ueda2012 dpp4 inhibitors-d.lobna

At clinical crossroads:

DPP4 Inhibitors

Lobna F El toony

Head Of Diabetes & Endocrinology Unit

Internal Medicine Department Assuit

University

UEDA – Aswan 2012

Growth of Diabetes Prevalence Worldwide

Adapted from WHO. Available at: http://www.who.int/dietphysicalactivity/publications/facts/diabetes/en/print.html.

Accessed February 6, 2009.

Peo

ple

wit

h d

iab

ete

s (

mil

lio

ns)

0

100

200

400

1985

300

Year

1995 2000 2030 (projected)

Prevalence (%) estimates of diabetes (20-79 years), 2010

Middle East and North African Region

http://www.google.com/imgres?imgurl=http://www.sceptertravel.com/images/egypt-flag.jpg&imgrefurl=http://www.sceptertravel.com/aboutegypt.html&h=320&w=400&sz=19&tbnid=dUi1r_RmLtkbWM:&tbnh=99&tbnw=124&prev=/search%3Fq%3DEgypt%2BFlag%2BPhoto%26tbm%3Disch%26tbo%3Du&zoom=1&q=Egypt+Flag+Photo&hl=en&usg=__QB7_smEqZq3irj3mZFWYpXfFH6Y=&sa=X&ei=tmSfTv_eF4boOcOsmaYF&ved=0CBkQ9QEwAg

Number of people with diabetes (20-79 years), 2010 and

2030

Act Now ……

Early Detection & Early and accurate Intervention

8

The Incretin Defect in Type 2 Diabetes

Insulin

Resistance

Incretin

“Defect”

Relative Insulin

Deficiency

Hyperglycemia

Type 2 Diabetes

Incretin effect accounts for up to 70% of the insulin response to oral glucose

intake1

1. Holst JJ, Gromada J. Role of incretin hormones in the regulation of insulin secretion in diabetic and nondiabetic humans. Am J Physiol Endocrinol Metab. 2004;287(2):E199-E206.

• Goals should be individualized based on

–Duration of diabetes

–Age/life expectancy

–Comorbid conditions

–Known CVD or advanced microvascular complications

–Hypoglycemia unawareness

Glycemic Recommendations for Adults with Diabetes

ADA. V. Diabetes Care. Diabetes Care 2011;34(suppl 1):S21. Table 10.

Earlier and Appropriate Intervention May

Improve Patients’ Chances of Reaching

Goal

OAD=oral antidiabetic agent. Adapted from Del Prato S et al. Int J Clin Pract. 2005;59(11):1345–1355. Copyright © 2005. Adapted with permission of Blackwell Publishing Ltd.

Published Conceptual Approach

Hb

A1c

Go

al

Mean HbA1c

of patients Duration of Diabetes

OAD

monotherapy

Diet and

exercise

OAD

combination

OAD

up-titration

OAD +

multiple daily

insulin

injections

OAD +

basal insulin

Conventional stepwise treatment approach

Earlier and more aggressive intervention approach

6

7

8

9

10

Glycemic Recommendations for Adults with Diabetes

A1C

<7.0%*

Preprandial capillary plasma

glucose

70–130 mg/dl*

Peak postprandial capillary

plasma glucose†

<180 mg/dl*

*Postprandial glucose measurements should be made 1–2 h after the beginning of the meal, generally peak levels in patients with diabetes.

ADA. V. Diabetes Care. Diabetes Care 2011;34(suppl 1):S21. Table 10.

Primary sites of action of oral

antidiabetic agents

Glucose

output

Insulin resistance

Biguanides

Insulin

secretion

Sulfonylureas/

meglitinides

Carbohydrate

breakdown/

absorption

-glucosidase

inhibitors

Insulin

resistance

Thiazolidinediones

Kobayashi M. Diabetes Obes Metab 1999; 1 (Suppl. 1):S32–S40.

Nattrass M & Bailey CJ. Baillieres Best Pract Res Clin Endocrinol Metab 1999; 13:309–329.

