Ιδιαίτερα χαρακτηριστικά και ιδιότητες της λιναγλιπτίνης στην καθημερινή κλινική πρακτική

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1 Ιδιαίτερα χαρακτηριστικά και ιδιότητες της λιναγλιπτίνης στην καθημερινή κλινική πρακτική Καλλιόπη Κώτσα Επικ. Καθηγήτρια Ενδοκρινολογίας-Διαβητολογίας Τμήμα Ενδοκρινολογίας & ΜεταβολισμούΔιαβητολογικό Κέντρο Α Παθολογική Κλινική- Γ.Π.Ν. ΑΧΕΠΑ Θεσσαλονίκης

2 ΤΙ ΘΑ ΣΥΖΗΤΗΣΟΥΜΕ Αναστολείς DPP-4 Ινκρετινικές και μη ινκρετινικές δράσεις Διαφοροποίηση Λιναγλιπτίνη-Κλινικές μελέτες Η θέση του φαρμάκου στη θεραπεία του ΣΔ2 Νεότερες μελέτες

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6 Πλειότροπες Δράσεις GLP-1 Heart Brain Neuroprotection Appetite Stomach Gastric Emptying Cardioprotection Cardiac Output GLP-1 _ Liver GI Tract Insulin Secretion β-cell Neogenesis Glucose Production Drucker DJ. Cell Metab. 2006;3: Muscle + β-cell Apoptosis Glucose Uptake Glucagon Secretion

7 GLP-1R-εξαρτώμενες ενδοκυττάριες σηματοδοτικές οδοί στο μυοκαρδιακό κύτταρο Ussher J R, Drucker D J Endocrine Reviews 2012;33: by Endocrine Society

8 Αντιαθηρογόνες δράσεις GLP-1. Ussher J R, Drucker D J Endocrine Reviews 2012;33: by Endocrine Society

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12 12 Οι αναστολείς της DPP-4 διαφέρουν ως προς τις μοριακές δομές και τις φαρμακολογικές ιδιότητες Χημική κατηγορία β-φαιναιθυλαμίνες1 Γενική ονομασία Σιταγλιπτίνη2 Μοριακή δομή F Βιλνταγλιπτίνη3 5 N N N N N C F3 NC O Αμινοπιπεριδίνη8 Σαξαγλιπτίνη3,6,7 H F N H2 O F Κυανοπυρρολιδίνες Λιναγλιπτίνη9,10 H N H2 N N H HO NC O HO Ανασταλτική δράση επί της DPP-4 (IC50) 18 nm 62 nm 50 nm 1 nm Ημιζωή 12,4 h ~2 3 h 2,5 h (μητρική ουσία) 3,1 h (μεταβολίτης) h DPP-4=διπεπτιδυλική πεπτιδάση Kim D et al. J Med Chem. 2005;48(1): EU-SPC for JANUVIA, Matsuyama-Yokono A et al. Biochem Pharmacol. 2008;76(1): Villhauer EB et al. J Med Chem. 2003;46(13): EU-SPC for GALVUS, Augeri DJ et al. J Med Chem. 2005;48(15): EU-SPC for Onglyza, Feng J et al. J Med Chem.2007;50(10): Lee B et al. Eur J Pharmacol. 2008;589(1 3): Christopher R et al. Clin Ther. 2008;30(3):

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14 DPP-4 Inhibitors: Selectivity for DPP-4 compared to QPP*/DPP-2, DPP-8 and DPP-9 Selectivity for DPP-4 compared to the DPP gene family (QPP/DPP-2, DPP-8 and DPP-9) QPP*/DPP-2 DPP-8 DPP-9 Linagliptin > 100,000 40,000 > 10,000 Sitagliptin > 5,500 > 2,660 > 5,500 Vildagliptin > 100, Saxagliptin > 50, Alogliptin > 14,000 > 14,000 > 14,000 * Quiescent cell proline dipeptidase Deacon CF. Diabetes, Obes Metab. 2011;13(1):7 18.

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18 Αναστολείς DPP-4: Φαρμακοδυναμικές Ιδιότητες Μεταβολισμός Οδός απέκκρισης Σιταγλιπτίνη Πρακτικά δεν μεταβολίζεται Νεφρική Βιλνταγλιπτίνη Ηπατικός μεταβολισμός (ανενεργός μεταβολίτης, δεν εξαρτάται από P450) (22% μητρική ουσία, 55% μεταβολίτης) Σαξαγλιπτίνη Ηπατικός μεταβολισμός (ενεργός μεταβολίτης, εξαρτάται από P450 (CYP3A4/5)). Νεφρική (12-29% μητρική ουσία, % μεταβολίτης) Κόπρανα (22%) Λιναγλιπτίνη Δεν μεταβολίζεται Χοληφόρα (>70% αμετάβλητα) <6% από τα νεφρά (Ελάχιστη ηπατική CYP3A4 και CYP2C8) C.F. Deacon. Diabetes, Obesity and Metabolism 13: 7 18, 2011 (80% ως η μητρική ουσία) Νεφρική

19 Κλινικές διαφορές Νεφρική ανεπάρκεια Σιταγλιπτίνη Ήπια (Cl cr >50 ml/min) Βιλδαγλιπτίνη Σαξαγλιπτίνη Λιναγλιπτίνη Ηπατική ανεπάρκεια Μέτρια (Cl cr ml/min) ½ δόση Ήπια/ Μέτρια Σοβαρή ¼ δόση? ½ δόση? ½ δόση ½ δόση Σοβαρή (Cl cr <30 ml/min) Έλεγχος ηπατικής βιοχημείας στην βιλδαγλιπτίνη, έλεγχος περιοδικός νεφρικής λειτουργίας στην σαξαγλιπτίνη Δεν συνιστάται

20 Linagliptin Normal (n=6) Creatinine clearance* (ml/min) >80 Mild Moderate Severe (n=6) (n=6) >50 to 80 >30 to 50 (n=6) 30 ESRD (n=6) <30 on HD Fold increase in exposure relative to normal renal function Fold increase in exposure relative to normal renal function No dose adjustment: Linagliptin is the only DPP-4 inhibitor that can be given in full dose even in patients with renal impairment Sitagliptin Normal1 Mild Moderate Severe (n=6) (n=6) >50 to 80 >30 to 50 (n=6) Creatinine clearance* (ml/min) > Saxagliptin (5-hydroxy saxagliptin metabolite)2 Normal (n=8) Creatinine clearance* (ml/min) >80 Mild Moderate Severe (n=8) (n=8) >50 to 80 >30 to 50 (n=7) 30 ESRD (n=8) <30 on HD Vildagliptin (LAY151 metabolite)3 Normal (n=8) Creatinine clearance* (ml/min) >80 Mild Moderate Severe (n=8) (n=8) >50 to 80 >30 to 50 Renal impairment status ESRD = end-stage renal disease; HD = Haemodialysis; * Estimated creatinine clearance values were calculated using the Cockcroft-Gault formula Source: Graefe-Mody U., et al Diabetes, Obes Metab. (in press) (n=6) on HD Renal impairment status Fold increase in exposure relative to normal renal function Fold increase in exposure relative to normal renal function Renal impairment status (n=6) 30 ESRD (n=7) 30 Renal impairment status ESRD (n=8) <30 on HD

