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PHAR152 > Diabetes 4 > Flashcards

Diabetes 4 Flashcards

1
Q

What is the MOA of metformin?

A

not fully understood but:
-decreases hepatic glucose production
-can enhance insulin sensitivity
-increases glucose utilization via action in the gut
-has effects on the gut microbiome which may explain some anti-inflammatory effects

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2
Q

How is metformin dosed?

A

start slow: initiate at 250-500mg OD
titrate up by 500mg weekly if no GI side effects
desired usual dose: 850-1000mg BID

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3
Q

What is the max dose of metformin?

A

850mg TID (2500mg)

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4
Q

What is the name of the XR version of metformin? How is it dosed?

A

Glumetza
OD or BID

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5
Q

What is something patients should be made aware of with Glumetza?

A

ghost shells

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6
Q

Describe the efficacy of metformin.

A

decreases A1C by 1-1.5% (up to 2% in drug naive with A1C of 9%)
decreases TG and LDL 8-15%
increases HDL by 2%
decreased MI and mortality in T2 patients with obesity

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7
Q

What are some drug interactions with metformin?

A

cimetidine (competes for renal tubular secretion)
-increases metformin levels by 60%
dolutegravir (increases metformin concentration)
alcohol (potentiates metformin’s effect on lactate metabolism)
-enhanced hypoglycemic effect
contrast media
-hold for 48hrs after imaging

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8
Q

What are the adverse effects of metformin?

A

common: GI (up to 30%, about 5% will d/c)
-DIARRHEA, nausea, abdominal discomfort
less common:
-metallic taste: only lasts a few weeks
-B12 deficiency: long term use (>5yrs)

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9
Q

What kind of impact does metformin have on hypoglycemia? What about weight gain?

A

very low risk of hypoglycemia as monotherapy
-increased with alcohol, not eating, SU
weight neutral to modest weight loss (~1kg)

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10
Q

If the GI side effects of metformin are bothersome what can be done?

A

take with food or try XR

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11
Q

What are some precautions with metformin?

A

lactic acidosis: decreased arterial pH and accumulation of lactate
-weakness, malaise, myalgias, laboured breathing
-metformin inhibits conversion of lactate into glucose in liver
-more of a concern with reduced eGFR
-rare and actual association is debated
renal impairment: decreased dose if ClCr <60ml/min

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12
Q

What is a scenario where the dose of metformin is reduced? Why?

A

impaired renal function
metformin is renally excreted, risk of lactate accumulation

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13
Q

Describe the dosing of metformin in renal impairment.

A

eGFR 45-59: 1500mg/d (divided doses)
eGFR 30-44: 1000mg/d (divided doses) check q3months
CI when eGFR <30ml/min

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14
Q

What are risk factors for lactic acidosis?

A

history of lactic acidosis
severe liver disease
alcohol abuse
radiologic problems
acute illness (severe infection, trauma)
severe dehydration

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15
Q

What is the MOA of sulfonylureas?

A

enhance secretion of insulin by binding to SU receptors on B cells of pancreas
-leads to closing of K+ channels and opening of Ca2+ channels
which stimulates insulin secretion
-they stimulate both basal and meal-stimulated insulin release

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16
Q

What are some sulfonylureas?

A

glyburide
gliclazide
glimepiride

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17
Q

What is the dosing of glyburide?

A

5-20mg/d (OD or BID)
usual dose is 5mg BID; may increase to 10mg BID

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18
Q

What is a CI of glyburide?

A

eGFR < 60ml/min

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19
Q

What is the dosing of gliclazide?

A

gliclazide: 80-160mg (80mg OD or 80mg BID)
gliclazide MR: 30-120mg OD

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20
Q

What is a caution of gliclazide? What about a CI?

A

caution in eGFR 30-60ml/min
CI in eGFR < 30 ml/min

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21
Q

What is something that can appear in the stool of a patient on gliclazide MR?

A

ghost shells

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22
Q

What is the dosing of glimepiride?

A

1-8mg/d

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23
Q

What is a caution of glimepiride? What about a CI?

A

caution in eGFR 30-60ml/min
CI in eGFR < 30ml/min

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24
Q

Which sulfonylureas are on the formulary?

A

gliclazide MR and glyburide
regular release gliclazide and glimepiride are not

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25
Q

How are sulfonylureas best taken?

A

with food and in the AM

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26
Q

Describe the efficacy of sulfonylureas.

A

decrease A1C 1-1.5% (up to 2% in drug naive and elevated A1C)
work quickly: can start titrating dose after 2wks based on fasting BG, then can titrate q1-2 weeks
bang for buck at lower doses (effective at 1/2 max dose and max effective dose is 60-75% of max dose)
better response if initiated early in diagnosis
must adjust in renal impairment

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27
Q

What is the effect of sulfonylureas on CV outcomes?

A

neutral CV outcomes

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28
Q

What is the effect of sulfonylureas on CV outcomes?

A

neutral CV outcomes

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29
Q

What are side effects of sulfonylureas?

A

hypoglycemia (2-30%)
-glyburide>glimepiride>gliclazide
-glyburide on BEERS list (avoid in elderly)
weight gain (~2kg)
less frequent: nausea, rash, photosensitivity
cross-sensitivity with sulfa allergy is rare

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30
Q

What are precautions/contraindications of sulfonylureas?

