A new easy dpp 4i

1,991 views
1,864 views

Published on

Published in: Health & Medicine
1 Comment
3 Likes
Statistics
Notes
No Downloads
Views
Total views
1,991
On SlideShare
0
From Embeds
0
Number of Embeds
0
Actions
Shares
0
Downloads
182
Comments
1
Likes
3
Embeds 0
No embeds

No notes for slide
  • 最後以這張投影片做總結再次強調效果上Trajenta可以明確的降低血糖值達1.2%持續104週的血糖降低效果不論診斷年數長短都可有效的降低血糖達0.67%在安全性與耐受性方面相較於Sulphonylurea, 減少79%的低血糖患者比例相較於Sulphonylurea,減少相對體重達2.9Kg在方便性方面因為主要是從膽汁及腸道排除所以不需要調整劑量唯一核准, 一天一次,單一劑量治療的DPP4抑制劑可用於合併或單一藥物治療
  • A new easy dpp 4i

    1. 1. A New Easy DPP-4Inhibitor Linagliptin
    2. 2. 織巢鳥,原產於非洲。織布鳥吸引異性的媒介是鳥巢。公鳥築巢,讓母鳥選巢,被母鳥選上的巢,就表示築巢的公鳥,雀屏中選。就像很多女性擇偶的條件之一是對方須是「有殼蝸牛」一樣。
    3. 3. ContentClinical background• Rationale for early intervention• Kidney in diabetes: Prevalence, implications and treatment limitationsLinagliptin• Overview of Linagliptin• What makes Linagliptin different 1.Efficacy 2.Tolerability 3.Safety
    4. 4. Early intensive glycemic control provides lasting protection : The legacy effect Microvascular Myocardial Any diabetes- Death from disease Infraction related endpoint any cause 0 -5 Relative Risk Reduction (%) -10 * * -15 ** ** * Trial end (1997) -20 Post-trial follow up (2007) † Data from sulfonylurea–insulin group shown -25 *** * P≤0.05; ** P≤0.01; *** P≤0.001; *** 10-year post-trial monitoring from 1997 to 2007 of UKPDS Study†• Randomized intervention to achieve either intensive or conventional targets - stopped at the trial end (1997)• Differences in mean HbA1c between the two groups were lost by year 1 of post-trial follow-up.• Relative reductions in risk in patients who had been treated to intensive goals, compared with conventional targets, persisted after 10 years 1. UKPDS 33 Study Group. Lancet. 1998;352:837-853; 2. Holman RR, et al. N Engl J Med. 2008;359:1577-1589. 3. Chalmers J and Cooper ME. N Engl J Med. 2008; 359: 1618–1620.
    5. 5. DCCT/EDIC: long-term follow-up and legacy effect 9 Glucose Conventional treatment similar BUT CV 8 events HbA1C (%) Intensive treatment still 7 higher 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 Years DCCT (intervention period) EDIC (observational follow-up)Cumulative incidence of 0.06non-fatal MI, stroke or 57% risk reduction in non-fatal MI, stroke or CVD death* Conventionaldeath from CVD 0.04 treatment 0.02 Intensive treatment 0 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 Years DCCT (intervention period) EDIC (observational follow-up) *Intensive vs conventional treatment. DCCT Research Group. N Engl J Med 1993; 329:977–986. Nathan DM, et al. N Engl J Med 2005; 353:2643–2653.
