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Diabetes Comprehensive T2DM Managementand the role of
Saxagliptin as an add on to achievecomprehensive glycemic control
Fermizet Rudy SpPD FINASIM
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Overview
1. Multiple Factors Contribute to T2DM
2. The Glucose Triad3. DPP-4 Inhibitors: Place in Therapy4. DPP-4 Inhibitors: Role of Saxagliptin
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1. Multiple FactorsContribute to T2DM
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The Ominous Octet
Islet b-cell
Decreased
GlucoseUptake
Islet a -cell
Increased
GlucagonSecretion
IncreasedLipolysis
Increased
GlucoseReabsorption
IncreasedHGP
DecreasedIncretin EffectImpaired
Insulin Secretion
Neurotransmitter Dysfunction
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2. Comprehensive Glycemic Control
THE GLUCOSE TRIAD
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PostprandialGlucose
+
FPG influenced by: Hepatic glucose
production Hepatic sensitivity
to insulin
PPG influenced by: Pre-prandial glucose Glucose load from meal Incretin level Insulin secretion Insulin sensitivity in
peripheral tissues
1. IDF. Guideline for Management of Postmeal Glucose. Available at: http://www.idf.org/webdata/docs/Guideline_PMG_final.pdf. Accessed Jul 26,2010.
2. WoerleHJ et al . Diabetes Res Clin Pract. 2007;77:280-285.3. Drucker DJ. Cell Metab . 2006;3:153-165.
Achieving A1C Target Requires Action onBoth FPG and PPG
FastingGlucose A1C
=
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Treatment decisions to controlhyperglycaemia should consider guidelines
on PPG and FPG 1-3Glycaemic targets for the management of patients withtype 2 diabetes as recommended by various organisations 2-4
Targeting both postmeal plasma glucose and fasting plasma glucose is an importantstrategy for achieving optimal glycaemic control 3
1. Monnier L, et al. Diabetes Metab. 2006;32:2S11-16. 2. ADA. Diabetes Care. 2012;35(S1): 11-63 3. IDF. International Diabetes Foundation.Guidelines for Postmeal Glucose. Available at: http://www.idf.org/webdata/docs/Guideline_PMG_final.pdf. Accessed 26 Jan 2009 . 4. AACE.
American College of Endocrinology. Endocr Pract. 2007; 13 (Suppl. 1):3-68. 5. PERKENI Konsensus Pengelolaan dan Pencegahan DiabetesMellitus Tipe 2 di Indonesia 2011
OrganisasiHbA1c
(%)PPG
(mg/dL)FPG
(mg/dL)
ADA 2
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What the Different Measures Tell Us A1C 1
Measures mean glycemia (past 3-4 months) Reflects risk for T2DM complications
Different glucose profiles can result in similar A1C values 2
FPG and PPG measures allow for daily glucose variations to be
assessed
1. Sacks DB et al. Clin Chem . 2002;48:436-472.
2. Del Prato S. Int J Obes Relat Metab Disord . 2002;26(suppl 3):S9-17. Permission for figure requested.
P l a s m
a G l u c o s e
Time
A1C7.5%
P l a s m
a G l u c o s e
Time
A1C7.5%
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Evolving Paradigm for Glycemic Control
Historical Paradigm 1
Many patients had baseline A1c levels >9.0%
PPG had modest contributionon A1c at these elevatedlevels
Therefore, therapy focused on
lowering FPG
Todays Paradigm
Goals more stringent(A1c 7.0) 2-4
Many patients have high PPGeven when A1c is satisfactory 5
Of patients diagnosed withT2DM based on elevatedPPG,1/3 have normal FPG 6
PPG in addition to FPG + A1c has become an importantgoal of therapy 3
1. Monnier L et al. Diabetes Metab 2006;32:2511-2516.2. Nathan DM et al. Diabetes Care . 2009;32:193-203
3. Rodbard HW et al. Endocr Pract. 2009;15:540-559.
4. CDA. Can J Diabetes. 2008;32(suppl 1):S29-S31.5. Bonora E et al. Diabetes Care . 2001;24:2023-2029.6. Leiter LA et al. Clin Ther. 2005;27 (suppl B):S42-S56.
