A New Easy DPP-4 Inhibitor Linagliptin
織巢鳥,原產於非洲。
織布鳥吸引異性的媒介是鳥巢。
公鳥築巢,讓母鳥選巢,被母鳥選上的巢,就表示築巢的公鳥,雀屏中選。
就像很多女性擇偶的條件之一是對方須是「有殼蝸牛」一樣。
Content
Clinical background• Rationale for early intervention• Kidney in diabetes: Prevalence, implications and treatment limitations
Linagliptin• Overview of Linagliptin• What makes Linagliptin different
1.Efficacy2.Tolerability3.Safety
Early intensive glycemic control provides lasting protection : The legacy effect
10-year post-trial monitoring from 1997 to 2007 of UKPDS Study†
• Randomized intervention to achieve either intensive or conventional targets - stopped at the trial end (1997)• Differences in mean HbA1c between the two groups were lost by year 1 of post-trial follow-up. • Relative reductions in risk in patients who had been treated to intensive goals, compared with conventional targets, persisted after 10 years
† Data from sulfonylurea–insulin group shown* P≤0.05; ** P≤0.01; *** P≤0.001; -25
-20
-15
-10
-5
0
Microvasculardisease
MyocardialInfraction
Any diabetes-related endpoint
Death fromany cause
Re
lati
ve
Ris
k R
ed
uc
tio
n (
%)
Trial end (1997)
Post-trial follow up (2007)
*
***
**
***
***
*
1. UKPDS 33 Study Group. Lancet. 1998;352:837-853; 2. Holman RR, et al. N Engl J Med. 2008;359:1577-1589.3. Chalmers J and Cooper ME. N Engl J Med. 2008; 359: 1618–1620.
57% risk reduction in non-fatal MI, stroke or CVD death*
Intensivetreatment
Cu
mu
lati
ve i
nci
de
nce
o
f n
on
-fat
al M
I, s
tro
ke o
r d
eath
fro
m C
VD Conventional
treatment
0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 Years
0.06
0.04
0.02
0
DCCT (intervention period) EDIC (observational follow-up)*Intensive vs conventional treatment. DCCT Research Group. N Engl J Med 1993; 329:977–986.
Nathan DM, et al. N Engl J Med 2005; 353:2643–2653.
0
7
1 6
Hb
A1
C (
%)
9
8
2 3 4 5 7 8 9
Conventional treatment
Intensive treatment
11 12 13 14 15 16 1710DCCT (intervention period)
YearsEDIC (observational follow-up)
DCCT/EDIC: long-term follow-up and legacy effect
Glucose similar BUT CV events still higher
Legacy Effect: milder complication
傳統積極
傳統積極
等量
等比例
1997 2007
Complication Playground
123
Complications go at the same time point.
But they make differentunder different genetic base.
1997 2007
Lin
P< 0.05
P< 0.05
The Action to Control Cardiovascular risk in Diabetes study group ( ACCOD trial )
ACCORD Results
Why was mortality increased in intensive treatment group in ACCORD?
• Not certain• Speed of HbA1c reduction ( 1.4 % vs. 0.6% in 4
months)• Drug combinations• Unidentified hypoglycemia• Weight gain• Hypoglycemia unawareness (associated cardiac
autonomic neuropathy)Analysis proves that the increased mortality rates are not
related to1. Specific OAD ( Rosiiglitazone, SU , Insulin etc)2. Changes in other medications( Statins, Aspirin etc)
Intensive Glycemic Control and the Prevention of Cardiovascular Events: Implications of
the ACCORD,ADVANCE, and VA Diabetes Trials Diabetes Care January 2009 vol. 32 no. 1 187-192
Increased Mortality, Myocardial Infarction, and
Hypoglycemia With Intensive Therapy:
ACCORD Trial
Mortality (% per year)≥1 severe hypoglycemia
(n = 705)
No hypoglycemia
(n = 9,546)
3.1
1.2
aDefined by requirement for medical or paramedical intervention, with
documented glucose <50 mg/dL and relief by parenteral or oral glucose or by glucagon.
