incretins 1

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


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%



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



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

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


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


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;


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


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

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


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


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


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


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


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


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


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



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


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



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



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 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


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


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


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


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


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%



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



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)



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


Sulfonylureaa


Intensive insulin


PioglitazoneNo hypoglycemia

Edema, CHF, Bone loss


GLP-1 agonistb

No hypoglycemia; Weight loss, Nausea/vomiting


Pioglitazone+

Sulfonylureaa


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

incretins 1

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