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The Role of DPP-IV Inhibitors in the Management of Type 2 Diabetes

The Role of DPP-IV Inhibitors in the Management of Type 2 Diabetes. Kimberly Purifoy, MSN, FNP-C Windy City Wellness, PC purifoyks@aol.com. OBJECTIVES. Discuss the role of GLP 1 in glycemic control. Where does it come from and what does it do?

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The Role of DPP-IV Inhibitors in the Management of Type 2 Diabetes

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  1. The Role of DPP-IV Inhibitors in the Management of Type 2 Diabetes Kimberly Purifoy, MSN, FNP-C Windy City Wellness, PC purifoyks@aol.com

  2. OBJECTIVES • Discuss the role of GLP 1 in glycemic control. Where does it • come from and what does it do? • Discuss the role of DPP-IV in Hyperglycemia. • Review DPP-IV Inhibitor medications currently available; to • include efficacy, dosing, risk factors, and appropriate • population. • Review case studies using DPP-IV Inhibitors. • Review current Guidelines for diagnosis, glycemic control, • and algorithm for treatment.

  3. DIABETES IS A GLOBAL ISSUE PROJECTED CASES BY 2030 NORTH AMERICA 2010: 37.4M 2030: 53.2M WESTERN PACIFIC 2010: 76.7M 2030: 112.8M EUROPE 2010: 55.2M 2030: 66.2M AMERICAS (Ex-US) 2010: 18M 2030: 29.6M SOUTH AFRICA 2010: 12.1 M 2030: 23.9M MIDDLE EAST / NORTH AFRICA 2010: 26.6 M 2030: 51.7M SOUTH-EAST ASIA 2010: 58.7M 2030: 101 M IDF Diabetes Atlas, 4th ed 2009.

  4. Case Study 1 MF-63 y/o AA male. OTR truck driver. Married. Diabetes 7 years. Exercises at least 5 days per week, Cardio and light weights. Carries food with him. 2005 A1c 8.6% Meds: Metformin 1,000mg bid, Actos 45mg qam, Prandin 1mg tid ac. 2006 A1c 11.6% Meds: Metformin 1,000mg bid, Actos 45mg qam, Prandin 2mg tid ac.

  5. Case Study 2 NG- 51 y/o C Female. Allergic to just about everything. Likes to do the “Natural” cure. Thin. No other health issues. A1c initially 13.6%. Had been started on Janumet 50/500mg 1 bid. Lantus was also added. C peptide obtained 0.5, AB +. WHOA!!! She is Type 1 LADA.

  6. Case Study 3 WH 45 y/o C Male. Moderately obese but has lost >100 in last 2 years. Was seeing “The Country Doctor” to treat his diabetes. Starting to have “issues” such as vision problems, tingling in his feet, etc. Started to feel a little better after starting meds A1c 11.6%, c peptide 1.8. Meds initiated by PCP Metformin 1,000mg bid, Lantus 20 units qhs.

  7. GLP-1: An Intestinal Hormone (Glucose Lowering Peptide-1) • Secreted from L cells in the intestinal mucosa after meals • Effects • Stimulates insulin secretion • Suppresses glucagon secretion • Delays gastric emptying • Enhances satiety • Enhances -cell mass/replication in animals • Rapidly degraded by the protease dipeptidyl peptidase IV (DPP-IV) ©2006, ICHE Drucker. Diabetes Care. 2003;26:2929.

  8. The Role of GLP1

  9. Effects of GLP-1 on  Cells • Enhances responsiveness of the cell to glucose • Improves the dynamics of the insulin response • Stimulates -cell transcription • Reduces -cell apoptosis Ahrén. Diabetes Care. 2003;26:2860. Farilla. Endocrinology. 2002;143:4397. ©2006, ICHE

  10. Oral (50 g) IV (isoglycemic infusion) The Incretin Effect Is Reduced in T2DM Compared With NGT -Cell SecretoryResponse IncretinEffect 38.9 72.8 34.7 23.5 Insulin(mmol/L/min) Contributions of Incretin Factors (%) 30.0 11.3 Glucose: Nauck. Diabetologia. 1986;29:46. ©2006, ICHE NGT=normal glucose tolerance

  11. Characteristics of Type 2 Diabetes: Overview Over time, manypatients requireinsulin • Absolute or relative insulin deficiency • Impaired beta cell function • Insulin resistance • Twin components • Fasting hyperglycemia • Postprandial hyperglycemia • Different agents will work on different aspects of glycemic control • For example: Rapid acting SUs (ie Starlix) will work better for postprandial control • For Example: Basal Insulin will work better for fasting Different agents maybe needed to treatboth aspects This is why many patients require combination therapy to achieve glycemic control. Especially long-term.

