![0 5000 10000 15000 20000
0.0
0.2
0.4
0.6
0.8
1.0
Linagliptin
koff = 0.00003 s-1
Vildagliptin
koff = 0.00021 s-1
Time [s]
(v
control
-
v
inhibitor
)/v
control
mean
+
SEM
Linagliptin: Xanthine based structure
Tight, fast binding to and slow dissociation from DPP-4 Enzyme
Linagliptin (light-blue carbon
atoms) bound to DPP-4
Eckhardt et al., J Med Chem. 2007;50(26):6450–3.
Thomas et al., J Pharmacol Exp Ther. 2008;325(1):175–82.
The calculated koff rate for linagliptin
was ~10-fold slower than the off-rate
for vildagliptin](https://image.slidesharecdn.com/linagliptin-speakertrainingkitindiafinal1234-230725044802-eac1d2a3/85/Linagliptin-Speaker-training-kit-India-final1234-pptx-10-320.jpg)
![11
DPP-4
enzyme
activity
[%
control]
Log dose [M]
0
20
40
60
80
100
120
- 12 - 10 - 8 - 6
IC501 [nM]
mean
1
19
Sitagliptin
24
Alogliptin
50
Saxagliptin
62
Vildagliptin
Thomas et al., J Pharmacol Exp Ther. 2008;325(1):175–82
1 Concentration of compound needed to inhibit 50% of DPP-4 activity, i.e. the lower the IC50,
the higher the potency to inhibit DPP-4 activity
Linagliptin concentration in
clinical use is 6-8 nmol/L,
resulting in >80% DPP-4
inhibition over 24 hours
Linagliptin
Linagliptin: Xanthine based structure
Highest potency inhibition in direct comparison to other DPP-4 inhibitors
Sitagliptin
Linagliptin
Saxagliptin
Alogliptin
Vildagliptin
Highest potency of
linagliptin in
inhibiting DPP-4
enzyme activity](https://image.slidesharecdn.com/linagliptin-speakertrainingkitindiafinal1234-230725044802-eac1d2a3/85/Linagliptin-Speaker-training-kit-India-final1234-pptx-11-320.jpg)
![Long-term efficacy and safety of linagliptin in patients
with type 2 diabetes and severe renal impairment
Conclusion:
Rates for any AE/ SAE were similar
with linagliptin (94.1% and 36.8%,
respectively) and PBO (92.3% and
41.5%).
Renal function remained stable
throughout the study in both
treatment arms, and numbers of
cardiovascular deaths in this
high-risk population were similarly
low (linagliptin, n=2 [2.9%];
PBO, n=3 [4.6%]).
Authors: J. Newman1, J.B. McGill2, S. Patel3, C. Friedrich4, C. Sauce5, H.-J. Woerle6; EASD Poster 821
0.72% reduction in HbA1c from baseline after 52 weeks of treatment](https://image.slidesharecdn.com/linagliptin-speakertrainingkitindiafinal1234-230725044802-eac1d2a3/85/Linagliptin-Speaker-training-kit-India-final1234-pptx-43-320.jpg)
More Related Content
Similar to Linagliptin - Speaker training kit India final1234.pptx
More from AmeetRathod3
Linagliptin - Speaker training kit India final1234.pptx
- 1. Role in T2DMmanagement Expert panel on Linagliptin Incretin-based Treatment Evolution (ELITE) Linagliptin
- 2. Diabetes: challenges tomanagement Adherence to therapy Coexisting risk of declining hepatic/renal/CV function Co morbidities Hypertension Need for Early and Aggressive Care for Sustained glucose control Treating to goal without hypoglycemia & glycemic variability
- 3. Gliptins: Addressing theunmet needs in T2DM Correct a core defect: Stabilize deterioration of beta cell function Overcome risks: Low risk of hypoglycemia and weight neutral Have acceptable safety profile: No serious adverse events were noted during the clinical trials A Ramachandran, AK Das, SR Joshi, CS Yajnik, S Shah, KM Prasanna Kumar. JAPI • JUNE 2010
- 4. Conducted between 2004and 2010 More than 40 countries worldwide More than 600 investigational sites More than 6,000 patients participated In total 4687 patients with type 2 diabetes & 453 healthy volunteers 3692 patients were treated for at least 24 wks, 2474 patients for at least 52 wks & 536 patients for more than 78 wks Europe - 44.3% patients Asia - 40.2% patients North America - 9.3% patients South America.- 6.2% patients Linagliptin: the first DPP-4th inhibitor gliptin? 624 829 5,002 0 2,000 4,000 6,000 Phas e I Phase II Phase III Currently approved in > 7 major countries US, EU, Brazil, Canada, Japan, Australia, Mexico, Taiwan, India Gliptin with largest clinical program before launch
- 5. 5 First in T2DM Firstin men Phase II 1st horizon 2nd horizon 3rd horizon Phase IV PK/PD studies PK studies in specific populations Phase IIIb Phase IIIa .50 .20 .23 .35 .16 .17 .18 .43 .63 .64 .61 .75 .36 .46 .6 .2 1218.1 .37 .27 .55 .34 .32 .84 .85 … .88 .86 … … … … … … … … .15 Overview on phase I-IV trials according to clinical evolvement DDI .60 CAROLINA .74 CV metaanalysis DARLINA .89 Add. CV- studies .3 .11 .26 .58 .5 .52 .78 .65 .66 Specific countries .83 .87 .40 Pivotal .62 .7 .7