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PPG Provides Greater Contribution to A1C inPatients With Lower Baseline A1C Levels
Reproduced from Peter R et al. Diabet Med . 2009;26:974-98 with permission from John Wiley & Sons Inc.
8.0% 8.0%
PPG FPG
2.5
2
1.5
1
0.5
0
3
E x c e s s
A 1 C
, % P =.335 P =.16
P =.003
P
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PPG and FPG Contributionto Overall Hyperglycemia
Postprandial glycemic excursion is a major contributor to A1c,particularly in patients with mild or moderate hyperglycemia(A1c
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Baseline
Time of Day, Hours
Breakfast
Daytime GlucoseNocturnal
Glucose Lunch Dinner
G l u c o s e
C o n c e n
t r a t i o n ,
m m o
l / L
2 4 6 8 10 12 14 240 16 18 20 22
7
9
11
13
15
5
PPG PPG PPG
Adapted from Monnier L et al. Diabetes Care . 2007;30:263-269 with permission from the American Diabetes Association.
24-Hour Glucose Profile in Patients With T2DMWith A1C 7 7.9% (n=32)
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Achieving A1C Goal Requires PPGControl
Woerle HJ et al. Diabetes Res Clin Pract . 2007;77:280-285.
PPG
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> on r u es o rea er ay ongGlycemia
Reproduced from Woerle HJ et al. Diabetes Res Clin Pract . 2007;77:280-285 with permission from Elsevier.
100
120
140
160
180
200
220
m g / d L
6 8 10 12 14 16 18 20 22 24Hours
A1C 7% A1C 7%
N=44N=120
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Comprehensive glycaemic managementdepends on all three components of the
glucose triad1
The glucose triad
1. Monnier L, et al. JAMA. 2006;295:1681-7.
Comprehensive Glycaemic Control
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ADA-EASD Position Statement:
Management of Hyperglycemia in T2DM
Patient-Centered Approach... providing care that is respectful of and responsive toindividual patient preferences, needs, and values - ensuring
that patient values guide all clinical decisions.
Inzucchi SE et al. Diabetes Care 2012;35:1364-1379
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The Role of GLP1
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Initial drug monotherapy
ADA/EASD Position Statement
Reprinted with permission from Inzucchi SE et al. Diabetes Care. 2012;35:1364-1379. Copyright 2012 American Diabetes Association. All rights reserved.
Combination therapy:2 drugs
Efficacy ( A1C)HypoglycemiaWeightSide effectsCosts
More-complexinsulin strategies
Combination therapy:3 drugs
Efficacy ( A1C)HypoglycemiaWeightSide effectsCosts
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Combination Therapy Is Often Necessaryto Achieve Glycemic Control
Because of the progressive nature of T2DM,combination therapy often is necessary toachieve glycemic control 1
A substudy of UKPDS found that- after 3 years, ~55% of patients needed >1agent to achieve A1C
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DPP-4 Inhibitors for Glycemic Control Rationale
Targets FPG and PPG via a glucose-dependantmechanism of action 1,2
May be more effective than traditional agents inpatients with mild or moderate hyperglycemia(A1C
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Glucose-Dependant MOA of DPP-4 InhibitorsComplementary to Other OADs
TraditionalOral Agent
Glucose-Lowering
Effect A1C ReductionAddition of DPP-4
Inhibitor
Complementary Action
MET FPG Up to 2%
Enhance suppression of
hepatic glucose outputRestore meal-related insulinsecretion and improve PPG
TZDs FPG, lessereffect on PPG Up to 2%Restore meal-related insulinsecretion and improve PPG
SUs FPG, lesser
effect on PPGUp to 1.5% Restore meal-related insulin
secretion and improve PPG
Adapted from Bode BW. Postgrad Med. 2009;121:82-93 with permission from JTE Multimedia, LLC.
