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PHS 933 > Block 1 Lecture 5 -- Incretins, DPP4-I, etc. > Flashcards

Block 1 Lecture 5 -- Incretins, DPP4-I, etc. Flashcards

1
Q

What is an incretin?

A

a hormone released from the intestines acting on beta cells

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2
Q

What are the 2 incretins

A

GIP, GLP1

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3
Q

GIP

A

glucose-dependent insulinotropic polypeptide

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4
Q

GLP-1

A

glucagon-like peptide-1

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5
Q

What are ADRs of GLP-1 receptor agonists?

A

1) n/v (decreases with time)

2) weight loss (can be desired)

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6
Q

What are C/I’s for GLP-1 receptor agonists?

A

f/h of thyroid cancer

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7
Q

Describe the structure of GLP-1.

A

peptide from preproglucagon precursor

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8
Q

half-life of GLP-1?

A

5 minutes

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9
Q

How is GLP-1 metabolized?

A

inactivated by DPP-4

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10
Q

What is DPP-4?

A

Dipeptidyl peptidase IV

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11
Q

What are the GLP-1 based therapies?

A

1) Exenatide (Byetta)
2) Liraglutaide (Victoza)
3) Albiglutide (Tanzeum)
4) Dulaglutide (Trulicity)

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12
Q

Describe the structure of Exenatide.

A

peptide from salivary gland of gila monster with 53% homology (more potent, not metabolized by DPP-4)

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13
Q

Describe the structure of Liraglutide.

A

97% homology to GLP-1 (more potent).

    • AA subs + FA group
    • avoids DPP-4
    • binds albumin SubQ
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14
Q

Describe the structure of Albiglutide.

A

recombinant GLP-1 dimer fused to albumin

– AA subs to avoid DPP-4

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15
Q

Describe the structure of Dulaglutide.

A

2 disulfide-linked recombinant GLP-1 analogs fused to human Ig
– AA subs to avoid DPP-4

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16
Q

When are GLP-1 receptor agonists used?

A

for T2DM…

1) as add-on therapy with metformin, sulfonylurea, TZD
2) as monotherapy after tx failure – not first line after diet/exercise

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17
Q

Other important notes for Exenatide:

A
    • 6-12% of pts develop Abs

- - C/I if ClCr less than 30

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18
Q

How is exenatide supplied?

A

1) IR: bid before meals

2) ER microsphere: q week

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19
Q

What is the half-life of IR exenatide?

A

3 hours

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20
Q

What is the half-life of ER exenatide?

A

2 weeks

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21
Q

How is liraglutide supplied?

A

only 1: subq once daily without regard to meals

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22
Q

What is the only incretin analog without thyroid tumor risk?

A

IR exenatide

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23
Q

What is the half-life of albiglutide’s formulation?

A

5 days

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24
Q

How is albiglutide supplied?

A

only 1: subq q week

– drug powder + diluent are separate

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25
Q

Other important considerations for albiglutide:

A

1) wait 5-10 mins after mixing powder + diluent

2) anti-drug Ab response in rodents avoided determining thyroid tumor potential

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26
Q

How is dulaglutide supplied?

A

only 1 – 1 dose q week

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27
Q

What is the half-life of dulaglutide’s formulation?

A

5 days

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28
Q

What DPP-4 inhibitors are on the market?

A

1) Sitagliptin (januvia)
2) saxagliptin (onglyza)
3) alogliptin (Nesina)
4) linagliptin (tradjenta)

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29
Q

What is DPP-4?

A

a protease on the surface of endothelial cells and circulating in blood that inactivates GLP-1 and GIP

30
Q

What is alpha-glucosidase?

A

GI enzyme that breaks down…

    • complex starches
    • oligosaccharides
    • disaccharides
31
Q

What alpha-glucosidase inhibitors are on the market?

A

1) acarbose (Precose)

2) miglitol (Glyset)

32
Q

What is the MoA of alpha-glucosidase inhibitors?

A

1) inhibits sucrose –> glucose + fructose

2) delays monosaccharide absorption from small intestine to blunt rise in postprandial glucose

33
Q

What are the ADRs of alpha-glucosidase inhibitors?

A

flatulence, cramping, diarrhea

34
Q

How to treat a hypoglycemic patient as a result of combo therapy with acarbose?

A

GIVE GLUCOSE=DEXTROSE (not sucrose)

35
Q

Describe ADME for acarbose.

A

not absorbed

36
Q

How is miglitol different from acarbose in terms of PK?

A

1) miglitol is absorbed
2) miglitol is excreted by the kidneys
- - reduce in severe renal failure

37
Q

How are alpha-glucosidase inhibitors adminstered?