- 6. Linagliptin: Indications Linagliptin inmonotherapy Linagliptin as add-on to metformin and as initial combination Linagliptin as add-on to SU Linagliptin + pioglitazone in initial combination Linagliptin as add-on to metformin + sulfonylurea Linagliptin head-to-head study vs. sulfonylurea (in combination with metformin) Linagliptin as monotherapy vs. -glucosidase inhibitor (voglibose) Linagliptin in patients with severe renal impairment Linagliptin as add-on to basal insulin (just completed) Linagliptin is a dipeptidyl peptidase-4 (DPP-4) inhibitor indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus • Should not be used in patients with type 1 diabetes or for the treatment of diabetic ketoacidosis • Has not been studied in combination with insulin
- 7. Unique Structure and related benefits Glycemiccontrol Safety and tolerability Special populations Beyond glycemic control – emerging data Linagliptin: not just a fourth gliptin
- 8. Unique Structure and related benefits Glycemiccontrol Safety and tolerability Special populations Beyond glycemic control – emerging data Linagliptin: not just a fourth gliptin
- 9. Linagliptin: Xanthine basedstructure Directly binds to the active site of the enzyme Saxagliptin Sitagliptin Vildagliptin Adapted from Deacon CF. Diabetes Obes Metab. 2011; 13: 7–18; 1 Davis JA. Indian J Pharmacol 2010;42:229-33, 2 Kirby M. Clinical Science (2010) 118, 31–41 Peptidomimetic DPP-4 inhibitors Linagliptin N N N N O O N N N NH2 DPP-4 inhibitors directly binding to the active site of the enzyme Non-peptidomimetic DPP-4 inhibitors N N N N O F F F F F F NH2 NH2 O HO N N OH N H N O N Non Covalent – fast binding/fast dissociation1 Covalent – slow binding/slow dissociation2 Non Covalent – Fast binding/slow dissociation
- 10. 0 5000 1000015000 20000 0.0 0.2 0.4 0.6 0.8 1.0 Linagliptin koff = 0.00003 s-1 Vildagliptin koff = 0.00021 s-1 Time [s] (v control - v inhibitor )/v control mean + SEM Linagliptin: Xanthine based structure Tight, fast binding to and slow dissociation from DPP-4 Enzyme Linagliptin (light-blue carbon atoms) bound to DPP-4 Eckhardt et al., J Med Chem. 2007;50(26):6450–3. Thomas et al., J Pharmacol Exp Ther. 2008;325(1):175–82. The calculated koff rate for linagliptin was ~10-fold slower than the off-rate for vildagliptin
- 11. 11 DPP-4 enzyme activity [% control] Log dose [M] 0 20 40 60 80 100 120 -12 - 10 - 8 - 6 IC501 [nM] mean 1 19 Sitagliptin 24 Alogliptin 50 Saxagliptin 62 Vildagliptin Thomas et al., J Pharmacol Exp Ther. 2008;325(1):175–82 1 Concentration of compound needed to inhibit 50% of DPP-4 activity, i.e. the lower the IC50, the higher the potency to inhibit DPP-4 activity Linagliptin concentration in clinical use is 6-8 nmol/L, resulting in >80% DPP-4 inhibition over 24 hours Linagliptin Linagliptin: Xanthine based structure Highest potency inhibition in direct comparison to other DPP-4 inhibitors Sitagliptin Linagliptin Saxagliptin Alogliptin Vildagliptin Highest potency of linagliptin in inhibiting DPP-4 enzyme activity
- 12. Linagliptin: Full 24h Duration of DPP-4 Inhibition, Not Observed with Other DPP-4 Inhibitors (Preclinical data) Thomas et al, J Pharmacol Exp Ther. 2008;325(1):175–82. HanWistar rats were administered the respective compounds in single dose at 1 or 10 mg/kg. Blood was taken for DPP-4 activity 7 and 24 h after dosing. Data are means ± SEM (n=5-10/group) Thomas et al., J Pharmacol Exp Ther. 2008;325(1):175–82. (linagliptin > sitagliptin, saxagliptin > vildagliptin)
- 13. Linagliptin: Good tissuedistribution, mainly bound to protein, long terminal half life, and does not accumulate Retlich et al. 2010 J Clin Pharm. J Clin Pharmacol. 50:873-85; Scheen et al. 2010, DOM 12: 648-658 1 In healthy subjects; distribution at steady state following a single 5 mg i.v. dose of linagliptin 2 US prescribing information Linagliptin Volume distribution, L Fraction bound to protein, % 70-80 11101 Terminal half life, hours Sitagliptin 198 38 12.4 Vildagliptin 71 9.3 2-3 Saxagliptin 151 very low 2.5 3.1 (active metabolite) >100
- 14. Unique Structure and related benefits Glycemiccontrol Safety and tolerability Special populations Beyond glycemic control – emerging data Linagliptin: not just a fourth gliptin
- 15. 1 21 41 61 81 101 0 4 812 16 20 24 Time (h) % DPP-4 Inhibition Linagliptin provides long-lasting DPP-4 inhibition in patients with T2DM Peak in 1.5 hours > 91% DPP-4 inhibition achieved 1. Steady state Achieved by 3rd dose 2. Linagliptin trough 6-8 nmol/L, resulting in >80% DPP-4 inhibition over 24 hours 3. GLP rise 3.2 fold rise in post-prandial active GLP-1 levels Forst T, et al. Diabetes Obes Metab. 2011;13: 542–550 Source: Adapted from Heise et al., Diabetes Obes Metab. 2009;11(8):786–94 5 mg tablet, in type 2 diabetes patients