1 Bloomgarden ZT. Diabetes Care. 2008;31(9):1913–1919. 2. Dluhy RG, McMahon GT. N Engl J Med. 2008;358:2630–2633.
Summary
• Intensive glycemic control slows down progress of diabetic complications, microvascular and probably macrovascular.
• Intensive glycemic control has patient risk hypoglycemia, and risk higher CV mortality.
• Severe hypoglycemia increased CV mortality 3.1X than otherwise. • Safety ( less hypoglycemia, no fear of hypoglycemia ) is a
dominant issue in the following era.
Ominous Octet
Ralph A. DeFronzo Diabetes, Vol. 58, April 2009
Beta cell, fat, muscle, liver, gut, alfa cell, kidney, brain
After glucose ingestion, two hypothalamic areas with consistent inhibition were noted: the lower posterior hypothalamus, which contains the ventromedial nuclei, and the upper posterior hypothalamus, which contains the paraventricular nuclei. In both of these hypothalamic areas, which are key centers for appetite regulation, the magnitude of the inhibitory response following glucose ingestion was reduced in obese, insulin-resistant, normal glucose tolerant subjects, and there was a delay in the time taken to reach the maximum inhibitory response, even though the plasma insulin response was markedly increased in the obese group.
Ralph A. DeFronzo Diabetes, Vol. 58, April 2009
Cerebral insulin resistance
① In animal models of both type 1 and type 2 diabetes, the maximal renal tubular reabsorptive capacity, or Tm, for glucose is increased. In humans with type 1 diabetes, Mogensen et al. have shown that the Tm for glucose is increased.
② Cultured human proximal renal tubular cells from type 2 diabetic patients demonstrate markedly increased levels of SGLT2 mRNA and protein and a fourfold increase in the uptake of -methyl-D-glucopyranoside (AMG), a nonmetabolizeable glucose analog
③ Thus, an adaptive response by the kidney to conserve glucose, which is essential to meet the energy demands of the body, especially the brain and other neural tissues, which have an obligate need for glucose, becomes maladaptive in the diabetic patient.
Ralph A. DeFronzo Diabetes, Vol. 58, April 2009
Increased Renal Glucose Reabsorption
Pathogenesis of type 2 DM: Implication for Therapy① Effective treatment of type 2 diabetes requires multiple
drugs used in combination to correct multiple pathophysiological defects.
② Treatment should be based on known pathogenic abnormalities and not simply on reduction of A1C.
③ Therapy must be started early in the natural history of type 2 diabetes to prevent progressive beta-cell failure.
In Clinical Aspects“Ideal oral drug”
• Targeting underlying pathogenesis, including lowering insulin resistance ( BG, TZD ), recovering beta-cell function ( SU, glinide, DPP-4i ) and reducing hepatic glucose production ( BG, DPP4i ).
• Safe, minimal hypoglycemia ( BG, ?TZD, AGI, DPP-4i, SGLT-2i )• No weight gain ( BG, AGI, DPP-4i, SGLT-2i)• Satiety promotion ( ? AGI, DPP-4i, BG; MC4R )• Increased beta-cell mass ( ? TZD, DPP 4i )• Reduced CV risk ( BG, AGI, DPP 4i )
Metformin & DPP-4 inhibitors: Combinations of oral glucose- lowering agents with complementary mechanisms of action
Target site Action Metformin DPP-4 inhibitors
Enhances glucose-dependent insulin secretion Suppresses glucagon secretion Lowers hepatic glucose production
Improves insulin resistance
Safety and Tolerability
Low risk of hypoglycemia No additional weight gain
Pancreatic β -cell
Pancreatic α -cell
Drucker DJ, Nauck MA. Lancet. 2006;368:1696–1705Del Prato S, et al. Int J Clin Pract 2005; 59:1345–1355.Inzucchi SE. JAMA. 2002;287:360–372.
Kidney in diabetes: Prevalence, implications and treatment
limitations
Approximately 40% of type 2 diabetes patients have renal complications†
* Normal kidney function, no sign of kidney damage** Albuminuria – kidney damage
†Based on data from 1462 patients aged ≥20 years with T2DM who participated in the Fourth National Health and Nutrition Examination Survey (NHANES IV) from 1999 to 2004.
