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New Drugs for Type 2 New Drugs for Type 2 Diabetes: The Diabetes: The IncretinsIncretins
Christa M. George, PharmD, BCPS, CDEChrista M. George, PharmD, BCPS, CDEAssistant ProfessorAssistant ProfessorDepartment of Clinical PharmacyDepartment of Clinical PharmacyUniversity of Tennessee Health Science University of Tennessee Health Science CenterCenterUT/St. Francis Family Practice CenterUT/St. Francis Family Practice Center
DisclosuresDisclosures
Spouse-UT Faculty & consultant Spouse-UT Faculty & consultant for Bayer, Ortho Pharmaceuticalsfor Bayer, Ortho Pharmaceuticals
No other disclosuresNo other disclosures Will discuss investigational agents Will discuss investigational agents Will notify of off-label useWill notify of off-label use
ObjectivesObjectives
Review recent safety concerns Review recent safety concerns relevant to FDA-approved incretin relevant to FDA-approved incretin agents for Type 2 diabetesagents for Type 2 diabetes
Review recently FDA-approved Review recently FDA-approved incretin agents for Type 2 diabetesincretin agents for Type 2 diabetes
Discuss characteristics of potential Discuss characteristics of potential candidates for incretin therapycandidates for incretin therapy
Diabetes MedicationsDiabetes Medications
1960 1995 2000 2005 2010
Insulin1922SUs
1957
MetforminAGIs1995
GlinidesTZDs1997
ExenatidePramlintide
2005
Sitagliptin2006
Liraglutide2010
Patlak M. Breakthroughs in Bioscience 2002. http://www.faseb.org/Portals/0/PDFs/opa/diabetes.pdf
Philippe J. Int J Clin Pract 2009;63:321-332
Saxagliptin2009
Incretin PhysiologyIncretin Physiology
GLP-1GLP-1– Stimulates glucose-dependent insulin Stimulates glucose-dependent insulin
secretion from beta cellssecretion from beta cells– Suppresses glucagon release from alpha cellsSuppresses glucagon release from alpha cells– Slows gastric emptying & reduces food Slows gastric emptying & reduces food
intakeintake– Degraded by DPP-4 enzymeDegraded by DPP-4 enzyme
GIPGIP– Increases glucose-dependent insulin releaseIncreases glucose-dependent insulin release– Degraded by DPP-4 enzymeDegraded by DPP-4 enzyme
2. Nauck MA. Am J Med 2009;122(Suppl 1):S3-S101. Drucker DJ, Nauck MA. Lancet 2006;368:1696-1705
L-cells
Muscle & Adipose Tissue
Alpha
Beta
Pancreas
Insulin
Rate of glucose disappearance
Amylin
Postprandial Glucagon
Liver
Plasma Glucose
GUT
Stomach
Brain Food Intake
GastricEmptying
GLP-1
GlucoseGlucose
DisposalDisposal
Glucose Homeostasis: Nondiabetic, Fed State
Rate of glucose
appearance
Edelman SV, Weyer C. Diabetes Tech Therapeutics 2002;4:175-189
7
Time, min
IR In
sulin
, mU
/L nm
ol/L
0.6
0.5
0.4
0.3
0.2
0.1
0
80
60
40
20
0
18060 1200
The Incretin Effect in Subjects Without and With Type 2 Diabetes
Control Subjects (n=8)
Patients With Type 2 Diabetes (n=14)
Time, min
IR In
sulin
, mU
/L nm
ol / L
0.6
0.5
0.4
0.3
0.2
0.1
0
80
60
40
20
0
18060 120 0
Oral glucose load
Intravenous (IV) glucose infusion
Incretin Effect
The incretin effect is diminished
in type 2 diabetes.
Adapted with permission from Nauck M et al. Diabetologia. 1986;29:46–52. Copyright © 1986 Springer-Verlag.