- 16. Linagliptin: Sustained HbA1creductions over 2 years1 0 -0.4 -0.8 -1.2 Change from baseline HbA1c Mean over time ± SE, percent; mean baseline HbA1c: 8.1% 24 Treatment duration in weeks 0 102 1429 1531 903 n Open-label extension Coefficient of durability2 of 0.14% meaning no relevant increase in HbA1c from week 24 to week 102 (p-value < 0.0001) Source: Gallwitz et al. EASD 2011 Placebo-controlled double-blind -0.8% HbA1c reduction at 102 weeks 1 Open-label extension of 4 double-blind randomized controlled trials over 24 weeks. Patients randomized to linagliptin treatment for the first 24 weeks continued on linagliptin for an extension of 78 weeks. The analysis shown is restricted to this arm of the trial. Analysis of secondary endpoint in full analysis set, observed cases 2 Coefficient of durability (COD) is defined as HbA1c at week 102 visit subtracted by HbA1c at week 24 visit
- 17. Linagliptin: meaningful HbA1creductions independent of time since diagnosis of type 2 diabetes Footnote: Pre-specified sub-group analysis on pooled data from 4 pivotal phase III randomized placebo-controlled trials including treatment in monotherapy, as add-on to metformin, as add-on to metformin + SU, or in initial combination with pioglitazone. Full Analysis Set (FAS), Last Observation Carried Forward (LOCF) ≤ 1 year p< 0.0001 p< 0.0001 p< 0.0001 n Mean baseline HbA1c, percent 120 8.2 1,045 8.2 381 8.2 570 8.1 227 8.0 261 8.1 > 1 to ≤ 5 years > 5 years Source: Data on file 0.5 0 -0.5 -1.0 0.7 -0.01 0.6 0.03 0.7 -0.17 Linagliptin Placebo Adjusted mean change in HbA1c (%) from baseline at week 24 Time since diagnosis
- 18. 1Poorly controlled =Baseline HbA1c ≥ 9% 2Del Prato S et al. 2011 DOM 13: 258-267 3Taskinen M R et al. 2011 DOM 13: 65-74 4Owens DR et al. Diabetes Obesity and Metabolism (in press) 2011 * Versus baseline 0.5 0 -0.5 -1.0 -1.5 -1.20 -0.40 -0.95 -0.23 -0.86 0.15 Linagliptin Placebo Add-on to metformin3 p <0.0001* Linagliptin monotherapy2 p <0.0001* Add-on to metformin + SU4 p <0.0001* Adjusted mean change in HbA1c (%) from baseline at week 24 n 24 96 29 55 Mean baseline HbA1c, percent 9.5 9.4 9.5 9.5 9.4 136 48 9.4 Source: Del Prato et al. American Diabetes Association, 71th Scientific Sessions, San Diego, CA, June 24-28, 2011; 1067-LB Meaningful HbA1c reduction in patients with baseline ≥9%1-4 Linagliptin achieves HbA1c decrease up to -1.2% 1 T2DM patients with >9% baseline A1c
- 19. Initial combination oflinagliptin and metformin achieves significant reductions in HbA1c 19 Combination regimens were superior to metformin monotherapy *** p<0.0001, combination therapy versus respective monotherapy 1 Randomized arm: 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 Source: Haak, et al. American Diabetes Association, 71th Scientific Sessions, San Diego, CA, June 24-28, 2011; 279-OR -1.0 -1.5 -2.0 -3.5 -4.0 -1.7 -3.7 0 -1.3 -0.5 8.7 140 11.8 66 LIN 2.5 + MET 1000 mg BID LIN 2.5 + MET 1000 mg BID Randomized arm1 (placebo-corrected) High baseline HbA1c Open-label arm2 Baseline HbA1c, % Patients, n Change in HbA1c from baseline, % 8.7 137 LIN 2.5 + MET 500 mg BID Initial combination of linagliptin 2.5 mg and metformin 500 mg BID is as effective as metformin 1000 mg BID
- 20. 1 Adapted fromDel Prato S et al. 2011 DOM 13: 258-267 2 Taskinen M R et al. 2011 DOM 13: 65-74 3 Owens DR et al. Diabetes Obesity and Metabolism (in press) 2011 4 Model includes continuous baseline HbA1c and treatment 5 Versus baseline 0.5 0 -0.5 -1.0 -1.5 -0.62 -0.64 -0.69 Linagliptin Placebo corrected Add-on to metformin2 p <0.00017 Monotherapy1 p <0.00015 Add-on to metformin + SU3 p <0.00017 Adjusted4 mean change in HbA1c (%) from baseline at week 24 n 513 333 Mean baseline HbA1c, percent 8.1 8.0 778 8.2 Linagliptin achieves meaningful HbA1c decrease in T2DM patients with 8.0 baseline A1c
- 21. Placebo-corrected, adjusted meanchange in FPG and PPG in mg/dl Monotherapy Linagliptin1 5 mg OD HbA1c baseline 8.0% 1Del Prato S, et al. Diabetes Obes Metab. 2011;13: 258–267; 2 Taskinen M R et al. 2011 DOM 13: 65-74 Linagliptin: achieves strong FPG and PPG decrease in type 2 diabetes patients Add on to Metformin Linagliptin2 5 mg OD Baseline HbA1c 8.1%
- 22. Rate of patientsachieving HbA1c target <7% 75.6 76.4 0 20 40 60 80 100 Linagliptin Glimepiride 2 year study: Linagliptin was non-inferior to glimepiride in treatment effect1 0.5 0 -0.5 -1.0 -1.5 Linagliptin vs glimepiride2 p <0.0001* Adjusted mean change in HbA1c (%) from baseline at week 104 n Mean baseline HbA1c, percent -0.60 -0.60 7.7 7.7 Rate of patients achieving HbA1c target <7% 271 233 Gallwitz B., et al. ADA 2011 Late Breaker 39-LB
