sign in sign up
<<
Home , PPAR agonist

.

GLP-1 RECEPTOR AGONIST SHOULD I TRY IT? VERONICA BRADY, PHD, BC-ADM, CDE PROJECT ECHO JUNE 21, 2018

. .

. .

SOMETHING TO CONSIDER

• IF YOU COULD PRESCRIBE A FOR YOUR PATIENT WITH THAT: • DECREASED A1C • DECREASED APPETITE • REDUCED WEIGHT (OR MINIMIZED WEIGHT GAIN) • REDUCED GLYCEMIC VARIABILITY • HAD LOW RISK OF HYPOGLYCEMIA • WITH POTENTIAL CARDIOPROTECTIVE BENEFITS WOULD YOU DO IT?

. .

OBJECTIVES

• OVERVIEW OF DIABETES DEFECTS • OVERVIEW OF DIABETES TREATMENT ALGORITHM • REVIEW MECHANISM OF ACTION OF GLP-1 RA • REVIEW OF AVAILABLE GLP-1 RA • CASE STUDIES

. .

. . ADA TREATMENT ALGORITHM

. .

GLP-1 IS RESPONSIBLE FOR THE INCRETIN EFFECT= THE RELEASE OF MORE BECAUSE OF HIGH BLOOD GLUCOSE AFTER A MEAL

. .

INCRETIN MIMETICS

Synthetic analog of exendin-4, a gila monster salivary polypeptide that mimics incretin and promotes glucose dependent insulin secretion, suppresses glucagon, suppresses hepatic glucose output and slows gastric emptying (reducing appetite)

. .

. .

INCRETIN MIMETIC

Lowers HbA1c 0.6% - 1.4%

Main Benefits Improves blood glucose control without weight gain, promotes weight loss by decreasing appetite Common adverse Diarrhea, nausea, vomiting effects

Cautious Use Risk for pancreatitis, renal failure

Contraindications Hypersensitivity, Renal impairment with CrCl < 30 mL/min, do not use liraglutide in patients with a history of or family history of medullary thyroid cancer. Do not use with DPP-4 inhibitors

. .

GLP-1 FORMULATIONS

. .

TWICE DAILY

. .

EXENATIDE (BYETTA) (2005)

Drug (Byetta)

Mechanism of action Promotes proliferation of beta-cells & islet-cell neogenesis from precursor cells Dosing Pen injection: 5 mcg first month, 10 mcg next month if tolerated. Twice daily, within 60 minutes before first meal and evening meal, at least 6 hours apart

Pharmcokinetics Peak plasma concentration in 2-3 hours—detectable up to 6 hours after administration Side effects Hypoglycemia with , nausea, vomiting, dizziness, feeling jittery, headache, pancreatitis, constipation, headache, injection site reaction

How supplied 5 mcg Prefilled pen, 10 mcg Prefilled pen

. .

ONCE DAILY

. .

LIRAGLUTIDE (VICTOZA) (2009)

Drug Liraglutide (Victoza) Mechanism of Action ?increase beta-cell mass; improved biphasic insulin secretion Dosing Pen injection: 0.6-mcg qd x 1 week then 1.2 mcg qd if no excessive nausea. Can increase to 1.8 mcg if needed.

Pharmacokinetics Peak plasma concentrations in 8-12 hours Side effects Hypoglycemia with sulfonylureas, nausea, vomiting, dizziness, feeling jittery, headache, pancreatitis, constipation, headache, injection site reaction

How supplied 18 mcg/3 ml Prefilled pen

. .

LIXISENATIDE (ADLYXIN) 2016

Drug (Adlyxin) Mechanism of Action ? Preservation of beta-cell mass Dosing Inject one hour before the first meal of the day Starting dose 10mcg SC daily x 14 days (green pen)then increase to 20mcg SC daily Pharmacokinetics Peak plasma concentrations in 1-3.5 hours Side effects Nausea, vomiting, constipation, headache, injection site irritation How supplied Starter dose (green pen) 50mcg/mL= 14 does of 10mcg/dose: Maintenance dose 100mcg/mL (burgundy pen)= 14 20mcg doses 3ml prefilled pens

. .

ONCE WEEKLY

. .

EXENATIDE ER [BYDUREON (BCISE)] (2012)

Drug Bydureon (Exenatide ER) Mechanism of Action (same as exenatide) Dosing 2 mg once weekly injection Any time of the day with or without food Pharmacokinetics Reaches therapeutic levels after 2 weeks; at 6-7weeks reaches maximum concentration Side effects Hypoglycemia with sulfonylureas, nausea, vomiting, dizziness, feeling jittery, headache, pancreatitis, constipation, headache, injection site reaction, possible antibody formation

How supplied 2mg in 0.85ml—4 count carton

. .

ABLIGLUTIDE (TANZEUM) 2014

Drug Abliglutide (Tanzeum) Mechanism of action Dosing 30 mg once weekly may increase to 50 mg once weekly Pharmacokinetics Mean plasma concentration reached in 3-5 days and steady state in 3-5 weeks Side effects How supplied 30mg and 50mg

. .

