Rafael Castillo, MD, FPCP, FPCC
PHA Scientific Sessions
Crowne Plaza Hotel
May 24, 2012
DISCLOSURES
 Received during the last 2 years consulting and/or
lecturing fees from Boehringer Ingelheim, Therapharma,
AstraZeneca, Abbott, LRI, Otsuka, Sanofi Aventis, Pfizer,
GSK and Takeda
 Received during the last 2 years research grants from
Boehringer Ingelheim, Novartis Philippines Inc., Unilab,
Therapharma
 Owns stocks in some pharmaceutical and
diagnostics/devices companies, and a medical publishing
company
THE INCRETIN EFFECT
DPP4 Therapy
Healthy controls
Normal
incretin effect
80
IR insulin (mU/L)
IR insulin (mU/L)
80
Type 2 diabetes
60
40
20
*
*
* * *
*
*
0
–10 –5
60
Diminished
incretin effect
40
*
* *
20
0
60
120
Time (minutes)
* Adapted om Nauck M et al Diabetologia 1986;29:46–52. fr
180
–10 –5
60
120
Time (minutes)
180
The incretins GLP-1 and GIP mediate
glucose-stimulated insulin release
Food intake
Pancreas
Increases glucose utilization
by muscle and adipose
Decreases hepatic glucose
release
Intestine
Active GLP-1 (7-36)
Active GIP
Glucose homeostasis
GLP-1=Glucagon-like peptide-1, secreted from L-cells in the distal gut;
GIP=glucose-dependent insulinotropic peptide, secreted from K-cells in the proximal gut.
Drucker DJ. Expert Opin Invest Drugs. 2003; 12(1): 87-100.
Ahrén B. Curr Diab Rep. 2003; 3: 365–372.
Effects of GLP-1 on the β Cell in Healthy Subjects
Postprandial
Insulin
release
GLP-1 Is Cleaved and Inactivated by DPP-4
DPP-4 inhibitors: mechanism of action
Food intake
Increases glucose utilization
by muscle and adipose
Pancreas
Decreased hepatic glucose release
improves overall glucose control
Intestine
Active GLP-1
(7–36)
DPP-4
inhibitors
DPP-4
Inactive GLP-1
(9–36) amide
His-Ala
cleaved from
amino terminus
Data from Drucker DJ. Expert Opin Invest Drugs. 2003; 12(1): 87–100.
Linagliptin inactivates the action of the DPP-4 serine
protease
DPP-4i
X
X
DPP-4i
Linagliptin clinical profile
Efficacy
Safety & Tolerability
Overall safety profile similar to placebo:
• No clinically relevant weight gain
• Very low risk of hypoglycemia
Meaningful and reliable efficacy
across complete range of oral
diabetes therapies
Sustained efficacy in
longer term treatment
up to 2 years
One dose fits all*
Once-daily
Most common adverse
reaction1: nasopharyngitis
Linagliptin
Not associated with
an increase in CV risk
Primarily excreted
via bile & gut
Renal excretion = 5%
With or without food
Convenience
No dose adjustment in
renal or hepatic impairment
Linagliptin CV meta-analysis
Cardiovascular risk with linagliptin in patients
with type 2 diabetes: A pre-specified,
prospective, and adjudicated meta-analysis
from a large phase 3 program
Johansen O-E., et al. ADA 2011 Late breaker 30-LB
Linagliptin CV meta-analysis: Setting and methodology
CV risk of linagliptin was assessed in a prospective, pre-specified meta-analysis on the
following 8 phase III double-blind randomized controlled trials
Study
Description
Duration
Treatments
Treated patients
NCT00641043
Efficacy and safety vs. placebo as add-on to pioglitazone
24 weeks
▪
▪
Linagliptin 5 mg
Placebo
259
130
NCT00621140
Efficacy and safety vs. placebo as monotherapy
24 weeks
▪
▪
Linagliptin 5 mg
Placebo
336
167
NCT00601250
Efficacy and safety vs. placebo as add-on to metformin
24 weeks
▪
▪
Linagliptin 5 mg
Placebo
523
177
NCT00602472
Efficacy and safety vs. placebo as add-on to metformin + SU
24 weeks
▪
▪
Linagliptin 5 mg
Placebo
792
263
NCT00622284
Efficacy and safety vs. glimepiride as add-on to metformin
52 Weeks