- 23. Unique Structure and related benefits Glycemiccontrol Safety and tolerability Special populations Beyond glycemic control – emerging data Linagliptin: not just a fourth gliptin
- 24. Linagliptin: Xanthine basedstructure: Lowest risk of "Off-target" DPP inhibition (i.e., inhibition of DPP-8/-9) Source: Deacon CF. 2011 DOM;13:7-18 1 Quiescent cell proline dipeptidase 2 Drucker, DJ. Diabetes Care June 2007 30 (6): 1335-1343 3 Demuth et al. Biochim. Biophys. Acta 2005, 1751, 33 ▪ "Off-target" DPP inhibition (i.e., inhibition of DPP-8/-9) has shown severe toxicity in preclinical studies3 QPP/DPP-21 DPP-8 DPP-9 Linagliptin Sitagliptin Vildagliptin Saxagliptin Alogliptin > 100,000 > 5,500 > 100,000 > 50,000 > 14,000 40,000 > 2,660 270 390 > 14,000 > 10,000 > 5,500 32 77 > 14,000 Leading Selectivity for DPP-42 compared to
- 25. Linagliptin shows favorabletolerability and safety 1 Categories of organ-specific adverse events described if mentioned in the labels of currently marketed DPP-4 inhibitors in the US 2 Linagliptin US prescribing information Placebo Linagliptin 2,523 1,049 Upper respiratory tract infection 3.3% 4.9% Nasopharyngitis 5.9% 5.1% Cough 1.7% 1.0% Blood and lymphatic system disorders 1.0% 1.2% Hypersensitivity 0.1% 0.1% Urinary tract infection 2.2% 2.7% Hepatic enzyme increase 0.1% 0.1% Headache 2.9% 3.1% Pancreatitis 1/538 0 /433 (in person years) 2 Serum creatinine increase 0.0% 0.1% Number of patients Source: Scherntharner et al. American Diabetes Association, 71th Scientific Sessions, San Diego, CA, June 24-28, 2011 Abstract 2327-PO Organ-specific adverse event (AE) rate for AE previously associated with the DPP-4 inhibitor class1 in a pooled analysis of 8 randomized, placebo- controlled, phase III trials
- 26. Linagliptin (2523) Placebo(1049) Hypoglycemia 8.2% 5.1% Severe hypoglycemia 0.2% 0.2% Receiving SU 20.7% 13.3%* Not receiving SU 0.6% 1.0% Linagliptin shows lower incidence of hypoglycemia *Notably, 38% of patients on sulphonylurea background therapy accounted for 96% of all hypoglycaemic events in the linagliptin-treated group The somewhat higher incidence of hypoglycaemia associated with linagliptin was almost exclusively attributable to the combination with sulphonylurea Source: Scherntharner et al. American Diabetes Association, 71th Scientific Sessions, San Diego, CA, June 24-28, 2011 Abstract 2327-PO
- 27. 0 10 20 30 40 50 Linagliptin 7.5 Glimepiride 36.1 Incidence of hypoglycemia1 Percentof patients over 104 weeks Adjusted2 weight change from baseline kg, over 104 weeks 2.0 1.5 0.5 0 -0.5 -1.5 -2.0 Significantly lower incidence of hypoglycemia with linagliptin as compared to glimepiride (p-value < 0.0001) Significant relative weight loss with linagliptin as compared to glimepiride (p-value < 0.0001) 12 28 52 104 weeks 78 80% lower -2.9 kg Linagliptin has significantly lower incidence of hypoglycemia and relative weight loss as compared to glimepiride Key secondary endpoints: Incidence of hypoglycemia: Treated set, n = 775 for glimepiride and n = 776 for linagliptin; Weight change: Full Analysis Set (FAS), Observed cases (OC), n=755 for glimepiride and n=764 for linagliptin 1 Hypoglycemic episode defined by a blood glucose ≤70 mg/dl 2 Model includes baseline HbA1c, baseline weight, number of prior OADs, treatment, week repeated within patients and week by treatment interaction Glimepiride Linagliptin Source: Gallwitz et al. American Diabetes Association, 71th Scientific Sessions, San Diego, CA, June 24-28, 2011; 39-LB
- 28. Potential CV safetyprofile: First gliptin with a prospective, pre-specified meta- analysis with independent adjudication of CV endpoints Incidence rate of CV events1 Number and percentage of patients Years of exposure 1,372 2,060 1 CV events as defined as primary endpoint 2 977 patients receiving placebo, 781 glimepiride, 162 voglibose 11 23 Comparator2 Linagliptin Source: Johansen et al. American Diabetes Association 71st Scientific Sessions, San Diego, CA, June 24-28, 2011; 30-LB Out of 3,319 patients = 0.3% Out of 1,920 patients = 1.2% Risk ratio 0.34 95% CI (0.15/0.74) p<0.05