21 Λιναγλιπτίνη-Επίσημες ενδείξεις 8-[(3R)-3-aminopiperidin-1-yl]-7-(but-2-yn-1-yl)-3methyl-1-[(4-methylquinazolin-2-yl)methyl]-3,7-dihydro1H-purine-2,6-dione

22 Μονοθεραπεία Θεραπευτικές ενδείξεις Σε ασθενείς με σακχαρώδη διαβήτη τύπου 2, η λιναγλιπτίνη ενδείκνυται για τη βελτίωση του γλυκαιμικού ελέγχου: ως μονοθεραπεία σε ασθενείς που δεν ελέγχονται επαρκώς με δίαιτα και άσκηση μόνον και για τους οποίους η μετφορμίνη δεν είναι κατάλληλη λόγω αντενδείξεων ή μη ανεκτικότητας

23 Linagliptin significantly lowers HbA1c in monotherapy Efficacy and safety of linagliptin vs. placebo in type 2 diabetes patients with Insufficient glycemic control Adjusted HbA1c (%) mean (SE) 8.5 Linagliptin (n=333) Placebo (n=163) % Baseline Week 6 Week 12 Week 18 Linagliptin showed a continuous placebo-adjusted change in HbA1c over time of -0.46% at 6 weeks to -0.69% at 24 weeks (both P<0.0001) Note: Baseline HbA1c: 8.0% linagliptin-treated group; 8.0% placebo group; Full analysis set (FAS), Last observation carried forward (LOCF) Del Prato S, et al. Diabetes Obes Metab. 2011;13: Week 24

24 Linagliptin in monotherapy: Best efficacy seen in patients with higher baseline HbA1c values Placebo corrected, adjusted HbA1c (%) mean (SE) change from baseline at Wk 24 Efficacy and safety of linagliptin vs. placebo in type 2 diabetes patients with insufficient glycemic control Baseline HbA1c 0 <7.5% 7.5% 8.0% -0,57-0,55 8.0% 9.0% 9.0% -0,2-0,4-0,6-0,71-0,8-1, ,2 n= p-value p p Del Prato S, et al. Diabetes Obes Metab. 2011;13: ; Linagliptin data on file

25 Linagliptin in monotherapy: Safety and tolerability profile Adverse events (AEs) % (n) Linagliptin 5 mg Placebo (336) (167) No. of patients with any AEs Patients with AEs leading to discontinuation of trial drug Patients with serious AEs 3.0* 4.2 Patients with investigator-defined drug-related AEs Blood and lymphatic system disorders Gastrointestinal disorders Infections and infestations Investigations Metabolism and nutrition disorders Musculoskeletal and connective tissue disorders Nervous system disorders Reproductive system and breast disorders Respiratory, thoracic and mediastinal disorders Skin and subcutaneous tissue disorders No. of patients Note: Some patients are present in more than 1 category; *None was considered drug-related by the investigator Del Prato S, et al. Diabetes Obes Metab. 2011;13:

26 2ο φάρμακο 4.1 Θεραπευτικές ενδείξεις Σε ασθενείς με σακχαρώδη διαβήτη τύπου 2, η λιναγλιπτίνη ενδείκνυται για τη βελτίωση του γλυκαιμικού ελέγχου: ως διπλή από του στόματος χορηγούμενη θεραπεία σε συνδυασμό με μετφορμίνη, όταν η δίαιτα και η άσκηση μαζί με μετφορμίνη μόνο δεν παρέχουν επαρκή γλυκαιμικό έλεγχο.

27 Linagliptin significantly lowers HbA1c as add-on to metformin Efficacy and safety of linagliptin vs. placebo added to metformin background therapy in patients with type 2 diabetes Adjusted HbA1c (%) mean (SE) 8,5 8,0-0.64% 7,5 7,0 Baseline Week 6 Placebo (n=175) Week 12 Week 18 Linagliptin 5mg + Metformin (n=513) Significant placebo-corrected improvement in mean HbA1c of -0.64% observed at Week 24 after treatment with linagliptin (P<0.0001) Note: Baseline HbA1c: 8.09% linagliptin-treated group; 8.02% placebo group; Full analysis set (FAS), Last observation carried forward (LOCF) Taskinen MR, et al. Diabetes Obes Metab. 2011;13: Week 24

28 Linagliptin significantly lowers FPG levels as add-on to metformin Efficacy and safety of linagliptin vs. placebo added to metformin background therapy in patients with type 2 diabetes Adjusted FPG (mg/dl) mean (SE) mg/dl Baseline Week 6 Placebo (n=175) Week 12 Week 18 Week 24 Linagliptin (n=513) The placebo-adjusted change in FPG for linagliptin 24 weeks was a reduction of 21.1 mg/dl (p<0.0001) Note: Baseline FPG: mg/dl linagliptin-treated group; mg/dl placebo group; Full analysis set (FAS), Last observation carried forward (LOCF) Taskinen MR, et al. Diabetes Obes Metab. 2011;13:65 74.

29 Linagliptin significantly lowers 2h PPG Levels as add-on to metformin Efficacy and safety of linagliptin vs. placebo added to metformin background therapy in patients with type 2 diabetes 3.0 Placebo Linagliptin Linagliptin placebo-corrected Adjusted mean (SE) change in 2hPPG (mmol/l) from baseline at wk *** n= Mean baseline 2hPPG The mean change from baseline in 2hPPG (postprandial glucose) for linagliptin at 24 weeks was a reduction of -3.7 mmol/l (***p<0.0001) versus placebo. Note: Meal tolerance test (MTT) set Taskinen MR, et al. Diabetes Obes Metab. 2011;13:65 74.

30 Linagliptin significantly improves ß-cell function as add-on to metformin Effect of linagliptin as add-on to metformin on C-peptide levels Effect of linagliptin as add-on to metformin on HOMA-%B Placebo-corrected adjusted mean change in Cpeptide (pmol/l) from baseline at wk 24 Placebo-corrected adjusted mean change in HOMA-%B [(mu/l) (mmol/l)] from baseline at wk % versus baseline at wk 24 The mean change from baseline in HOMA-%B for linagliptin at 24 weeks was an increase of 1.2 (mu/l)/(mmol/l) versus a decrease of 10.7 (mu/l)/(mmol/l) with placebo ( p=0.12) * 14% versus baseline at wk 24 The mean change from baseline in C-peptide for linagliptin at 24 weeks was an decrease of 64.1 (pmol/l) versus an increase of 70.3 (pmol/l) with placebo (* p=0.031) Note: Baseline HOMA-%B: 49.7 (mu/l)/mmol/l) linagliptin-treated group; 48.3 (mu/l)/mmol/l) placebo group Baseline Cpeptide: (pmol/l) linagliptin-treated group; (pmol/l) placebo group Relative change with linagliptin (placebo-corrected) compared to baseline Taskinen MR, et al. Diabetes Obes Metab. 2011;13:65 74.

