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DPP-4 Inhibitors in Type 2 Diabetes:
EXPANDING PATIENT REACH
DPP-4 Inhibitors in Type 2 Diabetes

Pathophysiology of Type 2 Diabetes: A Review Role of Incretins and DPP-4 Inhibition Are All DPP-4 Inhibitors The Same? Use of Sitagliptin in Different Patient Profiles Sitagliptin Safety Profile: Pooled Data Summary
Major Pathophysiologic Defects in Type 2 Diabetes Mellitus

Glucagon (alpha cell)
Islet-cell dysfunction
Pancreas Insulin (beta cell)
Insulin resistance
Glucose uptake in liver, muscle and fat
Liver Muscle
Hepatic glucose output
Hyperglycemia Liver
Adapted with permission from Kahn CR, Saltiel AR. Joslins Diabetes Mellitus. 14th ed. Lippincott Williams & Wilkins; 2005:145168. Del Prato S, Marchetti P. Horm Metab Res. 2004;36:775781. Porte D Jr, Kahn SE. Clin Invest Med. 1995;18:247254.
Adipose tissue
Manifestations of Beta-Cell Dysfunction in Type 2 Diabetes Mellitus
Abnormal pulsatile insulin response1
Increased proinsulin to insulin ratio1
Beta-Cell Dysfunction
Decreased beta-cell responsiveness to glucose2,3
Decreased insulin production4 Decreased insulin content Decreased insulin granule density
1. Buchanan TA. Clin Ther. 2003;25:B32-B46. 2. Buse JB et al. Williams Textbook of Endocrinology. 2003:14271483. 3. Ward WK et al. J Clin Invest. 1984;76:13181328. 4. Marchetti P et al. J Clin Endocrinol Metab. 2004;89:55355541.
Alpha-Cell Dysfunction Contributes to Excess Hepatic Glucose Production

Alpha-Cell Dysfunction
Dysregulation of glucagon secretion during fasting
Impaired suppression of glucagon secretion after a meal
Fasting and postprandial hyperglycemia in type 2 diabetes

1. Del Prato S et al. Horm Metab Res. 2004;36:775781. 2. Clark A et al. Diabetes Res. 1988;9:151159. 3. Butler PC et al. Diabetes. 1991;40:7381.
Insulin and Glucagon Dynamics in Response to Meals are Abnormal in T2DM

360
meal Normals (n=14)
Glucose (mg%)
80 120
Type 2 DM (n=12)
Insulin (/ml)
0 140
Delayed/depressed insulin response
Glucagon ( /ml)
Non-suppressed glucagon
90
-60
60
120
180
240
Adapted from Muller WA et al. N Engl J Med. 1970;283:109115.

The Incretin Effect
Nauck et al. 1988
GLP-1 and GIP are the 2 Major Incretins

GLP-1
Is released from L cells in ileum and colon1,2 Stimulates insulin response from beta cells in a glucose-dependent manner1 Inhibits glucagon secretion from alpha cells in a glucose-dependent manner1 Inhibits gastric emptyinga,1,2 Reduces food intake and body weighta,2
GIP
Is released from K cells in duodenum1,2 Stimulates insulin response from beta cells in a glucose-dependent manner1 Does not affect gastric emptying2 Has no significant effects on satiety or body weight2
GIP=glucose-dependent insulinotropic peptide; GLP-1=glucagon-like peptide-1. aEffects occur only with pharmacologic levels of GLP-1. 1. Drucker DJ. Diabetes Care. 2003;26:29292940. 2. Meier JJ et al. Best Pract Res Clin Endocrinol Metab. 2004;18:587606.
GLP-1 and GIP: Role in Glucose Homeostasis

Food ingestion
Glucose dependent
Release of active incretins GLP-1 and GIP
GI tract
Insulin (GLP-1 and GIP)

Pancreas
Beta cells Alpha cells
Glucose uptake by peripheral tissue
Blood glucose
Glucose production by liver
DPP-4 enzyme
Glucose dependent
Glucagon (GLP-1)
Inactive Inactive GLP-1 GIP
Incretin hormones GLP-1 and GIP are released by the intestine throughout the day; Incretin hormone levels increase in response to a meal
1. Kieffer TJ et al. Endocr Rev. 1999;20(6):876913. 2. Drucker DJ. Diabetes Care. 2003;26(10):29292940. 3. Holst JJ. Diabetes Metab Res Rev. 2002;18(6):430441.
in Type 2 Diabetes DPP-4 Inhibitors
Therapeutic Strategies to Enhance Incretin Action

GLP-1 agonists (GLP-1 receptor activators; incretin mimetics)
Purpose: Raise agonist plasma concentrations into the pharmacologic range DPP-4-resistant GLP-1 mimetics GLP-1 analogues with delayed absorption
DPP-4 inhibitors (incretin enhancers)

Purpose: Prevent degradation of endogenously released incretin hormones to elevate plasma levels of the active incretins
DPP-4=dipeptidyl peptidase-4; GLP-1=glucagon-like peptide-1. 1. Brubaker PL. Trends Endocrinol Metab. 2007;18(6):240245.
DPP-4 Inhibitors Recommended by ADA/EASD as Second Line Option for Type 2 Diabetes
2012 ADA/EASD Position Statement on Management of Hyperglycemia in Type 2 Diabetes
SUMMARY
Pancreatic - and -cell dysfunction coupled with insulin resistance play an important role in the development of hyperglycemia in T2DM.
Incretins (GLP-1 and GIP) are gut hormones released in response to an oral glucose meal.
GLP-1 and GIP both stimulate insulin secretion from the pancreas in a glucose-dependent manner. GLP-1 also suppresses glucagon secretion in a glucose-dependent manner. DPP-4 inhibition is one therapeutic strategy to prolong the physiologic effects of incretins. DPP-4 inhibitors are now recommended by ADA/EASD as second line agents for T2DM, reflecting their increasing relevance in achieving adequate glucose control.