9.5
50.8
8.611.1
17.7
2.3Data missing
no CKD
CKD stage 1
CKD stage 2
CKD stage 3
CKD stage 4/5
CKD prevalence was greater among people with diabetes than among those without diabetes (40.2% versus 15.4%)
CKD Stage eGFR (mL/min)
No CKD ≥90*
1 ≥90**
2 60–89
3 30–59
4 15–29
5 <15 or dialysis
1. Koro CE, et al. Clin Ther. 2009;31:2608–17; 2. Coresh J, et al. JAMA. 2007;298(17) 2038-2047
*Defined as not reaching the target HbA1c of 7.0%2. **Defined as defined as a urinary albumin-to-creatinine ratio ≥ 30 ug/mg† defined as hypertriglyceridemia in male subjects
At least 67% of all patients with type 2 diabetes have cardiovascular risk factors that also affect the kidneys
Prevalence of risk factors for declining renal function:
Risk factor Prevalence in T2DM patients
30%3
63%2
67%1
Microalbuminuria**3
1
Poor glycemic control*
2
ArterialHypertension
Dyslipidemia†4 24%** 4,5
1. CDC National Diabetes Fact Sheet 2011. http://www.cdc.gov/diabetes/pubs/factsheet11.htm (Accessed Sept 2011)2. Saydah SH, et al. JAMA. 2004;291:335–342; 3. Cheung BMY, et al. Am J Med. 2009;122:443–53.4. Mooradian A, Nat Clin Pract Endocrinol Metab. 2009:5;150–15; 5. Kannel WB. Am Heart J. 1985;110;1100–7.
Risk range is likely to be significantly higher than 67% due to overlap of risk factors in individuals
Declining renal function increases risk of severe hypoglycaemia
Decline in renal function dramatically increases the risk of hypoglycaemia in patients with type 2 diabetes
Ris
k fo
r se
vere
hyp
ogly
caem
ia(in
cide
nce
rate
rat
io)
0
1
2
3
4
5
6
7
8
9
+CKD / + Diabetes
– CKD / + Diabetes
+ CKD / –Diabetes
– CKD / –Diabetes
Moen MF, et al. Clin J Am Soc Nephrol. 2009 Jun;4(6):1121–1127
+ CKD+ Diabetes
– CKD+ Diabetes
+ CKD– Diabetes
– CKD– Diabetes
Around 74% of sulphonylurea-induced severe hypoglycaemic events (loss of consciousness) occur in patients with reduced renal function
Linagliptin is the first only DPP-4 inhibitor that does not require dose adjustment: Easy use
5mg5mg
5 m
g
100
mg
5 m
g
50 m
g2
5 mg
50 m
g B
ID5
0 mg
QD
2.5
mg
Linagliptin(Trajenta®)
Sitagliptin(Januvia®)
Vildagliptin(Galvus®)
Saxagliptin(Onglyza®)
No renal issues
At risk of renal impairment
Mild renal impairment
Moderate renal impairment
Severe renal impairment
Linagliptin Overview
* Please consult the prescribing information before prescribing1 In placebo controlled clinical trials adverse reactions that occurred in ≥5% of patients receiving linagliptinUS prescribing information
Convenience
Safety & Tolerability
No dose adjustment in renal or hepatic impairment
Efficacy
Meaningful and reliable efficacy across complete range of oral diabetes therapies
Durable efficacy in longer term treatment up to 2 years
Overall safety profile similar to placebo:• No clinically relevant weight gain• Very low risk of hypoglycemia
Most common adverse reaction1: nasopharyngitis
Not associated with an increase in CV risk
One dose fits all* Primarily excreted via bile & gut
Renal excretion = 5%Once-daily
With or without food
Linagliptin
Linagliptin – a DPP-4 inhibitor with a unique xanthine-based structure
Saxagliptin
Sitagliptin
Vildagliptin
Adapted from Deacon CF. Diabetes Obes Metab. 2011; 13: 7–18.