31 Linagliptin in initial combination with metformin: HbA1c change from baseline to week 24 Both combination regimens were superior to the respective metformin monotherapy arms Randomized arm1 (placebo-corrected) LIN 5 mg QD Placebo corrected, adjusted mean (SE) change in HbA1c from baseline at week 24, % Baseline HbA1c, % Patients, n MET 500 mg BID Open-label arm2 MET 1000 mg BID LIN MET 500 mg BID LIN MET 1000 mg BID LIN MET 1000 mg BID *** *** *** p<0.0001, combination therapy versus respective monotherapy 1 Randomized arm: adjusted mean (SE); full analysis set, last observation carried forward 2 Open-label arm in patients with poor glycemic control: mean (SE); full analysis set, observed cases (n = 48) BID = twice daily; FPG = fasting plasma glucose; LIN = linagliptin; MET = metformin; OAD = oral antidiabetic drug; QD = once daily; T2DM = type 2 diabetes mellitus Haak T, et al. ADA 2011 Oral Presentation 279-OR

32 Oral glucose-lowering with linagliptin plus metformin is a viable initial treatment strategy in patients with newly diagnosed Type 2 Diabetes and marked hyperglycaemia T2D, Type 2 Diabetes. Source: Gallwitz B, et al. EASD 2014, Poster 894.

33 Study design 1 week 24 weeks BID, twice daily; DPP4, dipeptidyl peptidase-4; QD, once daily. *Metformin (immediate-release tablet) was initiated at 1000 mg/day (500 mg BID) and was up-titrated in the 1st 6 weeks to 1500 mg/day (500 mg BID mg QD) or to a maximal dose of 2000 mg/day (1000 mg BID) if fasting plasma glucose (FPG) was > 6.1 mmol/l (110 mg/dl), and depending on tolerability. Titration was conducted under double-blind conditions. Registered with ClinicalTrials.gov: NCT Source: Gallwitz B, et al. EASD 2014, Poster 894.

34 Change in HbA1c at Week 24 (primary endpoint) Adjusted mean change from baseline at Week 24 Full-analysis set (LOCF) 9.73% 9.69% Baseline Linagliptin + metformin Linagliptin 9.79% 9.88% Adjusted mean (SE) change from baseline in HbA1c (%) Linagliptin Adjusted mean (SE) change from baseline in HbA1c (%) Baseline Linagliptin + metformin Treatment difference: -0.79% (95% CI -1.13, -0.46) p < Treatment difference: -0.99% (95% CI -1.33, -0.64) p < n = 132/159 n = 153/159 n = 113/157 n = 150/157 CI, confidence interval; FAS, full analysis set; HbA1c, glycosylated haemoglobin; PPCC, per-protocol completers cohort; SE, standard error. *ANCOVA (analysis of covariance) model includes continuous baseline HbA1c and treatment. PPCC = all randomised patients who received 1 dose of study drug, had a baseline HbA 1c measurement, had no important protocol violations, completed 24 weeks of treatment without receiving glycaemic rescue, and had an HbA 1c measurement at Week 24. FAS = all randomised patients who received 1 dose of study drug, had a baseline HbA1c measurement and 1 on-treatment HbA1c measurement. Source: Gallwitz B, et al. EASD 2014, Poster 894.

35 Change in HbA1c at Week 24 by baseline HbA1c Adjusted mean change from baseline at Week 24 by baseline HbA1c (PPCC) Adjusted* mean (SE) change from baseline in HbA1c (%) < 9.5% (< 80 mmol/mol) 9.5% ( 80 mmol/mol) Mean ± SE treatment difference: -0.69% (95% CI -1.23, 0.15) Mean ± SE treatment difference: % (95% CI -1.32, -0.35) CI, confidence interval; HbA1c, glycosylated haemoglobin; PPCC, per-protocol completers cohort; SE, standard error. *ANCOVA (analysis of covariance) model with terms for treatment, continuous baseline HbA 1c, subgroup by treatment interaction; for analysis of baseline HbA1c subgroups, the term for continuous baseline HbA1c was replaced by the categorical HbA1c. PPCC = all randomised patients who received 1 dose of study drug, had a baseline HbA 1c measurement, had no important protocol violations, completed 24 weeks of treatment without receiving glycaemic rescue, and had an HbA1c measurement at Week 24. Metformin was up-titrated in the 1st 6 weeks to a maximal dose of 2000 mg/day. Source: Gallwitz B, et al. EASD 2014, Poster 894.

36 Target HbA1c response rate at Week 24 Patients with HbA1c 7% at baseline who achieved HbA1c < 7% (< 53 mmol/mol) at Week 24 (PPCC [NCF]) Patients (%) Odds ratio*: 2.45 (95% CI ); p = Linagliptin + metformin Linagliptin CI, confidence interval; HbA1c, glycosylated haemoglobin; NCF, non-completers considered failures; PPCC, per-protocol completers cohort. *Logistic regression model with continuous baseline HbA1c and treatment. PPCC = all randomised patients who received 1 dose of study drug, had a baseline HbA 1c measurement, had no important protocol violations, completed 24 weeks of treatment without receiving glycaemic rescue, and had an HbA1c measurement at Week 24. Source: Gallwitz B, et al. EASD 2014, Poster 894.