DPP-4 Inhibitors: Molecular Structures and Pharmacologic Properties

Chemical Class -Phenethylamines1 Cyanopyrrolidines Aminopiperidine8 Xanthine
Generic Name
Sitagliptin2
Vildagliptin35
Saxagliptin3,6,7
Alogliptin9,10
Linagliptin11,12
Molecular Structure
FNH2O N N N N CF3 NC N
H N H HO N N C
H NH2 O
O H3C N N O N
CN N N O NH2 N
O N
N N NH2 N
HO
DPP-4 Inhibitory Activity (IC50) Half-life
18 nM
5.28 nM
3.37 nM
6.9 nM
~1 nM
12.4 h
~23 h
2.5 h (parent) 3.1 h (metabolite)
12.421.4 h
113131 h
1. Kim D et al. J Med Chem. 2005;48:141151. 2. EU-SPC for JANUVIA, 2010. 3. Matsuyama-Yokono A et al. Biochem Pharmacol. 2008;76:98107. 4. Villhauer EB et al. J Med Chem. 2003;46:27742789. 5. EU-SPC for Galvus, 2010. 6. Augeri DJ et al. J Med Chem. 2005;48:50255037. 7. EU-SPC for Onglyza, 2010. 8. Feng J et al. J Med Chem. 2007;50:22972300.9. Lee B et al. Eur J Pharmacol. 2008;589:30614. 10. Christopher R et al. Clin Ther. 2008;30:513527. 11. Thomas L et al. J Pharmacol Exp Ther. 2008;325:175182. 12. Heise T et al. Diabetes Obes Metab. 2009;11:786794.
DPP-4 Inhibitors: Extent of Inhibitory Activity

VILDAGLIPTINa Max ~95%; >80% 12h postdose
100 80 60 40 20 0 -20 100 80 60 40 20 0 -20 100 80 60 40 20 0 -20 0 4 8 12 16 20 24 Time (hr)
DPP-4 Inhibitors in Type 2 Diabetes Day 10 Day 14 Day 1
Placebo Vilda (50 mg) Vilda (100 mg)
ALOGLIPTINd Max ~90%; >75% 24h postdose
100
80
60 40 20 0
Day 14
Placebo Alogliptin (25 mg qd)
-20
SAXAGLIPTINb Max ~80%; ~70% 24h postdose
Placebo Saxagliptin (5 mg qd)
LINAGLIPTINe Max ~80%; >70% 24h postdose
100 80 60 40 20 0 -20 0 4 8 12 16 20 24 Time (hr)

Day 12
Placebo Linagliptin (5 mg qd)
SITAGLIPTINc Max ~97%; ~80% 24h postdose
Placebo Sitagliptin (100 mg qd)
Deacon CF. Diabetes, Obesity and Metabolism 2011; 13: 7-18.
Plasma DPP-4 Inhibitor Levels in Renally Impaired Subjects Reflect Their Route of Elimination
7 (relative to normal renal function)
Linagliptin
7 5 3 1
Sitagliptin
Fold increase in exposure
5 3 1
7 5 3 1
Saxagliptin
(primary metabolite)
7 5 3 1
Vildagliptin
(primary metabolite)
In pharmacokinetic studies, all DPP-4 inhibitors in clinical use have shown good Renal Function Renal Function tolerability when given in doses up to 8x the therapeutic dose
Modified from Graefe-Mody et al. Diabetes Obes Metab 2011
Rationale for Adjusting Sitagliptin Dose Depending on Renal Function

AUC Increases With Decreasing Creatinine Clearance Necessitating a Dose Reduction to Maintain Therapeutic Concentration
28 Dose-Adjusted (to 50 mg) AUC (uM.hr) 24 20 AUC GMR increase <2-fold when CrCl >50 mL/min Dose adjustments <30 mL/min dose 30 50 mL/min dose >50 mL/min full dose
16
12 8 4 0 10 30 50
70 90 110 130 150 170 190 210 230 Creatinine Clearance (mL/min)
1Bergman
AJ et al. Diabetes Care 2007; 30(7): 1862-1864.
DPP-4 Inhibitors: Selectivity Data

In Vitro Selectivity of DPP-4 Inhibitors (Fold Selectivity for DPP-4 vs Other Enzymes)
Inhibitor Sitagliptin Selectivity High QPP/DPP-2 >5550 >100000 >50000 >14000 PEP >5550 60000 Not reported >14000 FAP >5550 285 >4000 >14000 DPP-8 >2660 270 390 >14000 DPP-9 >5550 32 77 >14000
Vildagliptin Moderate Saxagliptin Moderate Alogliptin High
Linagliptin
Moderate
>100000
>100000
89
40000
>10000
Deacon CF. Diabetes, Obesity and Metabolism 2011; 13: 7-18.
DPP-4 Inhibitors: Other Differences

Vildagliptina Pooled safety analysis confirmed the trend for mild increases (3x ULN) in liver enzymes.
LFTs should be performed prior to initiation and monitored at 3-month intervals during the first year and periodically thereafter.
Dose reduction when administered with a sulfonylurea. Saxagliptinb Pooled analysis of five placebo-controlled studies demonstrated a small decrease in absolute lymphocyte count. Clinical significance unknown. Linagliptinc Administration with a potent inducer of P-glycoprotein (eg Rifampicin) resulted in a 39.6% decrease in linagliptin AUC, 43.8% decrease in Cmax and 30% decreased DPP-4 inhibition at trough.
Though still clinically efficacious, full efficacy might not be achieved.
a. Vildagliptin LPC April 2011 b. Saxagliptin LPC November 2009 c. Linagliptin LPC 2011
DPP-4 Inhibitors: Clinical Differences