Peptidomimetic DPP-4 inhibitors
Linagliptin
N
NN
N
O
O
N
NN
NH2
Xanthine-based structure
DPP-4 inhibitors mimicking dipeptides DPP-4 inhibitors directly binding to the active site of the enzyme
Non-peptidomimetic DPP-4 inhibitors
0
20
40
60
80
100
0 4 8 12 16 20 24
Linagliptin provides long-lasting DPP-4 inhibition in patients with type 2 diabetes
Adapted from Heise T et al. Diabetes Obes Metab. 2009;11(8):786–94
Time after administration (h)Steady State linagliptin 5mg once daily – oral application
DP
P-4
In
hib
itio
n [
%]
Tablet takenlinagliptin 5 mg
Tablet takenlinagliptin 5 mg
Steady-state plasma levels are already reached after the third dosing interval providing >91% of DPP-4 inhibition at peak levels
Linagliptin increases post-prandial* active GLP-1 levels in patients with type 2 diabetes
4.4
13.9
0
2
4
6
8
10
12
14
16
GLP
-1 (p
mol
/L)
Forst T, et al. Diabetes Obes Metab. 2011;13: 542–550.
Day 0 Day 29
3.2 foldincrease
n=15
* Mean plasma levels of active GLP-1 measured 30 min after a meal tolerance test.
Linagliptin 5 mg
Linagliptin restores ß-cell survival in isolated human islets
LipotoxicityGlucotoxicity Inflammatory stress
Oxidative stressPhysiological
conditionGlucotoxicity
With linagliptin, less apoptosis is seen under stress conditions. The study provides evidence of a direct protective effect of linagliptin on ß-cell survival and insulin secretion
Vehicle
Linagliptin (100 nM)
Insulin (ß-cell marker)
TUNEL (marker for apoptosis)
*
**** ** **
**
*
*
*
*
% T
UN
EL
+β
-ce
lls
0
1
2
3
4
5 Vehicle Linagliptin Example of TUNEL Staining
Note: Human isolated islets were exposed for 48 h. ß-cell apoptosis was analyzed by double labeling for the TUNEL assay and insulin. Results are means from 3 independent experiments from 3 donors *P<0.05 to 5.5 mM glucose alone, **P<0.05 to vehicle
Source: Shah P, et al. ADA 2010, Poster 1742-P
Meaningful efficacy across complete range of oral treatment algorithms
Linagliptin treatment effect across treatment lines
International*Metformin ineligible** Japan†
Add-on to met*
Add-on to SU**
Add-on to met + SU*
With metformin
(Low dose)*
Mono Dual combi
p <0.0001 for all studies vs. baseline, for initial combination vs. respective monotherapy
With metformin
(High dose)*
Initial combiTriple combi
Diet and exerciseDiet and exercise
-1.3%
-0.6%
-0.9%-0.7%
-0.6% -0.6%-0.5%
-1.7%
Placebo-corrected, adjusted mean change from baseline HbA1c
* 24 weeks treatment duration** 18 weeks treatment duration
† 12 weeks treatment durationDel Prato, et al. Diabetes Obes Metab. 2011;13:258-267 (International); Barnett, et al. EASD 2010, Poster 823-P (Metformin ineligible); Kawamori et al. EASD 2010 , Poster 696-P (Japan); Taskinen et al. Diabetes Obes Metab. 2011;13: 65-74 (Add-on to metformin); Lewin et al. EASD 2010, Poster 821-P (Add-on to SU); 3. Owens DR, et al. ADA 2010, Poster 548-P (Add-on to metformin + SU); Haak T., et al. ADA 2011 oral presentation 279-OR (Initial combi with met).
