cardiovascular safety of linagliptin
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Cardiovascular Safety of Linagliptin. Rafael Castillo, MD, FPCP, FPCC PHA Scientific Sessions Crowne Plaza Hotel May 24, 2012. DISCLOSURES. - PowerPoint PPT PresentationTRANSCRIPT
Cardiovascular Safety of Linagliptin
Rafael Castillo, MD, FPCP, FPCCPHA Scientific Sessions
Crowne Plaza HotelMay 24, 2012
DISCLOSURESReceived 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
* Adapted om Nauck M et al Diabetologia 1986;29:46–52. fr
Healthy controls Type 2 diabetes
Diminishedincretin effect
Normal incretin effect
Time (minutes)
0
40
60
80
IR in
sulin
(m
U/L
)
20
Time (minutes)
0
40
60
80
IR in
sulin
(m
U/L
)
20
–10 60 120 180–5 –10 60 120 180–5
** * * * *
** *
*
DPP4 Therapy
The incretins GLP-1 and GIP mediate glucose-stimulated insulin release
Drucker DJ. Expert Opin Invest Drugs. 2003; 12(1): 87-100.Ahrén B. Curr Diab Rep. 2003; 3: 365–372.
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.
Intestine
PancreasGlucose-dependent
insulin secretion
Increases glucose utilizationby muscle and adipose
Decreases hepatic glucose release
Glucose-dependent glucagon suppression
β-cells
α-cells
Glucose homeostasis
Food intake
Active GLP-1 (7-36)Active GIP
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
Data from Drucker DJ. Expert Opin Invest Drugs. 2003; 12(1): 87–100.Ahrén B. Curr Diab Rep. 2003; 3: 365–372.
Intestine
Food intake
Active GLP-1
(7–36)DPP-4
Inactive GLP-1
(9–36) amideHis-Ala
cleaved fromamino terminus
PancreasInsulin secretion
Increases glucose utilizationby muscle and adipose
Decreased hepatic glucose release improves overall glucose control
Glucagon suppression
β-cells
α-cells
DPP-4inhibitors
Linagliptin inactivates the action of the DPP-4 serine protease
DPP-4i DPP-4iX X
Linagliptin clinical profile
Convenience
Safety & Tolerability
No dose adjustment in renal or hepatic impairment
EfficacyMeaningful and reliable efficacy across complete range of oral diabetes therapies
Sustained efficacy in longer term treatment up to 2 years
Overall safety profile similar to placebo:• No clinically relevant weight
gain• Very low risk of
hypoglycemiaMost 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
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
Linagliptin CV meta-analysis: Setting and methodology
Study Description Duration Treatments Treated patients
NCT00641043 Efficacy and safety vs. placebo as add-on to pioglitazone 24 weeks ▪ Linagliptin 5 mg▪ Placebo
259130
NCT00621140 Efficacy and safety vs. placebo as monotherapy 24 weeks ▪ Linagliptin 5 mg▪ Placebo
336167
NCT00601250 Efficacy and safety vs. placebo as add-on to metformin 24 weeks ▪ Linagliptin 5 mg▪ Placebo
523177
NCT00602472 Efficacy and safety vs. placebo as add-on to metformin + SU 24 weeks ▪ Linagliptin 5 mg
▪ Placebo792263
NCT00622284 Efficacy and safety vs. glimepiride as add-on to metformin 52 WeeksInterim results
▪ Linagliptin 5 mg▪ Glimepiride 1 - 4 mg
778781
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
15916016280
NCT00819091 Efficacy and safety vs. placebo as add-on to SU 18 weeks ▪ Linagliptin 5 mg▪ Placebo
16184
NCT00740051Efficacy and safety vs. placebo where metformin therapy is inappropriate (placebo patients are switched to glimepiride after primary endpoint at 18 wks)
18 weeks interim results
▪ Linagliptin 5 mg▪ Placebo/Glimepiride
1 - 4 mg15176
Johansen O-E., et al. ADA 2011 Late breaker 30-LB
• 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
CV risk of linagliptin was assessed in a prospective, pre-specified meta-analysis on the following 8 phase III double-blind randomized controlled trials
Linagliptin CV meta-analysis: Existing morbidity and CV risk
characteristics at baselineLinagliptin (n = 3319)
Placebo(n = 977)
Active Comparator
(n = 943)
Total Comparator(n = 1920)
CV risk factors (%)• 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
• Ex-/current smoker 22.6/14.4 19.1/16.1 29.5/15.7 24.2/15.9
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
Framingham 10 year CV risk score
• Framingham risk score (%) 9.8 ±8.2 9.1 ±8.1 11.6 ±8.6 10.3 ±8.4
• Framingham risk > 15% (%) 27.8 24.7 37.8 31.1
Johansen O-E., et al. ADA 2011 Late breaker 30-LB
Linagliptin CV meta-analysis CV treatment regimens at baseline
Linagliptin (n = 3319)
Placebo(n = 977)
Active Comparator
(n = 943)
Total Comparator(n = 1920)
Acetylsalicylic acid (aspirin) (%) 29.5 28.8 32.2 30.5Anti-hypertension therapy* (%) 60.0 56.4 69.8 63.0Lipid lowering therapy (%) 39.5 36.5 47.9 42.1
Any of the above therapies (%) 72.8 69.7 81.5 75.5
Johansen O-E., et al. ADA 2011 Late breaker 30-LB; Linagliptin data on file
