PKPD Injectable Agents

Where do GLP-1 receptor agonists work?

liver, brain, pancreas, heart, muscle, and stomach

What do GLP-1s do in the liver?

decrease glucose production

What do GLP-1s do in the brain?

promotes satiety and reduces food intake

What do GLP-1s do in the pancreas?

increase beta cell function and insulin biosynthesis; decrease beta cell apoptosis ad glucagon secretion

What do GLP-1s do in the heart?

increase cardiac function, decrease CV risk, fatty acid metabolism, systolic blood pressure, inflammation, and plaque progression

What do GLP-1s do in the stomach?

decrease gastric emptying

What products are GLP-1 receptor agonists?

exenatide, liraglutide, dulaglutide, semaglutide, lixisenatide

What is the brand name of exenatide?

Byetta (IR), Bydureon (ER; D/C), Bydueron BCise (ER)

What is the brand name of liraglutide?

Victoza

What is the brand name of dulaglutide?

Trulicity

What is the brand name of the semaglutide?

Ozempic (SQ), Rybelsus (oral)

What is the brand name of lixisenatide?

Adlyxin (D/C)

What is the brand name of insulin degludec + liraglutide?

Xultphy

What is the brand name of insulin glargine + lixisenatide?

Soliqua

What is the key MOA of GLP-1s?

slows gastric emptying and promotes beta cell proliferationT

True or False: unlike sulfonylureas, GLP-1s only work in the presence of hyperglycemia, so there is less hypoglycemia risk

true

What is the dosing of Byetta (exenatide IR)?

5 mcg SQ BID, titrate to 10 mcg BID after 1 month

What is the formulation of Byetta (exenatide IR)?

pre-filled, multi-dose pens; either 5 mcg/dose or 10 mcg/dose

What is the dosing of Bydureon (exenatide ER)?

2 mg SC weekly (no titration needed)

What is the formulation of Bydureon (exenatide ER)?

pre-filled, single use pen that must be mixed prior to use

What is the dosing of Bydureon BCise (exenatide ER)?

2 mg SC weekly (no titration needed)

What is the formulation of Bydureon BCise (exenatide ER)?

pre-filled, single use pen; auto-injector

What are the key counseling points for Byetta?

give BID 30-60 mins before eating; need separate Rx for needles

What are the key counseling points for Bydureon?

must be reconstituted prior to use; given weekly without regard to meals; needles provided in box

What are the key counseling points for Bydureon BCise?

auto-injector given weekly without regard to meals; needle is in device

What do you do is you miss a dose of a weekly injection?

give within 72 hours then resume normal dosing; if more than 72 hours the day given will be the new weekly day

What do you do if you miss more than 3 weeks of weekly injections?

you will need to re-start dose titration; it does not have to be the LOWEST dose but at least lower than it was

What was added to liraglutide to make it last all day?

C-16 fatty acid chain

What is the dosing of liraglutide?

0.6 mg SQ daily, then titrate to 1.2mg SQ daily after 7 days; can further titrate to 1.8 mg SQ daily

What is the formulation of liraglutide?

pre-filled, multi-dose pens: all doses available in the same pen

What are the key counseling points of liraglutide?

given once daily without regard to meals, need Rx for needles, requires titration, reusable pen

What was added to dulaglutide to make it last a week?

IgG4 Fc + spacer

What is the dosing of dulaglutide?

starting 0.75 mg once weekly, then titrate to 1.5 mg once weekly after 4 weeks; can increase to 3 mg and 4.5 mg Q4wks

What is the formulation of dulaglutide?

pre-filled, single use pen

0.75 mg → yellow

1.5 mg → blue

3 mg → gray

4.5 mg → green

What are the key counseling points of dulaglutide?

given weekly without regard to meals; needle is self-contained in device; discard entire pen after each dose; requires titration

What was added to semaglutide (SC) to allow it to be long acting?

spacer and C18 fatty di-acid chain

What is the dosing for SQ semaglutide?

0.25 mg weekly x 4 weeks then 0.5 mg x 2-4 weeks; then up to 1 mg weekly for at least 4 weeks, then up to 2 mg weekly as needed

What is the formulation for SQ semaglutide?

pre-filled, multiple use pen

0.25, 0.5 mg / dose → 2mg/3mL pen

1 mg/dose → 4mg/3mL pen

2 mg/dose → 8mg/3mL pen

What are the key counseling points of SQ semaglutide?

given once weekly without regard to meals, needle given with device, reusable pen, requires titration, can microdose

What does PO semaglutide have to enable oral administration?

SNAC (a small fatty-acid derivative)

What is the dosing of PO semaglutide?

3 mg PO daily x 30 days; then 7 mg daily; then 14 mg daily

What is the formulation of PO semaglutide?

3 mg, 7 mg, 14 mg (R2: 1.5 mg, 4 mg, 9 mg)

What are the key counseling points of PO semaglutide?

taken orally, once a day with 4 oz of water, then eat 30 minutes later

What happens if a patient on PO semaglutide eats before the 30 minute time is up?

decreased drug efficacy

What happens if a patient on PO semaglutide eats after the 30 minute time passes?

increased side effects

What special considerations does Byetta have?

do not use if CrCl < 30 mL/min

What special considerations does semaglutide PO have?