GLP-1 AgonistsGLP-1 Agonists
Exenatide (ByettaExenatide (Byetta®®)) Exenatide LAR (Investigational)Exenatide LAR (Investigational) Liraglutide (VictozaLiraglutide (Victoza®®))
Exenatide (ByettaExenatide (Byetta®®))
Pancreatitis Pancreatitis – 30 reports (2007) acute pancreatitis30 reports (2007) acute pancreatitis– 6 reports (2008) hemorrhagic or 6 reports (2008) hemorrhagic or
necrotizingnecrotizing 2 deaths, 4 recovered2 deaths, 4 recovered
– Monitor for signs & symptomsMonitor for signs & symptoms– D/C drug if pancreatitis suspectedD/C drug if pancreatitis suspected– Do NOT rechallenge if pancreatitis Do NOT rechallenge if pancreatitis
diagnoseddiagnosed
http://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/ucm124713.htm
Exenatide (ByettaExenatide (Byetta®®))
Altered renal function (2009)Altered renal function (2009)– 78 cases 78 cases
ARF (62/78) 79%ARF (62/78) 79% Renal insufficiency (16/78) 21%Renal insufficiency (16/78) 21% Hospitalizations (71/78) 91%Hospitalizations (71/78) 91% Hemodialysis (18/78) 23%Hemodialysis (18/78) 23% Renal transplantation (2/78) 2.5%Renal transplantation (2/78) 2.5% Additional renal risk factors (74/78) 95%Additional renal risk factors (74/78) 95% Pre-existing CKD (14/78) 18%Pre-existing CKD (14/78) 18%
http://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/ucm113705.htm
Exenatide (ByettaExenatide (Byetta®®))
Altered renal function (2009)Altered renal function (2009)– Do not use if CrCL < 30 mL/min or ESRDDo not use if CrCL < 30 mL/min or ESRD– Caution when initiating or increasing dose Caution when initiating or increasing dose
in CrCL 30-50 mL/minin CrCL 30-50 mL/min– Monitor SCr, changes in urination, Monitor SCr, changes in urination,
unexplained peripheral edema, increases unexplained peripheral edema, increases in blood pressure, lethargy, appetite in blood pressure, lethargy, appetite changes, back painchanges, back pain
– Advise patients to report nausea, Advise patients to report nausea, vomiting, dehydration immediatelyvomiting, dehydration immediately
http://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/ucm113705.htm
Exenatide (ByettaExenatide (Byetta®®))
New indication (2009)New indication (2009)– Monotherapy for Type 2 diabetesMonotherapy for Type 2 diabetes– 232 treatment naïve T2DM patients232 treatment naïve T2DM patients– 5 mcg, 10 mcg, or placebo SQ BID x 5 mcg, 10 mcg, or placebo SQ BID x
24 weeks24 weeks– A1C: -0.7%, -0.9%, vs -0.2% (p < A1C: -0.7%, -0.9%, vs -0.2% (p <
0.001)0.001)– Previously approved as adjunctive Previously approved as adjunctive
therapy to diet/exercise, metformin, therapy to diet/exercise, metformin, sulfonylurea, or TZDsulfonylurea, or TZD
Moretto TJ, et al. Clin Ther 2008;30:1448-60
GLP-1 AgonistsGLP-1 Agonists
Exenatide (ByettaExenatide (Byetta®®)) Exenatide LAR (Investigational)Exenatide LAR (Investigational) Liraglutide (VictozaLiraglutide (Victoza®®))
Exenatide LAR (Inv)Exenatide LAR (Inv)
DURATION-1 Study (n=135)DURATION-1 Study (n=135)– 30 wks, controlled, open-label once weekly 30 wks, controlled, open-label once weekly
vs BID exenatidevs BID exenatide– 70 wks, open-ended assessment exenatide 70 wks, open-ended assessment exenatide
LAR 2mg once weeklyLAR 2mg once weekly– A1C: -1.8% from baseline (8.3 A1C: -1.8% from baseline (8.3 ++ 1%) 1%)– Weight: -3.6 kg from baseline (100 Weight: -3.6 kg from baseline (100 ++ 19 19