Renal Insufficiency
Mild (CrCl50ml/min) Moderate (CrCl30-50ml/min) Severe (CrCl 30ml/min)
Hepatic Insufficiency
Mild / Moderate Severe
Sitagliptin
(No dose
adjustment)
( Dose)
( Dose)
No clinical experience
Vildagliptin
(No dose
adjustment)
(50mg OD)
(50mg OD)
***
Not recommended
Saxagliptin
**
Dose**
Dose**
Linagliptin
(No dose
adjustment)
(No dose adjustment)
(No dose
adjustment)
a. Sitagliptin LPC 2010. b. Vildagliptin LPC April 2011 c. Saxagliptin LPC November 2009 d. Linagliptin LPC 2011
Saxagliptin vs Sitagliptin Head-to-Head Non-inferiority Study

Population:
801 T2DM patients 18 yo with HbA1c of 6.5% to 10.0% despite stable dose of metformin 1500 mg for at least 8 weeks.
Intervention:
Addition of Sitagliptin 100 mg (n=398) or Saxagliptin 5 mg (n=403) for 18 weeks.
Outcomes:
1o: change from baseline in HbA1c. 2o: change from baseline in FPG.
Methodology:
Multicenter, randomized, double-blind, parallel-group, activecontrolled trial.
Scheen et al. Diabetes Metab Res Rev. 2010 ;26(7): 540549. DPP-4 Inhibitors in Type 2 Diabetes
Numerically Greater Reduction in HbA1c and FPG with Sitagliptin

Baseline
0.00
7.69% n=343
7.68%
0.00
8.89 mmol/L n=392

0.30
8.86 mmol/L n=397
Change From Baseline in Adjusted Mean HbA1c (SE), %
0.15
0.30
Change From Baseline in FPG LS Mean (SE), mmol/L
n=334
0.60
0.45
0.60 0.75
0.60
0.90
0.52 0.62 0.09 (95% CI: 0.01, 0.20)a

(noninferiority margin=0.30%) Sitagliptin 100 mg + metformin 1500 mg
0.90
1.20
0.30 (95% CI: 0.08, 0.53)a
Saxagliptin 5 mg + metformin 1500 mg

Scheen et al. Diabetes Metab Res Rev. 2010 ;26(7): 540549.
Vildagliptin Versus Sitagliptin: Conflicting Results on Glycemic Variability

Marfella et al (2010)1 P
38 T2DM patients on Sitagliptin 100 mg OD or Vildagliptin 50 mg BID on top of maximal dose of metformin (3000 mg) for 3 months Sitagliptin 100 mg OD or Vildagliptin 50 mg BID on top of stable metformin dose Change in MAGE from baseline Cross-sectional study
Guerci et al (2012)2
38 T2DM patients with HbA1c of 6.5% - 8.0% on a maximally tolerated dose of metformin Sitagliptin 100 mg OD or Vildagliptin 50 mg BID on top of maximally tolerated dose of metformin for 8 weeks Change in MAGE from baseline Multicenter, prospective, randomized, open-label study
Rizzo et al (2012)3
90 T2DM patients inadequately controlled with metformin (HbA1c >7.5%)
Sitagliptin 100 mg OD or Vildagliptin 50 mg BID for 12 weeks
O M
Change in MAGE from baseline Multicenter, prospective, randomized, open-label study

1Marfella
R et al. Journal of Diabetes and Its Complications 2010; 24: 79-83. 2Guerci B et al. French Diabetes Society (SFD) Congress. Nice, France. 2012. Poster 299. 3Rizzo MR et al. Diabetes Care 2012; 1-7.
Marfella et al: Glycemic Variability as Measured by MAGE was Better with Vildagliptin than Sitagliptin
Sitagliptin 100 mg OD Variables Baseline After 3 months p Vildagliptin 50 mg BID Baseline After 3 months p
MAGE (mg/dL)
FPG (mg/dL) PPG (mg/dL) MPG (mg/dL)
6918
5916
NS
7022
347
.01
16924
14513
.01
17131
14614
.01
19622
16617
.01
19719
16515
.01
15931
13127
.01
15739
12836
.01
1Marfella
R et al. Journal of Diabetes and Its Complications 2010; 24: 79-83.
Guerci et al: Glycemic Variability Results were Similar between Sitagliptin and Vildagliptin1
P=0.83 At baseline At 8 weeks Variable, mg/dL
P=0.61
P=0.89
MAGE
SD of 24-h Mean Glycemia
MODD
1Guerci
B et al. Diabetes Metab 2012, http://dx.doi.org/10.1016/j.diabet.2012.06.001.
Rizzo et al: Better MAGE Reduction with Vildagliptin and Numerically Greater HbA1c Reduction with Sitagliptin
MAGE Sitagliptin Baseline 12 weeks 70.8 64.8 Vildagliptin 73.9 45.3 HbA1c Sitagliptin 8.5 7.3 Vildagliptin 8.2 7.2
0 -10 -20
NS
-0.5
-1 -30 -40
Rizzo MR et al. Diabetes Care 2012, published online.
p<0.001 p<0.001
p<0.001
-1.5
Effect of Linagliptin and Sitagliptin on Glycemic Control in Type 2 Diabetes Mellitus

Population:
121 T2DM patients, 18-80 yo, treatment nave or previously received monotherapy with OHAs, HbA1c 6.5% - 10.0%
Intervention:
Linagliptin 5 mg (n=40), Sitagliptin 100 mg (n=40), Placebo (n=41) once daily for 4 weeks
Outcomes:
1o: Change from baseline to day 28 in 24-hr weighted mean glucose (WMG) and intact GLP-1 AUC between 0 to 2 hours (AUC0-2h) following a meal tolerance test 2o: Change from baseline to day 28 in FPG and plasma glucose (AUC0-3h) following a meal tolerance test Phase 2a, multicenter, randomized, double-blind, placebocontrolled, parallel-group study
Methodology:
Rauch T et al. Diabetes Ther (2012) 3:10.
Numerically Greater Reduction in WMG with Sitagliptin Versus Linagliptin

Mean BL HbA1c (%) Mean BL WMG (mmol/L) 7.32 10.5 7.17 7.47 10.6
0.2 0 -0.2 -0.4 -0.6 -0.8 -1 -1.2 -1.4 -1.6