    6. 6. Legacy Effect: milder complication 1997 2007傳統 等量 1997 2007 P< 0.05積極傳統 P< 0.05 等比例積極 Complications go at the same time point. Complication But they make different Playground under different genetic base. 1 2 3 Lin
    7. 7. The Action to Control Cardiovascular riskin Diabetes study group ( ACCOD trial )
    8. 8. ACCORD Results
    9. 9. Why was mortality increased in intensive treatment group in ACCORD? • Not certain • Speed of HbA1c reduction ( 1.4 % vs. 0.6% in 4 months) • Drug combinations • Unidentified hypoglycemia • Weight gain • Hypoglycemia unawareness (associated cardiac autonomic neuropathy) Analysis proves that the increased mortality rates are not related to 1. Specific OAD ( Rosiiglitazone, SU , Insulin etc) 2. Changes in other medications( Statins, Aspirin etc)Intensive Glycemic Control and the Prevention of Cardiovascular Events: Implications of the ACCORD, ADVANCE, and VA Diabetes Trials Diabetes Care January 2009 vol. 32 no. 1 187-192
    10. 10. Increased Mortality, Myocardial Infarction, and Hypoglycemia With Intensive Therapy: ACCORD Trial Mortality (% per year) ≥1 severe hypoglycemia (n = 705) 3.1 No hypoglycemia 1.2 (n = 9,546) a Defined by requirement for medical or paramedical intervention, with documented glucose <50 mg/dL and relief by parenteral or oral glucose or by glucagon.1 Bloomgarden ZT. Diabetes Care. 2008;31(9):1913–1919. 2. Dluhy RG, McMahon GT. N Engl J Med. 2008;358:2630–2633.
    11. 11. Summary• Intensive glycemic control slows down progress of diabetic complications, microvascular and probably macrovascular.• Intensive glycemic control has patient risk hypoglycemia, and risk higher CV mortality.• Severe hypoglycemia increased CV mortality 3.1X than otherwise.• Safety ( less hypoglycemia, no fear of hypoglycemia ) is a dominant issue in the following era.
    12. 12. Ominous OctetBeta cell, fat, muscle, liver, gut, alfa cell, kidney, brain Ralph A. DeFronzo Diabetes, Vol. 58, April 2009
    13. 13. Cerebral insulin resistanceAfter glucose ingestion, two hypothalamic areas with consistentinhibition were noted: the lower posterior hypothalamus, whichcontains the ventromedial nuclei, and the upper posteriorhypothalamus, which contains the paraventricular nuclei. In bothof these hypothalamic areas, which are key centers for appetiteregulation, the magnitude of the inhibitory response followingglucose ingestion was reduced in obese, insulin-resistant, normal glucose tolerant subjects, and there was adelay in the time taken to reach the maximum inhibitoryresponse, even though the plasma insulin response was markedlyincreased in the obese group. Ralph A. DeFronzo Diabetes, Vol. 58, April 2009
    14. 14. Increased Renal Glucose Reabsorption In animal models of both type 1 and type 2 diabetes, the maximal renal tubular reabsorptive capacity, or Tm, for glucose is increased. In humans with type 1 diabetes, Mogensen et al. have shown that the Tm for glucose is increased. Cultured human proximal renal tubular cells from type 2 diabetic patients demonstrate markedly increased levels of SGLT2 mRNA and protein and a fourfold increase in the uptake of -methyl-D- glucopyranoside (AMG), a nonmetabolizeable glucose analog Thus, an adaptive response by the kidney to conserve glucose, which is essential to meet the energy demands of the body, especially the brain and other neural tissues, which have an obligate need for glucose, becomes maladaptive in the diabetic patient. Ralph A. DeFronzo Diabetes
    15. 15. Pathogenesis of type 2 DM:Implication for Therapy Effective treatment of type 2 diabetes requires multiple drugs used in combination to correct multiple pathophysiological defects. Treatment should be based on known pathogenic abnormalities and not simply on reduction of A1C. Therapy must be started early in the natural history of type 2 diabetes to prevent progressive beta-cell failure.