Linagliptin achieves HbA1c decrease of up to 1.2% in poorly controlled patients
Significant HbA1c reductions in type 2 diabetes patients with baseline HbA1c ≥ 9%
1. Del Prato S, et al. Diabetes Obesity and Metabolism 2011;13(3):258–267.2. Taskinen M-R, et al. Diabetes Obesity and Metabolism 2011;13(1):65–74.3. Owens DR, et al. Diabetic Medicine 2011;28,1352-1361
Ad
jus
ted
me
an c
han
ge
in H
bA
1c
(%)
fro
m b
ase
lin
e a
t w
eek
24
-1.5
-1
-0.5
0
0.5
-0.72-0.80
-1.01
Linagliptin monotherapy1
Add-on to metformin2
Add-on to metformin + SU3
n = 29 96
Mean baseline HbA1c (%) 9.5 9.4
48 13624 55
9.5 9.5 9.4 9.4
0.15
-0.23
-0.40
-0.86-0.95
-1.20
PlaceboLinagliptin
Linagliptin placebo-corrected
p <0.0001p <0.0001p <0.0001
p-values for between group difference (versus placebo)
-0.6
-0.6
Linagliptin
Glimepiride
HbA1c change over 2 yearsAdjusted1 mean over time ± SE, percent
Mean (± SE) of HbA1c Percent
7.5
7.0
6.5
6.0
Treatment duration Weeks10410095908580757065605550454035302520151050
1 Model includes treatment, baseline HbA1c and number of prior OADs2 As described previously by Seck et al. Int J Clin Pract 2010; 64: 562-576Source: Gallwitz et al. American Diabetes Association, 71th Scientific Sessions, San Diego, CA, June 24-28,
2011; 39-LB
Linagliptin, has similar efficacy as a SU over 104 weeks1,2
-1
-0.5
0
0.5
Linagliptin provides reliable HbA1C reductions independent of patient age
≤50 years
Change from baseline HbA1c by age1
Adjusted mean change from baseline at 24 weeks of treatment
p <0.0001p <0.0001p <0.0001
51 to 64 years 65 to 74 years ≥75 years
p =0.0002
n = 363 970
Mean baseline HbA1c (%) 8.2 8.2
194 442
Ad
jus
ted
me
an c
han
ge
in H
bA
1c
(%)
fro
m b
ase
lin
e a
t w
eek
24
8.2 8.2
152 398
8.1 8.1
19 66
8.1 8.0
-0.56
0.02
-0.54-0.64
-0.02
-0.66-0.60
-0.09
-0.69
0.03
-0.80-0.83
p-values for between group difference (versus placebo)
PlaceboLinagliptin
Linagliptin placebo-correctedSource: Patel S, et al. 2011 EASD Poster P-832
Pre-specified sub-group analysis on pooled data from 4 pivotal phase III randomized placebo-controlled trials: treatment in monotherapy, add-on to metformin, add-on to metformin + SU, initial combination with pioglitazone.
-0.17
0.03
-0.01
-0.66-0.59
-0.67
-0.49-0.62 -0.66
-1
-0.5
0
0.5
Linagliptin provides reliable HbA1c reductions independent of time since diagnosis of type 2 diabetes
≤ 1 year
Change from baseline HbA1c by time since diagnosis of type 2 diabetesAdjusted mean at 24 weeks of treatment, percent
p <0.0001p <0.0001p <0.0001
> 1 to ≤ 5 years > 5 years
Ad
jus
ted
me
an c
han
ge
in H
bA
1c
(%)
fro
m b
ase
lin
e a
t w
eek
24
n = 227 570
Mean baseline HbA1c (%) 8.2 8.1
381 1045120 261
8.0 8.1 8.2 8.2
p-values for between group difference (versus placebo)
PlaceboLinagliptin
Linagliptin placebo-correctedSource: Patel S, et al. 2011 EASD Poster P-832
Pre-specified sub-group analysis on pooled data from 4 pivotal phase III randomized placebo-controlled trials: treatment in monotherapy, add-on to metformin, add-on to metformin + SU, initial combination with pioglitazone.
Linagliptin significantly improves ß-cell function in monotherapy
Note: Baseline HOMA-%B: 66.9 (mU/l)/mmol/l) linagliptin-treated group; 62.3 (mU/l)/mmol/l) placebo group Baseline proinsulin:insulin: 0.20 linagliptin-treated group; 0.18 placebo group
The mean change from baseline in HOMA-%B for linagliptin at 24 weeks was an increase of 5.0 (mU/l)/(mmol/l) versus a decrease of 17.2 (mU/l)/(mmol/l) with placebo (*p<0.049)
Del Prato S, et al. Diabetes Obes Metab. 2011;13: 258–267.