37 Σύγκριση με σουλφονυλουρία μετά την αποτυχία της μονοθεραπείας με μετφορμίνη

38 In the full analysis set (FAS) linagliptin was similar to glimepiride in treatment effect1 HbA1c change over 2 years, FAS (LOCF) Mean over time ± SEM, percent Mean (± SEM) HbA1c Percent * Linagliptin Glimepiride * * * * Treatment duration (Weeks) Baseline Adjusted mean change from baseline Linagliptin + Metformin (n=764) 7.69 ± Glimepiride + Metformin (n=755) 7.69 ± HbA1c, % Difference in adjusted mean change 0.20 (0.11, 0.29)1 Note: Rate of patients achieving HbA1c target <7% after 104 weeks of treatment (FAS, non-completers considered failures): linagliptin + metformin 30%, glimepiride + metformin 35% 1 Non-inferiority in treatment effect has been established based on a pre-specified margin on HbA1c of 0.35% (97.5% upper CI 0.299) 2 p= Gallwitz B., et al. ADA 2011 Late Breaker 39-LB; Linagliptin data on file

39 Significant relative weight loss and lower incidence of hypoglycemia with linagliptin compared to glimepiride Incidence of hypoglycemia1 Percent of patients - Treated set2 Adjusted3 means for body weight change from baseline ± SE Kg - Full analysis set (OC) Linagliptin Glimepiride 50 * * p< * * 4.8x reduction * * * 10 0 * * Linagliptin Glimepiride * p< Hypoglycemic episode defined by a blood glucose 70 mg/dl 2 Treated Set: Linagliptin n=776, glimepiride n=775 3 Model includes baseline HbA1c, baseline weight, no. prior OADs, treatment, week repeated within patients and week by treatment interaction Gallwitz B., et al. ADA 2011 Late Breaker 39-LB 104 weeks -1.5 *

40 Linagliptin vs. glimepiride: Incidence of hypoglycaemia Total hypoglycemic event rate (%) 40 p-value < % patients with 4 hypoglycemic events % patients with 2-3 hypoglycemic events 20 % patients with 1 hypoglycemic event 10 0 Glimepiride Linagliptin Investigator-defined hypoglycaemia: linagliptin + metformin, 7.5% and glimepiride + metformin, 36.1% Patients with severe hypoglycaemia*: linagliptin + metformin, 1 and glimepiride + metformin, 12 Treated Set: linagliptin + metformin n=776; glimepiride + metformin n=775 Hypoglycemic episode defined by a blood glucose 70 mg/dl (<3.9 mmol/l) * Event requiring assistance of another person to actively administer carbohydrate, glucagon or other resuscitative actions (as defined by ADA Workgroup on hypoglycemia. Diabetes Care 2005;28: ) Source: Gallwitz B., et al. ADA 2011 Late Breaker 39-LB

41 Ασυμπτωματικά επεισόδια υπογλυκαιμίας δεν καταγράφονται 100 Patients, % In a cohort of patients with diabetes, more than 50% had asymptomatic (unrecognized) hypoglycemia, as identified by continuous glucose monitoring1 Other researchers have reported similar findings2, n=70 n=40 n=30 All patients with diabetes Type 1 diabetes Type 2 diabetes Patients With 1 Unrecognized Hypoglycemic Event, % 1. Copyright 2003 American Diabetes Association. Chico A et al. Diabetes Care. 2003;26(4): Reprinted with permission from the American Diabetes Association. 2. Weber KK et al. Exp Clin Endocrinol Diabetes. 2007;115(8): Zick R et al. Diab Technol Ther. 2007;9(6):

42 Η σοβαρή υπογλυκαιμία προκαλεί παράταση του QTc P= Mean QT interval, ms P=NS Significant QTc prolongation during hypoglycemia Euglycemic clamp (n=8) Baseline (t=0) Hypoglycemic clamp 2 weeks after glibenclamide withdrawal (n=13) End of clamp (t=150 min) Landstedt-Hallin L et al. J Intern Med. 1999;246: ACCORD?

43 Effect of linagliptin compared with glimepiride on post-prandial glucose metabolism, islet cell function, and vascular function parameters in patients with Type 2 Diabetes Mellitus on ongoing metformin treatment Source: Forst T et al. Diabetes Metab Res Rev. 2014;. doi: /dmrr [Epub ahead of print]

44 Study design Linagliptin (5 mg) n = 19 Assessment of eligibility Enrolled: 12 weeks Glimepiride (titrated individually 1 4 mg) Inclusion criteria T2DM HbA1c % Age years On metformin BL Testmeal* Administration 6 weeks Testmeal* Administration n = weeks Testmeal* Administration Evaluation criteria biomarkers; included Exclusion criteria included Glucose; insulin; intact proinsulin; GLP1; glucagon; Uncontrolled hypertension plasminogen activator inhibitor 1 (PAI-1); asymmetric MI or stroke in previous 6 months dimethylarginine (ADMA); cyclic Impaired hepatic or renal function > 1 unexplained severe hypoglycaemic guanosinmonophosphate (cgmp); HbA1c episode in previous 6 months *Testmeal experiment: observational period of 330 min, sampling every 30 min. HbA was measured at baseline and after 12 weeks of treatment. 1c Source: Forst T, et al. Diabetes Metab Res Rev. 2014; doi: /dmrr.2525 [Epub ahead of print].

45 Change in biomarkers, AUC0 300min Glucose and insulin Glucose (mmol/l*min), mean (SEM) change from baseline Week 6 Insulin (pmol/l*min), mean (SEM) change from baseline Week 6 Week 12 Week 12 * * * * * * * Glimepiride Linagliptin *p < 0.05 vs baseline; p < 0.05 between treatment groups. Source: Forst T, et al. Diabetes Metab Res Rev. 2014; doi: /dmrr.2525 [Epub ahead of print].

46 Change in biomarkers, AUC0 300min Intact proinsulin and proinsulin/insulin ratio Intact proinsulin (pmol/l*min), mean (SEM) change from baseline Week 6 Proinsulin/insulin ratio, mean (SEM) change from baseline Week 12 Week 6 Week 12 * * * * * Glimepiride Linagliptin Treatment with linagliptin significantly reduced post-prandial intact proinsulin and proinsulin/insulin ratio which are markers of deteriorating β-cell function *p < 0.05 vs baseline; p < 0.05 between treatment groups. Source: Forst T, et al. Diabetes Metab Res Rev. 2014; doi: /dmrr.2525 [Epub ahead of print].

47 Change in biomarkers, AUC0 300min GLP1 and glucagon Glucagon (pg/ml*min), mean (SEM) change from baseline GLP1 (pmol/l*min), mean (SEM) change from baseline Week 6 * Week 6 Week 12 Week 12 * Glimepiride Linagliptin Linagliptin increased GLP-1 levels, mediating glucose-dependent insulin secretion from β-cells Treatment with linagliptin attenuated post-prandial glucagon levels *p < 0.05 vs baseline; p < 0.05 between treatment groups. Source: Forst T, et al. Diabetes Metab Res Rev. 2014; doi: /dmrr.2525 [Epub ahead of print].

48 Treatment with the dipeptidyl peptidase 4 inhibitor linagliptin, or placebo followed by glimepiride, in Type 2 Diabetes patients with moderate to severe renal impairment: A 52-week, randomised, double-blind clinical trial Source: Laakso M, et al. Diabetes Care 2015 ;38(2) e15-7.