kg)kg)– TGs: -18%; TChol: -9.7 TGs: -18%; TChol: -9.7 ++ 3.4 mg/dL 3.4 mg/dL– SBP: -3.2 SBP: -3.2 ++ 1.2 mmHg 1.2 mmHg– Nausea: 8% (mild)Nausea: 8% (mild)– No severe hypoglycemiaNo severe hypoglycemia
2. Kim T, et al. Abstract 159-OR. ADA Scientific Sessions 20091. Drucker DJ, et al. Lancet 2008;372:1240-50
Exenatide LAR (Inv)Exenatide LAR (Inv)
DURATION-2 Study (n=491)DURATION-2 Study (n=491)– 26 wks, randomized, double-blind, double-26 wks, randomized, double-blind, double-
dummydummy– Exenatide 2mg weekly vs sitagliptin 100 mg Exenatide 2mg weekly vs sitagliptin 100 mg
daily vs pioglitazone 45 mg daily added to daily vs pioglitazone 45 mg daily added to metforminmetformin
– A1C: -1.55% vs -0.92% vs -1.23% (p < 0.05)A1C: -1.55% vs -0.92% vs -1.23% (p < 0.05) (8.5 (8.5 ++ 1.1% baseline) 1.1% baseline)
– Weight % change: -2.7 vs -0.9 vs +3.2 (p Weight % change: -2.7 vs -0.9 vs +3.2 (p < 0.05)< 0.05)
(88 (88 ++ 20.1 kg baseline) 20.1 kg baseline)
Bergenstal R, et al. Abstract 6-LB. ADA Scientific Sessions 2009
Exenatide LAR (Inv)Exenatide LAR (Inv)
DURATION-3 Study (n=467)DURATION-3 Study (n=467)– 26 wk, open-label, superiority26 wk, open-label, superiority– T2DM, stable metformin T2DM, stable metformin ++ sulfonylurea sulfonylurea– Exenatide 2 mg weekly vs adjusted Exenatide 2 mg weekly vs adjusted
glargineglargine– A1C: -1.5% vs -1.3%A1C: -1.5% vs -1.3%– Weight: -5.8 lbs vs +3.1 lbsWeight: -5.8 lbs vs +3.1 lbs– Hypoglycemia: Hypoglycemia:
4% vs 19% (metformin only)4% vs 19% (metformin only) 20% vs 44% (metformin + sulfonylurea)20% vs 44% (metformin + sulfonylurea)
http://www.amylin.com/assets/001/5107.pdf;
Exenatide LAR (Inv)Exenatide LAR (Inv)
DURATION-5 Study (n=250)DURATION-5 Study (n=250)– 24 week, open-label, superiority study24 week, open-label, superiority study– T2DM, uncontrolled on oral medicationsT2DM, uncontrolled on oral medications– Exenatide LAR 2 mg weekly OR exenatide Exenatide LAR 2 mg weekly OR exenatide
5 mcg BID x 4 weeks, then 10 mcg bid5 mcg BID x 4 weeks, then 10 mcg bid– A1C: -1.6% vs -0.9% A1C: -1.6% vs -0.9% – Weight: -5.1 lbs vs -3.0 lbs Weight: -5.1 lbs vs -3.0 lbs – Nausea: 14% vs 35%Nausea: 14% vs 35%– No major hypoglycemic eventsNo major hypoglycemic events
http://newsroom.lilly.com/releasedetail.cfm?sh_print=yes&releaseid=430179
Exenatide LAR (Inv)Exenatide LAR (Inv)
FDA request (March 15 2010)FDA request (March 15 2010)– Product labeling informationProduct labeling information– Manufacturing informationManufacturing information– Risk Evaluation and Mitigation Risk Evaluation and Mitigation
Strategy (REMS)Strategy (REMS)– No additional studies requiredNo additional studies required– Proposed name: BydureonProposed name: Bydureon®®
http://www.nytimes.com/aponline/2010/03/15/business/AP-US-Amylin-FDA.html?_r=1&scp=1&sq=exenatide&st=cse
GLP-1 AgonistsGLP-1 Agonists
Exenatide (ByettaExenatide (Byetta®®)) Exenatide LAR (Investigational)Exenatide LAR (Investigational) Liraglutide (VictozaLiraglutide (Victoza®®))
Liraglutide (VictozaLiraglutide (Victoza®®))
FDA approved January 2010 FDA approved January 2010 – Novo NordiskNovo Nordisk
Second GLP-1 receptor agonistSecond GLP-1 receptor agonist Adjunct to diet & exercise in patients Adjunct to diet & exercise in patients
