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.
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