49 Study design 2 weeks Placebo run-in Patients aged 18 years with: Previously diagnosed T2D HbA1c 7 to 10% ( 53 to 86 mol/mol) Moderate to severe RI (egfr < 60 ml/min/1.73 m2) 12 weeks 40 weeks egfr, estimated filtration rate; HbA1c, glycosylated haemoglobin; QD, once daily; RI, renal impairment; T2D, Type 2 Diabetes. *Placebo patients were switched to glimepiride 1 4 mg/day after 12 weeks. Glimepiride was up-titrated, starting from 1 mg QD to a maximum of 4 mg, at investigators discretion. Source: Laakso M, et al. Diabetes Care 2015 ;38(2) e15-7.

50 Change from baseline in HbA1c at Week 12 Adjusted* mean (SE) change in HbA1c (%) Adjusted mean change from baseline in HbA1c (%) at Week 12 in patients with moderate or severe renal disease (FAS, LOCF) Treatment difference: % CI: -0.60, p < At Week 12, HbA1c was decreased significantly with linagliptin compared with placebo in patients with T2D and CKD CI, confidence interval; CKD, chronic kidney disease; FAS, full analysis set; HbA 1c, glycosylated haemoglobin; LOCF, last observation carried forward; SE, standard error; T2D, Type 2 Diabetes. *Model includes treatment, baseline HbA1c, renal function impairment and prior use of anti-diabetes agents. Source: Laakso M, et al. Diabetes Care 2015 ;38(2) e15-7.

51 Change in HbA1c over 52 weeks (FAS, LOCF) Adjusted* mean change in HbA1c (%) Week -0.50% -0.64% Glimepiride dose, mg/day, mean (SD) 1.0 (0.0) 1.5 (0.5) 1.8 (0.8) 2.2 (1.2) 2.2 (1.2) 2.2 (1.3) 2.2 (1.3) 2.2 (1.3) Change in insulin dose, mean (SE) IU/day, in patients receiving background insulin Linagliptin (0.11) (0.75) (0.78) (0.88) (1.24) (1.42) (1.56) (2.16) (2.19) (2.53) (2.83) Placebo/ glimepiride (0.42) 0.44 (0.77) 0.17 (0.98) (1.07) (1.19) (1.25) (1.76) (1.97) (2.03) (2.25) FAS, full analysis set; HbA1c, glycosylated haemoglobin; IU, international units; LOCF, last observation carried forward; SD, standard deviation; SE, standard error. *Model includes treatment, baseline HbA1c, renal function impairment and prior use of anti-diabetes agents. Source: Laakso M, et al. Diabetes Care 2015 ;38(2) e15-7.

52 Adverse events Linagliptin (n = 113) Placebo (n = 122) Any AE, % Drug-related AEs*, % AEs leading to discontinuation,% Serious AEs Any AE, % AEs leading to discontinuation,% Serious AEs Week 12 (TS) 40-week extension (TS) Adjudicated cardiovascular events occurred in fewer linagliptin patients (n = 3) than glimepiride patients (n = 8); adjudicated hospitalisation for heart failure occurred in 7 and in 6 linagliptin and placebo/glimepiride patients, respectively. AEs, adverse events; T2D, Type 2 Diabetes; TS, treated set. *Considered as related to study drug by the investigator. Data are n (%). Source: Laakso M, et al. Diabetes Care 2015 ;38(2) e15-7.

53 Incidence of investigator-reported hypoglycaemia* Incidence of patients with investigator-defined hypoglycaemia over 52 weeks by treatment and study period (TS) Linagliptin Placebo Investigator-reported hypoglycaemia (% patients with 1 episode) Initial 12 weeks randomised treatment Patients with hypoglycaemia Total number of patients Glimepiride 40-week extension Placebo/glimepiride Full 52-week study period Severe hypoglycemia (requiring third-party assistance) occurred in 6 linagliptin and 6 placebo/glimepiride patients. TS, treated set. *Confirmed plasma glucose concentration 70 mg/dl ( 3.9 mmol/l) and/or symptoms attributed to hypoglycaemia. Data are for the treated set including the 6 patients from the non-compliant study site: linagliptin, n = 118; placebo, n = 123. Source: Laakso M, et al. Diabetes Care 2015 ;38(2) e15-7.

54 Mean (SE) egfr (ml/min/1.73 m2) egfr* from baseline to Week 52 (FAS, OC) Week Number of patients Linagliptin Placebo/ glimepiride egfr, estimated filtration rate; FAS, full analysis set; OC, observed cases; SE, standard error. *Estimated by the Modification of Diet in Renal Disease equation. Source: Laakso M, et al. Diabetes Care 2015 ;38(2) e15-7.

55 Σε συνδυασμό σουλφονυλουρία και μετφορμίνη Σε ασθενείς με σακχαρώδη διαβήτη τύπου 2, η λιναγλιπτίνη ενδείκνυται για τη βελτίωση του γλυκαιμικού ελέγχου: ως τριπλή από του στόματος χορηγούμενη θεραπεία σε συνδυασμό με μία σουλφονυλουρία και μετφορμίνη όταν η δίαιτα και η άσκηση μαζί με τη διπλή θεραπεία με αυτούς τους παράγοντες δεν παρέχει επαρκή γλυκαιμικό έλεγχο.

56

57 ΕΜΕΑ- λιναγλιπτίνη με ινσουλίνη 4.1 Θεραπευτικές ενδείξεις Η λιναγλιπτίνη ενδείκνυται επίσης ως προστιθέμενη θεραπεία στην ινσουλίνη (με ή χωρίς μετφορμίνη), όταν η δίαιτα και η άσκηση μαζί με σταθερή δοσολογία ινσουλίνης δεν παρέχουν επαρκή γλυκαιμικό έλεγχο. Updated on Tuesday, December 08, 2009

58 Efficacy and Safety of Linagliptin as Add-On to Basal Insulin in Patients With Type 2 Diabetes and Renal Impairment T2D, type 2 diabetes mellitus. Source: McGill J, et al. American Diabetes Association Congress Poster 1026-P.

59 Study design of parent trial Stable basal insulin dose Titration of basal insulin dose 24-week 28-week FPG target 110 mg/dl Treatment duration: 52 weeks Primary endpoint: change from baseline in HbA1c after 24 weeks of treatment Sub-analysis evaluated data for patients with normal renal function (egfr 90 ml/min), mild renal impairment (egfr 60 to < 90 ml/min), or moderate renal impairment (egfr 30 to < 60 ml/min) T2D, type 2 diabetes mellitus; qd, once daily; FPG, fasting plasma glucose; egfr, estimated glomerular filtration rate. Patients continued basal insulin and stable dose of any oral antidiabetes drugs. The primary efficacy endpoint was assessed over 24 weeks (see yellow boxed area). 1. Yki-Jarvinen H, et al. Diabetes Care. 2013;36: Source: McGill J, et al. American Diabetes Association Congress Poster 1026-P.