with T2DMwith T2DM– Not first-line choice due to risk for thyroid Not first-line choice due to risk for thyroid
c-cell tumorsc-cell tumors– Do not use in T1DM or DKADo not use in T1DM or DKA– No data in combination with insulin or No data in combination with insulin or
history of pancreatitishistory of pancreatitis
Product information for liraglutide (Victoza)http://m.victoza.com/hcp/prescribing-information/#17_1
Liraglutide (VictozaLiraglutide (Victoza®®))
LEAD-1 trial (n=1041)LEAD-1 trial (n=1041)– Liraglutide 0.6 mg, 1.2 mg, 1.8 mg vsLiraglutide 0.6 mg, 1.2 mg, 1.8 mg vs– Rosiglitazone 4 mg daily vs placeboRosiglitazone 4 mg daily vs placebo– Background: glimepiride 2-4 mg dailyBackground: glimepiride 2-4 mg daily– Duration: 26 weeksDuration: 26 weeks– A1C: A1C:
-0.6%, -1.08%, -1.13%, -0.44%, +0.23% -0.6%, -1.08%, -1.13%, -0.44%, +0.23% (p (p ≤ 0.001)≤ 0.001)
Liraglutide 1.2 mg & 1.8 mg vs rosiglitazone Liraglutide 1.2 mg & 1.8 mg vs rosiglitazone (p ≤ 0.0001) (p ≤ 0.0001)
Marre M, et al. Diabet Med 2009;26:268-78
Liraglutide (VictozaLiraglutide (Victoza®®))
LEAD-2 trial (n=1091)LEAD-2 trial (n=1091)– Liraglutide 0.6 mg, 1.2 mg, 1.8 mg vsLiraglutide 0.6 mg, 1.2 mg, 1.8 mg vs– Glimepiride 4 mg daily vs placeboGlimepiride 4 mg daily vs placebo– Background: metformin 1000 mg BIDBackground: metformin 1000 mg BID– Duration: 26 weeksDuration: 26 weeks– A1C: A1C:
-0.7%, -1%, -1%, -1%, +0.1% (p -0.7%, -1%, -1%, -1%, +0.1% (p ≤ 0.001)≤ 0.001)
Nauck M, et al. Diabetes Care 2009;32:84-90
Liraglutide (VictozaLiraglutide (Victoza®®))
LEAD-3 trial (n=746)LEAD-3 trial (n=746)– 52 weeks, monotherapy52 weeks, monotherapy– Liraglutide 1.2 mg, 1.8 mg, Liraglutide 1.2 mg, 1.8 mg,
glimepiride 8 mgglimepiride 8 mg– A1C: -0.84% vs -1.14% vs 0.51% A1C: -0.84% vs -1.14% vs 0.51%
(p (p ≤ 0.05)≤ 0.05)– Weight: -2.0 kg vs -2.5 kg vs +1.0 kg Weight: -2.0 kg vs -2.5 kg vs +1.0 kg
(p = 0.0001) (p = 0.0001)– Similar results after 2 years (n=440)Similar results after 2 years (n=440)
1. Garber A, et al. Lancet 2009;373:473-4812. Garber A et al. Abstract 162-OR. ADA Scientific Sessions 2009
Liraglutide (VictozaLiraglutide (Victoza®®))
LEAD-4 trial (n=533)LEAD-4 trial (n=533)– Liraglutide 1.2 mg, 1.8 mg, placeboLiraglutide 1.2 mg, 1.8 mg, placebo– Background: metformin 1000 mg Background: metformin 1000 mg
BID & rosiglitazone 8 mg daily BID & rosiglitazone 8 mg daily – Duration: 26 weeksDuration: 26 weeks– A1C: -1.5%, -1.5%, -0.5% A1C: -1.5%, -1.5%, -0.5% – Weight: -1.0 kg, -2.0 kg, +0.6 kg Weight: -1.0 kg, -2.0 kg, +0.6 kg
(p < 0.0001) (p < 0.0001)
Zinman B, et al. Diabetes Care 2009;32:1224-1230
Liraglutide (VictozaLiraglutide (Victoza®®))
LEAD-5 trial (n=581)LEAD-5 trial (n=581)– Liraglutide 1.8 mg, glargine, placeboLiraglutide 1.8 mg, glargine, placebo– Background: metformin 1000 mg BID, Background: metformin 1000 mg BID,
glimepiride 4 mg dailyglimepiride 4 mg daily– A1C:A1C:
-1.33% vs glargine -1.09% (p = 0.0015)-1.33% vs glargine -1.09% (p = 0.0015) -1.33% vs placebo -0.24% (p < 0.0001)-1.33% vs placebo -0.24% (p < 0.0001)
– Weight: Weight: -1.8 kg vs glargine +1.6 kg (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)-1.8 kg vs placebo -0.42 kg (p < 0.0001)
Russell-Jones D, et al. Diabetologia 2009;52:2046-55
Liraglutide (VictozaLiraglutide (Victoza®®))
LEAD-6 trial (n=464)LEAD-6 trial (n=464)– Liraglutide 1.8 mg, exenatide 10 mcg Liraglutide 1.8 mg, exenatide 10 mcg