Incretins Modulate Insulin and Glucagon to

Decrease Blood Glucose During Hyperglycemia

GLP-1=glucagon-like peptide-1; GIP=glucose-dependent insulinotropic polypeptide. Brubaker PL et al. Endocrinology 2004;145:2653–2659; Zander M et al. Lancet 2002;359:824–930; Ahren B. Curr Diab Rep 2003;3:365–372; Buse JB et al. In: Williams Textbook of Endocrinology,11th ed. Philadelphia: Saunders; 2008:1329–1389; Drucker DJ. Diabetes Care 2003;26:2929–2940.

Incretin hormones GLP-1 and GIP are released by the intestine throughout the day;

their levels increase in response to a meal.

Release of

active incretins

GLP-1 and GIPa

Blood glucose in

fasting and

postprandial states

Ingestion

of food

Glucagon

from alpha cells

(GLP-1)

Hepatic

glucose

production

GI tract

DPP-4

enzyme

Inactive

GLP-1

Insulin from

beta cells

(GLP-1 and GIP)

Glucose-dependent

Glucose-dependent

Pancreas

Inactive

GIP

Beta cells

Alpha cells

Peripheral

glucose

uptake

Sitagliptin improves

beta-cell function

and increases insulin

synthesis and

release.1

Sitagliptin reduces HGO through

suppression of glucagon from alpha

cells.2 Metformin decreases HGO by

targeting the liver to decrease

gluconeogenesis and

glycogenolysis.4

Metformin has insulin-

sensitizing properties.3–5

(Liver > Muscle, fat)

Beta-Cell Dysfunction

Hepatic Glucose Overproduction (HGO)

Insulin Resistance

1. Aschner P et al. Diabetes Care. 2006;29(12):2632–2637. 2. Data on file. 3. Abbasi F et al. Diabetes Care. 1998;21(8):1301–1305. 4. Kirpichnikov D et al. Ann Intern Med. 2002;137(1):25–33. 5. Zhou G et al. J Clin Invest. 2001;108(8):1167–1174.

Sitagliptin and Metformin Target the Core

Metabolic Defects of Type 2 Diabetes

Glycemic Control Algorithm, Endocr Pract. 2009;15(No. 6 540-559)

N

N

N

N

N

N

N

O

O

NH2

Linagliptin

Vildagliptin

N

O

N

N H

O H

N

N N

N

N

O

O

Alogliptin

Sitagliptin

F

F F O

F F

F

NH2

N

N N

N

DPP-4 Inhibitors Differ Chemically

Saxagliptin

N

O

OH

NH2

18

H740

S630

Y547

F357

S209

R358

E205

E206

R125

H126

1. Data on file, MSD.

Sitagliptin is Highly Selective & fit for DPP4

Site

DPP-4=dipeptidyl peptidase-4.

Yellow: sitagliptin

Green: vildagliptin

DPP-4 Inhibitors Have Different Durations of Action

% Plasma DPP-4 inhibition

Vildagliptin

40

100

80

0

60

20

Placebo

Saxagliptin (5 mg qd)

Saxagliptin

Adapted from Boulton et al

Poster 0606-P; ADA 2007

40

100

80

0

60

20

Placebo

Alogliptin (25 mg qd)

Day 14

-20

Covington et al,

Clin Ther 2008

40

100

80

0

60

20

Placebo

Linagliptin (5 mg qd)

Day 12

Heise et al,

Diab Obes Metab 2009

% Plasma DPP-4 inhibition

0 4 8 12 16 20 24 Time (hr)

Alogliptin

Linagliptin

Sitagliptin Bergman et al, Clin Ther 2006

Day 10

Sitagliptin (100 mg qd)

Placebo

0 4 8 12 16 20 24 Time (hr)

0

20

40

60

80

100

Nb: No direct comparisons of degree of inhibition

attained by different inhibitors

Adapted from He et al

J Clin Pharmacol 2007

100

80

60

40

20

0

Day 1

Vilda (50 mg)

