Cardiovascular Safety of Linagliptin

1. Cardiovascular Safety of Linagliptin Rafael Castillo, MD, FPCP, FPCC PHA Scientific Sessions Crowne Plaza Hotel May 24, 2012

2. DISCLOSURES • Received during the last 2 years consulting and/or lecturing fees from BoehringerIngelheim, Therapharma, AstraZeneca, Abbott, LRI, Otsuka, Sanofi Aventis, Pfizer, GSK and Takeda • Received during the last 2 years research grants from BoehringerIngelheim, Novartis Philippines Inc., Unilab, Therapharma • Owns stocks in some pharmaceutical and diagnostics/devices companies, and a medical publishing company

3. Healthy controls Type 2 diabetes Normal incretin effect Diminishedincretin effect * * * * * * * * * * THE INCRETIN EFFECT DPP4 Therapy 80 80 60 60 40 40 IR insulin (mU/L) IR insulin (mU/L) 20 20 0 0 –10 –5 60 120 180 –10 –5 60 120 180 Time (minutes) Time (minutes) * Adapted om Nauck M et al Diabetologia 1986;29:46–52. fr

4. The incretins GLP-1 and GIP mediate glucose-stimulated insulin release Food intake Glucose-dependent insulin secretion Increases glucose utilization by muscle and adipose Pancreas β-cells α-cells Glucose-dependent glucagon suppression 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.

5. Effects of GLP-1 on the β Cell in Healthy Subjects Postprandial Insulin release

6. GLP-1 Is Cleaved and Inactivated by DPP-4

7. DPP-4 inhibitors: mechanism of action Food intake Insulin secretion Increases glucose utilization by muscle and adipose Pancreas β-cells α-cells Glucagon suppression Decreased hepatic glucose release improves overall glucose control Intestine Active GLP-1 (7–36) DPP-4 Inactive GLP-1 (9–36) amide His-Ala cleaved from amino terminus DPP-4inhibitors Data from Drucker DJ. Expert Opin Invest Drugs. 2003; 12(1): 87–100. Ahrén B. Curr Diab Rep. 2003; 3: 365–372.

8. Linagliptin inactivates the action of the DPP-4 serine protease X X DPP-4i DPP-4i

9. 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 Most common adverse reaction1: nasopharyngitis Sustained efficacy in longer term treatment up to 2 years Not associated with an increase in CV risk Linagliptin Primarily excreted via bile & gut One dose fits all* Once-daily Renal excretion = 5% With or without food No dose adjustment in renal or hepatic impairment Convenience

10. 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

11. 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 • 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

12. Linagliptin CV meta-analysis: Existing morbidity and CV risk characteristics at baseline Johansen O-E., et al. ADA 2011 Late breaker 30-LB

13. Linagliptin CV meta-analysisCV treatment regimens at baseline * included beta-blockers, ACE inhibitors, ARBs, diuretics and others antihypertensive agents Breakdown: Use of anti-hypertension treatments at baseline (%) Johansen O-E., et al. ADA 2011 Late breaker 30-LB; Linagliptin data on file

14. 5 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 1,920 patients = 1.2% Out of 3,319 patients = 0.3% Comparator2 Linagliptin 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

15. 5 In a prospective, pre-specified meta-analysis, linagliptin was not associated with an increased CV risk Linagliptin n = 3,319 Total comparators n = 1,920 Individual components of composite primary endpoint* Number of events Non-fatal stroke Non-fatal MI Hospitalization due to unstable angina CV death 0.52 0.24 0.74 0.11 Hazard ratio 95% CI 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

16. 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 FDA custom MACE CV events 10 20 26 32 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 0.56 0.34 0.36 Hazard ratio 95% CI 0.17/0.78 0.33/0.94 0.15/0.75 Johansen O-E., et al. ADA 2011 Late breaker 30-LB

17. 6 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 inhibitors Total patients in analysis Primary endpoint Comments DPP-4 inhibitor better Comparator better Linagliptin1 Pre-specified/ independent adjudication CV death, MI, stroke, hospitalisation due to angina pectoris 5,239 0.34 0.15 0.74 No formal adjudication; Post-hoc analysis Med DRA terms for MACE 10,246 Sitagliptin2 1.12 0.41 0.68 Vildagliptin3 Pre-specified/ Independent adjudication Acute coronary syndrome, transient ischaemic attack, stroke, CV death 10,988 1.14 0.84 0.62 Pre-specified/ Independent adjudication MI, stroke, CV death Saxagliptin4 4,607 0.80 0.23 0.42 Pre-specified/ Independent adjudication Non-fatal MI, non-fatal stroke, CV death 3,489 Alogliptin5 0.21 1.19 0.63 1/8 1/4 1/2 1 2 4 8 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

18. Linagliptin CV Meta-analysis: Study 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

19. 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

20. CAROLINA1,2 compares Linagliptin with the current gold-standard as recommended by ADA and EASD ADA/EASD type 2 diabetes consensus algorithm for the initiation and adjustment of therapy. Diabetologia2009;52:17–30 (modified) Diabetes therapy algorithm and target patients for CAROLINA1,2 Consider other agents or insulin therapy Tier 2 Therapy algorithm TZDs or GLP-1 agonist Step 3 Add or intensify insulin Target patientsfor CAROLINA SU (2nd generation preferred) or basal insulin Tier 1 Step 2 Step 1 Lifestyle interventions/metformin 1. Rosenstock J., et al. ADA 2011 Poster 1103-P 2. Clinicaltrial.gov NCT01243424

21. 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 Linagliptin 5mg Glimepiride 1-4mg1 vs. 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 stroke 4. Hospitalization for unstable angina pectoris CAROLINA will evaluate CV safety of Linagliptin in patients with T2DM at highCV risk 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 1 16 weeks titration phase of glimepiride up to 4mg/day Rosenstock J., et al. ADA 2011 Poster 1103-P Clinicaltrial.gov NCT01243424

22. 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: • Previous CV diagnosis or manifestation • Evidence of vascular related end-organ damage1 • Age ≥ 70 years • 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

23. 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 pectoris 3 Major Adverse Cardiovascular Events (CV death, non-fatal MI, non-fatal stroke) ClinicalTrials Identifiers: 1. NCT01243424, 2. NCT00790205, 3. NCT01107886, 4. NCT00968708

24. 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.