Vilzap-M -A durable Synergy

Flow of the presentation

• Natural history of Type 2 Diabetes

• Glucose Triad & Diabetes Complications
• Hypoglycemia & Glycemic Variabiliy
• Evolving concept in Diabetes - Gliptins as a Solution
• Comparision of Vildagliptin with Other Existing Gliptins
• Effects of Vildagliptin on Glycemic variability & Hypoglycemia
• Clinical studies of Vildagliptins in Special population
• Conclusion
 Glucose Triad

 This relationship
between HbA1c, FPG
and PPG, plays a central
role in the metabolic
changes central to
T2DM and this triangle
is known as the glucose
triad
 Improved Glycemic Control Has Been
Shown to Reduce the Risk of Complications
Risk reduction with 1% decline in annual mean A1C

P <.0001 P = .035 P = .021 P = .0001

0%
12%
14%
16%
15% 19%

30% 37%
43%

45% Micro-vascular PVD MI Stroke Heart Cataract

Disease Failure Extraction

Stratton IM et al. BMJ. 2000;321:405-412.

 But still, Fewer individuals achieve goals
for HbA1c v/s lipids and blood pressure
80 72% 72%
70
58%
Individuals achieving
treatment goals (%)
60
46%
50

40

30

20 15%

10

0
HbA1c Total Triglycerides Systolic Diastolic
< 6.5% cholesterol < 150 mg/dL BP BP
< 175 mg/dL < 130 mmHg < 80 mmHg

Gaede P, et al. N Engl J Med 2003; 348:383–393.

Intensive Control Works… But at a Price:
DCCT & UKPDS
Severe Hypoglycemia
 Increased Mortality, MI & Hypoglycemia With
Intensive Therapy:
ACCORD Trial

The excess mortality risk was in those patients who failed to

achieve and sustain A1c levels between 6-7%.

Bloomgarden ZT. Diabetes Care. 2008;31(9):1913–1919. 2. Dluhy RG,

McMahon GT. N Engl J Med. 2008;358:2630–2633.
 Hypoglycemia & CV Events:
Pathophysiology

Diabetes Care. 2010; 33(6): 1389–1394.

 Glycemic Variability

HbA1c = 7% BAD
Blood Glucose

HbA1c = 7% GOOD

 Patients with similar mean glucose or HbA1c values can have

markedly different daily glucose profiles, with differences both in
number and duration of glucose excursions.
 Describing Glycemic Variability

 Within day variability

 With difference between fasting & Postprandial blood
glucose values throughout 24 hrs
 Between day variability
 Reflecting difference in blood glucose control day to day
Schematic view of the four domains of
blood glucose control

Crit Care. 2012 Nov 21;16(6):178

 Thrombosis
Oxidative stress
Mild chronic inflammation Endothelial
dysfunction

Peak Peak Peak

Blood glucose

Breakfast Lunch Dinner

 Glucose Variability is the New Enemy

Author's Conclusion
• Factors other than average blood glucose may contribute to
development of diabetic complications
• May be Glycemic fluctuations

Kilpatrick ES, et al Diabetes Care. 2009; 32(10): 1901–1903.

 The evolving concept in Diabetes
management
The Glycemic Triad The Glycemic Composite
Gliptins can addresses all the
aspects of the glycemic
composite
 Gliptins: Mechanism of Action
Ingestion of
food Glucose dependent
 Insulin Insulin
from beta cells increases
(GLP-1 and GIP)
peripheral
glucose
GI tract Release of Pancreas uptake
incretins from
the gut
β-cells
α-cells Improved Physiologic
Hyperglycemia
Glucose Control

X
DPP-4
Enzyme Glucagon
↑insulin and
↓glucagon
from alpha cells reduce hepatic
Gliptins (GLP-1) glucose
Glucose dependent output
Inactive
incretins DPP-4 = dipeptidyl peptidase 4

Adapted from Brubaker PL, Drucker DJ Endocrinology 2004;145:2653–2659; Zander M et al Lancet 2002;359:824–830; Ahrén B Curr Diab Rep 2003;3:365–372; Buse JB et al.
In Williams Textbook of Endocrinology. 10th ed. Philadelphia, Saunders, 2003:1427–1483.
 Clin Ther. 2012;34:1247–1258

 This meta-analysis was performed to compare the efficacy of different

incretin-based therapies.