- 29. Note: CV death,non-fatal MI, non-fatal stroke, hospitalization due to unstable angina pectoris 1. Johansen et al. American Diabetes Association 71st Scientific Sessions, San Diego, CA, June 24-28, 2011; 30-LB; 2. Sitagliptin Williams-Herman et al. 2010, BMC Endocrine disorders; 3. Vildagliptin; Schweizer et al. 2010, DOM; 4. Saxagliptin: Frederich et al. 2010, Postgraduate Medicines; 5. Alogliptin White et al 2010, ADA Scientific sessions 2010 Abstract 391-pp Total patients in analysis DPP-4 inhibitor better Comparator better 1 1/2 1/4 1/8 2 4 8 x Primary endpoint Comments 5,239 CV death, MI, stroke, hospitali- zation due to angina Prespecified/in- dependent adjudication Linagliptin1 0.34 0.15 0.74 10,246 Med DRA terms for MACE No formal adjudication Sitagliptin2 x 0.68 0.41 1.12 10,988 Acute coronary syndrome, transient ischaemic attack, stroke, CV death Prespecified/ independent adjudication Vildagliptin3 x 0.84 0.62 1.14 4,607 MI, stroke, CV death Prespecified/ independent adjudication Saxagliptin4 x 0.42 0.23 0.80 3,489 Non-fatal MI, non- fatal stroke, CV death Prespecified/ independent adjudication Alogliptin5 x 0.63 0.21 1.91 ▪ No increased risk of CV events was observed in patients randomly treated with DPP-4 inhibitors ▪ There are no clinical studies so far that conclusive establish macrovascular risk reduction with any anti-diabetic drug Potential CV safety profile: Risk ratios for major CV events for different DPP-4 inhibitors1-5
- 30. Linagliptin: CV riskmodulation potential1 Increases GLP-1 positively thus modulates lipid metabolism, reduces infarct size and improves cardiac function Reduces inflammation, stimulates endothelial repair, and blunts ischaemic injury Improves glycaemic control, including the lowering of postprandial glucose Possesses inherent anti- oxidative properties, most likely due to its xanthine- based molecular structure Johanssen OE et al. Cardiovascular Diabetology 2012, 11:3
- 31. 31 Linagliptin reduced infarctsize in an acute model of myocardial infarction Source: Sharkovska et al. American Diabetes Association 71th, Scientific Sessions, San Diego, CA, June 24–28, 2011; 974-P; Sharkovska et al EASD 2011 Representative cardiac section. Data are means ± SD. n=8-12 per group for the 7 day follow-up and n=16-18 for the 8 week follow-up. *p<0.05, **p<0.001 vs. respective vehicle group Reduced infarct size under linagliptin in an acute model of myocardial infarction Representative cardiac section after staining with triphenyl- tetrazolium-chloride. The infarcted area was defined as the area unstained by triphenyl-tetrazolium-chloride
- 32. Linagliptin reduces oxidativestress and inflammatory cell activation – indirect anti-oxidant effect 1 p<0.05 vs. control and #, p<0.05 vs. LPS. Source: Schuff et al. American Diabetes Association 71th, Scientific Sessions, San Diego, CA, June 24–28, 2011; 981-P Sharkovska et al. American Diabetes Association 71th, Scientific Sessions, San Diego, CA, June 24–28, 2011; 974-P ;EASD 2011 Effects of linagliptin (LG) on activation of white blood cells: Quantification of oxidative burst in isolated neutrophils (PMNs) Linagliptin inhibits oxidative burst in stimulated human neutrophils
- 33. 33 Outcomes trial: CAROLINA TheCAROLINA trial aims to investigate the long-term impact of Linagliptin on maintenance of glycemic control and on cardiovascular morbidity and mortality in patients with T2DM CAROLINA has an innovative design (only trial versus active comparator) and is unique in the diabetes environment, advancing scientific knowledge in this field Sub-studies within the CAROLINA protocol 1. Impact of linagliptin vs glimepiride on glycemic durability, need for rescue therapy, C-peptide etc in LADA1 patients (Europe and North America) 2. Impact of linagliptin vs glimepiride on silent myocardial infarction (incidence, outcomes) 3. Biomarker evaluation (outcome, biomarker for risk, etc) 4. Health economics
- 34. Unique Structure and related benefits Glycemiccontrol Safety and tolerability Special populations Beyond glycemic control – emerging data Linagliptin: not just a fourth gliptin
- 35. No signs orsymptoms until >70% of kidney function is lost1,2 CVD risk equivalent. 3 Serum creatinine rises only if >50% of renal function is already lost4 50% of beta cell function may be lost at diagnoses in T2DM. What about renal function at baseline? PCPs screen only 20% of their diabetic patients for kidney disease, before prescribing Hypoglycemia worsens in kidney impairment Kidney Disease in Diabetes: a silent killer ? 1. Keen and Viberti, J Clin Pathol. 1981;34:1261–6. 2. McLaughlin NG et al., Northeast Florida Medicine, 2005. 3. United States Renal Data System. Annual data reportt, 2009. http://www.usrds.org/atlas.htm 4. Jemel A et al., CA Cancer J Clin. 2007;57;43–66.