    16. 16. In Clinical Aspects “Ideal oral drug”• Targeting underlying pathogenesis, including lowering insulin resistance ( BG, TZD ), recovering beta-cell function ( SU, glinide, DPP-4i ) and reducing hepatic glucose production ( BG, DPP4i ).• Safe, minimal hypoglycemia ( BG, ?TZD, AGI, DPP-4i, SGLT-2i )• No weight gain ( BG, AGI, DPP-4i, SGLT-2i)• Satiety promotion ( ? AGI, DPP-4i, BG; MC4R )• Increased beta-cell mass ( ? TZD, DPP 4i )• Reduced CV risk ( BG, AGI, DPP 4i )
    17. 17. Metformin & DPP-4 inhibitors: Combinations of oral glucose- lowering agents with complementary mechanisms of action DPP-4Target site Action Metformin inhibitorsPancreatic β -cell Enhances glucose-dependent insulin secretion Pancreatic α -cell Suppresses glucagon secretion  Lowers hepatic glucose production   Improves insulin resistance Safety and Low risk of hypoglycemia  Tolerability No additional weight gain   Drucker DJ, Nauck MA. Lancet. 2006;368:1696–1705 Del Prato S, et al. Int J Clin Pract 2005; 59:1345–1355. Inzucchi SE. JAMA. 2002;287:360–372.
    18. 18. Kidney in diabetes:Prevalence, implications and treatment limitations
    19. 19. Approximately 40% of type 2 diabetes patients have renal complications† CKD prevalence was greater among people with diabetes than among those without diabetes (40.2% versus 15.4%) 2.3 Data missing 9.5 no CKD CKD stage 1 17.7 CKD stage 2 50.8 CKD stage 3 CKD stage 4/5 11.1 CKD Stage eGFR (mL/min) 8.6 No CKD ≥90* 1 ≥90*** Normal kidney function, no sign of kidney damage 2 60–89** Albuminuria – kidney damage 3 30–59†Based on data from 1462 patients aged ≥20 years with T2DM who participatedin the Fourth National Health and Nutrition Examination Survey (NHANES IV) 4 15–29from 1999 to 2004. 5 <15 or dialysis 1. Koro CE, et al. Clin Ther. 2009;31:2608–17; 2. Coresh J, et al. JAMA. 2007;298(17) 2038-2047
    20. 20. At least 67% of all patients with type 2 diabetes have cardiovascular risk factors that also affect the kidneys Prevalence of risk factors for declining renal function: Prevalence in T2DM Risk factor patients 1 Arterial 67%1 Hypertension 2 Poor glycemic 63%2 control* 3 Microalbuminuria** 30%3 4 Dyslipidemia† 24%** 4,5 Risk range is likely to be significantly higher than 67% due to overlap of risk factors in individuals*Defined as not reaching the target HbA1c of 7.0%2. **Defined as defined as a urinary albumin-to-creatinine ratio ≥ 30 ug/mg† defined as hypertriglyceridemia in male subjects1. CDC National Diabetes Fact Sheet 2011. http://www.cdc.gov/diabetes/pubs/factsheet11.htm (Accessed Sept 2011)2. Saydah SH, et al. JAMA. 2004;291:335–342; 3. Cheung BMY, et al. Am J Med. 2009;122:443–53.4. Mooradian A, Nat Clin Pract Endocrinol Metab. 2009:5;150–15; 5. Kannel WB. Am Heart J. 1985;110;1100–7.