Interim results
▪
▪
Linagliptin 5 mg
Glimepiride 1 - 4 mg
778
781
NCT00654381
Efficacy and safety vs. placebo and voglibose as
monotherapy (In Japanese subjects)
26 weeks of
controlled
treatment
▪
▪
▪
▪
Linagliptin 5 mg
Linagliptin 10 mg
Voglibose 0.6 mg
Placebo
159
160
162
80
NCT00819091
Efficacy and safety vs. placebo as add-on to SU
18 weeks
▪
▪
Linagliptin 5 mg
Placebo
161
84
NCT00740051
Efficacy and safety vs. placebo where metformin therapy is
inappropriate (placebo patients are switched to glimepiride
after primary endpoint at 18 wks)
▪
▪
Linagliptin 5 mg
Placebo/Glimepiride
1 - 4 mg
151
76
18 weeks
interim results
• CV events were adjudicated by an independent committee
• Composite primary endpoint was the occurrence, or time to first occurrence, of: CV death (including fatal
myocardial infarction and fatal stroke); Non-fatal myocardial infarction; Non-fatal stroke; Hospitalization
for unstable angina pectoris
Johansen O-E., et al. ADA 2011 Late breaker 30-LB
Linagliptin CV meta-analysis: Existing morbidity and CV risk
characteristics at baseline
Linagliptin
(n = 3319)
Placebo
(n = 977)
Active
Comparator
(n = 943)
Total
Comparator
(n = 1920)
• Metabolic syndrome
60.3
55.9
67.8
61.7
• Previous coronary artery disease
10.4
10.1
11.9
11.0
• Previous cerebrovascular disease
2.9
3.6
4.1
3.9
• Previous peripheral artery disease
2.3
2.7
3.3
3.0
• Hypertension
63.8
60.2
72.1
66.0
22.6/14.4
19.1/16.1
29.5/15.7
24.2/15.9
CV risk factors (%)
• Ex-/current smoker
eGFR (based on MDRD),%
•
Normal
55.4
58.3
52.3
55.4
•
Mildly impaired
37.3
34.9
41.4
38.1
•
Moderately impaired
4.3
4.5
4.1
4.3
•
Severely impaired
0.1
0.1
0.0
0.1
9.8 ±8.2
9.1 ±8.1
11.6 ±8.6
10.3 ±8.4
27.8
24.7
37.8
31.1
Framingham 10 year CV risk score
•
Framingham risk score (%)
•
Framingham risk > 15% (%)
Johansen O-E., et al. ADA 2011 Late breaker 30-LB
treatment regimens at baseline
Linagliptin
(n = 3319)
Placebo
(n = 977)
Active
Comparator
(n = 943)
Total
Comparator
(n = 1920)
Anti-hypertension therapy* (%)
29.5
60.0
28.8
56.4
32.2
69.8
30.5
63.0
Lipid lowering therapy (%)
39.5
36.5
47.9
42.1
Any of the above therapies (%)
72.8
69.7
81.5
75.5
Acetylsalicylic acid (aspirin) (%)
* included beta-blockers, ACE inhibitors, ARBs, diuretics and others antihypertensive agents
Breakdown: Use of anti-hypertension treatments at baseline (%)
Linagliptin
Placebo
Active
Comparator
Total Comparator
Beta-blockers
32.7
31.8
34.3
33.2
ACE inhibitors
44.8
45.6
34.3
43.5
ARBs
22.0
21.8
21.0
21.9
Diuretics
22.9
23.3
41.3
22.0
Others
46.9
64.0
77.7
49.6
Johansen O-E., et al. ADA 2011 Late breaker 30-LB; Linagliptin data on file
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
Risk ratio
0.34
95% CI
(0.15/0.74
)
p<0.05
Out of
3,319
patients
= 0.3%
Linagliptin
Years of exposure
2,060
Out of
1,920
patients
= 1.2%
Comparato
r2 1,372
1. CV events as defined as primary endpoint; 2. 977 patients receiving placebo, 781 glimepiride, 162 voglibose
Johansen O-E., et al. ADA 2011 Late breaker 30-LB
In a prospective, pre-specified meta-analysis, linagliptin
was not associated with an increased CV risk
Individual components of composite primary endpoint*
Linagliptin n = 3,319
Number of events
12
Total comparators n = 1,920
11
10
8
7
6
6
4
2
3
2
2
2
1
0
Non-fatal
stroke
Hazard ratio
95% CI
Non-fatal
MI
Hospitalization
due to
unstable
angina
CV death
0.11
0.52
0.24
0.74
0.02/0.51
0.17/1.54
0.02/2.34
0.10/5.33
*Individual components are tertiary endpoints
Johansen O-E., et al. ADA 2011 Late breaker 30-LB