60 Change in HbA1c over time to Week 52: normal renal function Adjusted mean (SE) change in HbA1c (%) Adjusted* mean change from baseline in HbA1c over time for patients with normal renal function (FAS; OC) Stable insulin dose Free insulin titration period Placebo-corrected difference = -0.46% (95% CI: -0.66, -0.25; p < ) 32 Treatment duration (weeks) Baseline Placebo, n Linagliptin, n HbA1c, glycated haemoglobin; FAS, full analysis set; OC observed cases; SE, standard error; CI, confidence interval. *ANCOVA model includes treatment, baseline HbA1c, concomitant OADs, baseline egfr (MDRD) and baseline renal impairment-by-treatment interaction. The primary efficacy endpoint was assessed over 24 weeks (see yellow boxed area). Source: McGill J, et al. American Diabetes Association Congress Poster 1026-P.

61 Change in HbA1c over time to Week 52: Mild renal impairment Adjusted mean (SE) change in HbA1c (%) Adjusted* mean change from baseline in HbA1c over time for patients with mild renal impairment (FAS; OC) Stable insulin dose Free insulin titration period Placebo-corrected difference = -0.56% (95% CI: -0.75, -0.38; p < ) 32 Treatment duration (weeks) Baseline Placebo, n Linagliptin, n HbA1c, glycated haemoglobin; FAS, full analysis set; OC observed cases; SE, standard error; CI, confidence interval. *ANCOVA model includes treatment, baseline HbA1c, concomitant OADs, baseline egfr (MDRD) and baseline renal impairment-by-treatment interaction. The primary efficacy endpoint was assessed over 24 weeks (see yellow boxed area). Source: McGill J, et al. American Diabetes Association Congress Poster 1026-P.

62 Change in HbA1c over time to Week 52: moderate renal impairment Adjusted mean (SE) change in HbA1c (%) Adjusted* mean change from baseline in HbA1c over time for patients with moderate renal impairment (FAS; OC) Stable insulin dose Free insulin titration period Placebo-corrected difference = -0.28% (95% CI: -0.68, 0.12; p = ) 32 Treatment duration (weeks) Baseline Placebo, n Linagliptin, n HbA1c, glycated haemoglobin; FAS, full analysis set; OC observed cases; SE, standard error; CI, confidence interval. *ANCOVA model includes treatment, baseline HbA1c, concomitant OADs, baseline egfr (MDRD) and baseline renal impairment-by-treatment interaction. The primary efficacy endpoint was assessed over 24 weeks (see yellow boxed area). Source: McGill J, et al. American Diabetes Association Congress Poster 1026-P.

63 Incidence of hypoglycaemia Frequency of patients with any asymptomatic or symptomatic hypoglycaemia* (TS) Patients with investigator-reported asymptomatic or symptomatic hypoglycemia (%) Severe episodes of hypoglycaemia were low for linagliptin and placebo across all renal function categories (normal renal function: 1.1% vs. 0.7%; mild renal impairment: 2.1% vs. 1.4%; and moderate renal impairment: 3.4% vs 1.5%, respectively) Percentages of patients with investigator-reported hypoglycaemia in the linagliptin group was similar to the percentage in the placebo group across all renal function categories TS, treated set; GFR, estimated glomerular filtration rate. *Asymptomatic or symptomatic hypoglycaemia reported as adverse events; asymptomatic = blood glucose 70 mg/dl without typical symptoms of hypoglycaemia, symptomatic = typical symptoms of hypoglycaemia (with or without blood glucose measurement) Requiring the assistance of another person to actively administer carbohydrate, glucagon or other resuscitative action. Source: McGill J, et al. American Diabetes Association Congress Poster 1026-P.

64 Combination of the dipeptidyl peptidase 4 inhibitor linagliptin with insulin-based regimens in Type 2 Diabetes and chronic kidney disease Source: McGill JB, et al. DiabetesVasc Dis Res. 2015;12(4):249 57

65 Mean HbA1c change from baseline over time up to 52 weeks for patients with mild, moderate and severe RI (FAS;* OC) Study 1 Mild RI Week 24 Study 2 Moderate RI Placebo-adjusted mean change: -0.59% (95% CI: -0.73, -0.45; p < 0.001) Week 24 Placebo-adjusted mean change: -0.69% (95% CI: -0.98, -0.40; p < 0.001) Severe RI CI, confidence interval; FAS, full analysis set; HbA1c, glycosylated haemoglobin; OC, observed cases; RI, renal impairment; SE, standard error. *All patients who had a baseline and 1 on-treatment HbA1c measurement. Source: McGill JB, et al. Diabetes Vasc Dis Res. 2015;12(4): Week 12 Placebo-adjusted mean change: -0.43% (95% CI: -0.75, -0.11; p = 0.008)

66 Mean change from baseline in basal insulin dose at Week 52 Mean change from baseline in basal insulin dose (IU) Study 1 Study 2 Linagliptin 5 mg Placebo (60 to < 90 ml/min/1.73 m2) (30 to < 60 ml/min/1.73 m2) (< 30 ml/min/1.73 m2) CI, confidence interval; HbA1c, glycosylated haemoglobin; RI, renal impairment. *All patients who had a baseline and 1 on-treatment HbA1c measurement. Source: McGill JB, et al. Diabetes Vasc Dis Res. 2015;12(4):249 57

67 Patients with any severe hypoglycaemic AEs* in Study 1 and Study 2 (treated set) Patients with any severe hypoglycaemic event (%) Study 1 Study 2 Linagliptin 5 mg Placebo (60 to < 90 ml/min/1.73 m2) (30 to < 60 ml/min/1.73 m2) (< 30 ml/min/1.73 m2) Investigator-reported hypoglycaemic events were lower with linagliptin compared with placebo in Study 1 (mild RI, 34.9% vs 37.5%; moderate RI, 35.6% vs 39.7%). In Study 2, 66.7% vs 49.1% of patients with severe RI experienced investigatorreported hypoglycaemic events AEs, adverse events; RI, renal impairment. *Event requiring the assistance of another person to actively administer carbohydrate, glucagon or other resuscitative actions. Any asymptomatic or symptomatic hypoglycaemia reported as AEs. Source: McGill JB, et al. Diabetes Vasc Dis Res. 2015;12(4):249 57

68 Improved glucose control with reduced hypoglycaemic risk when linagliptin is added to basal insulin in elderly patients with Type 2 Diabetes Source: Inzucchi SE, et al. Diabetes Obes Metab DOI: /dom

69 Time to first onset of hypoglycaemia in patients without background sulphonylurea Placebo Linagliptin Overall hypoglycaemia* Confirmed hypoglycaemia HR 0.60 (95% CI 0.37, 0.96); p < 0.05 Probability of hypoglycaemia Probability of hypoglycaemia HR 0.57 (95% CI 0.35, 0.93) p < Days Days Number at risk Number at risk Lina Lina Placebo Placebo BG, blood glucose; CI, confidence interval; HR, hazard ratio; Lina, linagliptin. *Any asymptomatic event with BG 70 mg/dl (3.9 mmol/l), or symptomatic event with or without BG 70 mg/dl. Event with BG 70 mg/dl, with or without symptoms. Source: Inzucchi SE, et al. Diab Obes Metab. 2015; Accepted.