Placebo

Vilda (100 mg)

Sitagliptin is a different molecule

Sitagliptin Vildagliptin

Molecular structure

Half Life (T1/2) 12.4 hrs 2-3 hrs

DPP-4 Inhibition* post 24 hrs 100mg QD 80-97% @ 24hrs 50 mg QD: 20% @ 24 hrs

50 mg BID: >80% @ 12hrs

DPP-4 Peak Inhibition ~97% ~95%

Selectivity for DPP-IV vs. DPP-8/DPP-9* 2600 fold for DPP4 vs. DPP-8

10,000 fold for DPP4 vs. DPP-9

270 fold for DPP4 vs. DPP-8

32 fold for DPP4 vs. DPP-9

Metabolism ~16% metabolized

69% metabolized

mainly renal

(inactive metabolite)

Bioavailability ~87% 85%

Liver Monitoring NO YES

Elimination Kidney (87%)

79% mostly unchanged

Kidney (85%)

23% unchanged

Liver (15%)

FDA YES NO

* All use different proprietary assays with different dilutions and therefore % DPP-4 inhibition cannot be compared across assays

H O

N H

O

N

N C

F

F

F O N

N H 2

N N N

C F 3

Data on file, MSD

• Hypoglycaemia

•Weigh gain Macrovascular

&

Microvascular

Risk Reduction

Tight Glycaemic

control

Efficacy and Safety of Treatment With

Sitagliptin or Glimepiride in Patients With

Type 2 Diabetes Inadequately Controlled

on Metformin Monotherapy

Diabetes Obes Metab. 2011

23

Efficacy: HbA1c reduction

“Addition of Sitagliptin or Glimepiride in Patients Inadequately Controlled on Metformin“

Arechavaleta R et al. Diabetes Obes Metab -2011

Week 30

Addition of Sitagliptin or Glimepiride in Patients Inadequately Controlled on

Metformin:

Study Design1

Continue stable dose of metformin

Single-blind Placebo Run-in

Double-blind Treatment Period

Week –2 Day 1

Patients ≥18 years of age with T2DM on stable dose of metformin (≥1500 mg/day) for ≥12 weeks and HbA1c 6.5%– 9.0%

Glimepiride (n=519)

(started at 1 mg qd and up-titrated until week 18 as needed up to maximum dose of 6 mg qd)

qd=once daily; R=randomization; T2DM=type 2 diabetes mellitus.

1. Arechavaleta R et al. Diabetes Obes Metab. 2011;13(2):160–168.

Sitagliptin 100 mg qd (n=516)

Week –4

R

Screening Period

HbA1c-Lowering Efficacy of Sitagliptin at

Week 30 Was Noninferior to That of

Glimepiride in Patients Inadequately Controlled

on Metformin1

LS=least squares; SE=standard error.

aMean dose of glimepiride (following the 18-week titration period) was 2.1 mg per day.


Week

LS

Mean

(±

SE

) H

bA

1c,

%

Per-Protocol Population

6.0

6.2

6.4

6.6

6.8

7.0

7.2

7.4

7.6

7.8

8.0

0 6 12 18 24 30

(95% CI)

0.07% (–0.03, 0.16)

Sitagliptin 100 mg + metformin (n=443)

Glimepiridea + metformin (n=436)

–0.47

–0.54

Adapted from T. Secket al. Int J Clin Pract, April 2010, 64, 5, 562–576.

Two Years extension Data

HbA1c With Sitagliptin or Glipizide as Add-on Combination With Metformin:

Comparable Efficacy

HbA1C

FPG

Add-on Sitagliptin With Metformina vs Glipizide With Metformin Study

aSitagliptin (100 mg/day) with metformin (≥1500 mg/day).

Initial Fixed-Dose Combination Therapy With JANUMET™ vs

Metformin Monotherapy: Change from Baseline in HbA1c by

Baseline HbA1c at Week 18

FAS=full analysis set; FDC=fixed-dose combination.