 Studies of DPP-4 inhibitors as well as GLP-1 analogs were included if they

were randomized controlled trials of 12-52 weeks’ duration and having
change from baseline HbA1c as the primary end point.
 Results: Change in HbA1c from Baseline

 Vildagliptin showed the highest change in HbA1c from

baseline as compared to alogliptin, linagliptin, saxagliptin &
sitagliptin

Clin Ther. 2012;34:1247–1258

Vildagliptin vs Other DPP4 inhibitors as
Add-on to Metformin
% HbA1c reduction

John Gerich, Diabetes Research & Clinical practice 90 (2010) 131-140

 24-Hour DPP- 4 inhibition with Gliptins

≥80% DPP4 inhibition?

Vildagliptin 100 mg/day Yes

Sitagliptin Yes

Saxagliptin ~70%

Linagliptin Yes
Reference: Scheen etal, Expert Opin Pharmacother (2012) 13(1): 81-99
Roberta Baetta and Alberto Corsini , Drugs 2011; 71 (11): 1441-1467

Data not from the same study, only for overview

24-hours DPP4 inhibition1

Teneligliptin 20 mg 53.9
Teneligliptin 40 mg 59.8% 21
1. PMDA - Report on the Deliberation Results: Review Report – Teneligliptin Hydrobromide Hydrate.
Submitted by Mitsubishi Tanabe Pharma Corporation. Published on April 5, 2012
Absolute HbA1c reduction at different FPG levels
with DPP-4 inhibitors
FPG 150
Vildagl Alogli Sitagli Saxagli Linagli
A1c iptin ptin ptin ptin ptin
7.6 -0.86 -0.79 -0.74 -0.65 -0.48
7.8 -0.92 -0.88 -0.83 -0.74 -0.59
8.0 -1.06 -0.96 -0.92 -0.84 -0.68
8.2 -1.16 -1.06 -1.01 -0.94 -0.77
8.4 -1.24 -1.16 -1.1 -1.03 -0.86
8.6 -1.34 -1.26 -1.21 -1.12 -0.96
8.8 -1.42 -1.35 -1.31 -1.23 -1.06
FPG 160
Vildagl Alogli Sitagli Saxagli Linagli
A1c iptin ptin ptin ptin ptin
7.6 -0.76 -0.69 -0.64 -0.55 -0.38
7.8 -0.82 -0.78 -0.73 -0.64 -0.49
8.0 -0.96 -0.86 -0.82 -0.74 -0.58
8.2 -1.06 -0.96 -0.91 -0.84 -0.67
8.4 -1.14 -1.06 -1 -0.93 -0.76
8.6 -1.24 -1.16 -1.11 -1.02 -0.86
8.8 -1.32 -1.25 -1.21 -1.13 -0.96
FPG 170
Vildagl Alogli Sitagli Saxagli Linagli
A1c iptin ptin ptin ptin ptin
7.6 -0.66 -0.59 -0.54 -0.45 -0.28
7.8 -0.72 -0.68 -0.63 -0.54 -0.39
8.0 -0.86 -0.76 -0.72 -0.64 -0.48
8.2 -0.96 -0.86 -0.81 -0.74 -0.57
8.4 -1.04 -0.96 -0.9 -0.83 -0.66
8.6 -1.14 -1.06 -1.01 -0.92 -0.76
8.8 -1.22 -1.15 -1.11 -1.03 -0.86

FPG 180
Vildagli Alogli Sitagli Saxagli Linagli
A1c ptin ptin ptin ptin ptin
A1c iptin ptin ptin ptin ptin
7.6 -0.56 -0.49 -0.44 -0.35 -0.18
7.8 -0.62 -0.58 -0.53 -0.44 -0.29
8.0 -0.76 -0.66 -0.62 -0.54 -0.38
8.2 -0.86 -0.76 -0.71 -0.64 -0.47
8.4 -0.94 -0.86 -0.8 -0.73 -0.56
8.6 -1.04 -0.96 -0.91 -0.82 -0.66
8.8 -1.12 -1.05 -1.01 -0.93 -0.76
FPG 190
Vildagl Alogli Sitagli Saxagli Linagli
7.6 -0.46 -0.39 -0.34 -0.25 -0.08
7.8 -0.52 -0.48 -0.43 -0.34 -0.19
8.0 -0.66 -0.56 -0.52 -0.44 -0.28
8.2 -0.76 -0.66 -0.61 -0.54 -0.37
8.4 -0.84 -0.76 -0.7 -0.63 -0.46
8.6 -0.94 -0.86 -0.81 -0.72 -0.56
8.8 -1.02 -0.95 -0.91 -0.83 -0.66

Reduction with Vildagliptin is highest across all baseline

of HbA1c & FPG BMJ Open 2015;5:e005892.
Vildagliptin & Glycemic Variability
 CSGM shows large Mean amplitude of Glycemic excursion (MAGE) decrements in
the vildagliptin group compared with the sitagliptin group (P<0.01).