    21. 21. Declining renal function increases risk of severe hypoglycaemia Decline in renal function dramatically increases the risk of hypoglycaemia in patients with type 2 diabetes Risk for severe hypoglycaemia 9 8 (incidence rate ratio) 7 6 5 4 3 2 1 0 + CKD +CKD / + ––CKD / + CKD + CKD / – + CKD – CKD – CKD / – + Diabetes Diabetes +Diabetes Diabetes Diabetes – Diabetes Diabetes – Diabetes Around 74% of sulphonylurea-induced severe hypoglycaemic events (loss of consciousness) occur in patients with reduced renal functionMoen MF, et al. Clin J Am Soc Nephrol. 2009 Jun;4(6):1121–1127
    22. 22. Linagliptin is the first only DPP-4 inhibitor that does not require dose adjustment: Easy use Linagliptin Sitagliptin Vildagliptin Saxagliptin (Trajenta®) (Januvia®) (Galvus®) (Onglyza®)No renal 100 mg 50 mg BID 5 mgissuesAt riskof renal 5 mgimpairmentMild 5mg5mgrenalimpairment 50 mg 25 mg 50 mg QD 2.5 mgModeraterenalimpairmentSevererenalimpairment
    23. 23. Linagliptin OverviewEfficacy Safety & Tolerability Overall safety profile similar to placebo: Meaningful and reliable efficacy across • No clinically relevant weight gain complete range of oral diabetes therapies • Very low risk of hypoglycemia Most common adverse Durable efficacy in longer reaction1: nasopharyngitis term treatment up to 2 years Not associated with an increase in CV risk Linagliptin Primarily excreted One dose fits all* via bile & gut Once-daily Renal excretion = 5% With or without food No dose adjustment inConvenience renal or hepatic impairment* Please consult the prescribing information before prescribing1 In placebo controlled clinical trials adverse reactions that occurred in ≥5% of patients receiving linagliptinUS prescribing information
    24. 24. Linagliptin – a DPP-4 inhibitor with a unique xanthine-based structure DPP-4 inhibitors mimicking dipeptides DPP-4 inhibitors directly binding to the active site of the enzyme O N N N N N Sitagliptin N O N NH2 Linagliptin Xanthine-based structure Saxagliptin Vildagliptin Peptidomimetic DPP-4 inhibitors Non-peptidomimetic DPP-4 inhibitorsAdapted from Deacon CF. Diabetes Obes Metab. 2011; 13: 7–18.
    25. 25. Linagliptin provides long-lasting DPP-4 inhibition in patients with type 2 diabetes Steady-state plasma levels are already reached after the third dosing interval providing >91% of DPP-4 inhibition at peak levels 100 80 DPP-4 Inhibition [%] 60 40 20 0 0 4 8 12 16 20 24 Time after administration (h) Steady State linagliptin 5mg once daily – oral application Tablet taken Tablet taken linagliptin 5 mg linagliptin 5 mgAdapted from Heise T et al. Diabetes Obes Metab. 2009;11(8):786–94
    26. 26. Linagliptin increases post-prandial* active GLP-1 levels in patients with type 2 diabetes 16 14 13.9 12 GLP-1 (pmol/L) 10 3.2 fold increase 8 6 4 4.4 2 0 Day 0 Day 29 n=15 Linagliptin 5 mg* Mean plasma levels of active GLP-1 measured 30 min after a meal tolerance test.Forst T, et al. Diabetes Obes Metab. 2011;13: 542–550.
    27. 27. Linagliptin restores ß-cell survival in isolated human isletsWith linagliptin, less apoptosis is seen under stress conditions. The study provides evidenceof a direct protective effect of linagliptin on ß-cell survival and insulin secretion 5 Vehicle Linagliptin * Example of TUNEL Staining * Insulin (ß-cell marker) 4 **% TUNEL +β-cells TUNEL (marker for apoptosis) 3 * * * Vehicle 2 ** ** ** ** 1 Linagliptin (100 nM) 0 Oxidative Physiological Glucotoxicity Glucotoxicity Lipotoxicity Inflammatory stress condition stressNote: 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
    28. 28. Meaningful efficacy across complete range of oral treatment algorithms Linagliptin treatment effect across treatment lines Placebo-corrected, adjusted mean change from baseline HbA1c Mono Dual combi Triple Initial combi combi Diet and exercise Diet and exercise With With Metformin Add-on Add-on Add-on to metformin metformin International* ineligible** Japan† to met* to SU** met + SU* (Low dose)* (High dose)* -0.5% -0.6% -0.6% -0.6% -0.7% -0.9% -1.3% p <0.0001 for all studies vs. baseline, for initial combination vs. respective monotherapy* 24 weeks treatment duration -1.7%** 18 weeks treatment duration† 12 weeks treatment durationDel Prato, et al. Diabetes Obes Metab. 2011;13:258-267 (International); Barnett, et al. EASD 2010, Poster 823-P (Metformin ineligible); Kawamori et al. EASD2010 , Poster 696-P (Japan); Taskinen et al. Diabetes Obes Metab. 2011;13: 65-74 (Add-on to metformin); Lewin et al. EASD 2010, Poster 821-P (Add-on toSU); 3. Owens DR, et al. ADA 2010, Poster 548-P (Add-on to metformin + SU); Haak T., et al. ADA 2011 oral presentation 279-OR (Initial combi with met).
