Block 1 Lecture 5 -- Incretins, DPP4-I, etc. Flashcards
What is an incretin?
a hormone released from the intestines acting on beta cells
What are the 2 incretins
GIP, GLP1
GIP
glucose-dependent insulinotropic polypeptide
GLP-1
glucagon-like peptide-1
What are ADRs of GLP-1 receptor agonists?
1) n/v (decreases with time)
2) weight loss (can be desired)
What are C/I’s for GLP-1 receptor agonists?
f/h of thyroid cancer
Describe the structure of GLP-1.
peptide from preproglucagon precursor
half-life of GLP-1?
5 minutes
How is GLP-1 metabolized?
inactivated by DPP-4
What is DPP-4?
Dipeptidyl peptidase IV
What are the GLP-1 based therapies?
1) Exenatide (Byetta)
2) Liraglutaide (Victoza)
3) Albiglutide (Tanzeum)
4) Dulaglutide (Trulicity)
Describe the structure of Exenatide.
peptide from salivary gland of gila monster with 53% homology (more potent, not metabolized by DPP-4)
Describe the structure of Liraglutide.
97% homology to GLP-1 (more potent).
- AA subs + FA group
- avoids DPP-4
- binds albumin SubQ
Describe the structure of Albiglutide.
recombinant GLP-1 dimer fused to albumin
– AA subs to avoid DPP-4
Describe the structure of Dulaglutide.
2 disulfide-linked recombinant GLP-1 analogs fused to human Ig
– AA subs to avoid DPP-4
When are GLP-1 receptor agonists used?
for T2DM…
1) as add-on therapy with metformin, sulfonylurea, TZD
2) as monotherapy after tx failure – not first line after diet/exercise
Other important notes for Exenatide:
- 6-12% of pts develop Abs
- - C/I if ClCr less than 30
How is exenatide supplied?
1) IR: bid before meals
2) ER microsphere: q week
What is the half-life of IR exenatide?
3 hours
What is the half-life of ER exenatide?
2 weeks
How is liraglutide supplied?
only 1: subq once daily without regard to meals
What is the only incretin analog without thyroid tumor risk?
IR exenatide
What is the half-life of albiglutide’s formulation?
5 days
How is albiglutide supplied?
only 1: subq q week
– drug powder + diluent are separate
Other important considerations for albiglutide:
1) wait 5-10 mins after mixing powder + diluent
2) anti-drug Ab response in rodents avoided determining thyroid tumor potential
How is dulaglutide supplied?
only 1 – 1 dose q week
What is the half-life of dulaglutide’s formulation?
5 days
What DPP-4 inhibitors are on the market?
1) Sitagliptin (januvia)
2) saxagliptin (onglyza)
3) alogliptin (Nesina)
4) linagliptin (tradjenta)
What is DPP-4?
a protease on the surface of endothelial cells and circulating in blood that inactivates GLP-1 and GIP
What is alpha-glucosidase?
GI enzyme that breaks down…
- complex starches
- oligosaccharides
- disaccharides
What alpha-glucosidase inhibitors are on the market?
1) acarbose (Precose)
2) miglitol (Glyset)
What is the MoA of alpha-glucosidase inhibitors?
1) inhibits sucrose –> glucose + fructose
2) delays monosaccharide absorption from small intestine to blunt rise in postprandial glucose
What are the ADRs of alpha-glucosidase inhibitors?
flatulence, cramping, diarrhea
How to treat a hypoglycemic patient as a result of combo therapy with acarbose?
GIVE GLUCOSE=DEXTROSE (not sucrose)
Describe ADME for acarbose.
not absorbed
How is miglitol different from acarbose in terms of PK?
1) miglitol is absorbed
2) miglitol is excreted by the kidneys
- - reduce in severe renal failure
How are alpha-glucosidase inhibitors adminstered?
orally before meals
titrate dose to balance glucose with ADRs
When are alpha-glucosidase inhibitors used?
often in recently-diagnosed pts with mild hyperglycemia
- monotherapy
- in combo with sulfonylureas
What is amylin?
a peptide produced in beta cells that is secreted with insulin
What is another name for amylin?
amyloid polypeptide
What are the amylin analogs on the market?