1. Reasner C et al. Poster presented at: American Diabetes Association 69th Scientific Sessions. New Orleans, LA. June 5–9, 2009.

2. Data on file, MSD.

Hb

A1

c L

S M

ean

Ch

an

ge

fro

m B

aseli

ne,

%

Baseline HbA1c,% <8 ≥8 and <9 ≥9 and <10 ≥10 and <11 ≥11 FAS (Week 18)

P=0.009

P<0.001

P<0.001

Mean HbA1c,% 7.6 8.4 9.5 9.4 10.4 12.2

n=

–1.1

–1.6

–2.0

–2.9 –2.7

–2.1

–1.7

–1.1

–0.8

–4.0

–3.5

–3.0

–2.5

–2.0

–1.5

–1.0

–0.5

0

Sitagliptin/metformin FDC

Metformin

99 95 99 111 87 101 124 109 150 148

P=0.158

P=0.111

–3.6

28

Safety Of The Drug

Hypoglycemic events

Addition of Sitagliptin or Glimepiride in Patients

Inadequately Controlled on Metformin: Clinical

Assessment of Hypoglycemia Over 30 Weeks1

APaT Population

APaT=all patients as treated; CI=confidence interval.

aMean dose of glimepiride (following the 18-week titration period) was 2.1 mg per day.


7

22

0

5

10

15

20

25

Patients

With ≥

1

Hypogly

cem

ic E

pis

ode,

%

(95% CI)

–15.0% (–19.3, –10.9)

(P<0.001)

Sitagliptin 100 mg + metformin (n=516)

Glimepiridea + metformin (n=518)

30

Sitagliptin With Metformin Provided Much

Lower Incidence of Hypoglycemia

aSitagliptin (100 mg/day) with metformin (≥1500 mg/day); bAll-patients-as-treated population.

Least squares mean between-group difference at Week 52 (95% CI): change in body weight = –2.5 kg [–3.1, –2.0] (P<0.001);

Least squares mean change from baseline at week 52: glipizide: +1.1 kg; sitagliptin: –1.5 kg (P<0.001).

Adapted from Nauck et al. Diabetes Obes Metab. 2007;9:194–205.

Hypoglycemiab

P<0.001

32%

5%

0

10

20

30

40

50

Week 52

% o

f P

atie

nts

With

≥ O

ne

Ep

iso

de

Sulfonylurea + metformin (n=584)

Sitagliptin + metformin (n=588)

Add-on Sitagliptin With Metformina vs Glipizideb With Metformin Study

31

Vicious circle of hypoglycemia awareness

Hypoglycemic

events

lead

hypoglycaemic

events

Frequent hypoglycemias

<60 mg/dl

Adapted from Hermanns et al. Diabetologie 2009; 4: R 93-R112

Symptoms of hypoglycemia:

- weaker

- appear later

- change

Awareness of hypoglycemia:

- more difficult

- less reliable

32

Complications and Effects of Severe

Hypoglycemia

Plasma glucose level

10

20

30

40

50

60

70

80

90

100

110

1

2

3

4

5

6

mg/dL

mmol/L

1. Landstedt-Hallin L et al. J Intern Med. 1999;246:299–307.

2. Cryer PE. J Clin Invest. 2007;117(4):868–870.

Increased Risk of

Cardiac Arrhythmia1

Progressive

Neuroglycopenia2

Abnormal prolonged

cardiac

repolarization—

↑ QTc and QTd

Sudden death

Cognitive impairment

Unusual behavior

Seizure

Coma

Brain death

33

Severe Hypoglycemia Causes QTc

Prolongation

P=NS

P=0.0003

Landstedt-Hallin L et al. J Intern Med. 1999;246:299–307.

Euglycemic clamp (n=8)

Hypoglycemic clamp

2 weeks after glibenclamide withdrawal

(n=13)

0

360

370

380

390

400

410

420

430

440

450

Me

an

QT

in

terv

al,

ms

Baseline (t=0)

End of clamp (t=150 min) ACCORD?