70 Risk of Hypoglycemia in People Receiving Linagliptin: Pooled Data From 1489 Adults Aged 65 Years With Type 2 Diabetes Mellitus T2D, type 2 diabetes mellitus. Source: Khunti, K, et al. American Diabetes Association Congress Poster 138-LB.

71 Methodology: populations evaluated and endpoints T2D, type 2 diabetes mellitus; qd, once daily; HbA1c, glycated haemoglobin; AEs, adverse events; egfr, estimated glomerular filtration rate. *Treated set. Included insulin, but no insulin secretagogues (such as sulphonylureas), a secretagogue, but no insulin, or no insulin and no secretagogues. To isolate treatment effects of background insulin and secretagogues, patients receiving both drugs were not analyzed as a subgroup. Source: Khunti, K, et al. American Diabetes Association Congress Poster 138-LB.

72 Change in HbA1c from baseline to Week 24 Adjusted mean (SE) change from baseline in HbA1c (%)* Change from baseline to Week 24 in HbA1c in elderly patients with T2D (FAS LOCF) Placebo-adjusted difference (0.04) (95% CI: -0.69, -0.51) p < Mean (SD) baseline HbA1c (%) 8.1 (0.8) 8.1 (0.8) Treatment with linagliptin significantly reduced HbA 1c by Week 24 compared with placebo HbA1c, glycated haemoglobin; FPG, fasting plasma glucose; SE, standard error; CI, confidence interval; SD standard deviation; FAS, full analysis set; LOCF, last observation carried forward. *Model includes treatment, baseline HbA1c, washout, and study. Source: Khunti, K, et al. American Diabetes Association Congress Poster 138-LB.

73 Frequency of composite endpoint of HbA1c < 7.5% without hypoglycemia Patients with HbA1c <7.5% and no confirmed hypoglycemia (%) Patients with HbA1c < 7.5% and no confirmed hypoglycaemia at Week 24 (FAS) Baseline HbA1c n/n (lina/pbo) 380/ / /255 37/133 96/306 14/187 24/140 4/82 The composite endpoint of HbA1c < 7.5% without hypoglycaemia was achieved by more patients treated with linagliptin than placebo regardless of baseline HbA1c HbA1c, glycated haemoglobin; TS, treated set; lina, linagliptin; pbo, placebo; FAS, full analysis set. Source: Khunti, K, et al. American Diabetes Association Congress Poster 138-LB.

74 Για ποιον λοιπόν ασθενή είναι κατάλληλη η λιναγλιπτίνη; Για τον ασθενή που δεν μπορεί να λάβει μετφορμίνη (λόγω ΓΕΣ δυσανεξίας ή καρδιακής ανεπάρκειας). Για τον ασθενή που δεν ρυθμίζεται μόνο με την μετφορμίνη αντί για σουλφονυλουρία όταν οι υπογλυκαιμίες ή το σωματικό βάρος μας ενδιαφέρουν. Για τον ασθενή που λαμβάνει ήδη διπλό συνδυασμό με μετφορμίνη και σουλφονυλουρία. Για τον ασθενή που λαμβάνει ινσουλίνη και μετφορμίνη (αντί για σουλφονυλουρία).

75 Antihyperglycemic therapy in type 2 diabetes: general recommendations. Silvio E. Inzucchi et al. Dia Care 2015;38: by American Diabetes Association

76 Αλγόριθμος NICE HbA1C 6.5%* μετά από προσπάθεια αλλαγής τρόπου ζωής Μετφορμίνη Συνήθης πρακτική SU Όταν ο έλεγχος είναι ανεπαρκής με την μέγιστη ανεκτή δόση μετφορμίνης Σκεφτείτε την Σουλφονυλουρία σε άτομα που Ηλικιωμένοι Δεν είναι υπέρβαρα Νεφροπαθείς Απαιτούν ταχεία μείωση λόγω συμπτωμάτων υπεργλυκαιμίας Ηπατοπαθείς Δεν μπορούν να ανεχτούν την μετφορμίνη λόγω ΓΕΣ ή η μετφορμίνη Αλκοόλ αντενδείκνυται. Ανεπίγνωστες HbA1C 6.5%*υπογλυκαιμίες Ασθενείς με ΚΑ νοσήματα Εναλλακτικά Άνθρωποι που μένουν μόνοι DPP-4 inhibitor Σκεφτείτε το αντί για SU όπου Οι ασθενείς είναι σε σημαντικό κίνδυνο υπογλυκαιμίας ή των συνεπειών της Οι ασθενείς δεν μπορούν να ανεχτούν την SU Είναι προτιμότερες από την πιογλιταζόνη όπου Δεν είναι επιθυμητή η αύξηση του βάρους (πιθανή επιδείνωση προβλημάτων που σχετίζονται με την αύξηση του βάρους) Οι γλιταζόνες αντενδείκνυνται Όταν και τα δυο είναι κατάλληλα λαμβάνεται υπόψιν η προτίμηση του ασθενούς TZD (πιογλιταζόνη) Σκεφτείτε το αντί για SU όπου Οι ασθενείς είναι σε σημαντικό κίνδυνο υπογλυκαιμίας ή των συνεπειών της Οι ασθενείς δεν μπορούν να ανεχτούν την SU Είναι προτιμότερες από DPP-4 inhibitors όπου Ο ασθενής έχει σημαντική αντίσταση στην ινσουλίνη Οι DPP-4 αντενδείκνυνται Όταν και τα δυο είναι κατάλληλα λαμβάνεται υπόψιν η προτίμηση του ασθενούς * Or individually agreed target. Monitor patient following initiation of a new therapy and continue only if beneficial metabolic response occurs (refer to guideline for suggested metabolic responses). Discuss potential risks and benefits of treatments with patients so informed decision can be made. When selecting a TZD take into account up-to-date advice from the relevant regulatory bodies, cost, safety and prescribing issues. Do not commence or continue a TZD in people who have heart failure, or who are at higher risk of fracture.

