Effect of vildagliptin twice daily vs. sitagliptin
once daily on 24-hour acute glucose fluctuations
Author: Raffaele Marfella, et al.
Publication: Journal of Diabetes and Its Complications 24 (2010) 79-83
1
DPP-4 inhibitor therapy should target not only reducing HbA1c but also
flattening acute glucose fluctuation over a daily period
Continuous subcutaneous glucose monitoring (CSGM) shows large MAGE
decrements in vildagliptin group compared with sitagliptin group
A marked increase in GLP-1 occurred during interprandial period in
vildagliptin bid-treated toward sitagliptin 100 mg once daily
Glucagon was more suppressed during interprandial period in receiving
vildagliptin compared to those receiving sitagliptin
2
3
Rapid glucose fluctuation over daily period plays
importance role on diabetic complication
Exposure to glycemic disorder can be described as a function of two
components
- The duration and magnitude of chronic sustained
hyperglycemia (HbA1c)
- Acute fluctuations of glucose over a daily period; when
MAGE is greater, glycemic instability is higher
Acute fluctuations of glucose around a mean value has been proved
independent of mean glycemic and may be due to
1. Defects in insulin secretion
2. Suppression of glucagon secretion
4
Example of MAGE calculation
48 hr continuous blood glucose analyses (CBGA)
24 h
24 h
MAGE is calculated for
each subject by taking the
arithmetic mean of blood
glucose increase or
decrease (nadir to peak)
when both ascending and
descending segments
exceeded the value of one
standard variation of blood
glucose for the same 24-hr
295
125
143
126
116
332
149
Glucose excursions
counted only those > 1 SD
SD = 62 mg/dl in day 1
= 74 mg/dl in day 2
Graph are from Service et al. Diabetes 1970; 19 (9): 645-655
= 125+295+116+143+126
+332+149
MAGE = 1286/7 = 184 mg/dl
5
6
The effect of DPP-4 inhibitors on glycemic control
 Many studies have shown that DPP-4 inhibitors (Vildagliptin and Sitagliptin)
can enhance GLP-1 level and prolong its effects for glycemic control
 They have been proved to enhance glucose-induced insulin secretion,
decrease glucagon secretion, and reduce postprandial glycemic
excursions
 By mechanism of action, the potency of stabilizing DPP-4 inhibition offer
the better regulation of daily glucose fluctuations
 Chronic hyperglycemia has been associated with increased risk of diabetic
complication and mean amplitude glucose excursion (MAGE) is also linked
with the activation of oxidative stress, which is the main mechanisms that
lead to chronic diabetic complication
7
Effect of Vildagliptin vs Sitagliptin on 24-hr acute
glucose fluctuation (MAGE)
A cross-sectional study of acute glucose fluctuation on pre- and post- treatment
Vildagliptin n = 20
MAGE (mg/dl)
80
* P <0.01
100
70 ± 22
69 ± 18
59 ± 16
80
60
34 ± 7
40
20
MAGE (mg/dl)
100
Sitagliptin n = 18
60
40
20
0
0
At baseline
After 3 mo treatment
At baseline
After 3 mo treatment
 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 mo.
 CSGM shows large MAGE decrements in the vildagliptin group compared with Sitagliptin group
*P <0.01 difference from baseline
Marfella R et al. J Diabetes Complications. 2009 doi:10.1016 (in Press)
8
Effect of Vildagliptin vs Sitagliptin on Plasma
Levels of Intact GLP-1
Intact GLP-1 (pmol/L)
30
25
The difference can be seen as early as 1.5 - 3
hrs post dose so that different regimen (bid
vs od) should not be the main cause of the
difference
Vildagliptin 50 mg bid
+ metformin
Sitagliptin 100 mg qd
+ metformin
20
15
10
5
0
-20 0 15 30 60 90 120 180
Breakfast
240 300 0 15 30 60 90 120
Lunch
180
240 300
0 15 30 60 90 120 180
240 300 min
Dinner
P<0.05 vs. vildagliptin group, Plasma levels during 24-h sampling comprising three standardized meals after 3 months of
treatment in type 2 diabetic patients.
Marfella R et al. J Diabetes Complications. 2009 doi:10.1016 (in Press)
9
Higher suppress Plasma Levels of Glucagon with
Vildagliptin versus Sitagliptin
Vildagliptin 50 mg bid
+ metformin
Plasma glucagon (mg/dl)
90
Sitagliptin 100 mg qd
+ metformin
80
70
60
50
40
30
20
0
Breakfast
300 0
min
Lunch
300
min
0
300 min
Dinner
P<0.05 vs. vildagliptin group, Plasma levels during 24-h sampling comprising three standardized meals after
3 months of treatment in type 2 diabetic patients.
Marfella R et al. J Diabetes Complications. 2009 doi:10.1016 (in Press)
10
The rational for the stabilized DPP-4 inhibition
over daily period
- The difference of binding kinetics provided that
Vildagliptin is tight binding to DPP-4 enzyme with high affinity and posses slow
dissociation rate (t1/2 for dissociation = 55 min) resulting in the more stabilized DPP-4
inhibition (~ 97% inhibition over a daily basis)1
Vildagliptin:
(slow tightbinding
substrate)
K1
+
Vildagliptin
K −1
DPP-4
K2
+
Very
slow
Vildagliptin:
DPP-4 complex
DPP-4
Inactive
vildagliptin
Sitagliptin is binding to DPP-4 enzyme with high affinity but does not have slow
dissociation resulting in fast binding and fast dissociation (~ 80% inhibition over daily
basis)2
Sitagliptin
+
DPP-4
1
Mari et al, 2005 J Clin Endoclin Metab 90: 4888-4894
K1
K2
K −1
fast
Sitagliptin:
DPP-4 complex
2
+
Inactive
Sitagliptin
DPP-4
Herman et al. 2006 J Clin Endoclin Metab 91 : 4612-4619
11
Conclusion
12
Only H2H study between vilda vs. sita
Galvus stronger efficacy in 4 dimension:
1. Glucagon suppression
2. GLP-1 raising
3. MAGE reduction
4. DPP-4 activity inhibition during 24 hrs
Differentiate Galvus as Best-in-class efficacy to support -1.1% A1C
reduction message.
13
14
15