Pramlintide (SymlinPen)
Describe the structure of Pramlintide.
synthetic amylin analog with AA modifications
- increases SubQF
- prevents aggregation
What are the effects of amylin/amylin analogs?
bind amylin receptors in brain to…
1) decrease glucagon release
2) delay gastric emptying
3) increase satiety
When is Pramlintide used?
for T1/T2DM injected immediately before eating as adjunct to insulin
What should you do if an insulin-treated diabetic as also started on pramlintide?
reduce prandial insulin dose by 50% and re-titrate
What is bromocriptine?
a semi-synthetic ergot alkaloid derivative that acts in the brain as a DA receptor agonist
How does bromocriptine treat hyperglycemia?
not known…
1) may increase DA signaling to decrease cortisol and SNS outflow
2) may reset circadian rhythms altered by obesity
For what diseases is bromocriptine usually used?
parkinsons
What are the available SGLT2 inhibitors?
canagliflozin (Invokana)
dapagliflozin (Farxiga)
empagliflozin (Jardiance)
What is SGLT2?
Sodium-Glucose Co-Transporter 2
– main site of filtered glucose reabsorption in the kidney
What is the MoA for SGLT2 inhibitors?
inhibiting SGLT increases urinary glucose excretion to reduce plasma [glucose]
When should SGLT2 inhibitors be avoided?
severe renal impairment
they have reduced efficacy
What is a major ADR of SGLT2 inhibitors?
UTIs
How are DPP-4 inhibitors administered?
once daily without regard to meals
What are ADRs of DPP-4 inhibitors?
they are rare…
– major advantage over GLP-1 receptor agonists
What is the MoA of DPP-4 inhibitors?
increase [GIP] and [GLP-1]
- increase insulin secretion
- decrease [glucagon]
- improve fasting and postprandial hyperglycemia
What are disadvantages of DPP-4 inhibitors compared to GLP-1 receptor agonists?
1) less effective at insulin production, first-phase response, and glucagon output
2) no effect on satiety, body weight, gastric emptying
With what drugs do DPP-4 inhibitors have additive effects?
1) metformin
2) TZDs
3) sulfonylureas
4) insulin
With what drugs are DPP-4 inhibitors combined?
1) metformin
2) pioglitazone
Why is GIP not a good drug candidate?
- it increases glucagon release
- - no glucose lowering activity although it is minorly insulinotropic
How are incretins secreted?
from gut in response to quantity of nutrients ingested
What is the function of incretins?
mediate stimulation of insulin secretion
- gets it going before peak [glucose]
- needs basal [glucose] for stimulation
Why don’t GLP-1 receptor agonists cause hypoglycemia?
incretins require at least a 70mg/dL basal level of insulin for stimulation
What are the effects of GLP-1?
1) glucose-dependent insulinotrophy
2) beta-cell proliferation
3) inhibits of glucagon secretion if high [glucose]
4) inhibits gastric motility
5) promotes satiety
What is the purpose of reducing gastric motility?
reducing postprandial glucose spike
How does GLP-1 promote satiety?
hits some receptors in the brain
What should be done if pt started incretin analog in addition to sulfonylurea therapy?
need lower dose of sulfonylureas
How do GLP-1 and GIP have effects on the beta cell?
own beta-cell receptor
- activates adenylyl cyclase to increase cAMP
- activates PKA
- PKA amplifies Ca-mediated secretion
What is the main MoA for GLP-1’s insulinotropic effects?
1) transcription of proinsulin gene for increased insulin synthesis
2) stimulation of secretion (GPCR)
What is the basis for GLP-1 receptor agonists’ black box warning?
ER forms caused thyroid tumors in rats/mice, although no human evidence
What are the restrictions on GLP-1 receptor agonists?
REMS
