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 MEDICATION FOR YOUR PATIENT WITH DIABETES 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 INSULIN 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 Common adverse effects Improves blood glucose control without weight gain, promotes weight loss by decreasing appetite Diarrhea, nausea, vomiting 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 Mechanism of action Dosing Pharmcokinetics Side effects How supplied Exenatide (Byetta) Promotes proliferation of beta-cells & islet-cell neogenesis from precursor cells 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 Peak plasma concentration in 2-3 hours detectable up to 6 hours after administration Hypoglycemia with sulfonylureas, nausea, vomiting, dizziness, feeling jittery, headache, pancreatitis, constipation, headache, injection site reaction 5 mcg Prefilled pen, 10 mcg Prefilled pen
ONCE DAILY
LIRAGLUTIDE (VICTOZA) (2009) Drug Mechanism of Action Dosing Pharmacokinetics Side effects How supplied Liraglutide (Victoza)?increase beta-cell mass; improved biphasic insulin secretion 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. Peak plasma concentrations in 8-12 hours Hypoglycemia with sulfonylureas, nausea, vomiting, dizziness, feeling jittery, headache, pancreatitis, constipation, headache, injection site reaction 18 mcg/3 ml Prefilled pen
LIXISENATIDE (ADLYXIN) 2016 Drug Mechanism of Action Dosing Pharmacokinetics Side effects How supplied Lixisenatide (Adlyxin)? Preservation of beta-cell mass 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 Peak plasma concentrations in 1-3.5 hours Nausea, vomiting, constipation, headache, injection site irritation 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 Mechanism of Action Dosing Pharmacokinetics Side effects How supplied Bydureon (Exenatide ER) (same as exenatide) 2 mg once weekly injection Any time of the day with or without food Reaches therapeutic levels after 2 weeks; at 6-7weeks reaches maximum concentration Hypoglycemia with sulfonylureas, nausea, vomiting, dizziness, feeling jittery, headache, pancreatitis, constipation, headache, injection site reaction, possible antibody formation 2mg in 0.85ml 4 count carton
ABLIGLUTIDE (TANZEUM) 2014 Drug Mechanism of action Dosing Pharmacokinetics Side effects How supplied Abliglutide (Tanzeum) 30 mg once weekly may increase to 50 mg once weekly Mean plasma concentration reached in 3-5 days and steady state in 3-5 weeks 30mg and 50mg
DULAGLUTIDE (TRULICITY) (2014) Drug Dosing Phamacokinetics Side effects How supplied Dulaglutide (Trulicity) Initial dose 0.75mg SC once weekly; may increase to 1.5mg once weekly Any time of the day Peak plasma levels in 24-48 hours Nausea, vomiting and diarrhea 4 single dose pens
SEMAGLUTIDE (OZEMPIC) (2017) Drug Dosing Pharmacokinetics Side effects How supplied 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 Peak plasma levels 1-3 days GI side effects 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 1 ST 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 SEMAGLUTIDE 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 DRUGS 1 SAVOR-TIMI 53 2 (n=16,492) 1,222 3P-MACE EXAMINE 3 (n=5380) 621 3P-MACE ORIGIN 6 (n=12,537) 3P-MACE TECOS 5 (n=14,671) 1300 4P-MACE AleCardio 7 (n=7226) 3P-MACE DEVOTE 10 (n=7637) 3P-MACE CARMELINA 15 (n=8300) 4P-MACE + renal TOSCA IT25 (n=3371) 4P-MACE CAROLINA 16 (n=6041) 631 4P-MACE OMNEON 17 (n=4000) 4P-MACE 2013 2014 2015 2016 2017 2018 2019 2020 DPP-4 inhibitor SGLT-2 inhibitor GLP1 RA Insulin PPAR agonist TZD ELIXA 4 (n=6068) 805 4P-MACE EMPA-REG OUTCOME 8 (n=7028) 691 3P-MACE LEADER 9 (n=9341) 611 3P-MACE SUSTAIN-6 11 (n=3297) 3P-MACE FREEDOM CVO 13 (n=4000) 4P-MACE CANVAS-R 12 (n=5820) Albuminuria EXSCEL 18 (n=14,000) 1591 3P-MACE CANVAS 14 (n=4339) 420 3P-MACE TIMINGS REPRESENT ESTIMATED COMPLETION DATES AS PER CLINICALTRIALS.GOV STELLA-LONG TERM 22 (n=11,412) 3P-MACE + Tumors HARMONY Outcomes 24 (n=9400) 3P-MACE REWIND 20 (n=9622) 1067 3P-MACE CREDENCE 21 (n=4200) Renal + 5P-MACE 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 DECLARE-TIMI 58 19 (n=17,150) 1390 3P-MACE Ertugliflozin CVOT 23 (n=3900) 3P-MACE
COMPARISON OF AVAILABLE GLP-1 RA Drug Weight loss A1c lowering Cardiovascular benefits Exenatide (Byetta) + + - ++ Exenatide ER (Bydureon, Bcise) + +++ (-0.9-1.9%) + (HR-0.91) + Liraglutide (Victoza) + ++(-0.8-1.5%) ++ (HR= 0.87) ++ Dulaglutide (Trulicity) Lixisenatide (Adlyxin) Semaglutide (Ozempic) + ++(-0.59-1.51%) Ongoing trial ++ + ++(1.1%-combo) - (HR=1.02) + ++ ++(-1.4-1.6%) ++ (HR=0.74) + GI side effects
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) MEDICATIONS: 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 LABS: BG 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 METFORMIN, 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???