Significant QTc prolongation

during

hypoglycemia

34

ß-cell:

MoA:

SUs work by closing K+ATP channels

35

Heart: Glibenclamide (K+ATP closer)

leads to QTc prolongation

Najeed SA et al. Am J Cardiol 2002; 90: 1103-1106

36

Weight gain

Safety Of The Drug

37 UKPDS 34. Lancet 1998:352:854–865. n=at baseline;

Change in w

eig

ht

(kg)

Years from randomisation

*diet initially then sulphonylureas, insulin and/or metformin if FPG >15 mmol/l

0

1

5

0 3 6 9 12

8

7

6

4

3

2

Insulin (n=409)

Glibenclamide (n=277)

Metformin (n=342)

Conventional treatment (n=411)*

Insulin

SU

Conv. Met

SU and weight gain (UPKPS 34)

Sitagliptin With Metformin Provided Weight Reduction

(vs Weight Gain)

Add-on Sitagliptin With Metformin vs Glimepride With Metformin Study

LS

Mean C

hange (±

SE

) in

Bo

dy

Weig

ht

Fro

m B

aselin

e,

kg

Week

0 6 12 18 24 30

–1

0

1

2

APaT Population

Sitagliptin 100 mg + metformin

Glimepiridea + metformin

= –2.0 kg

(P<0.001)

–0.8 kgb

1.2 kgb

APaT=all patients as treated; LS=least squares; SE=standard error.

aMean dose of glimepiride (following the 18-week titration period) was 2.1 mg per day. bLS mean body weight change at 30 weeks.


Two Years extension Data- 2010 Sitagliptin With Metformin Provided Weight Reduction

(vs Weight Gain)

Adapted from T. Secket al. Int J Clin Pract, April 2010, 64, 5, 562–576.


aSitagliptin (100 mg/day) with metformin (≥1500 mg/day);

- Blocks +Promotes

Foley JE, et al. Vasc Health Risk Manag. 2010 Aug 9;6:541-8.

DPP-4 inhibitors have weight-neutral effect in T2D patients, either as monotherapy and as add-on therapy to other oral agents

DPP-4 inhibitors

Some medications have a weight-neutral effect

FFA

+ Lipolysis

+ Fat oxidation

Apo B-48 Intestinal TG absorption -

41

Beta-cell function

42

ADOPT: Progressive deterioration of glucose

control

Conclusions

Initial combination of Sitagliptin & Metformin enhanced the responsiveness of pancreatic B cells to glucose in both fasting & post-prandial states.

Initial combination therapy demonstrated greater improvements in B cell function than individual monotherapies.

Improvements in B cell function were maintained over 2 years treatment period.

Diabetes, Obesity and Metabolism 14: 67–76, 2012.

45

Sitagliptin and -cell Mass

Mu J. et al. Eur J Pharm 2009; 623: 148-154

Week

LS

me

an

ch

an

ge

fro

m b

as

elin

e ±

SE

0.05

0.03

0.01

-0.01

-0.03

-0.05

0 24 52

Sitagliptin 100 mg

Glipizide

Per protocol population.

Nauck MA et al. Diabetes Obes Metab 2007;9:194–205.

Data on file, MSD________.

Sitagliptin Lowered and Glipizide Increased

the Proinsulin-to-Insulin Ratio


aSitagliptin (100 mg/day) with metformin (≥1500 mg/day

Effect of Sitagliptin in

Patients With Type 2 Diabetes and Inadequate

Glycemic Control on Insulin Therapy (Alone or

in Combination With Metformin)

Diabetes, Obesity and Metabolism 2010

Addition of Sitagliptin to Insulin Therapy: Study Design

Single-blind placebo run-in

period

• Continue on a stable dose of insulin with or without metformin

• Begin single-blind run-in period

Randomization Week 24

24-Week Stable Insulin Dose Period

QD=daily.