BIDBID– Background: metformin, sulfonylurea, or Background: metformin, sulfonylurea, or
bothboth– A1C: -1.12% vs exenatide -0.79% A1C: -1.12% vs exenatide -0.79%
(p < 0.0001)(p < 0.0001)– Weight: -3.2 kg vs exenatide -2.9 kg Weight: -3.2 kg vs exenatide -2.9 kg
(p = 0.2235)(p = 0.2235)– Treatment satisfaction > with liraglutideTreatment satisfaction > with liraglutide
Buse JB, et al. Lancet 2009;374:39-47
Liraglutide (VictozaLiraglutide (Victoza®®))
AvailabilityAvailability– Pre-filled, multi-dose disposable penPre-filled, multi-dose disposable pen– 0.6 mg, 1.2 mg, 1.8 mg0.6 mg, 1.2 mg, 1.8 mg
Dosing/AdministrationDosing/Administration– Start 0.6 mg SQ once daily, anytime, Start 0.6 mg SQ once daily, anytime,
independent of mealsindependent of meals– Use with Novo pen needlesUse with Novo pen needles– Increase weekly to max 1.8 mg if neededIncrease weekly to max 1.8 mg if needed– Consider lowering dose of secretagoguesConsider lowering dose of secretagogues
Product information for liraglutide (Victoza)http://m.victoza.com/hcp/prescribing-information/#17_1
Liraglutide (VictozaLiraglutide (Victoza®®))
Adverse effectsAdverse effects– Nausea (28%)Nausea (28%)
LEAD-6: Liraglutide 2.5% vs exenatide 8.6%LEAD-6: Liraglutide 2.5% vs exenatide 8.6%
– Hypoglycemia (minor)Hypoglycemia (minor) LEAD-6: Liraglutide 25.5% vs exenatide 33.6%LEAD-6: Liraglutide 25.5% vs exenatide 33.6%
– Hypoglycemia (major)Hypoglycemia (major) LEAD-6: Liraglutide 0 pts vs exenatide 2 ptsLEAD-6: Liraglutide 0 pts vs exenatide 2 pts
– PancreatitisPancreatitis Liraglutide 8 cases (1 death)Liraglutide 8 cases (1 death) Causality unknownCausality unknown
Buse JB, et al. Lancet 2009;374:39-47
Liraglutide (VictozaLiraglutide (Victoza®®))
WarningsWarnings– Thyroid C-cell tumors in rats and miceThyroid C-cell tumors in rats and mice– Dose & treatment duration dependentDose & treatment duration dependent– 5 cases thyroid c-cell hyperplasia in 5 cases thyroid c-cell hyperplasia in
clinical trials of liraglutideclinical trials of liraglutide– Counsel on risk & symptoms of thyroid Counsel on risk & symptoms of thyroid
tumorstumors– ContraindicationsContraindications
Personal or family history of MTCPersonal or family history of MTC Personal history of MEN 2Personal history of MEN 2
Product information for liraglutide (Victoza)http://m.victoza.com/hcp/prescribing-information/#17_1
Liraglutide (VictozaLiraglutide (Victoza®®))
Drug InteractionsDrug Interactions– Take oral contraceptives & Take oral contraceptives &
antibiotics 1 hour before injecting antibiotics 1 hour before injecting liraglutideliraglutide
– Potential for decreased absorption Potential for decreased absorption and lower drug concentrationsand lower drug concentrations
Product information for liraglutide (Victoza)http://m.victoza.com/hcp/prescribing-information/#17_1
Liraglutide (VictozaLiraglutide (Victoza®®))
Liraglutide vs exenatideLiraglutide vs exenatide– Once daily vs BID dosingOnce daily vs BID dosing
Increased treatment satisfactionIncreased treatment satisfaction
– Nausea less frequent, abates fasterNausea less frequent, abates faster– Less hypoglycemiaLess hypoglycemia– Reduces A1C 1.0-1.5% vs 0.7-0.9%Reduces A1C 1.0-1.5% vs 0.7-0.9%– Caution with renal dysfunction, h/o Caution with renal dysfunction, h/o