    29. 29. Linagliptin achieves HbA1c decrease of up to 1.2% in poorly controlled patients Significant HbA1c reductions in type 2 diabetes patients with baseline HbA1c ≥ 9% Linagliptin Add-on to Add-on to monotherapy 1 metformin 2 metformin + SU3 0.5 p <0.0001 p <0.0001 p <0.0001 Adjusted mean change in HbA1c 0.15 (%) from baseline at week 24 0 -0.23 -0.5 -0.40 -0.72 -0.80 -1 -0.86 -0.95 -1.01 -1.20 -1.5 n= 24 55 29 96 48 136 Mean baseline HbA1c (%) 9.5 9.4 9.5 9.5 9.4 9.4 Placebop-values for between group difference (versus placebo) Linagliptin1. Del Prato S, et al. Diabetes Obesity and Metabolism 2011;13(3):258–267.2. Taskinen M-R, et al. Diabetes Obesity and Metabolism 2011;13(1):65–74. Linagliptin placebo-corrected3. Owens DR, et al. Diabetic Medicine 2011;28,1352-1361
    30. 30. HbA1c change over 2 years Adjusted1 mean over time ± SE, percent Mean (± SE) of HbA1c Percent Linagliptin Glimepiride 7.5 7.0 -0.6 6.5 -0.6 6.0 0 5 10 15 20 25 30 35 40 45 50 55 60 65 70 75 80 85 90 95 100 104 Treatment duration Weeks Linagliptin, has similar efficacy as a SU over 104 weeks1,21 Model includes treatment, baseline HbA1c and number of prior OADs2 As described previously by Seck et al. Int J Clin Pract 2010; 64: 562-576Source: Gallwitz et al. American Diabetes Association, 71th Scientific Sessions, San Diego, CA, June 24- 28, 2011; 39-LB
    31. 31. Linagliptin provides reliable HbA1C reductions independent of patient age Change from baseline HbA1c by age1 Adjusted mean change from baseline at 24 weeks of treatment 0.5 ≤50 years 51 to 64 years 65 to 74 years ≥75 years Adjusted mean change in HbA1c p =0.0002 (%) from baseline at week 24 p <0.0001 p <0.0001 p <0.0001 0.02 0.03 0 -0.02 -0.09 -0.5 -0.54 -0.56 -0.60 -0.66 -0.64 -0.69 -0.80 -0.83 -1 194 442 363 970 152 398 19 66 n=Mean baseline HbA1c (%) 8.2 8.2 8.2 8.2 8.1 8.1 8.1 8.0 Pre-specified sub-group analysis on pooled data from 4 pivotal phase III randomized Placebo placebo-controlled trials: treatment in monotherapy, add-on to metformin, add-on to metformin + SU, initial combination with pioglitazone. Linagliptin p-values for between group difference (versus placebo) Linagliptin placebo-corrected Source: Patel S, et al. 2011 EASD Poster P-832
    32. 32. Linagliptin provides reliable HbA1c reductions independent of time since diagnosis of type 2 diabetes Change from baseline HbA1c by time since diagnosis of type 2 diabetes Adjusted mean at 24 weeks of treatment, percent 0.5 ≤ 1 year > 1 to ≤ 5 years > 5 years Adjusted mean change in HbA1c p <0.0001 p <0.0001 p <0.0001 (%) from baseline at week 24 0.03 0 -0.01 -0.17 -0.5 -0.49 -0.59 -0.62 -0.66 -0.67 -0.66 -1 n= 120 261 227 570 381 1045 Mean baseline HbA1c (%) 8.2 8.1 8.0 8.1 8.2 8.2Pre-specified sub-group analysis on pooled data from 4 pivotal phase III randomized Placeboplacebo-controlled trials: treatment in monotherapy, add-on to metformin, add-on tometformin + SU, initial combination with pioglitazone. Linagliptinp-values for between group difference (versus placebo) Linagliptin placebo-correctedSource: Patel S, et al. 2011 EASD Poster P-832
