New Drugs for Type 2 Diabetes: The Incretins

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

Metformin AGIs 1995

Sitagliptin Saxagliptin 2006 2009

1960

1995

2000

2005

2010

Glinides TZDs 1997

Exenatide Pramlintide 2005

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

Glucose Homeostasis: Nondiabetic, Fed State

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

Edelman SV, Weyer C. Diabetes Tech Therapeutics 2002;4:175-189

The Incretin Effect in Subjects Without and With Type 2 Diabetes

Control Subjects (n=8)
80 0.6

Patients With Type 2 Diabetes (n=14)

80

Incretin Effect

0.5

IR Insulin, mU/L

60

IR Insulin, mU/L

0.4

60

The incretin effect is diminished in type 2 diabetes.

0.6 0.5 0.4

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) Exenatide LAR (Investigational) Liraglutide (Victoza)

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)

Altered renal function (2009)

78 cases
ARF (62/78) 79% Renal insufficiency (16/78) 21% Hospitalizations (71/78) 91% Hemodialysis (18/78) 23% Renal transplantation (2/78) 2.5% Additional renal risk factors (74/78) 95% Pre-existing CKD (14/78) 18%

http://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/ucm1 13705.htm

Exenatide (Byetta)

Altered renal function (2009)

Do not use if CrCL < 30 mL/min or ESRD Caution when initiating or increasing dose in CrCL 30-50 mL/min Monitor SCr, changes in urination, unexplained peripheral edema, increases in blood pressure, lethargy, appetite changes, back pain Advise patients to report nausea, vomiting, dehydration immediately

http://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/ucm1 13705.htm

Exenatide (Byetta)

New indication (2009)

Monotherapy for Type 2 diabetes 232 treatment nave T2DM patients 5 mcg, 10 mcg, or placebo SQ BID x 24 weeks A1C: -0.7%, -0.9%, vs -0.2% (p < 0.001) Previously approved as adjunctive therapy to diet/exercise, metformin, sulfonylurea, or TZD

Moretto TJ, et al. Clin Ther 2008;30:1448-60

GLP-1 Agonists

Exenatide (Byetta) Exenatide LAR (Investigational) Liraglutide (Victoza)

Exenatide LAR (Inv)

DURATION-1 Study (n=135)

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

Exenatide LAR (Inv)

DURATION-2 Study (n=491)

26 wks, randomized, double-blind, doubledummy Exenatide 2mg weekly vs sitagliptin 100 mg daily vs pioglitazone 45 mg daily added to metformin A1C: -1.55% vs -0.92% vs -1.23% (p < 0.05)

(8.5 + 1.1% baseline)

Weight % change: -2.7 vs -0.9 vs +3.2 (p < 0.05)

(88 + 20.1 kg baseline)

Bergenstal R, et al. Abstract 6-LB. ADA Scientific Sessions 2009

Exenatide LAR (Inv)

DURATION-3 Study (n=467)

26 wk, open-label, superiority T2DM, stable metformin + sulfonylurea Exenatide 2 mg weekly vs adjusted glargine A1C: -1.5% vs -1.3% Weight: -5.8 lbs vs +3.1 lbs Hypoglycemia:

4% vs 19% (metformin only) 20% vs 44% (metformin + sulfonylurea)

http://www.amylin.com/assets/001/5107.pdf;

Exenatide LAR (Inv)

DURATION-5 Study (n=250)

24 week, open-label, superiority study T2DM, uncontrolled on oral medications Exenatide LAR 2 mg weekly OR exenatide 5 mcg BID x 4 weeks, then 10 mcg bid A1C: -1.6% vs -0.9% Weight: -5.1 lbs vs -3.0 lbs Nausea: 14% vs 35% No major hypoglycemic events

http://newsroom.lilly.com/releasedetail.cfm?sh_print=yes&releaseid=430179

Exenatide LAR (Inv)

FDA request (March 15 2010)

Product labeling information Manufacturing information Risk Evaluation and Mitigation Strategy (REMS) No additional studies required Proposed name: Bydureon

http://www.nytimes.com/aponline/2010/03/15/business/AP-US-AmylinFDA.html?_r=1&scp=1&sq=exenatide&st=cse

GLP-1 Agonists

Exenatide (Byetta) Exenatide LAR (Investigational) Liraglutide (Victoza)

Liraglutide (Victoza)

FDA approved January 2010

Novo Nordisk

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

Product information for liraglutide (Victoza) http://m.victoza.com/hcp/prescribing-information/#17_1

Liraglutide (Victoza)

LEAD-1 trial (n=1041)

Liraglutide 0.6 mg, 1.2 mg, 1.8 mg vs Rosiglitazone 4 mg daily vs placebo Background: glimepiride 2-4 mg daily Duration: 26 weeks A1C:

-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)

Marre M, et al. Diabet Med 2009;26:268-78

Liraglutide (Victoza)

LEAD-2 trial (n=1091)

Liraglutide 0.6 mg, 1.2 mg, 1.8 mg vs Glimepiride 4 mg daily vs placebo Background: metformin 1000 mg BID Duration: 26 weeks A1C:

-0.7%, -1%, -1%, -1%, +0.1% (p 0.001)

Nauck M, et al. Diabetes Care 2009;32:84-90

Liraglutide (Victoza)

LEAD-3 trial (n=746)

52 weeks, monotherapy Liraglutide 1.2 mg, 1.8 mg, glimepiride 8 mg A1C: -0.84% vs -1.14% vs 0.51% (p 0.05) Weight: -2.0 kg vs -2.5 kg vs +1.0 kg (p = 0.0001) Similar results after 2 years (n=440)

1. Garber A, et al. Lancet 2009;373:473-481 2. Garber A et al. Abstract 162-OR. ADA Scientific Sessions 2009

Liraglutide (Victoza)