A

orally before meals

titrate dose to balance glucose with ADRs

38
Q

When are alpha-glucosidase inhibitors used?

A

often in recently-diagnosed pts with mild hyperglycemia

    • monotherapy
    • in combo with sulfonylureas
39
Q

What is amylin?

A

a peptide produced in beta cells that is secreted with insulin

40
Q

What is another name for amylin?

A

amyloid polypeptide

41
Q

What are the amylin analogs on the market?

A

Pramlintide (SymlinPen)

42
Q

Describe the structure of Pramlintide.

A

synthetic amylin analog with AA modifications

    • increases SubQF
    • prevents aggregation
43
Q

What are the effects of amylin/amylin analogs?

A

bind amylin receptors in brain to…

1) decrease glucagon release
2) delay gastric emptying
3) increase satiety

44
Q

When is Pramlintide used?

A

for T1/T2DM injected immediately before eating as adjunct to insulin

45
Q

What should you do if an insulin-treated diabetic as also started on pramlintide?

A

reduce prandial insulin dose by 50% and re-titrate

46
Q

What is bromocriptine?

A

a semi-synthetic ergot alkaloid derivative that acts in the brain as a DA receptor agonist

47
Q

How does bromocriptine treat hyperglycemia?

A

not known…

1) may increase DA signaling to decrease cortisol and SNS outflow
2) may reset circadian rhythms altered by obesity

48
Q

For what diseases is bromocriptine usually used?

A

parkinsons

49
Q

What are the available SGLT2 inhibitors?

A

canagliflozin (Invokana)
dapagliflozin (Farxiga)
empagliflozin (Jardiance)

50
Q

What is SGLT2?

A

Sodium-Glucose Co-Transporter 2

– main site of filtered glucose reabsorption in the kidney

51
Q

What is the MoA for SGLT2 inhibitors?

A

inhibiting SGLT increases urinary glucose excretion to reduce plasma [glucose]

52
Q

When should SGLT2 inhibitors be avoided?

A

severe renal impairment

they have reduced efficacy

53
Q

What is a major ADR of SGLT2 inhibitors?

A

UTIs

54
Q

How are DPP-4 inhibitors administered?

A

once daily without regard to meals

55
Q

What are ADRs of DPP-4 inhibitors?

A

they are rare…

– major advantage over GLP-1 receptor agonists

56
Q

What is the MoA of DPP-4 inhibitors?

A

increase [GIP] and [GLP-1]

    • increase insulin secretion
    • decrease [glucagon]
    • improve fasting and postprandial hyperglycemia
57
Q

What are disadvantages of DPP-4 inhibitors compared to GLP-1 receptor agonists?

A

1) less effective at insulin production, first-phase response, and glucagon output
2) no effect on satiety, body weight, gastric emptying

58
Q

With what drugs do DPP-4 inhibitors have additive effects?

A

1) metformin
2) TZDs
3) sulfonylureas
4) insulin

59
Q

With what drugs are DPP-4 inhibitors combined?

A

1) metformin

2) pioglitazone

60
Q

Why is GIP not a good drug candidate?

A
    • it increases glucagon release

- - no glucose lowering activity although it is minorly insulinotropic

61
Q

How are incretins secreted?

A

from gut in response to quantity of nutrients ingested

62
Q

What is the function of incretins?

A

mediate stimulation of insulin secretion

    • gets it going before peak [glucose]
    • needs basal [glucose] for stimulation
63
Q

Why don’t GLP-1 receptor agonists cause hypoglycemia?

A

incretins require at least a 70mg/dL basal level of insulin for stimulation

64
Q

What are the effects of GLP-1?

A

1) glucose-dependent insulinotrophy
2) beta-cell proliferation
3) inhibits of glucagon secretion if high [glucose]
4) inhibits gastric motility
5) promotes satiety

65
Q

What is the purpose of reducing gastric motility?

A

reducing postprandial glucose spike

66
Q

How does GLP-1 promote satiety?

A

hits some receptors in the brain

67
Q

What should be done if pt started incretin analog in addition to sulfonylurea therapy?

A

need lower dose of sulfonylureas

68
Q

How do GLP-1 and GIP have effects on the beta cell?

A

own beta-cell receptor

    • activates adenylyl cyclase to increase cAMP
    • activates PKA
    • PKA amplifies Ca-mediated secretion
69
Q

What is the main MoA for GLP-1’s insulinotropic effects?

A

1) transcription of proinsulin gene for increased insulin synthesis
2) stimulation of secretion (GPCR)

70
Q

What is the basis for GLP-1 receptor agonists’ black box warning?

A

ER forms caused thyroid tumors in rats/mice, although no human evidence

71
Q

What are the restrictions on GLP-1 receptor agonists?

A

REMS

PHS 933 (14 decks)

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