0
5
10
15
20
25
30
35
40
Pla
ceb
o-c
orr
ecte
d a
dju
sted
mea
n c
han
ge
in
(HO
MA
-%B
[(m
U/l
) ×
(m
mo
l/l)
] fr
om
bas
elin
e at
wk
24
+ 22.2
-0.07
-0.06
-0.05
-0.04
-0.03
-0.02
-0.01
0
- 0.04
Pla
ceb
o-c
orr
ecte
d a
dju
sted
mea
n c
han
ge
in
pro
insu
lin
/in
suli
n r
atio
fro
m b
asel
ine
at w
k 24
The mean change from baseline in proinsulin/insulin for linagliptin at 24 weeks was an decrease of 0.02 versus an increase of 0.02 with placebo (†p<0.025)
Effect of linagliptin monotherapyon HOMA-%B
Effect of linagliptin monotherapyon proinsulin/insulin ratio
†
*
+35% change from baselinerelative to placebo
at 24 weeks
- 21% change from baselinerelative to placebo
at 24 weeks
First in man study - Linagliptin Phase I: Single rising dose study
During controlled clinical trials in healthy subjects, with single doses of up to 600 mg of linagliptin (equivalent to 120 times the recommended daily dose) there were no dose related clinical adverse drug reactions. There is no experience with doses above 600 mg in humans.
>100-fold therapeutic window
Source: Hüttner et al. 2008 J. Clin. Pharmacol. 48: 1171-8
Recommended dose: 5mg QD
600 mg dose well tolerated (therapeutic dose is 5 mg)
Selectivity for DPP-4 compared to the DPP gene family (QPP/DPP-2, DPP-8 and DPP-9)
DPP-4 Inhibitors:Selectivity for DPP-4 compared to QPP*/DPP-2, DPP-8 and DPP-9
Deacon CF. Diabetes, Obes Metab. 2011;13(1):7–18.
QPP*/DPP-2 DPP-8 DPP-9
Linagliptin > 100,000 40,000 > 10,000
Sitagliptin > 5,500 > 2,660 > 5,500
Vildagliptin > 100,000 270 32
Saxagliptin > 50,000 390 77
Alogliptin > 14,000 > 14,000 > 14,000
* Quiescent cell proline dipeptidase
Linagliptin is well tolerated
1. Organ-specific adverse events taken from label of currently marketed DPP-4 inhibitor in the US; * Linagliptin US PISchernthaner G., et al. ADA 2011 Abstract 2327-PO. Pooled data from 8 studies
Organ-specific adverse event (AE) rate for AE previously associated with the DPP-4 inhibitor class1
Upper respiratory tract infection
Nasopharyngitis
Cough
Blood and lymphatic system disorders
Hypersensitivity
Urinary tract infection
Hepatic enzyme increase
Headache
Pancreatitis:
Pancreatitis was reported more often in patients randomized to linagliptin
(1 per 538 person years versus zero in 433 person years for comparator)* Serum creatinine increase
nLinagliptin
2,523
3.3%
5.9%
1.7%
1.0%
0.1%
2.2%
0.1%
2.9%
0.0%
Placebo1,049
4.9%
5.1%
1.0%
1.2%
0.1%
2.7%
0.1%
3.1%
0.1%
75.6 76.4
0
20
40
60
80
100
Linagliptin brings patients to target (HbA1c <7%) with significantly less hypoglycemia and relative weight loss compared to glimepiride
Linagliptin Glimepiride
Rate of patients achieving HbA1c target <7%Percent of patients at week 104 completers cohort3
1 Treated Set: Linagliptin n=776, glimepiride n=7752 Model includes baseline HbA1c, baseline weight, no. prior OADs, treatment, week repeated within patients and week by treatment interaction3 Completers cohort: linagliptin n=233, glimepiride n=271
7.5
Incidence of hypoglycemiaPercent of patients - Treated set1
Adjusted2 means for body weight change from baseline ± SE Kg - FAS (OC)
2.0
1.5
1.0
0.5
0
-0.5
-1.0
-1.5
-2.0
GlimepirideLinagliptin
p<0.0001
28 104weeks
52 7812
-2.9
0
10
20
30
40
50
Linagliptin Glimepiride
p<0.0001
Gallwitz B., et al. ADA 2011 Late Breaker 39-LB
+1.4
-1.5