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
* included beta-blockers, ACE inhibitors, ARBs, diuretics and others antihypertensive agents
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
Comparator2
Linagliptin
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
In a prospective, pre-specified meta-analysis, linagliptin was not associated with an increased CV risk
*Individual components are tertiary endpoints
Johansen O-E., et al. ADA 2011 Late breaker 30-LB
21
6
2 23
7
11
0
2
4
6
8
10
12
CV deathHospitalization due to
unstable angina
Non-fatal MI
Non-fatal stroke
Total comparators n = 1,920Linagliptin n = 3,319
Individual components of composite primary endpoint*N
umbe
r of
eve
nts
95% CI 0.11
Hazard ratio 0.52
0.740.240.02/0.51 0.17/1.54 0.10/5.330.02/2.34
Linagliptin CV meta-analysis: Incidence for secondary composite CV endpointsIncidence rate per 1,000 patient-years
FDA custom MACE
All major CV events
CV death/MI/stroke
LinagliptinTotal comparators
CV events
Exposure, years
Patient
20
1,372
1,920
10
2,060
3,319
32
1,372
1,920
26
2,060
3,319
19
1,372
1,920
9
2,060
3,319
Johansen O-E., et al. ADA 2011 Late breaker 30-LB
95% CI 0.36Hazard
ratio0.56 0.34
0.17/0.78 0.33/0.94 0.15/0.75
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
3,489
Primaryendpoint
CV death, MI, stroke,hospitalisation due to angina pectoris
Med DRA termsfor MACE
Acute coronary syndrome, transient ischaemic attack, stroke, CV deathMI, stroke, CV death
Non-fatal MI, non-fatalstroke, CV death
Comments
Pre-specified/independent adjudication
No formal adjudication;Post-hoc analysis
Pre-specified/Independent adjudication
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
Alogliptin5
0.34
0.68
0.84
0.42
0.63
0.15 0.74
0.41 1.12
0.62 1.14
0.23 0.80
0.21 1.19
No increased risk of CV events was observed in patients randomly treated with DPP-4 inhibitors
Linagliptin CV Meta-analysis: Study summary
▪ 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
Source: Johansen O-E., et al. ADA 2011 Late breaker 30-LB
CV risk of linagliptin was assessed in a prospective, pre-specified meta-analysis on the 8 phase III double-blind randomized controlled trials
1. Rosenstock J., et al. ADA 2011 Poster 1103-P2. Clinicaltrials.gov - NCT01243424
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-PClinicaltrial.gov NCT01243424
Diabetes therapy algorithm and target patients for CAROLINA1,2
Target patients
for CAROLINA
ADA/EASD type 2 diabetes consensus algorithm for the initiation and adjustment of therapy. Diabetologia 2009;52:17–30 (modified)
TZDs or GLP-1 agonistAdd or intensify insulin
SU (2nd generation preferred) or basal
insulinLifestyle interventions/metformin
Consider other
agents or insulin therapy
Step 1
Step 2
Step 3
Tier 1
Tier 2
Therapy algorithm
CAROLINA1,2 compares Linagliptin with the current gold-standard as recommended by ADA and EASD
1. Rosenstock J., et al. ADA 2011 Poster 1103-P2. Clinicaltrial.gov NCT01243424
With or without metformin background therapy (including patients with contraindication to Metformin use in renal
impairment)
n= 6,000; approx. 6-7 year follow up
Inclusion if at least one of the following is fulfilled
1. Previous vascular complications 2. Evidence of end organ damage such as e.g. albuminuria3. Age > 70 years4. Two or more specified traditional CV risk factors
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
3. Non-fatal stroke4. Hospitalization for unstable angina pectoris
Glimepiride 1-4mg1Linagliptin 5mg vs.
1 16 weeks titration phase of glimepiride up to 4mg/day
CAROLINA will evaluate CV safety of Linagliptin in patients with T2DM at high CV risk
Rosenstock J., et al. ADA 2011 Poster 1103-PClinicaltrial.gov NCT01243424
CAROLINA: Main inclusion criteria
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
• 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 manifestationB. Evidence of vascular related end-organ damage1
C. Age ≥ 70 yearsD. 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
Rosenstock J., et al. ADA 2011 Poster 1103-PClinicaltrial.gov NCT01243424
CAROLINA1 TECOS2 SAVOR-TIMI533 EXAMINE4
DPP-4 inhibitor Linagliptin Sitagliptin Saxagliptin Alogliptin
Comparator SU (Active) Placebo Placebo Placebo
Number of patients 6,000 14,000 16,500 5,400
Trial initiation Oct 2010 Nov 2008 May 2010 Sept 2009
Background diabetes therapy per protocol
Predominantly on metformin Any Any Any
Expected diabetes disease stage Early Advanced Advanced All, but limited
to CV events
CAROLINA has a truly unique trial design
PRIMARY ENDPOINTS:1,2,4 CV death, non-fatal MI, non-fatal stroke, hospitalization due to unstable angina
pectoris3 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.