*p<0.0001 vs placebo; BL baseline Rauch T et al. Diabetes Ther (2012) 3:10; www.ClinicalTrials.gov
+0.01
Sitagliptin 100 mg Linagliptin 5 mg Placebo
-1.1* -1.4
From a Lower Baseline, Sitagliptin Produced Numerically Greater Reduction in FPG versus Linagliptin
Mean Baseline FPG (mmol/L) 9.2 8.8 9.4
0 -0.1 -0.2 -0.01
-0.3
-0.4 -0.5 -0.6 -0.7 -0.8 -0.9 -1
*p 0.0283 vs placebo Rauch T et al. Diabetes Ther (2012) 3:10; www.ClinicalTrials.gov
Sitagliptin 100 mg Linagliptin 5 mg
-0.6*
Placebo
-0.9
Effect of Linagliptin and Sitagliptin on Other Outcome Measures

Linagliptin Number of participants analyzed GLP1 AUEC0-2h Units: pmol*h/L Mean SE Plasma glucose AUEC0-3h Units: mg*h/dL 39 18.5 2* Sitagliptin 40 15.3 2.0 Placebo 38 0.4 2.1
-98.4 14.7*
-119.1 13.3
- 8.1 15.1
The increase in intact GLP-1 during the first 2 hours (GLP1 AUEC0-2h) was numerically greater with Linagliptin. However, the reduction in plasma glucose AUEC0-3h was numerically greater with Sitagliptin.
*p<0.0001 vs placebo Rauch T et al. Diabetes Ther (2012) 3:10; www.ClinicalTrials.gov
SUMMARY
DPP-4 inhibitors differ in terms of their metabolism, dosing, elimination, specificity, and clinical usage. In the head-to-head trial of Sitagliptin versus Saxagliptin, Sitagliptin produced numerically greater reduction in HbA1c and FPG. Trials comparing the effect of Sitagliptin versus Vildagliptin on glycemic variability produced inconsistent results.
In the trial comparing Linagliptin versus Sitagliptin and placebo, Sitagliptin produced numerically greater reduction in weighted mean glucose and FPG despite a lower baseline.

Sitagliptin in Elderly Patients with T2DM

Population:
T2DM patients 65 yo with HbA1c inadequately controlled by diet and exercise OHA (7.0% - 10.0%).
Intervention:
Sitagliptin 50 mg or 100 mg OD depending on renal function (n=102) or placebo (n=104) for 24 weeks.
Outcome:
Change from baseline in HbA1c and FPG at week 24 and average blood glucose on treatment days 3 and 7.
Methodology:
Randomized, double-blind, placebo-controlled, parallel group study.
Barzilai N et al. Curr Med Res Opin 2011; 27: 1049-1058.
Significant Reduction in HbA1c and Response to Therapy as Early as Day 3 among Elderly T2DM Patients Given Sitagliptin versus Placebo
Full Analysis Set
HbA1c LS Mean Change From Baseline, % Day 3 1.1 mmol/L P<0.001 Day 7 1.3 mmol/L P<0.001
0.6
0.4
0.3
0.3
0.2 0.2% 0.0 0.2 0.4 0.6 0 6 12 Week Placebo (n=91) Mean BL HbA1c=7.71% Sitagliptin (n=101) Mean BL HbA1c=7.82% Mean BL 10.9 10.7 4-point fingerstick glucose, mmol/L 18 24 LS mean difference 0.7%; P<0.001 0.5% n=55
0 0.3 0.6 0.9 1.2

0.9 n=55 n=59
n=62
0.1
1.5 1.8
1.4 10.8 10.7
Barzilai N et al. Curr Med Res Opin 2011; 27: 1049-1058.
Sitagliptin vs Sulfonylurea During Ramadan: A Model for Skipping Meals

Population:
T2DM Muslim patients 18 yo treated with a stable dose of SU Metformin for 3 months; had an HbA1c of 10%; expressed their intention to daytime fast during Ramadan.
Intervention:
Switch to Sitagliptin 100 mg OD (n=421) or remain on their SU (n=427).
Outcome:
Overall incidence of hypoglycemic episodes.
Methodology:
Multicenter, open-label, randomized study
Aravind SR et al. Curr Med Res Opin 2012; 28: 1289-1296.
Switching to Sitagliptin was Associated with a Significantly Lower Incidence of Symptomatic Hypoglycemia versus Remaining on SU among Fasting Diabetic Muslim Patients during Ramadan
APaT Population RRR (95% CI) = 0.52 (0.29, 0.94) p=0.028
8 7 6 5 7.3
Sitagliptin 100mg qd Metformin (n=421) SU Metformin (n=427)
4
3 2 1 0 3.8
Median doses of SUs : 2 mg/day for glimepiride; 10 mg/day for glibenclamide; 6.1 mg; 80 mg/day for gliclazide APat=all patients as treated; CI=confidence interval; RRR=relative risk ratio; SU=sulfonylurea Aravind SR et al. Curr Med Res Opin 2012; 28: 1289-1296.
Lower Proportion of Patients Reporting Hypoglycemic Events of Any Type with Sitagliptin
12 10 8 6 4 2 0.2 0 Symptomatic or Asymptomatic Hypoglycemic Events Requring Non-medical Assistance 1.6 4.8 RR 0.49 (0.29, 0.83) p = 0.006 9.6
Sitagliptin Metformin (n = 421) SU Metformin (n = 427)
Requiring Medical Assistance
Aravind SR et al. Curr Med Res Opin 2012; 28: 1289-1296.
Sitagliptin Add-On to Insulin vs Insulin Dose-Increase Therapy in Type 2 Diabetes