79%reduction
~ 5% of orally administered linagliptin is excreted via the
kidneys
The majority of linagliptin is excreted unchanged via bile and gut
Metabolism
~90% transferred unchanged
~10% (inactive) metabolite
~ 95% of orally administered linagliptin is excreted via the
bile and gut
Excretion1:
~95% bound to plasma proteins(in essence DPP-4)
Absolute bioavailability: ~30%, with or without food
Tablet intake: 5mg QD, independent of food
Absorption
Source: US prescribing information
1 At steady state
Share of renal excretion
All other DPP-4 inhibitors are primarily excreted via the kidneys
They all require dose-adjustment, or are not recommended in patients with renal impairment. Drug-related kidney monitoring may also be required
No dose adjustment and/or no additional drug monitoring required1
60-71
Saxagliptin4
Vildagliptin3
Sitagliptin287
Linagliptin1
1. Linagliptin US prescribing information2. Vincent SH et al. Drug Metab Dispos. 2007;35(4): 533–5383. He H, et al. Drug Metab. Dispos.2009 37(3):536–5444. Saxagliptin US prescribing information5. Christopher R et al. Clin Ther. 2008;30(3):513–527.
* of currently globally approved DPP-4 inhibitorsData from multiple trials, includes metabolites and unchanged drug; excretion after single dose administration of [14C] labeled drug
Linagliptin is the only DPP-4 inhibitor which is primarily excreted by bile and gut*
5.00000000000
057
85.0000000000
09775.0000000000
085
%
%
%
%
Saxagliptin
(5-hydroxy saxagliptin metabolite)2
1234567
Normal Mild Moderate Severe ESRD
Vildagliptin
(LAY151 metabolite)3
1234567
Normal Mild Moderate Severe ESRD
Sitagliptin
1234567
Normal1 Mild Moderate Severe ESRD
Linagliptin
1234567
Normal Mild Moderate Severe ESRD
No dose adjustment: Linagliptin is the only DPP-4 inhibitor that can be given in full dose even in patients with renal impairment
ESRD = end-stage renal disease; HD = Haemodialysis; * Estimated creatinine clearance values were calculated using the Cockcroft-Gault formula
(n=6) (n=6) (n=6) (n=6) (n=6)>80 >50 to ≤80 >30 to ≤50 ≤30 <30 on HD
Renal impairment status
Creatinine clearance* (mL/min)
Source: Graefe-Mody U., et al. 2011 Diabetes, Obes Metab. (in press)
(n=6) (n=6) (n=6) (n=6) (n=6)>80 >50 to ≤80 >30 to ≤50 ≤30 on HD
Renal impairment status
Creatinine clearance* (mL/min)
(n=8) (n=8) (n=8) (n=7) (n=8)>80 >50 to ≤80 >30 to ≤50 ≤30 <30 on HD
Renal impairment status
Creatinine clearance* (mL/min)
(n=8) (n=8) (n=8) (n=7) (n=8)>80 >50 to ≤80 >30 to ≤50 ≤30 <30 on HD
Renal impairment status
Creatinine clearance* (mL/min)
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Renal/ functionbaseline1
Diabetes treatment Renal function1
Normal renal function2
(n=1,216 )linagliptin120 ± 33 119 ± 34
Mild renal impairment2
(n=314)linagliptin67 ± 8 69 ± 13
Moderate renal impairment2
(n=27)linagliptin45 ± 5 48 ± 8
Severe renal impairment3
(n=68)linagliptin22 ± 6 22 ± 7
In clinical trials renal function was unaffected by treatment with linagliptin
1. Mean GFR ± SEM according to Cockcroft-Gault in mL/min (for normal, mild and moderate renal impairment) and according to MDRD (for severe renal impairment); 24 weeks trial duration for normal, mild, moderate, 12 weeks for severe