DPP-4, dipeptidyl peptidase-4; FPG, fasting plasma glucose; MET, metformin; MOA, mechanism of action; OAD, oralantidiabetic agent; PPG, postprandial glucose; TZD, thiazolidinedione.
l f h i S
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Role of the Incretin Systemin Glucose Homeostasis
DPP=dipeptidyl peptidase; GLP=glucagon-like peptide;GIP=gastric inhibitory peptide.
Adapted with permission from Drucker DJ et al. Cell Metab . 2006;3:153-165.
Betacells
Alphacells
Enhanced incretin release
+ -
Bloodglucose
homeostasis
Incretins (GLP-1 and GIP)released throughout the day
Effect of incretins
Increasedinsulin
Decreasedglucagon
Pancreas
GI tract
Liver Muscle
Decreasedglucose outputby liver
Increasedglucoseuptake bymuscles
DPP4
enzymesrapidly
degradeincretins
Caloric intake
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DPP-4 Inhibitors Comparison to Other OralAgents (Efficacy)
Phung OJ et al. JAMA. 2010;303:1410-1418.
% Change in A1CAdd-on Therapy to METvs Add-on Placebo No. of Trials WMD (95% CI)DPP-4 inhibitors 8 0.79 ( 0.94 to 0.63)
Incretin mimetics 2 0.99 ( 1.19 to 0.78)
TZDs 3 1.00 ( 1.62 to 0.38)
SUs 3 0.79 ( 1.15 to 0.43)
AGIs 2 0.65 ( 1.11 to 0.19)
Glinides 2 0.71 ( 1.24 to 0.18)
CI, confidence interval; MET, metformin; WMD, weighted mean difference.
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DPP-4 Inhibitors Comparison to Other OralAgents (Safety)
Phung OJ et al. JAMA. 2010;303:1410-1418. Supplementary Online Content
RR, relative risk; WMD, weighted mean difference.
Overall Hypoglycemia Change in Body Weight, kg
Class vs Placebo
No. of
Trials RR* (95% CI)
No. of
Trials WMD (95% CI)DPP-4 inhibitors 8 0.63 (0.26 to 1.71) 4 0.14 ( 0.94 to 0.63)
Incretin mimetics 2 0.89 (0.22 to 3.96) 2 1.74 ( 3.11 to 0.48)
TZDs 2 0.56 (0.19 to 1.69) 1 2.08 (0.98 to 3.17)
SUs 3 4.57 (2.11 to 11.45) 2 2.06 (1.15 to 2.96)
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4. Comprehensive Glycemic Control
DPP-4 INHIBITORS:ROLE OF SAXAGLIPTIN
S li i M f i P id Si ifi
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Saxagliptin + Metformin Provides SignificantReductions in A1C, FPG, and PPG at Week 24
-22.0
-58.2
1.2
-18.0
-80
-70
-60
-50
-40
-30
-20
-10
0
10
SAXA 5 mg + MET Placebo + MET
*P
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Saxagliptin + Metformin provided sustainedclinically reduction A1C over 102 weeks 1
1. DeFronzo RA, et al. Diabetes Care. 2009;58 (Suppl1): A147, Abstract 547-P55. (Poster presen ted at ADA, June 5 -9 , 2009, New Orleans, LA)
Mean change in A1C from baseline during ST+LTE treatment period (LOCF)
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As add-on to metformin alone, Saxagliptin helps more patientsachieve target A1C compared to placebo plus metformin 1
Percentage of patients reaching A1C
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Saxagliptin + Thiazolidinedione provides significant reductions inA1c, FPG, and PPG at Week 24
-0.9
-0.3
-1.2
-1
-0.8
-0.6
-0.4
-0.2
0
*P < 0.0001 vs placebo + TZD.P < 0.0005 vs placebo + TZD.