DULAGLUTIDE (TRULICITY) (2014)

Drug (Trulicity) Dosing Initial dose 0.75mg SC once weekly; may increase to 1.5mg once weekly Any time of the day Phamacokinetics Peak plasma levels in 24-48 hours Side effects Nausea, vomiting and diarrhea How supplied 4 single dose pens

. .

SEMAGLUTIDE (OZEMPIC) (2017)

Drug Dosing Start at 0.25mg/week x 4 weeks and increase to 0.5mg/ week x 4weeks can increase to 1mg if needed Any time of the day; with or without food Pharmacokinetics Peak plasma levels 1-3 days Side effects GI side effects How supplied 0.25 & 0.5mg one prefilled pen (2mg)= 1.5mL 1mg 2 prefilled pens (4mg)= 3mL

. .

COMBINATIONS

. .

INSULIN + GLP-1

• SOLIQUA 100/33 (GLARGINE 100/LIXISENATIDE 33MCG PER ML) • USING <60UNITS OF BASAL OR LIXISENATIDE • IF <30 UNITS/DAY --START WITH 15 UNITS (15GLARGINE/5MCG LIXISENATIDE); • 30-60 UNITS/DAY—START 30 UNITS • MAX DOSE 60 UNITS (60G/20 LIXISENATIDE) • ONE HOUR PRIOR TO 1ST MEAL • SUPPLIED IN 3ML PREFILLED PENS

. .

INSULIN + GLP-1

• XULTOPHY 100/3.6 (100 UNITS DEGLUDEC/3.6 MG LIRAGLUTIDE • USING LESS THAN 50 UNITS BASAL OR LIRAGLUTIDE < 1.8 • STARTING DOSE 16 UNITS (16 UNITS DEGLUDEC/0.58MG • MAX DOSE 50 UNITS (50 UNITS DEGLUDEC/1.8MG LIRAGLUTIDE • INDEPENDENT OF FOOD • SUPPLIED IN 3ML PREFILLED PENS

. .

NEW AND NOVEL

. .

ORAL GLP-1 RA

• ORAL – PIONEER STUDY • ORAL FORMULATION OF SEMAGLUTIDE COMBINED WITH ABSORPTION ENHANCER • DOSES—2.5,5,10,20, 40MG • REDUCED A1C BY 0.9-1.8% • SIDE EFFECTS: NAUSEA, VOMITING DIARRHEA

. .

IMPLANTABLE GLP-1 RA

• ITCA 650 (FREEDOM TRIAL) • OSMOTI MINIPUMP PROVIDING CONTINUOUS INFUSION OF EXENATIDE • 20MCG/ DAY X 12 WEEKS THEN 60MCG/DAY • CONTINUOUS DELIVERY FOR 3-6 MONTHS • DECREASED A1C 2.8% • SIDE EFFECTS: NAUSEA, VOMITING, DIARRHEA—DECREASES OVERTIME

. . OVERVIEW OF CVOTS OF GLUCOSE-LOWERING DRUGS1

TOSCA IT25 (n=3371) ORIGIN6 AleCardio7 4P-MACE SAVOR-TIMI 532 (n=12,537) (n=7226) CAROLINA®16 (n=16,492) 3P-MACE 3P-MACE 1,222 3P-MACE (n=6041) ≥ 631 4P-MACE 17 5 10 OMNEON 3 TECOS DEVOTE EXAMINE CARMELINA15 (n=4000) (n=5380) (n=14,671) (n=7637) ≥ 1300 4P-MACE 3P-MACE (n=8300) 4P-MACE 621 3P-MACE 4P-MACE + renal

2013 2014 2015 2016 2017 2018 2019 2020

4 18 20 ELIXA 11 EXSCEL REWIND (n=6068) SUSTAIN-6 (n=14,000) (n=9622) ≥ 805 4P-MACE (n=3297) ≥ 1591 3P-MACE ≥ 1067 3P-MACE DPP-4 inhibitor 3P-MACE 19 14 DECLARE-TIMI 58 13 CANVAS (n=17,150) SGLT-2 inhibitor FREEDOM CVO (n=4339) EMPA-REG (n=4000) ≥ 1390 3P-MACE OUTCOME8 ≥ 420 3P-MACE 4P-MACE 21 GLP1 RA (n=7028) CREDENCE ≥ 691 3P-MACE LEADER9 CANVAS-R12 (n=4200) Renal + 5P-MACE Insulin (n=9341) (n=5820) ≥ 611 3P-MACE Albuminuria STELLA-LONG TERM22 CVOT23 PPAR agonist (n=11,412) (n=3900) 3P-MACE + Tumors 3P-MACE TZD HARMONY Outcomes24 (n=9400) 3P-MACE TIMINGS REPRESENT ESTIMATED COMPLETION DATES AS PER CLINICALTRIALS.GOV

1. JOHANSEN OE. 2015 6. ORIGIN. 2012 11. NCT01720446 16. NCT01243424 21. NCT02065791 2. SCIRICA BM ET AL. 2013 7. LINCOFF AM ET AL. 2014 12. NCT01989754 17. NCT01703208 22. NCT02479399 3. WHITE WB ET AL. 2013 8. ZINMAN B ET AL. 2015 13. NCT01455896 18. NCT01144338 23. NCT01986881 4. PFEFFER MA ET AL. 2015 9. MARSO SP ET AL. 2016 14. NCT01032629 19. NCT01730534 24. NCT02465515 5. GREEN JB ET AL. 2015 10. NCT01959529 15. NCT01897532 20. NCT01394952 25. NCT00700856

. .