Population:
T2DM patients, 30-70 yo, on insulin injections 3 months at a dose of 10 U/day; HbA1c of 7.0% - 10.0%.
Intervention:
Addition of Sitagliptin 100 mg OD (n=70) or insulin increase therapy* (n=70) for 24 weeks.
Outcome:
Change from baseline in HbA1c, FPG, PPG.
Methodology:
Randomized, active-controlled, parallel group study.
*Subjects
were guided to increase insulin dose by 10% at random and by a further 10% at 12 weeks if HbA1c is not within target (<7%). In addition, subjects were allowed to increase insulin dose by 2U/week based on their SMBG. Hong ES et al. Diabetes, Obesity and Metabolism 2012; 14: 795-802
Significantly Greater Reduction in HbA1c and 2-hour PPG with Sitagliptin-Adding Versus Insulin-Increasing Regimen
9.5
FPG (mg/dL) 200 180 160 140 120 0 12 Time (months) 24
9 HbA1c (%) = -0.42% (-0.91, -0.11)
*+
8.5
*+
2-hr PPG (mg/dL)
350 300 250
8 0 12 Time (months) 24
*+
200 0 12 Time (months)
*+
24
Sitagliptin adding
Insulin increasing
* p<0.05 between arms; + p<0.05 vs baseline Hong ES et al. Diabetes, Obesity and Metabolism 2012; 14: 795-802.
Significantly Greater Percentage of Patients with HbA1c 7% and Less Incidence of Hypoglycemic Events with Sitagliptin-Adding Versus Insulin-Increasing Regimen
HbA1c <7%
25% 20% 15% 10% 5% 0% Sitagliptin Add-on Insulin Increasing 10% 5% 0% Sitagliptin Add-on Insulin Increasing p = 0.051 15% 20% p = 0.021
HbA1c <7% without hypoglycemia
Hypoglycemia
20% 15%
Severe Hypoglycemia
20% 15% 10% 5% 0%
10%
5% 0%
Sitagliptin Add-on
Insulin Increasing
Sitagliptin Add-on
Insulin Increasing
* p<0.05 between arms Hong ES et al. Diabetes, Obesity and Metabolism 2012; 14: 795-802.
Decline in Obesity Parameters with SitagliptinAdding Regimen Versus Insulin-Increasing Regimen

Week 0 (mean SD) Week 24 (mean SD) LS mean change from baseline (95% CI) Difference in LS mean change (95% CI)
Body weight (kg) Sitagliptin adding 68.6 11.6 68.1 11.4 -0.7 (-1.4, -0.1)
Insulin increasing
66.2 10.6
67.4 9.7
1.1 (0.2, 1.8)
-1.7 (-2.5, -0.5)*
Waist circumference Sitagliptin adding Insulin increasing 90.1 11.0 88.7 7.1 89.0 9.8 89.8 7.4 -0.8 (-2.1, 0.3) 1.2 (0.4, 1.9) -2.0 (-3.4, -0.6)*
p <0.05 for the between-treatment difference Hong ES et al. Diabetes, Obesity and Metabolism 2012; 14: 795-802.
Sitagliptin Versus Glipizide in Diabetic Patients with Chronic Kidney Disease

PN O631 P: 277 T2DM patients 30yo with moderate to severe renal insufficiency (eGFR <50mL/min/1.73m2) not on dialysis I: Sitagliptin 25 mg or 50 mg qd (n=135) versus Glipizide 2.5 mg qd titrated to 10 mg bid (n=142) for 54 weeks O: 1o Change from baseline HbA1c at week 54; Other endpoints change in FPG, percent of patients achieving HbA1c goals, change in lipid parameters M: Multicenter, randomized, double blind, active-controlled study PN O732 P: 129 T2DM patients 30yo with ESRD on hemodialysis or peritoneal dialysis for > 6 months I: Sitagliptin 25 mg qd (n=64) versus Glipizide 2.5 mg qd titrated to 10 mg bid (n=65) for 54 weeks O: 1o Change from baseline HbA1c at week 54; Other endpoints change in FPG, percent of patients achieving HbA1c goals M: Multicenter, randomized, double blind, active-controlled study
1. Ferreira et al. Diabetes Care 2012 (in press) 2. Ferreira et al. American Journal of Kidney Disease 2012 (in press).
Sitagliptin was not Inferior to Glipizide in HbA1c Reduction among T2DM Patients with CKD
Moderate/severe renal insufficiency1 End stage renal disease on dialysis2
0
7.8
7.6 7.4 7.2 7.0 6.8
= -0.11% (-0.29, 0.06)
HbA1c from baseline (%)
-0.2 -0.4 -0.6 -0.8 -1.0 0 12
= 0.15% (-0.18, 0.49)
HbA1c (%)
12
24
36
48
24
36
48
Time (weeks) Sitagliptin Glipizide
Time (weeks)
Lower Incidence of Symptomatic Hypoglycemia with Sitagliptin vs Glipizide in T2DM Patients with CKD
Moderate/severe renal insufficiency1
18
End stage renal disease on dialysis2

12
*
17.0
Percent of Patients #
Percent of Patients #
15 12 9 6 3 0
1.4 All Hypo AEs 6.2 2.8
Sitagliptin (n=210) Glipizide (n=212)
10 8 6 4 2 0
6.3
10.8
*
7.7
Sitaglitin (n=64) Glipizide (n=65)
*
6.2
0.0 1.4
1.4
2.4 All Hypo AEs
0.0
0.0
1.5
0.0
Severe Required Required Hypo AEs Non-medical Medical Assistance Assistance
Severe Required Required Hypo AEs Non-medical Medical Assistance Assistance
No Worsening of Renal Function with Sitagliptin vs Glipizide in T2DM Patients with CKD
Change in Glomerular Filtration Rate
0.30
1 0 -1 -2 -3 -4 -5 0 6 12 18 30 42 54 0.26 0.22 0.18 0.14
Change in Albumin-Creatinine Ratio
0.10
0.06 0.02 -0.02 -0.06 -0.10 BL Wk 6 Month 6 Year 1
Week
Time
Sitagliptin
Glipizide
Reduction of Albuminuria in T2DM Patients with Sitagliptin