 A marked increase in GLP-1 occurred during interprandial period in vildagliptin

bid-treated toward sitagliptin 100 mg once daily (P<0.01).
J Diabetes Complications. 2010;24(2):79-83. 
 Results…

 Glucagon was more suppressed during interprandial period in subjects

receiving vildagliptin compared to those receiving sitagliptin (P<0.01).

Vildagliptin targets not only in reducing HbA1c, PPG, and mean hyperglycemia
but also flattening acute glucose fluctuations over a daily period.

J Diabetes Complications. 2010;24(2):79-83. 
Vildagliptin & Hypoglycemia
 Vildagliptin & Low Risk of Hypoglycemia

 Clinical evidence has shown that vildagliptin caused fewer hypoglycemic events
than insulin secretagogues, no matter of whether it was used as a monotherapy
or combined with other agents.

 Active GLP-1 and GIP concentrations are increased two- to threefold by

vildagliptin, lowering blood sugar in a glucose-dependent way after a meal,
which contributes to the low risk of hypoglycemia.

 Furthermore, vildagliptin not only suppresses inappropriate glucagon secretion

in response to glucose or mixed meals, but also enhances α-cell responsiveness
to the stimulatory effect of hypoglycemia

Ther Clin Risk Manag. 2013;9:247-57. 

 Vildagliptin improves α-cell sensitivity
thus reducing hypoglycemia

The bifunctional effect on glucagon by vildagliptin can explain the low risk
of hypoglycemia when glycemic control is achieved.

Ther Clin Risk Manag. 2013;9:247-57. 

 CV Trials with Gliptins
Gliptin Study name RR (95% CI) for RR (95% CI) for
MACE HF

Sitagliptin TECOS 1 [0.908 - 1.101] 0.997 [0.832;

1.194]

Saxagliptin SAVOR-TIMI-53 0.998[0.896 - 1.112] 1.257 [1.060;

1.491]

Alogliptin EXAMINE 0.957 [0.826 - 1.110] 1.067 [0.789;

1.443]

Vildagliptin McInnes G. et al 0.82 (0.61-1.11) 1.08 (0.68-1.70)

2015 (Meta-analysis of 40
studies)
Schweizer A, et al. (Meta- 0.84 (0.62–1.14) -
analysis of 25 studies)
Bekiari et al. (Meta-analysis 0.91 (0.73 to 1.14) 0.77 (0.46-
of 9 studies) 1.30)

Teneligliptin No data available - -

 Prescribing Information – Vildagliptin ; Saxagliptin & Sitagliptin, Linagliptin

Safety of Vildagliptin vs other DPP4

inhibitors in Renal Impairment

Vildagliptin may have a cost benefit in moderate /severe renal impairment

139 elderly patients each to the
vildagliptin and placebo groups.
37 (27%) patients in the placebo
and 72 (52.6%) patients in the

Vildagliptin group achieved their

target A1c (set target was <7%)

The overall safety and tolerability

was similar in the vildagliptin and
placebo groups, with low incidence
of hypoglycaemia and no
emergence of new safety signals.

Lancet 2013; 382: 409–16

 Safety in Elderly patients

Indian label for vildagliptin –

• In patients treated with Vildagliptin ≥ 65 years of age and ≥ 75 years of age, no

differences were observed in the overall safety, tolerability, or efficacy between this elderly
population and younger patients.
• No dosage adjustments are therefore necessary in the elderly patients

India Package Insert (vildagliptin), dated 27May 2011 based on global IPL dated 29 April 2011
 Conclusion

 The optimal glycemic control equation includes HbA1c, FPG & PPG control, along with
avoidance of hypoglycemia & glycemic variability: The Glycemic Composite
 Among the available drugs in its class, vildagliptin is a potent, highly selective, and
reversible DPP-4 inhibitor
 Significant HbA1c reduction as compared to sitagliptin with a higher control over FPG
 Demonstrates better control over glucose fluctuations & thus reduces glycemic
variability due to its effect on basal hyperglycemia
 Can be used extensively in renally impaired as well as in elderly patients