LEAD-4 trial (n=533)

Liraglutide 1.2 mg, 1.8 mg, placebo Background: metformin 1000 mg BID & rosiglitazone 8 mg daily Duration: 26 weeks A1C: -1.5%, -1.5%, -0.5% Weight: -1.0 kg, -2.0 kg, +0.6 kg (p < 0.0001)

Zinman B, et al. Diabetes Care 2009;32:1224-1230

Liraglutide (Victoza)

LEAD-5 trial (n=581)

Liraglutide 1.8 mg, glargine, placebo Background: metformin 1000 mg BID, glimepiride 4 mg daily A1C:

-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:

Russell-Jones D, et al. Diabetologia 2009;52:2046-55

Liraglutide (Victoza)

LEAD-6 trial (n=464)

Liraglutide 1.8 mg, exenatide 10 mcg BID Background: metformin, sulfonylurea, or both A1C: -1.12% vs exenatide -0.79% (p < 0.0001) Weight: -3.2 kg vs exenatide -2.9 kg (p = 0.2235) Treatment satisfaction > with liraglutide

Buse JB, et al. Lancet 2009;374:39-47

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

Product information for liraglutide (Victoza) http://m.victoza.com/hcp/prescribing-information/#17_1

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

Buse JB, et al. Lancet 2009;374:39-47

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

Personal or family history of MTC Personal history of MEN 2

Product information for liraglutide (Victoza) http://m.victoza.com/hcp/prescribing-information/#17_1

Liraglutide (Victoza)

Drug Interactions
Take oral contraceptives & antibiotics 1 hour before injecting liraglutide Potential for decreased absorption and lower drug concentrations

Product information for liraglutide (Victoza) http://m.victoza.com/hcp/prescribing-information/#17_1

Liraglutide (Victoza)

Liraglutide vs exenatide
Once daily vs BID dosing

Increased treatment satisfaction

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

Pharmacists Letter March 2010;26:260304

DPP-4 Inhibitors

Sitagliptin (Januvia) Saxagliptin (Onglyza)

Sitagliptin (Januvia)

First DPP-IV inhibitor (2006) Acute pancreatitis (2006-2009)

Total cases: 88
Hospitalization 58/88 (66%) ICU stay 4/58 (6.9%) Hemorrhagic/necrotizing 2/88 (2.3%) First 30 days of therapy 19/88 (21%) Resolved after drug d/c 47/88 (53%) One other risk factor 45/88 (51%)

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

Sitagliptin (Januvia) Saxagliptin (Onglyza)

Saxagliptin (Onglyza)

FDA approved July 2009

Bristol-Myers Squibb

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

1. Product information for saxagliptin (Onglyza) http://packageinserts.bms.com/pi/pi_onglyza.pdf 2. http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm174780.htm

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)

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

Saxagliptin (Onglyza)

SAX or PBO + MET (n=743)

Duration: 24 weeks SAX 2.5 mg/MET: A1C -0.59% SAX 5 mg/MET: A1C -0.69% SAX 10 mg/MET: A1C -0.58% PBO/MET: A1C +0.13% All p < 0.0001 vs placebo No significant difference in hypoglycemia

DeFronzo RA, et al. Diabetes Care 2009;32:1649-1655

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

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 CrCL 50 mL/min Hemodialysis

Product information for saxagliptin (Onglyza) http://packageinserts.bms.com/pi/pi_onglyza.pdf

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

Monotherapy 3.6%, 2% vs PBO 3%

Product information for saxagliptin (Onglyza) http://packageinserts.bms.com/pi/pi_onglyza.pdf

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

Product information for saxagliptin (Onglyza) http://packageinserts.bms.com/pi/pi_onglyza.pdf

Saxagliptin (Onglyza)

Warnings
Hypoglycemia with secretagogues

Drug interactions
Strong CYP 3A4/5 inhbitors

Ketoconazole, itraconazole Atazanavir, indinavir, ritonavir, saquinavir, nelfinavir Clarithromycin Nefazodone

No difference AUC with rifampin (inducer)

Product information for saxagliptin (Onglyza) http://packageinserts.bms.com/pi/pi_onglyza.pdf

Saxagliptin (Onglyza)

Saxagliptin vs sitagliptin
No head-to-head studies Similar A1C lowering efficacy Drug interactions

Saxagliptin > sitagliptin

Adjust doses of both in renal dysfunction Cost

Saxagliptin (all strengths): $206 per month Sitagliptin (all strengths): $206 per month

Pharmacists Letter March 2010;26:260304

Role of Incretins in Type 2 Diabetes

Diabetes Care 2009;32:193-203

Tier 1

Lifestyle + Metformin + Basal insulin

Lifestyle + Metformin + Intensive insulin

Lifestyle + Metformin

Lifestyle + Metformin + Sulfonylureaa

Step 1 Tier 2 Step 2 Lifestyle + Metformin + Pioglitazone
No hypoglycemia Edema, CHF, Bone loss

Step 3 Lifestyle + Metformin + Pioglitazone + Sulfonylureaa

Lifestyle + Metformin + GLP-1 agonistb

No hypoglycemia; Weight loss, Nausea/vomiting

Lifestyle + Metformin + Basal insulin

AACE/ACE Algorithm

Included all major classes of drugs

Emphasize drugs with low risk of hypoglycemia and weight gain Considered A1C lowering effect, cost, fasting & postprandial glucose lowering

Metformin cornerstone of therapy GLP-1 & DPP-4 may be used as adjunctive therapy early in treatment

AACE/ACE Algorithm Endocr Pract 2009;15:540-559

Potential Candidates for Incretin Therapy

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)

Avoid or Use Incretins Cautiously

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