Population:
36 patients with HbA1c 6.5% despite diet, exercise and medical treatment for 6 months. eGFR 60 mL/min/1.73 m2
Intervention:
Sitagliptin 50 mg daily for 6 months.
Outcome:
Change in blood pressure, glucose markers, inflammatory markers, and urinary albumin excretion at 6 months.
Hattori S. Endocrine Journal 2011; 58(1): 69-73.
Treatment with Sitagliptin Produced a Significant Reduction in Albuminuria without Lowering eGFR
dACR (mg/g Cr) 10 0 -10 -20 -30 78 -20.6
2.3
76
eGFR 74 72 70 -6 mos
Hattori S. Endocrine Journal 2011; 58(1): 69-73.
77
75.3
73.3 0 mo 6 mos
SUMMARY
In elderly patients with T2DM, treatment with Sitagliptin led to rapid and sustained glucose-lowering over 24 weeks with clinically significant effects as early as day 3. Among diabetic patients who skip meals, Sitagliptin is associated with less risk for hypoglycemia compared to SU. Among patients already on insulin, addition of Sitagliptin is associated with better glycemic control versus insulin uptitration with a lower risk for hypoglycemia and weight gain. In diabetic patients with CKD, Sitagliptin demonstrated similar efficacy with Glipizide without accelerating renal disease progression and lower incidence of hypoglycemia.

Pooled Safety Analysis of Sitagliptin from Randomized Clinical Trials

19 randomized, double-blind, controlled clinical studies up to 2 years in durationa
Sitagliptin 100 mg/day (5429 patients) 1805 patients treated for at least 1 year; 584 of these patients treated for 2 years Non-exposed (4817 patients) 1320 patients treated for at least 1 year; 470 of these patients treated for 2 years
No difference from non-exposed group for side effects or adverse events including: Hypoglycemia (except when compared to SU, where sitagliptin has significantly lower rate Nausea or gastrointestinal side effects Nasopharyngitis Upper respiratory tract infections Urinary tract infections Headache Pancreatitis Any malignancy Bone fracture
aStudies
with results available as of July 2009. 1. Williams-Herman D et al. BMC Endocr Disord. 2010;10:7. \
Sitagliptin on Major Adverse Cardiovascular Events: Pooled Analysis from 19 Clinical Trials
Sitagliptinexposed (100mg/d) (N=5439) Nonexposed (PBO or active comparator (N=4817) Betweengroup difference [95% CI] Risk Ratio [95% CI]
MACE incidence rate/100 patient-years (64 total events)
0.6
0.9
-0.3 [-0.7 to 0.1]
0.68 [0.41 to 1.12]
Williams-Herman et al. BMC Endocrine Disorders 2010; 10: 7
Sitagliptin on Major Adverse Cardiovascular Events: Updated Pooled Analysis from 25 Clinical Trials
14,611 patients; 7,726 exposed to Sitagliptin
Overall incidence of MACE: 0.65 per 100 patientyears for Sitagliptin 0.74 in the nonexposed group Versus placebo: 0.80 for Sitagliptin 0.76 for placebo Versus SU: 0.00 for Sita 0.86 for SU
Williams-Herman et al. BMC Endocrine Disorders 2010; 10: 7
DPP-4 Inhibitors CV Outcomes Trials

TECOS:
Trial Evaluating Cardiovascular Outcomes with Sitagliptin
Started Dec 2008 Time to 1st occurence of composite CV outcome (>14 000 patients; documented CV disease; >4 yr or until
occurence of 13 000 primary endpoints)
EXAMINE:
EXamination of CArdiovascular OutcoMes: AlogliptIN vs Standard CarE in Patients with Type 2 Diabetes Mellitus and Acute Coronary Syndrome
Started Sept 2009 Time to 1st occurence of primary major adverse cardiac events (~5 400 acute coronary syndrome patients; 5 yr )
SAVOR:
Saxagliptin Assessment of Vascular Outcomes Recorded in Patients with Diabetes Mellitus

Started May 2010 To evaluate the effect on major CV events (~12 000 high CV risk patients; >5 yr study)
EXSCEL:
EXenatide Study of Cardiovascular Event Lowering

Started June 2010; Superiority design To evaluate the effect of exenatide (once weekly) on major CV events (>9 000 patients; >5 yr study)
LEADER:
Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Outcome Results

Started Aug 2010 To evaluate the effect of liraglutide on CV outcomes (~9 000 high CV risk patients; 5 yr study)
CAROLINA:
CARdiovascular Safety Of LINAgliptin

Started Nov 2010; Active comparator (glimepiride) Time to 1st occurence of major CV events (~6 000 high CV risk patients; >5 yr study)
SUMMARY
Pooled safety analysis of patients exposed to Sitagliptin from 19 clinical trials did not show an increased incidence of any adverse events of interest including pancreatitis, cancer and major adverse cardiovascular events (MACE).
In an updated analysis which included 25 clinical trials, Sitagliptin was not associated with increased cardiovascular risk. Cardiovascular outcome trials are now ongoing to investigate if incretin-based therapies can reduce CV events among patients with T2DM.
Thank You
JANUVIA (sitagliptin, MSD): Indications

For patients with type 2 diabetes mellitus, JANUVIA is indicated to improve glycemic control as monotherapy in patients inadequately controlled by diet and exercise alone and for whom metformin is inappropriate due to contraindications or intolerance; as dual oral therapy in combination with metformin when diet and exercise plus metformin alone do not provide adequate glycemic control; in combination with a sulfonylurea when diet and exercise plus maximal tolerated dose of a sulfonylurea alone do not provide adequate glycemic control and when metformin is inappropriate due to contraindications or intolerance; in combination with a PPAR agonist (ie, a thiazolidinedione) when use of a PPAR agonist is appropriate and when diet and exercise plus the PPAR agonist alone do not provide adequate glycemic control; as triple oral therapy in combination with a sulfonylurea and metformin when diet and exercise plus dual therapy with these agents do not provide adequate glycemic control; and in combination with a PPAR agonist and metformin when use of a PPAR agonist is appropriate and when diet and exercise plus dual therapy with these agents do not provide adequate glycemic control. JANUVIA is also indicated as add-on to insulin (with or without metformin) when diet and exercise plus stable dose of insulin do not provide adequate glycemic control.
JANUVIA (sitagliptin, MSD): Selected Safety Information