Linagliptin CV meta-analysis: Incidence for secondary composite CV endpoints
Incidence rate per 1,000 patient-years
Linagliptin
Total comparators
CV death/MI/stroke All major CV events
CV events
10
20
26
32
FDA custom MACE
9
19
Exposure, years
2,060
1,372
2,060
1,372
2,060
1,372
Patient
3,319
1,920
3,319
1,920
3,319
1,920
Hazard ratio
95% CI
0.36
0.56
0.34
0.17/0.78
0.33/0.94
0.15/0.75
Johansen O-E., et al. ADA 2011 Late breaker 30-LB
Safety observations so far are promising, therefore all DPP-4
compounds are currently involved in outcome studies
No increased risk of CV events was observed in patients randomly treated with DPP-4
Total
inhibitors
patients in
Primary
DPP-4 inhibitor better
Comparator better
analysis
Linagliptin1
0.15
Sitagliptin2
0.34
0.41
Vildagliptin3
0.68
1.12
0.62 0.84 1.14
Saxagliptin4
0.23
Alogliptin5
0.21
1/8
0.80
0.42
0.63
1.19
1/4
1/2
1
2
4
1-5
Risk ratio for major CV events
Comments
CV death, MI, stroke,
hospitalisation due to
angina pectoris
Pre-specified/
independent
adjudication
10,246
Med DRA terms
for MACE
No formal
adjudication;
Post-hoc analysis
10,988
Acute coronary syndrome, Pre-specified/
transient ischaemic attack, Independent
adjudication
stroke, CV death
5,239
0.74
endpoint
4,607
MI, stroke, CV death
Pre-specified/
Independent
adjudication
3,489
Non-fatal MI, non-fatal
stroke, CV death
Pre-specified/
Independent
adjudication
8
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
summary
CV risk of linagliptin was assessed in a prospective, pre-specified meta-analysis
on the 8 phase III double-blind randomized controlled trials
▪
This pre-specified, prospective, and independently adjudicated CV
meta-analysis of a large Phase III program provides new insight on
the CV safety profile of linagliptin
▪
Although a meta-analysis, with distinct limitations, the data
support a potential reduction of CV events with linagliptin
compared with pooled comparators
▪
This hypothesis is being tested prospectively in CAROLINA, a large
CV outcomes trial of linagliptin that is currently ongoing1,2
1. Rosenstock J., et al. ADA 2011 Poster 1103-P
2. Clinicaltrials.gov - NCT01243424
Source: Johansen O-E., et al. ADA 2011 Late breaker 30-LB
CAROLINA:
Cardiovascular safety of Linagliptin or
glimepiride in subjects with type 2 diabetes
mellitus at high CV risk
Clinical characteristics and associated increased
cardiovascular risk in type 2 diabetes mellitus
Rosenstock J., et al. ADA 2011 Poster 1103-P
Clinicaltrial.gov NCT01243424
CAROLINA1,2 compares Linagliptin with the current gold-standard as
recommended by ADA and EASD
Diabetes therapy algorithm and target patients for CAROLINA1,2
Consider
other agents
or insulin
therapy
Tier 2
TZDs or GLP-1 agonist
Step 3
Tier 1
Add or intensify insulin
Step 2
SU (2nd generation
preferred) or basal insulin
Step 1
Lifestyle interventions/metformin
Therapy
algorithm
Target
patients
for CAROLINA
ADA/EASD type 2 diabetes consensus algorithm for the initiation and
adjustment of therapy. Diabetologia 2009;52:17–30 (modified)
1. Rosenstock J., et al. ADA 2011 Poster 1103-P
2. Clinicaltrial.gov NCT01243424
CAROLINA will evaluate CV safety of Linagliptin in patients with T2DM at high
CV risk
Inclusion if at least one of the following is fulfilled
1. Previous vascular complications
2. Evidence of end organ damage such as e.g. albuminuria
3. Age > 70 years
4. Two or more specified traditional CV risk factors
With or without metformin background therapy (including
patients with contraindication to Metformin use in renal
impairment)
Linagliptin 5mg
vs.