  12. What the heck is DPP-IV? • Dipeptidyl peptidase-4 (DPP4), also known as adenosine deaminase complexing • protein 2 or CD26 (cluster of differentiation 26) is a protein that, in humans, is encoded • by the DPP4gene. • The protein encoded by the DPP4 gene is an antigenic enzyme expressed on the • surface of most cell types and is associated with immune regulation, signal • transduction and apoptosis. It is an intrinsic membrane glycoprotein and a serine • exopeptidase that cleaves X-proline dipeptides from the N-terminus of polypeptides. • It is a rather indiscriminate enzyme for which a diverse range of substrates are • known.[2] The substrates of CD26/DPPIV are proline(or alanine)-containing peptides and • include growth factors, chemokines, neuropeptides, and vasoactive peptides. • DPP4 is related to FAP, DPP8 and DPP9. • DPP-4 plays a major role in glucose metabolism. It is responsible for the degradation of • incretins such as GLP-1.[3] • Furthermore, it appears to work as a suppressor in the development of cancer and • tumours.

  13. DPP-IV ACTION • Cleaves GLP-1 • Results in decreased signal to the pancreas—limiting insulin response. • That in turn decreases the signal to the liver resulting in increased hepatic glucose production. • HYPERGLYCEMIA X

  14. FPG and PPG: Contribution to A1C Postprandial Fasting A1C (%) <7.3 70% 30% 7.3–8.4 50% 50% 8.5–9.2 45% 55% 9.3–10.2 40% 60% % Contributionto A1C 30% 70% >10.2 Monnier. Diabetes Care. 2003;26:881.

  15. The DPP-IV Drugs • Sitagliptin (Januvia) Approved October 2006 • Sitagliptin/Metformin (Janumet) Approved 2007 • Merck • Saxagliptin (Onglyza) Approved July 2009 • Bristol-Myers-Squibb and AstraZeneca

  16. Sitagliptin (Januvia®) • Availability 25mg, 50mg, 100mg tablets • Dosed once a day in the morning, best before morning meal • Available in Combination with Metformin Janumet 50/500mg and 50/1000mg • Dosed twice a day, best before morning and evening meals • Renal function needs to be considered when dosing • Earlier this year did obtain approval to be used with insulin

  17. S e c t i o n 14.1 Monotherapy Studies: As Is Typical in Trials of Agents to Treat Type 2 Diabetes, Mean Response to JANUVIA™ (sitagliptin phosphate) in A1C Lowering Appears to Be Related to the Degree of A1C Elevation at Baseline Inclusion Criteria: 7%–10% Pooled Analysis* Baseline A1C(%) Overall <8 ≥8–<9 ≥9 0.0 -0.2 -0.4 n=411** n=769** n=239** -0.6 –0.6 -0.8 –0.7 –0.7 Change in A1C (%) -1.0 -1.2 n=119** -1.4 –1.4 -1.6 -1.8 The magnitude of A1C lowering by strata varied by study. Reductions are placebo-subtracted. *P<0.001 overall and for treatment by subgroup interactions. ** Combined number of Patients on JANUVIA or Placebo

  18. Dosage Adjustment in Patients With Moderate, Severe and End Stage Renal Disease (ESRD) 50 mg once daily • Moderate • CrCl ≥30 to <50 mL/min • ~Serum Cr levels [mg/dL] Men: >1.7– ≤3.0; Women: >1.5– ≤2.5 25 mg once daily • Severe • CrCl <30 mL/min • Serum Cr levels (mg/dl) Men: >3.0 Women: >2.5 *** Watch Renal Function***

  19. Adverse Events • In clinical studies, the adverse reactions reported, regardless of investigator assessment of causality, in >5% of patients treated with JANUVIA as monotherapy and in combination therapy and more commonly than in patients treated with placebo, were upper respiratory tract infection, nasopharyngitis, and headache.