• Patients with type 2 diabetes

• Age >21 years

• Receiving insulin (including glargine, detemir, ultralente, NPH, lente, or premixed insulin) alone or with metformin ≥1500 mg/day

• Not receiving premeal short-acting insulin

• HbA1c ≥7.5% and ≤11%

Placebo (n=319)

Sitagliptin 100 mg QD (n=322)

R

Screening

visit Week –2

0 6 12 18 24

0.1

Addition of Sitagliptin to Insulin Therapy: HbA1c Change From

Baseline Over Time

aBaseline mean HbA1c: 8.72% for sitagliptin, 8.64% for placebo

FAS=full analysis set; LOCF=last observation carried forward; LS=least squares; SE=standard error.


FAS Population (LOCF)

Placeboa

Sitagliptina

Difference = –0.56%

(P<0.001)

Hb

A1

c L

S M

ean

Ch

an

ge

Fro

m B

aselin

e, %

(S

E)

Weeks

0.0

–0.8

–0.7

–0.6

–0.5

–0.4

–0.3

–0.2

–0.1

–0.8

–0.03%

–0.59%

(n=305)

(n=312)

Sitagliptin

Placebo

Addition of Sitagliptin to Insulin Therapy: HbA1c Change From Baseline by

Insulin Type

FAS Population at 24 Weeks (LOCF)a

P-value for treatment by subgroup interaction = 0.949

aExcluding data after initiation of rescue therapy.



Hb

A1

c L

S M

ean

Ch

an

ge

Fro

m B

aselin

e, %

(S

E)

–1.0

0.0

–0.8

–0.6

–0.4

–0.2

Receiving Premixed

Insulin

Receiving Long- or Intermediate-acting

Insulin

–0.58

–0.02

–0.61

–0.04

n=80 n=80

n=225 n=232

P<0.001 P<0.001

Mean baseline HbA1c, % 8.59 8.50 8.76 8.69

Addition of Sitagliptin to Insulin Therapy: HbA1c Change From Baseline by

Metformin Use

Not Receiving Metformin

Receiving Metformin

N=223 N=229

Sitagliptin

Placebo

P-value for treatment by subgroup interaction = 0.437

Hb

A1

c L

S M

ean

Ch

an

ge

Fro

m B

aselin

e, %

(S

E)

–1.0

0.4

–0.8

–0.6

–0.4

–0.2

0.2

0.0

–0.55

0.10

–0.66

–0.13

P<0.001 P<0.001

n=82 n=83 n=223 n=229





Mean baseline HbA1c, % 8.68 8.76 8.73 8.60

Addition of Sitagliptin to Insulin Therapy: Change from

Baseline 2-h PPG and FPG

–18.5

–3.5

–30

–20

–10

0

–30.9

5.2

–60

–40

–20

0

20

LS

Mean

Ch

an

ge

Fro

m

Baseli

ne 2

-h P

PG

, m

g/d

L

LS

Mean

Ch

an

ge F

rom

Baseli

ne F

PG

, m

g/d

L

n=310 n=313

n=240 n=257

Sitagliptin

Placebo


P<0.001

P<0.001


FAS=full analysis set; FPG=fasting plasma glucose; LOCF=last observation carried forward; LS = least squares;

PPG=postprandial glucose.


Mean baseline

PPG, mg/dL 290.9 292.1 Mean baseline

FPG, mg/dL 175.8 179.1

Sitagliptin and Hepatic

Functions

54

Diabetic Patients & Fatty Liver

• In Western countries, the prevalence of

NAFLD in the general population ranges from

15-39% (3,4). Thus, the prevalence of NAFLD

is increasing and the disease is becoming a

major target disease for treatment.

• NAFLD is considered as a hepatic

manifestation of the metabolic syndrome and

is particularly associated with insulin

resistance (IR), obesity, hypertension and

abnormalities of glucose and lipid metabolism

. However, effective drug therapy for NASH

has not been established at present.

Fatty liver among Diabetics …..

Iwasaki, et al. www.hepato-gastroenterology.org

DOI 10.5754/hge11263

2011; 58(112): Ahead of print.