- 36. Liver Disease inDiabetes 1 Cusi K. Curr Opin Endocrinol Diabetes Obes 2009; 16: 141–9. 2 Nordenstedt H, White DL, El-Serag HB. Dig Liver Dis 2010; 42(Suppl 3): S206–14. 3 Garcia-Compean D, Jaquez-Quintana JO, Gonzalez-Gonzalez JA, Maldonado-Garza H. World J Gastroenterol 2009; 15: 280–8. 70% of patients with T2DM have nonalcoholic fatty liver disease1 Patients with T2DM frequently suffer from various forms of liver disease 30% of patients with cirrhosis have diabetes, potentially both a cause and consequence of diabetes2,3
- 37. ~ 5% oforally administered linagliptin is excreted via the kidneys The majority of linagliptin is excreted unchanged via non-renal route 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
- 38. Linagliptin undergoes limitedmetabolism and is primarily excreted unchanged (about 90%)1 0 0.5 1 1.5 Fold increase in exposure relative to normal hepatic function Fold Increase in exposure relative to normal hepatic function Source: Graefe-Mody et al. 4th International Congress on Prediabetes and the Metabolic Syndrome, Madrid, Spain, April 6-9, 2011 Healthy Mild (Grade A) Moderate (Grade B) Severe (Grade C) n=7 n=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 No dosage adjustment for linagliptin is necessary for patients with hepatic impairment
- 39. Linagliptin: No clinicallyrelevant drug-drug interactions There are no clinically relevant drug-drug interactions between linagliptin and... Commonly used oral glucose-lowering medications • Metformin • Glyburide • Pioglitazone Commonly used cardiovascular medications • Digoxin • Warfarin • Simvastatin P-glycoprotein/CYP 3A4 inducer: The efficacy of linagliptin may be reduced when administered in combination (e.g., with rifampin). Use of alternative treatments is strongly recommended. Source: Linagliptin US prescribing information
- 40. Linagliptin is theonly DPP-4 inhibitor with no need for dose adjustment even in patients with RI 40 1 Estimated creatinine clearance values were calculated using the Cockcroft-Gault formula 2 90% confidence intervals not available 3 n numbers, 90% confidence intervals and definitions of RI according to creatine clearance not available for vildagliptin (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 clearance1 (mL/min) Fold increase in exposure relative to normal renal function Linagliptin 0 1 2 3 4 5 6 7 ESRD Severe Moderate Mild Normal (n=8) (n=8) (n=8) (n=8) (n=8) >80 >50 to ≤80 >30 to ≤50 <30 on HD Renal impairment status Creatinine clearance1 (mL/min) Fold increase in exposure relative to normal renal function Saxagliptin (5-hydroxy saxagliptin metabolite)2 0 1 2 3 4 5 6 7 ESRD Severe Moderate Mild Normal (n=6) (n=6) (n=6) (n=6) (n=6) >80 50 to ≤80 30 to ≤50 <30 on HD Renal impairment status Creatinine clearance1 (mL/min) Fold increase in exposure relative to normal renal function Sitagliptin 0 1 2 3 4 5 6 7 ESRD Severe Moderate Mild Normal Renal impairment status Fold increase in exposure relative to normal renal function Vildagliptin (LAY151 metabolite)3 Source: Graefe-Mody et al. 1011 DOM in press, Bergman et al. Diabetes Care 2007, 30:1862-1864; Boulton et al. Clin Pharmacokinet 2011, 50:253-265; European Medicines Agency (EMEA). Galvus (vildagliptin). European Public Assessment Report (EPAR) Two-fold safety margin 0 1 2 3 4 5 6 7 Normal Severe Mild Moderate ESRD
- 41. -1 -0.5 0 0.5 Linagliptin provides reliableHbA1C reductions in elderly Change from baseline HbA1c by age1 Adjusted mean change from baseline at 24 weeks of treatment p<0.0001 65 to 74 years ≥75 years p=0.0002 n = Mean baseline HbA1c (%) Adjusted mean change in HbA 1c (%) from baseline at week 24 152 398 8.1 8.1 19 66 8.1 8.0 -0.09 -0.69 0.03 -0.80 p-values for between group difference (versus placebo) Source: Linagliptin data on file 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 Placebo
- 42. -0.18 -0.28 -0.56 -1.18 -1.5 -1 -0.5 0 Severe renal impairment Severe renal impairment Adjusted mean change in HbA 1c (%) from baseline at week 24 Linagliptinprovides reliable HbA1c reductions in severe renal function <0.0001 p-value between group difference (versus placebo) Mean baseline HbA1c (%) 8.3 8.2 62 66 n = 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. 13 11 >9 >9 0.8% reduction in HbA1c from baseline after 12 weeks of treatment Sloan L et al. Poster: 413-PP, ADA, 2011
- 43. Long-term efficacy andsafety of linagliptin in patients with type 2 diabetes and severe renal impairment Conclusion: Rates for any AE/ SAE were similar with linagliptin (94.1% and 36.8%, respectively) and PBO (92.3% and 41.5%). Renal function remained stable throughout the study in both treatment arms, and numbers of cardiovascular deaths in this high-risk population were similarly low (linagliptin, n=2 [2.9%]; PBO, n=3 [4.6%]). Authors: J. Newman1, J.B. McGill2, S. Patel3, C. Friedrich4, C. Sauce5, H.-J. Woerle6; EASD Poster 821 0.72% reduction in HbA1c from baseline after 52 weeks of treatment