pancreatitispancreatitis– CostCost
Liraglutide 1.8 mg daily $360 per monthLiraglutide 1.8 mg daily $360 per month Exenatide 10 mcg BID $240 per monthExenatide 10 mcg BID $240 per month
Pharmacists Letter March 2010;26:260304
DPP-4 InhibitorsDPP-4 Inhibitors
Sitagliptin (JanuviaSitagliptin (Januvia®®)) Saxagliptin (OnglyzaSaxagliptin (Onglyza®®))
Sitagliptin (JanuviaSitagliptin (Januvia®®))
First DPP-IV inhibitor (2006)First DPP-IV inhibitor (2006) Acute pancreatitis (2006-2009)Acute pancreatitis (2006-2009)
– Total cases: 88Total cases: 88 Hospitalization 58/88 (66%)Hospitalization 58/88 (66%) ICU stay 4/58 (6.9%)ICU stay 4/58 (6.9%) Hemorrhagic/necrotizing 2/88 (2.3%)Hemorrhagic/necrotizing 2/88 (2.3%) First 30 days of therapy 19/88 (21%)First 30 days of therapy 19/88 (21%) Resolved after drug d/c 47/88 (53%)Resolved after drug d/c 47/88 (53%) One other risk factor 45/88 (51%)One other risk factor 45/88 (51%)
http://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/DrugSafetyInformationforHeathcareProfessionals/ucm183764.htm
Sitagliptin (JanuviaSitagliptin (Januvia®®))
Acute pancreatitisAcute pancreatitis– Monitor for nausea, vomiting, Monitor for nausea, vomiting,
anorexia, abdominal painanorexia, abdominal pain– D/C if pancreatitis suspected & D/C if pancreatitis suspected &
institute supportive careinstitute supportive care– Use with caution & appropriate Use with caution & appropriate
monitoring in history of pancreatitis monitoring in history of pancreatitis (no data) (no data)
http://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/DrugSafetyInformationforHeathcareProfessionals/ucm183764.htm
DPP-4 InhibitorsDPP-4 Inhibitors
Sitagliptin (JanuviaSitagliptin (Januvia®®)) Saxagliptin (OnglyzaSaxagliptin (Onglyza®®))
Saxagliptin (OnglyzaSaxagliptin (Onglyza®®))
FDA approved July 2009FDA approved July 2009– Bristol-Myers SquibbBristol-Myers Squibb
Second DPP-IV inhibitorSecond DPP-IV inhibitor Adjunct to diet & exercise to Adjunct to diet & exercise to
improve glycemic control in improve glycemic control in patients with T2DMpatients with T2DM– Do not use in T1DM or DKADo not use in T1DM or DKA– No data in combination with insulinNo data in combination with insulin
1. Product information for saxagliptin (Onglyza) http://packageinserts.bms.com/pi/pi_onglyza.pdf2. http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm174780.htm
Saxagliptin (OnglyzaSaxagliptin (Onglyza®®))
Saxagliptin monotherapySaxagliptin monotherapy– 2.5 mg, 5 mg, 10 mg, 20 mg, 40 mg, 2.5 mg, 5 mg, 10 mg, 20 mg, 40 mg,
100 mg vs placebo100 mg vs placebo– A1CA1C11: -0.7-0.9% vs -0.27% placebo : -0.7-0.9% vs -0.27% placebo
(p < 0.007) (p < 0.007)– A1CA1C22: -0.43-0.54% vs +0.19% placebo : -0.43-0.54% vs +0.19% placebo
(p < 0.0001) (p < 0.0001)– Weight neutralWeight neutral– No significant difference in side No significant difference in side
effectseffects1. Rosenstock J, et al. Diabetes Obes Metab 2008;10(5):376-862. Rosenstock J, et al. Curr Med Res Opin 2009;25(10):2401-11
Saxagliptin (OnglyzaSaxagliptin (Onglyza®®))
SAX/MET vs monotherapy (n=1306)SAX/MET vs monotherapy (n=1306)– Duration: 24 weeksDuration: 24 weeks– SAX 5 mg/MET: A1C -2.5%SAX 5 mg/MET: A1C -2.5%– SAX 10 mg/MET: A1C -2.5%SAX 10 mg/MET: A1C -2.5%– SAX 10 mg: A1C -1.7%SAX 10 mg: A1C -1.7%– MET 2000 mg: A1C -2.0%MET 2000 mg: A1C -2.0%– All p < 0.0001 vs monotherapyAll p < 0.0001 vs monotherapy– No significant difference in No significant difference in