SAXA 5 mg + TZD Placebo + TZDA1c, %* FPG, mg/dL PPG, mg/dL*
n = 183 180 185 181 134 127
Baseline Mean 8.4 8.2 162 162
A M
F r o m
B a s e
l i n e ,
%
A M
F r o m
B a s e
l i n e , m
g / d L
1. Hollander P et al. J Clin Endocrinol Metab. 2009;94:4810-4819.
-18,0
-72,0
-3,6
-18,0
-90
-80
-70
-60
-50
-40
-30
-20
-10
0
10
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When added to glitazones alone, Saxagliptin results in significantincreases in the percentage of patients reaching A1C
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Saxagliptin + Sulfonylurea Provides SignificantReductions in A1C, FPG, and PPG at Week 24
-10.0
1.0
-80
-70
-60
-50
-40
-30
-20
-10
0
10
SAXA 5 mg + SU Placebo + SUA1C, %* FPG, mg/dL PPG, mg/dL*
n = 250 264 252 265 202 206
Baseline Mean 8.5 8.4 175 174 315 323
A M
F r o m
B a s e
l i n e ,
%
A M
F r o m
B a s e
l i n e , m
g / d L
*P
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When added to sulphonylureas alone, Saxagliptin results insignificant increases in the percentage of patients reaching A1C
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Low incidence in Hypoglycemia with
Saxagliptin 5 mg
SAXA + MET(N=428)
GLIP + MET(N=430)
Number (%) of patients with ahypoglycemic event 13 (3.0) 156 (36.3)
Difference in proportions vs GLIP + MET
Difference 33.3%
P value
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Combination Therapy With Saxagliptin 5 mgWas Weight Neutral
24 weeks study
Onglyza 5 mg(n) Body weight
changes (kg) 4Placebo(n)
Add-ontherapy
+ Metformin 1191
179
+ Sulfonilurea 2253
267
+ Glitazone 3186
184
-3 -2 -1 0 1 2 3
1. DeFronzo RA, et al. Diabetes Care. 2009;32(9):1649-55.2. Chacra AR et al. Int J Clin Pract. 2009;63:1395-1406.3. Hollander P, et al. J Clin Endocrinol Metab. 2009;94(12):4810-9.4. FDA Briefing Document. April 2009. Available at: http://www.fda.gov/OHRMS/DOCKETS/ac/09/briefing/2009-4422b1-02-Bristol.pdf. Accessed on 7
May 2009.
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% of Patients
SAXA 5 mg Placebo
Add-on therapy and monotherapy * N=882 N=799
Upper respiratory tract infection 7.7 7.6
Urinary tract infection 6.8 6.1
Headache 6.5 5.9
Adverse Reactions Occurring in 5% of Patients:Pooled Data From Clinical Trials
* Data pooled from 5 placebo-controlled trials: 2 monotherapy trials and 1 add-on combination therapy trial with each of the following: metformin,thiazolidinedione, or glyburide; table shows 24-week data regardless of glycemic rescue.
Rosenstock J. Expert Rev Endocrinol Metab 2010; 5(6): 809 - 823.
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Analysis of pooled data from 20 clinical trials in
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Analysis of pooled data from 20 clinical trials inpatient T2DM:Saxagliptin did not increase CV risk
Saxagliptin has the strongest evidence among DPP4-I afterSAVOR results and this ensure that we are giving our patients themost effective and safe medication helping them managing their
diabetes efficientlyIqbal Et al. Cardiovascular Diabetology 2014;13:33
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Summary Comprehensive Glycemic Control
A1C reflects mean long-term glycemic controlElevated FPG, PPG, or both contribute to increased A1C A1C most affected by PPG at A1C
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Saxagliptin Assessment of Vascular OutcomesRecorded in Patients with Diabetes Mellitus
(SAVOR) TIMI 53Deepak L. Bhatt, MD, MPH
On behalf of the SAVOR-TIMI 53Steering Committee and Investigators
European Society of Cardiology, Amsterdam - September 2, 2013
NCT01107886; Funded by AstraZeneca and Bristol-Myers Squibb
TIMI STUDY GROUP / HADASSAH MEDICAL ORG
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For Full Details, Please Go towww.NEJM.org
Scirica BM, Bhatt DL, Braunwald E, et al. Raz I. NEJM 2013 at
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THANK YOU