    33. 33. Linagliptin significantly improves ß-cell function in monotherapy Effect of linagliptin monotherapy Effect of linagliptin monotherapy on HOMA-%B on proinsulin/insulin ratio proinsulin/insulin ratio from baseline at wk 24 Placebo-corrected adjusted mean change in 40 0 Placebo-corrected adjusted mean change in (HOMA-%B [(mU/l) × (mmol/l)] from baseline 35 * -0.01 30 -0.02 25 at wk 24 -0.03 20 + 22.2 - 0.04 -0.04 15 -0.05 10 -0.06 5 † 0 -0.07 +35% change from baseline - 21% change from baseline relative to placebo relative to placebo at 24 weeks at 24 weeks The mean change from baseline in HOMA-%B for The mean change from baseline in linagliptin at 24 weeks was an increase of 5.0 proinsulin/insulin for linagliptin at 24 weeks was (mU/l)/(mmol/l) versus a decrease of 17.2 an decrease of 0.02 versus an increase of 0.02 (mU/l)/(mmol/l) with placebo (*p<0.049) with placebo (†p<0.025)Note: Baseline HOMA-%B: 66.9 (mU/l)/mmol/l) linagliptin-treated group; 62.3 (mU/l)/mmol/l) placebo group Baseline proinsulin:insulin: 0.20 linagliptin-treated group; 0.18 placebo groupDel Prato S, et al. Diabetes Obes Metab. 2011;13: 258–267.
    34. 34. First in man study - Linagliptin Phase I: Single rising dose study During controlled clinical trials in healthy subjects, with single doses of up to 600 mg of linagliptin (equivalent to 120 times the recommended daily dose) there were no dose related clinical adverse drug reactions. There is no experience with doses above 600 mg in humans. 600 mg dose well tolerated (therapeutic dose is 5 mg) >100-fold therapeutic window Recommended dose: 5mg QDSource: Hüttner et al. 2008 J. Clin. Pharmacol. 48: 1171-8
    35. 35. 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 > 100,000 270 32 Saxagliptin > 50,000 390 77 Alogliptin > 14,000 > 14,000 > 14,000* Quiescent cell proline dipeptidaseDeacon CF. Diabetes, Obes Metab. 2011;13(1):7–18.
    36. 36. Linagliptin is well tolerated Organ-specific adverse event (AE) rate for AE previously associated with the DPP-4 inhibitor class1 Linagliptin Placebo n 2,523 1,049 Headache 2.9% 3.1% Upper respiratory tract 3.3% 4.9% infection Pancreatitis: Pancreatitis was reported Nasopharyngitis 5.9% 5.1% more often in patients Cough 1.7% 1.0% randomized to linagliptin (1 per 538 person years Hepatic enzyme increase 0.1% 0.1% versus zero in 433 person years for comparator)* Serum creatinine increase 0.0% 0.1% Urinary tract infection 2.2% 2.7% Blood and lymphatic 1.0% 1.2% system disorders Hypersensitivity 0.1% 0.1%1. Organ-specific adverse events taken from label of currently marketed DPP-4 inhibitor in the US; * Linagliptin US PISchernthaner G., et al. ADA 2011 Abstract 2327-PO. Pooled data from 8 studies
    37. 37. Linagliptin brings patients to target (HbA1c <7%) with significantly less hypoglycemia and relative weight loss compared to glimepiride Incidence of hypoglycemia Adjusted2 means for body weight change Percent of patients - Treated set1 from baseline ± SE Kg - FAS (OC) 50 Linagliptin p<0.0001 Glimepiride 40 2.0 30 1.5 +1.4 79% 20 1.0 reduction 0.5 10 7.5 Rate of patients achieving 0 HbA1c target <7% 12 28 52 78 104 0 -0.5 weeks Linagliptin Glimepiride Percent of patients at week 104 completers cohort3 -1.0 -1.5 100 -1.5 -2.0 p<0.0001 -2.9 80 75.6 76.4 60 40 20 0 Linagliptin Glimepiride1 Treated Set: Linagliptin n=776, glimepiride n=7752 Model includes baseline HbA1c, baseline weight, no. prior OADs, treatment, week repeated within patients and week by treatment interaction3 Completers cohort: linagliptin n=233, glimepiride n=271Gallwitz B., et al. ADA 2011 Late Breaker 39-LB