- 44. DARLINA study: safetyand efficacy in patients at risk of renal impairment 44
- 45. Unique Structure and related benefits Glycemiccontrol Safety and tolerability Special populations Beyond glycemic control – emerging data Linagliptin: not just a fourth gliptin
- 46. The progressive natureof established Type 2 diabetes is well recognized, and occurs despite attempts to maintain glucose as near to normal as possible The major reason for the decline in glucose tolerance seems to be a progressive loss of beta-cell function, based on the UKPDS and the longitudinal assessment in Pima Indians Need to stabilize deteriorating beta cell function early Hyperglycemia (glucose toxicity) Beta cell Insulin resistance Lipotoxicity (elevated FFA, TG) TG accumulation Genetics Amyloid plaque deposits Insulin Resistance and Beta Cell dysfunction: both are typically present very early in the natural history of the disease Authors: Kahn SE J Clin Endocrinology 2001;88:4047-4058 Ludwig DS JAMA 2002; 287:2414-2423
- 47. Beta cell function:Linagliptin Shows Significant Improvements in β-cell Function Across Individual Pivotal Phase IIIa Trials aIn this study, the placebo arm consisted of pioglitazone + placebo ADA 70th Scientific Sessions 2010. Poster numbers: 1. Del Prato S et al., 695-P; 2. Taskinen M-R et al., 579-P; 3 Gallwitz B., et al. ADA 2011 Late Breaker 39-LB • Monotherapy1 - 33% • Add on to metformin2 - 24% % improvement in HOMA %B at 24 weeks • Monotherapy1 - 20% • Compared to Glimepiride3 - 21% % reduction in Proinsulin: Insulin ratio at 24 weeks • Compared to Glimepiride3 – 16.5% % reduction in HOMA IR at 24 weeks • Monotherapy2 - • Combination with pioglitazone Disposition Index
- 48. Beta cell function:Linagliptin restores ß-cell survival in isolated human islets in T2DM Lipotoxicity Glucotoxicity Inflammatory stress Oxidative stress Physiological condition Glucotoxicity With linagliptin, less apoptosis is seen under stress conditions Vehicle Linagliptin (100 nM) Insulin (ß-cell marker) TUNEL (marker for apoptosis) * ** ** ** ** ** * * * * % TUNEL +β-cells 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
- 49. Linagliptin: Improves HepaticSteatosis in DIO Mice A MRS and Histology Based Study A: Red oil staining of liver specimen from DIO mice fed with a) HFD vehicle b) HFD + 30 mg/kg/d linagliptin c) HFD + linagliptin 3 mg/kg/d d) chow diet control; HFD for 4 months, treatment for 21 days B: Quantification of red oil staining by histological scoring, mean + SEM, n=9 animals per group (*P<0.05, **P<0.01; ***P<0.001) Klein et al., ADA 70th Scientific Sessions 2010. Poster number 577-P; Date of preparation: March 2010 A B
- 50. 51 Linagliptin improves woundhealing in the ob/ob mouse1 Source: Schurmann et al. American Diabetes Association 70th, Scientific Sessions, Orlando, Florida, June 25–29, 2010; - P; Linke et al. American Diabetes Association 69th, Scientific Sessions, June 2009 -P 1 Obese mouse model for type 2 diabetes mellitus Linagliptin improves wound healing through accelerated re- epithelialization Quantification of wound size in ob/ob mice following 12 days treatment with 3 mg/kg linagliptin (n=10) or control (n=9) Decreased wound size with linagliptin treatment compared to control
- 51. 52 Linagliptin decreases inflammationin wounds of ob/ob mice Source: Schurmann et al. American Diabetes Association 70th, Scientific Sessions, Orlando, Florida, June 25–29, 2010; - P; Linke et al. American Diabetes Association 69th, Scientific Sessions, June 2009 –P Note: Mock- (ctrl) and linagliptin-treated ob/ob mice Immunoblot showing the presence of GR1 protein, a marker for neutrophil infiltrate, in 10 day wound tissue Linagliptin decreases neutrophil infiltration in wounds of ob/ob mice Stained for neutrophil infiltrate using the anti-Ly6C (GR1) antibody. Immunopositive signals (brown) are indicated by arrows Neutrophil (PMN) cell numbers from total 10 day wound sections * p<0.05 as compared to control mice. Means ± SD from 3 wounds from 3 animals (n=3)
- 52. Linagliptin: place intherapy Adherence to therapy Coexisting risk of declining hepatic/ renal/ CV function Co morbidities Hypertension Lack of early and Aggressive Care for Sustained glucose control Treating to goal without hypoglycemia & glycemic variability Effective as monotherapy and initial combination with metformin Sustained Efficacy across treatment populations Well tolerated Least off target inhibition Low discontinuation due to AEs No dose adjustment required One dose fits all Proven CV safety profile No clinically relevant drug interactions
- 53.