  20. Adverse Events • There have been postmarketing reports of acute pancreatitis, including fatal and nonfatal hemorrhagic or necrotizing pancreatitis, in patients taking JANUVIA. After initiating JANUVIA, observe patients carefully for signs and symptoms of pancreatitis. It is unknown whether patients with a history of pancreatitis are at increased risk of developing pancreatitis while taking JANUVIA. • JANUVIA has not been studied in patients with a history of pancreatitis. It is unknown whether patients with a history of pancreatitis are at increased risk of developing pancreatitis while taking JANUVIA.

  21. Important Limitations of Use • JANUVIA should not be used in patients with type 1 diabetes or for the treatment of diabetic ketoacidosis. • There are no adequate and well-controlled studies in pregnant women. Therefore, JANUVIA should be used during pregnancy only if clearly needed. • It is not known whether sitagliptin is excreted in human milk. Therefore, caution should be exercised when JANUVIA is administered to a nursing woman. • Has not been studied in children

  22. Saxagliptin (Onglyza®) • Availability • 2.5 mg, 5 mg tablets • Dosing/Administration • 2.5 mg or 5 mg once daily • Give without regard to meals • Limit dose to 2.5 mg daily • Concurrent CYP 3A4/5 inhibitor (ie ketokonazole) • CrCL ≤ 50 mL/min • Hemodialysis ***Saxagliptin + metformin combination went before FDA March 2010

  23. Saxagliptin (Onglyza®) • Saxagliptin monotherapy • 2.5 mg, 5 mg, 10 mg, 20 mg, 40 mg, 100 mg vs placebo • A1C1: -0.7-0.9% vs -0.27% placebo (p < 0.007) • A1C2: -0.43-0.54% vs +0.19% placebo (p < 0.0001) • Weight neutral • No significant difference in side effects 1. Rosenstock J, et al. Diabetes Obes Metab 2008;10(5):376-86 2. Rosenstock J, et al. Curr Med Res Opin 2009;25(10):2401-11

  24. Saxagliptin (Onglyza®) • SAX/MET vs monotherapy (n=1306) • Duration: 24 weeks • SAX 5 mg/MET: A1C -2.5% • SAX 10 mg/MET: A1C -2.5% • SAX 10 mg: A1C -1.7% • MET 2000 mg: A1C -2.0% • All p < 0.0001 vs monotherapy • No significant difference in hypoglycemia Jadzinsky M, et al. Diabetes Obes Metab 2009;11(6):611-622

  25. Saxagliptin (Onglyza®) • SAX vs PBO + TZD • Duration: 24 weeks • SAX 2.5 mg/TZD: A1C -0.66% (p = 0.0007) • SAX 5 mg/TZD: A1C -0.94% (p < 0.0001) • PBO/TZD: A1C -0.30% • Hypoglycemia: 4.1%, 2.7% vs PBO 3.8% • Peripheral edema: 3.1%, 8.1% vs PBO 4.3% Hollander P, et al. J Clin Endocrinol Metab 2009;94:4810-19

  26. Onglyza Adverse Events • Adverse reactions reported in ≥5% of patients treated with ONGLYZA and more commonly than in patients treated with placebo are: upper respiratory tract infection, urinary tract infection, and headache. • Peripheral edema was reported more commonly in patients treated with the combination of ONGLYZA and a thiazolidinedione (TZD) than in patients treated with the combination of placebo and TZD • Hypoglycemia was reported more commonly in patients treated with the combination of ONGLYZA and sulfonylurea than in patients treated with the combination of placebo and sulfonylurea. • • Hypersensitivity-related events (e.g., urticaria, facial edema) were reported more commonly in patients treated with ONGLYZA than in patients treated with placebo.

  27. Onglyza Drug Interactions Coadministration with strong CYP3A4/5 inhibitors (e.g., ketoconazole) significantly increases saxagliptin concentrations. Recommend limiting ONGLYZA dose to 2.5 mg once daily.

  28. DPP-IV Inhibitors demonstrate effective glycemic control as monotherapy or in combination with other glycemic agents. As with any oral glycemic agent, risk and benefits along with other co-morbid conditions needs to be assessed before initiating drug therapy. Glycemic control, tolerability, adverse event, renal function need to be assessed regularly.

  29. Initial Treatment Algorithm

  30. ? QUESTIONS

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