    38. 38. The majority of linagliptin is excreted unchanged via bile and gut Absorption Metabolism Tablet intake: 5mg QD, independent of food Absolute bioavailability: ~30%, with or without food ~90% ~10% transferred (inactive) unchanged ~95% bound to plasma proteins metabolite (in essence DPP-4) Excretion1: ~ 95% of orally administered ~ 5% of orally administered linagliptin is excreted via the linagliptin is excreted via the bile and gut kidneys1 At steady stateSource: US prescribing information
    39. 39. Linagliptin is the only DPP-4 inhibitor which is primarily excreted by bile and gut* Share of renal excretion % No dose adjustment Linagliptin1 5 and/or no additional drug monitoring required1 87% Sitagliptin2 All other DPP-4 inhibitors are primarily excreted via the kidneys % Vildagliptin3 85 They all require dose- adjustment, or are not Saxagliptin4 75% recommended in patients with renal impairment. Drug-related kidney 60-71 monitoring may also be required* of currently globally approved DPP-4 inhibitorsData from multiple trials, includes metabolites and unchanged drug; excretion after single dose administration of [14C] labeled drug1. Linagliptin US prescribing information2. Vincent SH et al. Drug Metab Dispos. 2007;35(4): 533–5383. He H, et al. Drug Metab. Dispos.2009 37(3):536–5444. Saxagliptin US prescribing information5. Christopher R et al. Clin Ther. 2008;30(3):513–527.
    40. 40. No dose adjustment: Linagliptin is the only DPP-4 inhibitor that can be given in full dose even in patients with renal impairment 7 7 Sitagliptin normal renal function Linagliptin normal renal function exposure relative to exposure relative to 6 6 Fold increase in Fold increase in 5 5 4 4 3 3 2 2 1 1 Normal Mild Moderate Severe ESRD Normal1 Mild Moderate Severe ESRD (n=6) (n=6) (n=6) (n=6) (n=6) (n=6) (n=6) (n=6) (n=6) (n=6)Creatinine clearance* >80 >50 to ≤80 >30 to ≤50 ≤30 <30 on HD Creatinine clearance* >80 >50 to ≤80 >30 to ≤50 ≤30 on HD(mL/min) (mL/min) Renal impairment status Renal impairment status normal renal function normal renal function 7 7 exposure relative to exposure relative to Saxagliptin Vildagliptin Fold increase in Fold increase in 6 6 (5-hydroxy saxagliptin metabolite) 2 (LAY151 metabolite)3 5 5 4 4 3 3 2 2 1 1 Normal Mild Moderate Severe ESRD Normal Mild Moderate Severe ESRD (n=8) (n=8) (n=8) (n=7) (n=8) (n=8) (n=8) (n=8) (n=7) (n=8)Creatinine clearance* >80 >50 to ≤80 >30 to ≤50 ≤30 <30 on HD Creatinine clearance* >80 >50 to ≤80 >30 to ≤50 ≤30 <30 on HD(mL/min) (mL/min) Renal impairment status Renal impairment statusESRD = end-stage renal disease; HD = Haemodialysis; * Estimated creatinine clearance values were calculated using the Cockcroft-Gault formulaSource: Graefe-Mody U., et al. 2011 Diabetes, Obes Metab. (in press)
