glimepiride is Efficacious Without Relevant Increase in Weight and With a

Low Incidence of Hypoglycemia

44

*P<0.001. FAS was used for HbA1c and FPG analyses. Safety set was used for hypoglycemia and weight analyses. # Hypoglycemic events are defined as

symptoms suggestive of hypoglycemia with a plasma glucose measurement <3.1 mmol/L. BL, baseline; EP, endpoint; FPG, fasting plasma glucose; FAS,

full analysis set; Glim, glimepiride; HbA1c, glycosylated hemoglobin A1c; Met, metformin; SE, standard error; Vilda, vildagliptin; Wk, week.

Study 23152, Novartis Data on file, PT-Table 14.2-2.1; PT-Table 14.2-2.3; PT-Table 14.3.1-2.3; PT-Table 14.3-3.1.

HbA1c Change from BL to EP

BL = 8.808.75

N = 160152

*

Vilda 50 mg bid + Met + Glim

Placebo + Met + Glim

Between-treatment difference

BL = 9.529.34

N = 160152

*

FPG Change from BL to EP

73.7

72.3

157 160N =

Hypoglycemic Events#

Weight by Visit

45

Vildagliptin + Insulin

Objective and Study Design

Objective: To assess the efficacy and safety of vildagliptin 50 mg bid compared with placebo as add-on therapy in patients with type 2 diabetes inadequately controlled by insulin with/without concomitant metformin.

*Insulin background treatment was to be maintained stable throughout the study. Patient enrollment was stratified by metformin use to achieve an

approximately 60/40 ratio of patients receiving/not receiving concomitant stable metformin treatment.

Efficacy data are censored at major change in insulin background therapy; major change in insulin background therapy is defined as having insulin as

rescue therapy for ≥ 5 days consecutively or ≥ 7 days in any 30 day period or having major change for reason other than rescue (defined as increases

in daily insulin dose ≥ 10% of baseline or changes in insulin type or dose frequency).

Study 23135, Novartis Data on file, CSR Section 9.1 and Figure 9.1.46

Placebo + insulin (± metformin) N = 221

Vildagliptin 50 mg bid + insulin (± metformin) N = 228

Screening Period Double-blind Treatment Period

24 weeks2 weeks

Insulin (± metformin)*

N = 449

Vildagliptin as Add-on Therapy to Insulin is Efficacious Without

Relevant Increases in Hypoglycemia or Weight

HbA1c /weight : FAS, hypoglycemia : safety set, insulin : randomized set .*P < 0.001.Study 23135, Novartis Data on file, PT-Table 14.2-1.1; 14.2-7.2; 14.3-1.8; 14.3.1-2.3a.

47

8.80

Vildagliptin 50 mg bidPlacebo Between-treatment difference

Weight Change from BL to EP

227 221N =

Hypoglycemic Events

BL = 8.84

N = 215221

HbA1c Change from BL to EP

*

BL = 78.878.1

N = 215222

Mean change (SE)

in body weight, kg

Insulin Change from BL to EP

Mean change (SE) in

Insulin dose, U

BL = 42.140.0

N = 221228

Study Conclusions

● 24-week treatment with vildagliptin 50 mg bid as add-on to stable

insulin therapy demonstrated a clinically and statistically

significant reduction in HbA1c at study endpoint compared to

placebo in the overall study population, as well as in the

subgroups with or without metformin therapy.

● The reduction in HbA1c was achieved without clinically relevant

increased risk for hypoglycemia or weight gain.

● Treatment with vildagliptin 50 mg bid as add-on to stable insulin

therapy with or without metformin therapy was generally well

tolerated.

48HbA1c, glycosylated hemoglobin A1c.

감사합니다 !!!