3 mg dose does not affect blood glucoses; take 30 minutes BEFORE eating first meal of the day

What special considerations does Bydureon have?

do not use if CrCl < 30 mL/min

What special considerations does Bydureon BCise have?

do not use if CrCl < 30 mL/min

True or False: dulaglutide requires renal dosing adjustment

false

True or False: semaglutide does not require renal adjustment

true

What are the side effects of GLP-1 receptor agonists?

GI: N/V/D, GERD, dyspepsia, bowel obstruction; depression, suicidal ideation, URI/cough, pancreatitis, gallbladder disease, cholelithiasis, retinopathy

True or False: semaglutide (PO and SQ) is 99% albumin bound

true

What medications in combination with GLP-1s can cause hypoglycemia?

androgens, insulins/SU, pegvisomant

What medications in combination with GLP-1s can cause hyperglycemia?

corticosteroids, thiazide diuretics, danazol, LHRH, somatropin

What is the BBW for GLP-1s?

thyroid C-cell tumors (MTC or MEN2)

What GLP-1 does NOT have a BBW for thyroid C-cell tumor?

lixisenatide

What are the contraindications of GLP-1s?

MTC, MEN2, Renal impairment (ESRD or CrCl < 30 mL/min for exenatide)

What are precautions for GLP-1s?

severe GI diseases, pancreatitis, depression/suicidal ideation

What should be monitored for GLP-1s?

renal function (for exenatide), FBG/PPG, GI symptoms, patient use of device (has to be fully against the skin)

What is the time to peak effect for GLP-1s?

6-8 weeks (depending on the titration schedule)

What are key counseling points for GLP-1s?

may cause upset stomach (should decrease over time) so don’t overeat, avoid larger meals, eat smaller meals more frequently; prior to initial use store in fridge; after initial use can be stored at room temperature

Which medication is a GIP + GLP-1 receptor agonist?

tirzepatide

What is the brand name of tirzepatide?

Mounjaro

What is the MOA of tirzepatide?

increases glucose dependent insulin, decreases inappropriate glucagon secretion, slows gastric emptying

What is the dosing of tirzepatide?

initially 2.5 mg once weekly x 4 weeks; then increase to 5 mg once weekly x 4 weeks; continue to increase by 2.5 mg increments every 4 weeks

What is the formulation of tirzepatide?

pre-filled, single use pens

What are the side effects of GIP + GLP-1?

GI: constipation, N/V/D; sinus tachycardia, injection site rxn, alopecia, cholelithiasis, pancreatitis, gallbladder disease, retinopathy, depression/suicidal ideations, bowel obstruction

What drugs when used in combination with a GIP + GLP-1s can cause hypoglycemia?

androgens, beta-blockers, insulins/SU, quinolones

What drugs when used in combination with a GIP + GLP-1s can cause hyperglycemia?

beta-blockers, quinolones, thiazide diuretics

True or False: tirzepatide may decrease OC effectiveness when starting or increasing a dose

true

True or False: tirzepatide requires renal adjustments

false

What needs to be monitored for a GIP + GLP-1?

FBG,PPG, GI symptoms, patient use of device

Which products have an FDA indication for weight management?

liraglutide, semaglutide (SQ), tirzepatide

True or False: GLP-1s that are FDA indicated for weight management have a different brand name than the products used for other indications

true

Which medication is an amylin analog?

pramlintide

What is the brand name of pramlintide?

Symlin

What is the MOA of pramlintide?

amylin works in concert with insulin to regulate post-prandial hyperglycemia; slows gastric emptying, suppression of post-prandial glucagon secretion, centrally mediated modulation of appetite

What is amylin?

a hormone co-secreted with insulin from pancreatic bet cells

True or False: amylin production is absent in T1DM

true

What is the indication for pramlintide?

DM; adjuvant treatment for those who use mealtime insulin and whose glycemic targets have not been met

What is the dosing of pramlintide for T1DM?

start at 15 micrograms SQ immediately prior to each meal; target dose is 60 micrograms

What is the dosing of pramlintide for T2DM?

start at 60 micrograms SQ immediately prior to each meal; target dose is 120 micrograms

When is pramlintide dosed in reference to insulin?

dosed with insulin at the same time

What are the side effects of pramlintide?

hypoglycemia (severe), nausea, headache, vomiting, fatigue, arthralgia

What drug interactions does pramlintide have?

potassium salts (delayed absorption) and anticholinergics (additive effect)

What BBW does pramlintide have?

but be co-administered with insulin

What contraindications does pramlintide have?

hypoglycemia unawareness, gastroparesis, hypersensitivity

When should pramlintide be used with caution?

bariatric surgery, condition or medications that impair gastric motility, other IR medications, A1C > 9%, non-compliant patients

What is pramlintide’s effect on A1C?

it does NOT lower; used primarily to decrease insulin requirements

What should be monitored when on pramlintide?

PPG, GI intolerance, injection technique

What are the key counseling points of pramlintide?

hypoglycemia symptoms, should not be mixed with insulin, if you skip a meal skip the injection, can keep in fridge or room temperature, discard after 28 days once open