hypoglycemiahypoglycemia
Jadzinsky M, et al. Diabetes Obes Metab 2009;11(6):611-622
Saxagliptin (OnglyzaSaxagliptin (Onglyza®®))
SAX or PBO + MET (n=743)SAX or PBO + MET (n=743)– Duration: 24 weeksDuration: 24 weeks– SAX 2.5 mg/MET: A1C -0.59%SAX 2.5 mg/MET: A1C -0.59%– SAX 5 mg/MET: A1C -0.69%SAX 5 mg/MET: A1C -0.69%– SAX 10 mg/MET: A1C -0.58%SAX 10 mg/MET: A1C -0.58%– PBO/MET: A1C +0.13%PBO/MET: A1C +0.13%– All p < 0.0001 vs placeboAll p < 0.0001 vs placebo– No significant difference in No significant difference in
hypoglycemiahypoglycemia
DeFronzo RA, et al. Diabetes Care 2009;32:1649-1655
Saxagliptin (OnglyzaSaxagliptin (Onglyza®®))
SAX vs PBO + TZDSAX vs PBO + TZD– Duration: 24 weeksDuration: 24 weeks– SAX 2.5 mg/TZD: A1C -0.66% SAX 2.5 mg/TZD: A1C -0.66%
(p = 0.0007) (p = 0.0007)– SAX 5 mg/TZD: A1C -0.94% SAX 5 mg/TZD: A1C -0.94%
(p < 0.0001) (p < 0.0001)– PBO/TZD: A1C -0.30%PBO/TZD: A1C -0.30%– Hypoglycemia: 4.1%, 2.7% vs PBO 3.8%Hypoglycemia: 4.1%, 2.7% vs PBO 3.8%– Peripheral edema: 3.1%, Peripheral edema: 3.1%, 8.1%8.1% vs PBO vs PBO
4.3%4.3%
Hollander P, et al. J Clin Endocrinol Metab 2009;94:4810-19
Saxagliptin (OnglyzaSaxagliptin (Onglyza®®))
AvailabilityAvailability– 2.5 mg, 5 mg tablets2.5 mg, 5 mg tablets
Dosing/AdministrationDosing/Administration– 2.5 mg or 5 mg once daily 2.5 mg or 5 mg once daily – Give without regard to mealsGive without regard to meals– Limit dose to 2.5 mg dailyLimit dose to 2.5 mg daily
Concurrent CYP 3A4/5 inhibitorConcurrent CYP 3A4/5 inhibitor CrCL CrCL ≤ 50 mL/min≤ 50 mL/min HemodialysisHemodialysis
Product information for saxagliptin (Onglyza) http://packageinserts.bms.com/pi/pi_onglyza.pdf
Saxagliptin (OnglyzaSaxagliptin (Onglyza®®))
Adverse effectsAdverse effects– Headache, URI, UTI (Headache, URI, UTI (≥ 5%)≥ 5%)– HypoglycemiaHypoglycemia
Monotherapy: 4.0%, 5.6% vs PBO 4.1%Monotherapy: 4.0%, 5.6% vs PBO 4.1% SAX + Glyburide: SAX + Glyburide: 13.3%, 14.6%13.3%, 14.6% vs vs
PBO 10.1%PBO 10.1%
– Peripheral edemaPeripheral edema Monotherapy 3.6%, 2% vs PBO 3%Monotherapy 3.6%, 2% vs PBO 3%
Product information for saxagliptin (Onglyza) http://packageinserts.bms.com/pi/pi_onglyza.pdf
Saxagliptin (OnglyzaSaxagliptin (Onglyza®®))
Adverse effectsAdverse effects– Absolute lymphocyte countAbsolute lymphocyte count
Decreased by 100-120 cells/microLDecreased by 100-120 cells/microL SAX 5 mg: 1.5% had SAX 5 mg: 1.5% had ≤ 750 cells/microL≤ 750 cells/microL Did not recur on rechallenge for mostDid not recur on rechallenge for most Clinical significance unknownClinical significance unknown
Product information for saxagliptin (Onglyza) http://packageinserts.bms.com/pi/pi_onglyza.pdf
Saxagliptin (OnglyzaSaxagliptin (Onglyza®®))
WarningsWarnings– Hypoglycemia with secretagoguesHypoglycemia with secretagogues
Drug interactionsDrug interactions– Strong CYP 3A4/5 inhbitorsStrong CYP 3A4/5 inhbitors
Ketoconazole, itraconazoleKetoconazole, itraconazole Atazanavir, indinavir, ritonavir, saquinavir, Atazanavir, indinavir, ritonavir, saquinavir,
nelfinavirnelfinavir ClarithromycinClarithromycin NefazodoneNefazodone
– No difference AUC with rifampin (inducer)No difference AUC with rifampin (inducer)