    41. 41. In clinical trials renal function was unaffected by treatment with linagliptin Renal/ function Diabetes baseline1 treatment Renal function1 Normal renal function2 120 ± 33 linagliptin 119 ± 34 (n=1,216 ) Mild renal impairment2 67 ± 8 linagliptin 69 ± 13 (n=314) Moderate renal impairment2 45 ± 5 linagliptin 48 ± 8 (n=27) Severe renal impairment3 22 ± 6 linagliptin 22 ± 7 (n=68)1.Mean GFR ± SEM according to Cockcroft-Gault in mL/min (for normal, mild and moderate renal impairment) and according to MDRD(for severe renal impairment); 24 weeks trial duration for normal, mild, moderate, 12 weeks for severe2. Pooled analysis of three PIII clinical trials (normal, mild and moderate renal impairment). Cooper M., et al. ADA 2011, Poster 1068-P3. Individual analysis (severe renal impairment). Sloan L., et al. ADA 2011 Poster 413-PP
    42. 42. Influence of hepatic impairment on pharmacokinetics & exposure of LinagliptinPatients 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 1.5 Fold Increase in exposurerelative to B Significant functional compromise 7-9 Fold increase in exposure relative C Decompensated disease 10-15 normal hepatic function to normal hepaticfunction 1 0.5 0 Healthy Mild (Grade A) Moderate (Grade B) Severe (Grade C) Hepatic impairment (Child-Pugh classification) n=8 n=7 n=9 n=8 No dosage adjustment for linagliptin is necessary for patients with mild, moderate or severe hepatic impairmentSource: Data on file
    43. 43. Clinical characteristics of Linagliptin compared to other DPP-4 inhibitors Characteristics Linagliptin Sitagliptin Vildagliptin Saxagliptin One dose fits all*  No dose adjustment in renal impairment  No dose adjustment in hepatic impairment    No dose adjustment based on drug-drug-interactions    No drug-related monitoring of renal function  No skin toxicity in pre-clinical studies1   No liver toxicity1    No reports of decrease in renal function1   * Without limitations in renal or hepatic impairment: please consult the label before prescribing1. Linagliptin, Sitagliptin, Saxagliptin US prescribing informations. Other sources: Vildagliptin EU SmPC
    44. 44. 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 Out of 3,319 patients 1,920 patients = 0.3% = 1.2% Linagliptin Comparator2 Years of exposure 2,060 1,3721. CV events as defined as primary endpoint; 2. 977 patients receiving placebo, 781 glimepiride, 162 vogliboseJohansen O-E., et al. ADA 2011 Late breaker 30-LB
    45. 45. Safety observations so far are promising, therefore all DPP-4 compounds are currently involved in outcome studiesNo increased risk of CV events was observed in patients randomly treated with DPP-4 inhibitors Total patients Primary DPP-4 inhibitor better Comparator better in analysis endpoint Comments Linagliptin1 CV death, MI, stroke, Pre-specified/ 0.15 0.34 0.74 5,239 hospitalisation due to independent angina pectoris adjudication Sitagliptin2 1.12 10,246 Med DRA terms No formal 0.41 0.68 for MACE adjudication; Post-hoc analysis Vildagliptin3 0.62 0.84 1.14 10,988 Acute coronary syndrome, Pre-specified/ transient ischaemic attack, Independent stroke, CV death adjudication MI, stroke, CV death Pre-specified/ Saxagliptin4 0.23 0.42 0.80 4,607 Independent adjudication 1/8 1/4 1/2 1 2 4 8 Risk ratio for major CV events1-51. 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
    46. 46. Linagliptin can be used with no dose adjustment in various patient populations Hepatic impairment Declining renal Any age group function including geriatric No limitations No dose Cardiovascular adjustment Ethnicity disease Long disease Obese vs lean durationSource: Linagliptin US prescribing information
    47. 47. Thanks for your attention!!

    ×