Christa M. George, PharmD, BCPS, CDE Assistant Professor Department of Clinical Pharmacy University of Tennessee Health Science Center UT/St. Francis Family Practice Center
Disclosures
Spouse-UT Faculty & consultant for Bayer, Ortho Pharmaceuticals No other disclosures Will discuss investigational agents Will notify of off-label use
Objectives
Review recent safety concerns relevant to FDA-approved incretin agents for Type 2 diabetes Review recently FDA-approved incretin agents for Type 2 diabetes Discuss characteristics of potential candidates for incretin therapy
Diabetes Medications
Insulin 1922 SUs 1957
1960
1995
2000
2005
2010
Liraglutide 2010
Philippe J. Int J Clin Pract 2009;63:321-332 Patlak M. Breakthroughs in Bioscience 2002. http://www.faseb.org/Portals/0/PDFs/opa/diabetes.pdf
Incretin Physiology
GLP-1
Stimulates glucose-dependent insulin secretion from beta cells Suppresses glucagon release from alpha cells Slows gastric emptying & reduces food intake Degraded by DPP-4 enzyme
GIP
Increases glucose-dependent insulin release Degraded by DPP-4 enzyme
1. Drucker DJ, Nauck MA. Lancet 2006;368:1696-1705 2. Nauck MA. Am J Med 2009;122(Suppl 1):S3-S10
Brain
Food Intake
Gastric Emptying
Liver
Rate of glucose appearance
Postprandial Glucagon
Alpha
Stomach
Plasma Glucose
Pancreas
Beta
GUT
Rate of glucose disappearance Glucose Disposal
Muscle & Adipose Tissue
GLP-1
L-cells
Insulin Amylin
Incretin Effect
0.5
IR Insulin, mU/L
60
IR Insulin, mU/L
0.4
60
nmol / L
nmol/L
40
0.3 0.2
40
0.3 0.2
20 0.1 0 0
20 0.1 0 0
60
120
180
60
120
180
Time, min
Oral glucose load Intravenous (IV) glucose infusion
Time, min
Adapted with permission from Nauck M et al. Diabetologia. 1986;29:4652. Copyright 1986 Springer-Verlag.
GLP-1 Agonists
Exenatide (Byetta)
Pancreatitis
30 reports (2007) acute pancreatitis 6 reports (2008) hemorrhagic or necrotizing
2 deaths, 4 recovered
Monitor for signs & symptoms D/C drug if pancreatitis suspected Do NOT rechallenge if pancreatitis diagnosed
http://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/ucm124 713.htm
Exenatide (Byetta)
http://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/ucm1 13705.htm
Exenatide (Byetta)
http://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/ucm1 13705.htm
Exenatide (Byetta)
GLP-1 Agonists
30 wks, controlled, open-label once weekly vs BID exenatide 70 wks, open-ended assessment exenatide LAR 2mg once weekly A1C: -1.8% from baseline (8.3 + 1%) Weight: -3.6 kg from baseline (100 + 19 kg) TGs: -18%; TChol: -9.7 + 3.4 mg/dL SBP: -3.2 + 1.2 mmHg Nausea: 8% (mild) No severe hypoglycemia
1. Drucker DJ, et al. Lancet 2008;372:1240-50 2. Kim T, et al. Abstract 159-OR. ADA Scientific Sessions 2009
http://www.amylin.com/assets/001/5107.pdf;
http://newsroom.lilly.com/releasedetail.cfm?sh_print=yes&releaseid=430179
http://www.nytimes.com/aponline/2010/03/15/business/AP-US-AmylinFDA.html?_r=1&scp=1&sq=exenatide&st=cse
GLP-1 Agonists
Liraglutide (Victoza)
Second GLP-1 receptor agonist Adjunct to diet & exercise in patients with T2DM
Not first-line choice due to risk for thyroid c-cell tumors Do not use in T1DM or DKA No data in combination with insulin or history of pancreatitis
Liraglutide (Victoza)
-0.6%, -1.08%, -1.13%, -0.44%, +0.23% (p 0.001) Liraglutide 1.2 mg & 1.8 mg vs rosiglitazone (p 0.0001)
Liraglutide (Victoza)
Liraglutide (Victoza)
1. Garber A, et al. Lancet 2009;373:473-481 2. Garber A et al. Abstract 162-OR. ADA Scientific Sessions 2009
Liraglutide (Victoza)
Liraglutide (Victoza)
-1.33% vs glargine -1.09% (p = 0.0015) -1.33% vs placebo -0.24% (p < 0.0001) -1.8 kg vs glargine +1.6 kg (p < 0.0001) -1.8 kg vs placebo -0.42 kg (p < 0.0001)