JANUVIA is contraindicated in patients who are hypersensitive to any component of this product. JANUVIA should not be used in patients with type 1 diabetes or for the treatment of diabetic ketoacidosis. There have been postmarketing reports of acute pancreatitis in patients taking JANUVIA. Patients should be informed of the characteristic symptom of acute pancreatitis: persistent, severe abdominal pain. Resolution of pancreatitis has been observed after discontinuation of JANUVIA (with or without supportive treatment), but very rare cases of necrotizing or haemorrhagic pancreatitis and/or death have been reported. If pancreatitis is suspected, JANUVIA and other potentially suspect medicinal products should be discontinued. When sitagliptin was added to a sulfonylurea or to insulin, the incidence of hypoglycemia was increased over that of placebo. To reduce the risk of hypoglycemia, a lower dose of sulfonylurea or insulin may be considered. As the experience is limited, patients with moderate to severe renal impairment should not be treated with JANUVIA. JANUVIA is not recommended for use in children below 18 years of age due to a lack of data on its safety and efficacy. JANUVIA should not be used during pregnancy or during breast-feeding. Postmarketing reports of serious hypersensitivity reactions in patients treated with JANUVIA have been reported including anaphylaxis, angioedema, and exfoliative skin conditions including Stevens-Johnson syndrome. Onset of these reactions occurred within the first 3 months after initiation of treatment with JANUVIA, with some reports occurring after the first dose. If a hypersensitivity reaction is suspected, discontinue JANUVIA, assess for other potential causes for the event, and institute alternative treatment for diabetes.
JANUVIA (sitagliptin, MSD): Selected Safety Information (continued)

In clinical studies as monotherapy and in combination with other agents, drug-related adverse reactions reported, in excess (>0.2% and difference >1 patient) of placebo in double-blind studies included decreased blood glucose, headache, somnolence, diarrhoea, dry mouth, nausea, flatulence, constipation, upper abdominal pain, vomiting, hypoglycemia, influenza, peripheral edema, and dizziness. Adverse events (reported regardless of causal relationship to medicinal product) occurring in at least 5% and more commonly in patients treated with sitagliptin included upper respiratory tract infection and nasopharyngitis. Additional adverse experiences, occurring more frequently (not reaching the 5% level but occurring >0.5%) with JANUVIA than in the control group included osteoarthritis and pain in extremity. For additional adverse experience information, see the product circular. No dosage adjustment is required based on age. Age did not have a clinically meaningful impact on the pharmacokinetics of sitagliptin based on a population pharmacokinetic analysis of phase I and phase II data. Elderly subjects (65 to 80 years) had approximately 19% higher plasma concentrations of sitagliptin compared to younger subjects. Care should be exercised in patients 75 years of age (limited safety data available). Before initiating therapy, please consult the full prescribing information.
JANUMET (sitagliptin/metformin, MSD): Indications

For patients with type 2 diabetes mellitus: JANUMET is indicated as an adjunct to diet and exercise to improve glycemic control in patients inadequately controlled on their maximal tolerated dose of metformin alone or those already being treated with the combination of sitagliptin and metformin. JANUMET is indicated in combination with a sulfonylurea or a PPAR agonist (triple combination therapy) as an adjunct to diet and exercise in patients inadequately controlled on their maximal tolerated dose of metformin and a sulfonylurea or a PPAR agonist, respectively. JANUMET is also indicated as an addon to insulin (triple combination therapy) as an adjunct to diet and exercise to improve glycemic control in patients when stable dose of insulin and metformin alone do not provide adequate glycemic control.
JANUMET (sitagliptin/metformin, MSD): Selected Safety Information

JANUMET is contraindicated in patients with hypersensitivity to any component of this product; diabetic ketoacidosis, diabetic pre-coma; moderate or severe renal impairment (creatinine clearance <60 ml/min); acute conditions with the potential to alter renal function, (eg, dehydration, severe infection, shock, contrast agents); acute or chronic disease that may cause tissue hypoxia (eg, cardiac or respiratory failure, recent myocardial infarction, shock) hepatic impairment; and acute alcohol intoxication or alcoholism; and in patients who are lactating. JANUMET should not be used in patients with type 1 diabetes and must not be used for the treatment of diabetic ketoacidosis. There have been postmarketing reports of acute pancreatitis in patients taking sitagliptin. Patients should be informed of the characteristic symptom of acute pancreatitis: persistent, severe abdominal pain. Resolution of pancreatitis has been observed after discontinuation of sitagliptin (with or without supportive treatment), but very rare cases of necrotizing or haemorrhagic pancreatitis and/or death have been reported. If pancreatitis is suspected, JANUMET and other potentially suspect medicinal products should be discontinued. Serum creatinine concentrations should be determined at least once a year in patients with normal renal function and at least 2 to 4 times a year in patients with serum creatinine levels at or above the upper limit of normal and in elderly patients. Patients receiving JANUMET in combination with a sulfonylurea or with insulin may be at risk of hypoglycaemia. Therefore, a reduction in the dose of the sulfonylurea or insulin may be necessary.
JANUMET (sitagliptin/metformin, MSD): Selected Safety Information (continued)