Glimepiride 1-4mg1
n= 6,000; approx. 6-7 year follow up
Primary endpoint: Time to the first occurrence of the primary composite endpoint:
1. CV death (including fatal stroke and fatal MI)
2. Non-fatal MI
1 16 weeks titration phase of glimepiride up to 4mg/day
Rosenstock J., et al. ADA 2011 Poster 1103-P
Clinicaltrial.gov NCT01243424
3. Non-fatal stroke
4. Hospitalization for unstable
angina pectoris
CAROLINA: Main inclusion criteria
• Insufficient glycemic control (HbA1c 6.5% - 7.5% / 6.5% - 8.5% depending on
medication)
• High risk of CV events defined as any one (or more) of the following:
A. Previous CV diagnosis or manifestation
B. Evidence of vascular related end-organ damage1
C. Age ≥ 70 years
D. At least two of the following CV risk factors:
– T2DM > 10 years
– Systolic blood pressure > 140 mmHg (or on at least one blood pressure
lowering treatment)
– Current daily cigarette smoking
– LDL cholesterol ≥ 135 mg/dL (3.5 mmol/L) or on specific current
treatment for lipid abnormality
• Body Mass Index ≤ 45 kg/m2
• Age ≥ 40 and ≤ 85 years
1 A) MDRD defined moderate renal impairment: eGFR 30-59 mL/min/1.73 m2, B) Random spot urinary
albumin:creatinine ratio ≥ 30 μg/mg in two of three unrelated specimens in previous 12 months prior Visit 1a, C)
Retinopathy
Rosenstock J., et al. ADA 2011 Poster 1103-P
Clinicaltrial.gov NCT01243424
CAROLINA has a truly unique trial design
CAROLINA1
TECOS2
SAVORTIMI533
EXAMINE4
DPP-4 inhibitor
Linagliptin
Sitagliptin
Saxagliptin
Alogliptin
Comparator
SU (Active)
Placebo
Placebo
Placebo
6,000
14,000
16,500
5,400
Oct 2010
Nov 2008
May 2010
Sept 2009
Predominantly
on metformin
Any
Any
Any
Early
Advanced
Advanced
All, but limited
to CV events
Number of patients
Trial initiation
Background diabetes therapy
per protocol
Expected diabetes disease
stage
PRIMARY ENDPOINTS:
1,2,4 CV death, non-fatal MI, non-fatal stroke, hospitalization due to unstable angina pectoris
3
Major Adverse Cardiovascular Events (CV death, non-fatal MI, non-fatal stroke)
ClinicalTrials Identifiers: 1. NCT01243424, 2. NCT00790205, 3. NCT01107886, 4. NCT00968708
Summary:
Linagliptin is a novel DPP4 inhibitor that gives meaningful
and sustained HbA1c reductions.
It is the only DPP4 inhibitor that is excreted mainly through
the bile and gut – providing care to the kidneys of patients
with type 2 DM.
Meta-analysis on 8 Phase III clinical trials showed potential
reductions of CV events – this hypothesis is being tested
presently with the CAROLINA study.