Dr. Fermizet Rudy, Sp. PD

8/11/2019 Dr. Fermizet Rudy, Sp. PD

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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

Dr. Fermizet Rudy, Sp. PD

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