Product information for saxagliptin (Onglyza) http://packageinserts.bms.com/pi/pi_onglyza.pdf
Saxagliptin (OnglyzaSaxagliptin (Onglyza®®))
Saxagliptin vs sitagliptinSaxagliptin vs sitagliptin– No head-to-head studiesNo head-to-head studies– Similar A1C lowering efficacySimilar A1C lowering efficacy– Drug interactionsDrug interactions
Saxagliptin > sitagliptinSaxagliptin > sitagliptin
– Adjust doses of both in renal Adjust doses of both in renal dysfunction dysfunction
– CostCost Saxagliptin (all strengths): $206 per monthSaxagliptin (all strengths): $206 per month Sitagliptin (all strengths): $206 per monthSitagliptin (all strengths): $206 per month
Pharmacists Letter March 2010;26:260304
Role of Incretins in Role of Incretins in Type 2 DiabetesType 2 Diabetes
Lifestyle+
Metformin
Lifestyle + Metformin+
Basal insulin
Lifestyle + Metformin+
Sulfonylureaa
Lifestyle + Metformin+
Intensive insulin
Lifestyle + Metformin+
PioglitazoneNo hypoglycemia
Edema, CHF, Bone loss
Lifestyle + Metformin+
GLP-1 agonistb
No hypoglycemia; Weight loss, Nausea/vomiting
Lifestyle + Metformin+
Pioglitazone+
Sulfonylureaa
Lifestyle + Metformin+
Basal insulin
Step 1 Step 2 Step 3
Tier 1
Tier 2
Diabetes Care 2009;32:193-203
AACE/ACE AlgorithmAACE/ACE Algorithm
Included all major classes of drugsIncluded all major classes of drugs– Emphasize drugs with low risk of Emphasize drugs with low risk of
hypoglycemia and weight gainhypoglycemia and weight gain– Considered A1C lowering effect, cost, Considered A1C lowering effect, cost,
fasting & postprandial glucose loweringfasting & postprandial glucose lowering Metformin cornerstone of therapyMetformin cornerstone of therapy GLP-1 & DPP-4 may be used as GLP-1 & DPP-4 may be used as
adjunctive therapy early in adjunctive therapy early in treatmenttreatment
AACE/ACE Algorithm Endocr Pract 2009;15:540-559
Potential Candidates Potential Candidates for Incretin Therapyfor Incretin Therapy Need to avoid hypoglycemiaNeed to avoid hypoglycemia Need to avoid weight Need to avoid weight
gain/achieve weight lossgain/achieve weight loss Intolerant of/contraindications to Intolerant of/contraindications to
other agentsother agents Relatively close to A1C goal (DPP-Relatively close to A1C goal (DPP-
4)4)
Avoid or Use Incretins Avoid or Use Incretins CautiouslyCautiously Caution in history of pancreatitisCaution in history of pancreatitis Caution in renal insufficiencyCaution in renal insufficiency Liraglutide contraindicated in Liraglutide contraindicated in
MTC, MEN2 MTC, MEN2 Exenatide, liraglutide, saxagliptin Exenatide, liraglutide, saxagliptin
have not been studied with have not been studied with insulininsulin
ConclusionsConclusions
Consider potential risks of pancreatitis, Consider potential risks of pancreatitis, renal dysfunctionrenal dysfunction
Potential approval of exenatide LARPotential approval of exenatide LAR Liraglutide: convenient dosing, less Liraglutide: convenient dosing, less
nausea, more potent A1C lowering vs nausea, more potent A1C lowering vs exenatideexenatide
Saxagliptin: equal potency vs sitagliptin, Saxagliptin: equal potency vs sitagliptin, drug interactions > sitagliptindrug interactions > sitagliptin
Consider individual patient Consider individual patient appropriateness for incretin therapyappropriateness for incretin therapy
QuestionsQuestions