77 DPP4 inhibitors are safe from a CV standpoint and may possibly decrease risk of adverse CV events.

78 Cardiovascular safety of linagliptin in Type 2 Diabetes: A comprehensive patient-level pooled analysis of prospectively adjudicated cardiovascular events Source: Rosenstock J, et al. Cardiovasc Diabetol. 2015; doi: /s

79 Study selection and endpoints Pre-specified patient-level pooled analysis of all available 12-week, double-blind, randomised, controlled trials of linagliptin versus placebo/active treatment (19 trials, 9459 subjects) Primary endpoint: Composite of prospectively adjudicated CV death, non-fatal myocardial infarction, non-fatal stroke and hospitalisation for unstable angina (4PMACE) Hospitalisation for CHF was also evaluated; adjudication of CHF was introduced during the Phase III program (8 trials; 3314 subjects) 4P-MACE was assessed in placebo-controlled trials (subgroup of 18 trials; 7746 subjects) Investigator-reported events suggestive of CHF from 24 placebo-controlled, < 12-week trials (8778 subjects) were also analysed CHF, congestive heart failure; CV, cardiovascular. Source: Rosenstock J, et al. Cardiovasc Diabetol. 2015; doi: /s

80 Change in CV risk factors from baseline to last treatment* Mean (SEM) Total cholesterol, mg/dl Baseline Change from baseline LDL, mg/dl Baseline Change from baseline HDL, mg/dl Baseline Change from baseline Triglyceride, mg/dl Baseline Change from baseline HbA1c, % Baseline Change from baseline Weight Baseline Change from baseline Systolic BP Baseline Change from baseline Diastolic BP (mmhg) Baseline Change from baseline Heart rate, bpm Baseline Change from baseline Linagliptin (n = 5758) Active comparators (n = 918) Placebo (n = 2618) Total comparators (n = 3536) 187 (0.6) 1 (0.5) 186 (1.3) 2 (1.1) 187 (0.9) 2 (0.7) 187 (0.8) 2 (0.6) 107 (0.5) 1 (0.4) 104 (1.1) 4 (0.9) 107 (0.7) 1 (0.6) 106 (0.6) 1 (0.5) 47 (0.2) 1 (0.1) 48 (0.4) 1 (0.2) 47 (0.3) 1 (0.2) 47 (0.2) 1 (0.1) 173 (1.8) 7 (1.5) 180 (4.1) 8 (4.2) 174 (2.9) 3 (2.6) 176 (2.4) 5 (2.2) 8.1 (0.01) 0.7 (0.01) 7.8 (0.03) 0.5 (0.03) 8.3 (0.02) 0.3 (0.02) 8.1 (0.02) 0.3 (0.02) 79.5 (0.25) 0.1 (0.05) 83.8 (0.58) 1.3 (0.15) 81.1 (0.39) 0.1 (0.07) 81.9 (0.32) 0.4 (0.06) 131 (0.2) 1 (0.2) 134 (0.5) 1 (0.5) 132 (0.3) 1 (0.3) 132 (0.3) 1 (0.3) 78 (0.1) 1 (0.1) 80 (0.3) 1 (0.3) 78 (0.2) 1 (0.2) 79 (0.2) 1 (0.2) 74 (0.1) 1 (0.1) 73 (0.4) 1 (0.3) 74 (0.2) 1 (0.3) 74 (0.2) 1 (0.2) BP, blood pressure; bpm, beats per minute; CV, cardiovascular; HbA 1c, glycated hemoglobin; HDL, high-density lipoprotein; LDL, low-density lipoprotein. *Treated set; Analysis includes data obtained after initiation of glycemic rescue. Source: Rosenstock J, et al. Cardiovasc Diabetol. 2015; doi: /s

81 No significant difference between incidence and incidence rates of primary, secondary and tertiary endpoints with linagliptin versus total comparators Linagliptin (n = 5847) Total comparators (n = 3612) Incidence n (%) Incidence rate (per 1000 years) Incidence n (%) Incidence rate (per 1000 years) 60 (1.0) (1.7) 18.9 CV death, stroke or MI 42 (0.7) (1.3) 14.0 All major CV events 96 (1.6) (2.6) 29.1 FDA-custom MACE 39 (0.7) (1.3) 13.7 CV death 11 (0.2) (0.2) 2.4 Non-fatal MI 23 (0.4) (0.6) 6.1 Non-fatal stroke 9 (0.2) (0.5) 5.8 TIA 1 (0.02) (0.2) 2.4 UAP with hospitalisation 22 (0.4) (0.4) 4.8 Hospitalisation for CHF* 12 (0.6) (0.7) 8.4 Total mortality 18 (0.3) (0.4) 4.8 Primary endpoints CV death, stroke, MI or UAP with hospitalisation Secondary endpoints Tertiary endpoints CHF, congestive heart failure; CV, cardiovascular; FDA, Food and Drug Administration; MACE, major adverse CV events; MI, myocardial infarction; TIA, transient ischemic attack; UAP, unstable angina pectoris. *Includes data only from trials with prospective independent adjudication of hospitalization for CHF (n = 3314). Source: Rosenstock J, et al. Cardiovasc Diabetol. 2015; doi: /s

82 HR estimates favour linagliptin for secondary composite CV endpoints versus total comparators* Significantly reduced HR for stroke and TIA favouring linagliptin compared with total comparators CI, confidence interval; CV, cardiovascular; FDA, Food and Drug Administration; HR, hazard ratio; MACE, major adverse CV events; MI, myocardial infarction; TIA, transient ischemic attack; *Based on Cox hazard model. Source: Rosenstock J, et al. Cardiovasc Diabetol. 2015; doi: /s

83

84 CAROLINA is an ongoing RCT designed to assess if linagliptin 5 mg once daily is non-inferior, and if so, superior compared with glimepiride 1 4 mg once daily with respect to CV events in adults with relatively early T2D at increased risk of CV events and with less than optimised glycaemic control CAROLINA is the first head-to-head CV outcome trial of a DPP4 inhibitor versus a single active comparator (glimepiride) that is sufficiently powered to demonstrate differences in CV events CAROLINA substudies will provide insights beyond CV outcomes, including effects on cognition, glycaemic variability, β-cell function, and latent autoimmune diabetes in adulthood (LADA) 6041 patients were treated, with median T2D duration of 6.2 years, 40.0% were female, mean HbA1c 7.2%, 66% on 1 and 24% on 2 glucose-lowering agents and 34.5% had previous CV complications The outcome of the CAROLINA trial may generate the most robust evidence in the decision-making process for selecting a second glucose-lowering agent after metformin in T2D CV, cardiovascular; DPP4, dipeptidyl peptidase 4 inhibitor; RCT, randomised controlled trial; T2D, type 2 diabetes. Source: Marx N, et al. DiabVasc Dis Res. 2015;12:

85 Οδηγίες και αλγόριθμοι για την αντιμετώπιση του ΣΔ2

86 Νεφρική νόσος Αντενδείξεις HbA1c Κόστος Κίνδυνος υπογλυκαιμιών Ευκολία χρήσης Αλληλεπίδραση με άλλα φάρμακα Σχέση σακχάρων νηστείας και μεταγευματικών Επιθυμία ασθενούς