Temporarily discontinue JANUMET in patients undergoing surgery or radiologic studies involving intravascular administration of iodinated contrast materials and in those with intercurrent serious conditions or infection. Promptly evaluate a patient who develops laboratory abnormalities or clinical illness for evidence of ketoacidosis or lactic acidosis. If acidosis occurs, discontinue JANUMET immediately and initiate appropriate corrective measures. JANUMET is not recommended for use in children below 18 years of age due to a lack of data on its safety and efficacy. JANUMET should not be used during pregnancy or during breast-feeding. Postmarketing reports of serious hypersensitivity reactions in patients treated with sitagliptin have been reported including anaphylaxis, angioedema, and exfoliative skin conditions including Stevens-Johnson syndrome. Onset of these reactions occurred within the first 3 months after initiation of treatment with sitagliptin, with some reports occurring after the first dose. If a hypersensitivity reaction is suspected, discontinue JANUMET, assess for other potential causes of the event, and institute alternative treatment for diabetes.
JANUMET (sitagliptin/metformin, MSD): Selected Safety Information (continued)

In clinical studies of sitagliptin added to metformin alone or in combination with other agents (ie, triple combination), drug-related adverse reactions reported in excess (>0.2% and difference >1 patient) of placebo in double-blind studies included decreased blood glucose, headache, somnolence, diarrhoea, nausea, constipation, upper abdominal pain, vomiting, dry mouth, hypoglycaemia, and peripheral edema. In monotherapy studies with sitagliptin, adverse reactions considered as drug-related in excess (>0.2% and difference >1 patient) of placebo included headache, hypoglycaemia, constipation, and dizziness. Adverse events (reported regardless of causal relationship to medicinal product) occurring in at least 5% and more commonly in patients treated with sitagliptin included upper respiratory tract infection and nasopharyngitis. Adverse reactions identified from clinical trial and postmarketing data with metformin included metallic taste, nausea, vomiting, diarrhoea, abdominal pain, and loss of appetite. For additional adverse experience information, see the product circular. Before initiating therapy, please consult the full prescribing information. No dose adjustment is required based on age. Age did not have a clinically meaningful impact on the pharmacokinetics of sitagliptin based on a population pharmacokinetic analysis of phase I and phase II data. Elderly subjects (65 to 80 years) had approximately 19 % higher plasma concentrations of sitagliptin compared to younger subjects. In elderly patients, use caution in situations where renal function may become impaired (eg, when initiating antihypertensive or diuretic therapy or when starting treatment with a nonsteroidal anti-inflammatory drug [NSAID]). Before initiating therapy, please consult the full prescribing information.
Before initiating therapy, please consult the full prescribing information. MSD does not recommend the use of any product in any different manner than as described in the Prescribing Information.

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DPP-4 Inhibitors in Type 2 Diabetes:

EXPANDING PATIENT REACH

DPP-4 Inhibitors in Type 2 Diabetes

DPP-4 Inhibitors in Type 2 Diabetes:

EXPANDING PATIENT REACH

DPP-4 Inhibitors in Type 2 Diabetes

Major Pathophysiologic Defects in Type 2 Diabetes Mellitus

Pancreas Insulin (beta cell)

Hepatic glucose output

DPP-4 Inhibitors in Type 2 Diabetes

Manifestations of Beta-Cell Dysfunction in Type 2 Diabetes Mellitus

Abnormal pulsatile insulin response1

Increased proinsulin to insulin ratio1

DPP-4 Inhibitors in Type 2 Diabetes

Alpha-Cell Dysfunction Contributes to Excess Hepatic Glucose Production

Dysregulation of glucagon secretion during fasting

Impaired suppression of glucagon secretion after a meal

Fasting and postprandial hyperglycemia in type 2 diabetes

DPP-4 Inhibitors in Type 2 Diabetes

Insulin and Glucagon Dynamics in Response to Meals are Abnormal in T2DM

meal Normals (n=14)

Delayed/depressed insulin response

Adapted from Muller WA et al. N Engl J Med. 1970;283:109115.

DPP-4 Inhibitors in Type 2 Diabetes

DPP-4 Inhibitors in Type 2 Diabetes:

EXPANDING PATIENT REACH

DPP-4 Inhibitors in Type 2 Diabetes

The Incretin Effect

Nauck et al. 1988

DPP-4 Inhibitors in Type 2 Diabetes

GLP-1 and GIP are the 2 Major Incretins

DPP-4 Inhibitors in Type 2 Diabetes

GLP-1 and GIP: Role in Glucose Homeostasis

Insulin (GLP-1 and GIP)

Glucose uptake by peripheral tissue

Inactive Inactive GLP-1 GIP

in Type 2 Diabetes DPP-4 Inhibitors

Therapeutic Strategies to Enhance Incretin Action

DPP-4 inhibitors (incretin enhancers)

DPP-4 Inhibitors in Type 2 Diabetes

2012 ADA/EASD Position Statement on Management of Hyperglycemia in Type 2 Diabetes

DPP-4 Inhibitors in Type 2 Diabetes:

EXPANDING PATIENT REACH

DPP-4 Inhibitors in Type 2 Diabetes

DPP-4 Inhibitors: Molecular Structures and Pharmacologic Properties

DPP-4 Inhibitory Activity (IC50) Half-life

2.5 h (parent) 3.1 h (metabolite)

DPP-4 Inhibitors in Type 2 Diabetes

DPP-4 Inhibitors: Extent of Inhibitory Activity

Placebo Vilda (50 mg) Vilda (100 mg)

ALOGLIPTINd Max ~90%; >75% 24h postdose

Placebo Alogliptin (25 mg qd)

SAXAGLIPTINb Max ~80%; ~70% 24h postdose

Placebo Saxagliptin (5 mg qd)

LINAGLIPTINe Max ~80%; >70% 24h postdose

100 80 60 40 20 0 -20 0 4 8 12 16 20 24 Time (hr)

Placebo Linagliptin (5 mg qd)

SITAGLIPTINc Max ~97%; ~80% 24h postdose

Placebo Sitagliptin (100 mg qd)

Deacon CF. Diabetes, Obesity and Metabolism 2011; 13: 7-18.

Fold increase in exposure

Rationale for Adjusting Sitagliptin Dose Depending on Renal Function

AJ et al. Diabetes Care 2007; 30(7): 1862-1864.