COMPARISON OF AVAILABLE GLP-1 RA

Drug Weight loss A1c lowering Cardiovascular GI side effects benefits Exenatide (Byetta) + + - ++ Exenatide ER + +++ (-0.9-1.9%) + (HR-0.91) + (Bydureon, Bcise) Liraglutide (Victoza) + ++(-0.8-1.5%) ++ (HR= 0.87) ++ Dulaglutide + ++(-0.59-1.51%) Ongoing trial ++ (Trulicity) Lixisenatide + ++(1.1%-combo) - (HR=1.02) + (Adlyxin) Semaglutide ++ ++(-1.4-1.6%) ++ (HR=0.74) + (Ozempic)

. .

CASE STUDIES

. .

A CASE FOR GLP-1INHIBITORS

• INITIAL PRESENTATION • B. J. IS A 65 YEAR OLD FEMALE WITH A >20 YEAR H/O T2DM • PMH: CAD, HTN, HLD, CKD, OBESITY (BMI-41) • : LANTUS 10-15 UNITS AT HS, HUMALOG 5-10 UNITS WITH MEALS, ACTOS 15MG DAILY • LABS: SMBG 98-286MG/DL (AVG 207MG/DL); A1C 8.6% • VITALS: WEIGHT-243#, BP 131/61,HR-71

. .

A CASE FOR GLP-1 (CONT)

• FOLLOW-UP • B.J. RETURNS TO CLINIC AFTER 4-5 MONTHS • MEDICATIONS: HUMALOG 2-4 UNITS (OCC.), ACTOS 15MG QD, LIRAGLUTIDE 1.8MG/D • LABS: SMBG 78-223 (AVG 128)MG/DL, A1C 7.5% • VITALS: WEIGHT-236#, BP- 130/68, HR-67

. .

CASE # 2

• HM IS A 45 YEAR OLD MALE WITH A 8 YEAR H/O T2DM • PMH: HTN, HYPERLIPIDEMIA, OBESITY (BMI – 33) • CURRENT MEDICATIONS: LANTUS 40 UNITS DAILY, NOVOLOG 10 UNITS TIDAC, GLIMIPERIDE 4MG BID AND TRADJENTA 5MG • LABS: A1C 8.9%, BG READINGS 77-361MG/DL, LDL- 158MG/DL • VITALS: BP 153/100, 85, WEIGHT 232# • HE REPORTS MISSING HIS LANTUS DOSE 3-4 TIMES A WEEK. HE DOES NOT TAKE HIS NOVOLOG BECAUSE HE “HATES SHOTS”

. .

CASE #2 (CONT) 3 MONTHS LATER

• MEDICATIONS: LANTUS 40 UNITS, NOVOLOG 12 UNITS TIDAC, TRADJENTA 5MG • GLABS: B READINGS 79-269MG/DL, A1C 9.6% • VITALS: WEIGHT 232#, BP 175/106

• STARTED LIRAGLUTIDE

. .

CASE #2 (CONT) ONE YEAR LATER

• MEDICATIONS: LANTUS 40 (MISSING DOSES 4X/WEEK), NOVOLOG 12 (NOT TAKING), VICTOZA 1.8 (NO MISSED DOSES) • LABS: BG READINGS 151-263MG/DL, A1C 9.1% • VITALS: WEIGHT 218 (BMI- 31), BP 113/74

• CHANGED TO XULTOPHY

. .

TAKE HOME MESSAGE

. .

TAKE HOME MESSAGE

• GLP-1 RECEPTOR AGONISTS ARE SOME OF THE MOST WELL TOLERATED, EFFECTIVE THERAPIES IN THE BATTLE AGAINST TYPE 2 DIABETES. • THEY ARE MORE AFFECTIVE IN PROMOTING WEIGHT LOSS AND LOWERING A1C THAN , DDP-4 INHIBITORS AND SULFONYLUREAS • GLP-1 RAS ARE SYNERGISTIC WITH SGLT-2 INHIBITORS , METFORMIN AND INSULIN • KEEP IN MIND THAT THE PRIMARY GOAL OF DIABETES MANAGEMENT IS THE MITIGATION OF CARDIOVASCULAR EVENTS.

. .

SPECIAL THANKS

• THOMAS BERG, MS –LILLY • TOBY DAMRON, PHARMD-NOVONORDISK

. .

QUESTIONS???

.