Sitagliptin Improves Hepatic Functions

The DPP -4 I in Cardiovascular

Disease

Sitagliptin

N=3415

n (%)

Nonexposed N=2724

n (%)

Between-Groups

Difference,

% (95% CI)a

Serious clinical adverse experiences ≥0.2% in any group

Coronary artery disease 5 (0.1) 7 (0.3) –0.1 (–0.4, 0.1)

Myocardial infarction 4 (0.1) 5 (0.2) –0.1 (–0.3, 0.1)

Noncardiac chest pain 4 (0.1) 9 (0.3) –0.2 (–0.5, 0.0)

Cholelithiasis 6 (0.2) 2 (0.1) 0.1 (–0.1, 0.3)

Pneumonia 4 (0.1) 5 (0.2) –0.1 (–0.3, 0.1)

aPositive differences indicate that the proportion for the sitagliptin group is higher than the proportion for the

nonexposed group.

“0.0” represents rounding for values that are slightly greater than zero.

Williams-Herman D et al. BMC Endocr Disord. 2008;8:14. Copyright BioMed Central.

Incidences of Serious Adverse Events Were Generally Similar Between

Treatment Groups With or Without Sitagliptin

Sitagliptin pooled safety and tolerability analysis

http://circ.ahajournals.org/content/124/21/2285/F1.large.jpg

Sitagliptin and Renal

Functions

Renal Function • Although sitagliptin is eliminated mostly through the kidney , it

is tolerated well in patients with mild, moderate and severe

renal failure (including those on dialysis) (Bergman, Cote et al.

2007).

• sitagliptin is approved in patients with mild renal impairment

(creatinine clearance [CCr] ≥ 50 mL/min) However, in patients

with moderately (CCr ≥30 to < 50 mL/min) and severely (CCr <

30 mL/min) impaired renal function / end stage renal disease

(ESRD) it can be given in a reduced dose .

•

• Deacon 2011 , Tatjana Ábel National Health Center

• Hungary 2011).

Risks & Benefits

DPP-IV inhibitors

EFFICACY

↓A1c 0.7%

(up to 1.5% if starting A1c higher)

COST

$200 / month*

* Source – drugstore.com

SIDE EFFECTS (common)

- none

SIDE EFFECTS (putative)

- Pancreatitis - Pharyngitis

CONTRAINDICATIONS

- h/o pancreatitis

► DPP-4 is found on the surface of lymphocytes

► It inhibits breakdown of multiple cytokines and hormones including many involved in immune cell regulation

BUT

► Meta-analysis of 12 Phase IIb / III trials involving 3,415 patients on sitagliptin vs. 2,724 patients on placebo showed incidence of infections 34.5% vs. 32.9% (NS)

► Incidence of nasopharyngitis was 7.1% vs. 5.9% (NS)

Risks: Immunodeficiency

From: Williams-Herman, D et al. (2008). BMC End Dis 8(14)

► 88 cases of pancreatitis in patients on sitagliptin have been reported to the FDA by 09/2009

BUT

► Retrospective study of 786,656 patients including patients with h/o chronic pancreatitis and other pancreatitis risk factors

► 15,826 patients on sitagliptin

► Incidence of pancreatitis increased in patients with diabetes; no difference for sitagliptin

Risks: Pancreatitis

From: Garg R et al. (2010). Diabetes Care online 08/03/10

Conclusions—

DPP-4 Inhibitors

• Sitagliptin (Januvia ) have a major role in diabetes management , both in monotherapy and in combination therapy with metformin (Janumet ) , glitazones, sulfonylurea, or insulin,

• It can effectively reduce fasting and postprandial blood glucose levels and also HbA1c value.

• Based on studies and clinical experience, they

can be tolerated very well, and they cause no

increase of body weight, hypoglycemia and

gastrointestinal side effects.

Conclusions—

Cont. • Based on animal and in vitro studies ,they

can preserve or enhance beta cell

function.

• Ability to use in renal insufficiency, heart failure, and hepatic disease markedly increases therapeutic options for our patients

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ueda2012 dpp4 inhibitors-d.lobna

Health & Medicine

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