2. Pooled analysis of three PIII clinical trials (normal, mild and moderate renal impairment). Cooper M., et al. ADA 2011, Poster 1068-P3. Individual analysis (severe renal impairment). Sloan L., et al. ADA 2011 Poster 413-PP
Influence of hepatic impairment on pharmacokinetics & exposure of Linagliptin
No dosage adjustment for linagliptin is necessary for patients with mild, moderate or severe hepatic impairment
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Source: Data on file
Healthy Mild (Grade A) Moderate (Grade B) Severe (Grade C)
Hepatic impairment (Child-Pugh classification)
n=7n=8 n=9 n=8
Patients with mild moderate and severe hepatic impairment(according to the Child-Pugh classification A-C)
Child-Pugh Grade Points
A Well-compensated disease 5-6
B Significant functional compromise
7-9
C Decompensated disease 10-15
Clinical characteristics of Linagliptin compared to other DPP-4 inhibitors
* Without limitations in renal or hepatic impairment: please consult the label before prescribing
Characteristics Linagliptin Sitagliptin Vildagliptin Saxagliptin
One dose fits all* No dose adjustment in renal impairment No dose adjustment in hepatic impairment No dose adjustment based on drug-drug-interactions No drug-related monitoring of renal function No skin toxicity in pre-clinical studies1 No liver toxicity1 No reports of decrease in renal function1
1. Linagliptin, Sitagliptin, Saxagliptin US prescribing informations. Other sources: Vildagliptin EU SmPC
In a prospective, pre-specified meta-analysis, Linagliptin was not associated with an increased CV risk
Incidence rate of CV events1
Number and percentage of patients
Out of 3,319 patients= 0.3%
1. CV events as defined as primary endpoint; 2. 977 patients receiving placebo, 781 glimepiride, 162 voglibose
Comparator2Linagliptin
Out of 1,920 patients= 1.2%
Risk ratio0.34 95% CI(0.15/0.74) p<0.05
Johansen O-E., et al. ADA 2011 Late breaker 30-LB
Years of exposure 2,060 1,372
Safety observations so far are promising, therefore all DPP-4 compounds are currently involved in outcome studies
Risk ratio for major CV events1-5
1. Johansen O-E., et al. ADA 2011 Late breaker 30-LB; 2. Williams-Herman D, et al. BMC Endocr Disord. 2010;10:7. 3. Schweizer A, et al. Diabetes Obes Metab. 2010;12(6):485–494; 4. Frederich R, et al. Postgrad Med. 2010;122(3):16–27;5. White et al. 2010, ADA Scientific Sessions. Abstract 391-PP
Total patients in analysis
5,239
10,246
10,988
4,607
Primaryendpoint
CV death, MI, stroke,hospitalisation due to angina pectoris
Med DRA termsfor MACE
Acute coronary syndrome, transient ischaemic attack, stroke, CV death
MI, stroke, CV death
Comments
Pre-specified/independent adjudication
No formal adjudication;Post-hoc analysis
Pre-specified/Independent adjudication
Pre-specified/Independent adjudication
DPP-4 inhibitor better Comparator better
11/21/41/8 2 4 8
Linagliptin1
Sitagliptin2
Vildagliptin3
Saxagliptin4
0.34
0.68
0.84
0.42
0.15 0.74
0.41 1.12
0.62 1.14
0.23 0.80
No increased risk of CV events was observed in patients randomly treated with DPP-4 inhibitors
Linagliptin can be used with no dose adjustment in various patient populations
Source: Linagliptin US prescribing information
No limitationsNo dose
adjustment
Hepatic impairment
Any age group including geriatric
Ethnicity
Long disease duration
Obese vs lean
Cardiovascular disease
Declining renal function
Thanks for your attention!!