- 54. Summary: Linagliptin 55 Unique xanthinebased structure Rapid and sustained action Sustained Efficacy across treatment regimens Independent of age, duration of disease, insulin resistance, baseline A1c, special populations Acceptable Safety and tolerability Least potential for off target inhibition Low risk of hypoglycemia and weight gain Proven CV safety profile Special populations No dose adjustment in any grade of on renal and hepatic dysfunction Beyond glycemic control Emerging data on preservation of beta cell function and immuno- modulatory effects
- 55. Linagliptin clinical profile 56 1Please consult the Trajenta prescribing information before prescribing 2 In placebo controlled clinical trials adverse reactions that occurred in ≥5% of patients receiving linagliptin Convenience ▪ One dose fits all1 ▪ Once-daily ▪ With or without food ▪ Primarily excreted via bile and gut ▪ Share of renal excretion: 5% No dose adjustment in renal or hepatic impairment ▪ Overall safety profile similar to placebo: – No clinically relevant weight gain – Very low risk of hypoglycemia Efficacy ▪ Meaningful and reliable efficacy across complete range of oral diabetes therapies ▪ Durable efficacy in longer term treatment up to 2 years Safety & Tolerability ▪ Most common adverse reaction2: nasopharyngitis ▪ Not associated with increase in CV risk Source: US prescribing information
- 56. Summary on glycemiccontrol 57 Age Insulin resistance Renal Elderly CV risk 2 year data Duration of disease Special populations A1c baselines Efficacy across disease continuum Source: US prescribing information
- 57. Linagliptin Significantly LowersHbA1c in Initial Combination Therapy with Pioglitazone By Week 24, the linagliptin + pioglitazone group showed a significantly greater mean HbA1c reduction compared with the pioglitazone + placebo group (P<0.0001) Baseline HbA1c: 8.60% linagliptin-treated group; 8.58% placebo group; Last observation carried forward (LOCF) Gomis R et al., ADA 70th cientific Sessions 2010. Poster number 551-P 0.65% Baseline HbA1c: 8.60% linagliptin-treated group; 8.58% placebo group;
- 58. Clinical characteristics oflinagliptin compared to other DPP-4 inhibitors 59 Source: US prescribing information; EMEA summary of product characteristics 1 Without limitations in renal or hepatic impairment: please consult the Trajenta prescribing information before prescribing 2 As per US prescribing information Characteristics Vilda- gliptin Saxa- gliptin Sita- gliptin Lina- gliptin One dose fits all1 No dose adjustment in renal impairment No dose adjustment based on drug-drug-interactions No drug-related monitoring of renal function No skin toxicity in preclinical studies2 No liver toxicity (e.g. hepatic dysfunction)2 No reports of acute renal failure2 No dose adjustment in hepatic impairment Linagliptin is the first one dose, once daily oral antidiabetic drug (OAD)
- 59. Linagliptin can beused with no dose adjustment in various patient populations 60 Declining renal function Hepatic insufficiency Long disease duration Obese vs. lean Cardiovascular disease Ethnicity Any age group including geriatric No limitations No dose adjustment Source: US prescribing information
- 60.
- 61. Del Prato S,et al. Diabetes Obes Metab. 2011;13: 258–267. Del Prato S et al., ADA 70th Scientific Sessions 2010. Poster number 695-P Monotherapy Linagliptin (336) Placebo (167) Hypoglycemia (mild) 0.3% (n=1) 0.6% (n=1) Weight Difference 0.28 kg Waist circumference -0.6 cm 0.4 cm Metformin Add On Linagliptin (336) Placebo (167) Hypoglycemia 0.6% (n=3) 2.8% (n=5) Weight -0.4 kg -0.5 kg Taskinen MR, et al. Diabetes Obes Metab. 2011;13:65–74. Linagliptin shows lower incidence of hypoglycemia Metformin + SU Add On Linagliptin (792) Placebo (263) Hypoglycemia 14.8% (n=3) 22.7% (n=5) Weight Difference 0.33 kg Weight -0.2 kg 0.0 kg
- 62. Del Prato S,et al. Diabetes Obes Metab. 2011;13: 258–267. Del Prato S et al., ADA 70th Scientific Sessions 2010. Poster number 695-P Taskinen MR, et al. Diabetes Obes Metab. 2011;13:65–74. Linagliptin shows lower incidence of hypoglycemia *Notably, 38% of patients on sulphonylurea background therapy accounted for 96% of all hypoglycaemic events in the linagliptin-treated group The somewhat higher incidence of hypoglycaemia associated with linagliptin was almost exclusively attributable to the combination with sulphonylurea
- 63. DECODE: Importance ofPost prandial glucose reduction Compared with men with normal FPG (<110 mg/dL), men with newly diagnosed T2DM by the ADA fasting criteria (>126 mg/dL) had a hazard ratio for death of 1·81; for women it was 1·79. For IFPG ( 110– 125 mg/dL), the hazard ratios were 1·21 and 1·08. For the WHO criteria (200 mg/dL), the ratios for newly T2DM were 2·02 in men and 2·77 in women, and for IGT (140-200 mg/dL) were 1·51 and 1·60. Trial design: To assess mortality associated with the ADA fasting glucose criteria compared with the WHO 2 h post-challenge glucose criteria. 18 048 men and 7316 women aged 30 years or older followed for a mean of 7·3 years for CV events Results Conclusions •FPG alone do not identify individuals at increased risk of death associated with hyperglycaemia. The OGTprovides additional prognostic information. L a n c e t 1999; 3 5 4 : 6 1 7 – 2 1 Relative Risk of Mortality Increased with Increasing 2-Hr Glucose Level
- 64. New Treatment Algorithmfrom IDF PPG control deteriorates earlier (HbA1c ~6.5%) indicating that people with relatively normal FPG values can exhibit abnormal elevations of PPG No severe hypoglycaemia was observed in a study targeting PPG The IDF sets of a target of 160 mg/dl for PPG 71
- 65.
- 66.
- 67. Glycemic variability atsame A1c can be different for different individuals 74 Graphic representations of glycemic control with a high mean glucose level and high (a) or low (b) variability.