Weight:
Liraglutide (Victoza)
Liraglutide (Victoza)
Availability
Pre-filled, multi-dose disposable pen 0.6 mg, 1.2 mg, 1.8 mg
Dosing/Administration
Start 0.6 mg SQ once daily, anytime, independent of meals Use with Novo pen needles Increase weekly to max 1.8 mg if needed Consider lowering dose of secretagogues
Liraglutide (Victoza)
Adverse effects
Nausea (28%)
LEAD-6: Liraglutide 2.5% vs exenatide 8.6% LEAD-6: Liraglutide 25.5% vs exenatide 33.6% LEAD-6: Liraglutide 0 pts vs exenatide 2 pts Liraglutide 8 cases (1 death) Causality unknown
Hypoglycemia (minor)
Hypoglycemia (major)
Pancreatitis
Liraglutide (Victoza)
Warnings
Thyroid C-cell tumors in rats and mice Dose & treatment duration dependent 5 cases thyroid c-cell hyperplasia in clinical trials of liraglutide Counsel on risk & symptoms of thyroid tumors Contraindications
Liraglutide (Victoza)
Drug Interactions
Take oral contraceptives & antibiotics 1 hour before injecting liraglutide Potential for decreased absorption and lower drug concentrations
Liraglutide (Victoza)
Liraglutide vs exenatide
Once daily vs BID dosing
Nausea less frequent, abates faster Less hypoglycemia Reduces A1C 1.0-1.5% vs 0.7-0.9% Caution with renal dysfunction, h/o pancreatitis Cost
Liraglutide 1.8 mg daily $360 per month Exenatide 10 mcg BID $240 per month
DPP-4 Inhibitors
Sitagliptin (Januvia)
http://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders /DrugSafetyInformationforHeathcareProfessionals/ucm183764.htm
Sitagliptin (Januvia)
Acute pancreatitis
Monitor for nausea, vomiting, anorexia, abdominal pain D/C if pancreatitis suspected & institute supportive care Use with caution & appropriate monitoring in history of pancreatitis (no data)
http://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders /DrugSafetyInformationforHeathcareProfessionals/ucm183764.htm
DPP-4 Inhibitors
Saxagliptin (Onglyza)
Second DPP-IV inhibitor Adjunct to diet & exercise to improve glycemic control in patients with T2DM
Do not use in T1DM or DKA No data in combination with insulin
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
Saxagliptin (Onglyza)
Saxagliptin (Onglyza)
Saxagliptin (Onglyza)
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
Saxagliptin (Onglyza)
Adverse effects
Headache, URI, UTI ( 5%) Hypoglycemia
Monotherapy: 4.0%, 5.6% vs PBO 4.1% SAX + Glyburide: 13.3%, 14.6% vs PBO 10.1%
Peripheral edema
Saxagliptin (Onglyza)
Adverse effects
Absolute lymphocyte count
Decreased by 100-120 cells/microL SAX 5 mg: 1.5% had 750 cells/microL Did not recur on rechallenge for most Clinical significance unknown
Saxagliptin (Onglyza)
Warnings
Hypoglycemia with secretagogues
Drug interactions
Strong CYP 3A4/5 inhbitors
Saxagliptin (Onglyza)
Saxagliptin vs sitagliptin
No head-to-head studies Similar A1C lowering efficacy Drug interactions
Tier 1
Lifestyle + Metformin
AACE/ACE Algorithm
Metformin cornerstone of therapy GLP-1 & DPP-4 may be used as adjunctive therapy early in treatment
Need to avoid hypoglycemia Need to avoid weight gain/achieve weight loss Intolerant of/contraindications to other agents Relatively close to A1C goal (DPP-4)
Caution in history of pancreatitis Caution in renal insufficiency Liraglutide contraindicated in MTC, MEN2 Exenatide, liraglutide, saxagliptin have not been studied with insulin
Conclusions
Consider potential risks of pancreatitis, renal dysfunction Potential approval of exenatide LAR Liraglutide: convenient dosing, less nausea, more potent A1C lowering vs exenatide Saxagliptin: equal potency vs sitagliptin, drug interactions > sitagliptin Consider individual patient appropriateness for incretin therapy
Questions