A

pregnancy/breast-feeding (all cross placenta except glyburide)
CI in severe hepatic and renal impairment
hold in acute illness

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31
Q

How are sulfonylureas metabolized?

A

metabolized in liver
excreted in kidney

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32
Q

How are sulfonylureas handled in the elderly?

A

initiate at half normal dose and titrate up

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33
Q

What are drug interactions of sulfonylureas?

A

increased risk of hypoglycemia:
-sulfonamides, salicylates, warfarin
-alcohol
-cimetidine, clarithromycin, fluconazole, NSAIDs, BB, MAOIs
increased blood sugar:
-phenytoin
-rifampin
-colesevelam (separate by 4hrs)
-bosentan

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34
Q

What is the MOA of repaglinide?

A

binds to a site adjacent to the SU receptor, resulting in stimulation of the secretion of insulin from the pancreas
-similar to SUs but faster onset and shorter D of A
-peak levels within 1hr and half-life is 1hr

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35
Q

Describe the efficacy of repaglinide.

A

decreases A1C 1-1.5%
works primarily to decrease PPG: it is intended to be taken before meals to improve early phase meal-induced insulin secretion

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36
Q

Describe the dosing of repaglinide.

A

A1C<8%: initiate at 0.5mg before each meal + titrate up
A1C>8%: initiate at 1-2mg before each meal + titrate up
max dose: 4mg before each meal (max dose 16mg/d)
start at a low dose and titrate up q1-2 weeks until target BG achieved

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37
Q

How should repaglinide be administered?

A

right before a meal (within 30 minutes) due to short D of A
-skip a meal, skip a dose
-add a meal, add a dose

38
Q

What is the eGFR that requires caution with repaglinide?

A

<30ml/min

39
Q

What are the adverse effects of repaglinide?

A

hypoglycemia (more so when combined with other agents)
weight gain (~0.3-1kg)
similar to SUs but to a lesser extent

40
Q

How is repaglinide metabolized? What is a precaution and CI?

A

in the liver by CYP 450
precaution with moderate hepatic impairment
CI with severe liver disease

41
Q

What are drug interactions of repaglinide?

A

increased repaglinide with:
-3A4 inhibitors (cyclosporine, clarithromycin, grapefruit, azoles)
-2C8 (gemfibrozil, clopidogrel; these are CI)
decreased repaglinide with 3A4 inducers (carbamazepine, rifampin)

42
Q

What is the MOA of acarbose?

A

inhibits a-glucosidase enzymes in the small intestine
-these enzymes breakdown polysaccharides into absorbable
glucose
results in delay in rate of digestion of CHO and glucose absorption
net effect is reduction in PPG levels

43
Q

Describe the efficacy of acarbose.

A

decreases A1C 0.5-0.8%
does not affect body weight or lipids

44
Q

What is the dosing of acarbose?

A

initial 25-50mg OD, titrate up every couple of weeks to 50mg TID
assess for efficacy q4-8wks to a max dose of 100mg TID
take with the first bite of each meal

45
Q

What are the adverse effects of acarbose?

A

GI
-flatulence (40-80%)
-diarrhea (30%)
may elevate ALT: monitor LFTs first 6-12 months
hypoglycemia: only negligible risk
weight neutral

46
Q

How should hypoglycemia be treated for a patient on acarbose?

A

glucose
digestion of sucrose is impaired by acarbose

47
Q

What are drug interactions with acarbose?

A

digestive enzyme preparations
may decrease digoxin effect

48
Q

What are cautions and CI of acarbose?

A

caution: GI conditions or IBD
CI: eGFR <25ml/min and severe liver disease

49
Q

What are the thiazolidinediones?

A

rosiglitazone
pioglitazone

50
Q

What is the MOA of thiazolidinediones?

A

bind to PPAR receptors which are primarily found in adipose tissue, activation alters genes that influence glucose and lipid metabolism
enhance insulin sensitivity at muscle, liver, and fat tissues
-they decrease insulin resistance
decrease hepatic glucose production
convert LDL particles to fluffy LDL that is less dense and less atherogenic

51
Q

Describe the efficacy of thiazolidinediones.

A

decrease A1C 1-1.5%
effect on TGs: PIO decreases by 10-20%, ROSI is neutral
effects on LDL: ROSI increases LDL 5-15%, PIO is neutral
effects on HDL: both may increase HDL to some degree

52
Q

Describe the dosing of the thiazolidinediones.

A

rosi: initiate at 2-4mg OD; may increase to 4mg BID or 8mg OD
pio: initiate at 15mg OD; titrate up 30-45mg OD
have a delayed onset: wait 4-8wks for dose adjustments (max effect 3mo)
larger people require a larger dose

53
Q

What are cautions and CI of the thiazolidinediones?

A

caution in eGFR <60ml/min (no dose adjustment required)
mainly metabolized by liver:
-caution in severe liver disease

54
Q

What is the EDS criteria of the thiazolidinediones?

A

must have tried a SU and metformin first

55
Q

What are drug interactions of thiazolidinediones?

A

metabolized by CYP 2C8
-increased effects with inhibitors (gemfibrozil, TMP)
-decreased effects with inducers (rifampicin)

56
Q

What are the adverse effects of thiazolidinediones?

A

peripheral edema (~5%); combined with insulin (~15%)
new onset/worsening of HF
weight gain (2.5-4.8kg; dose related)
increased distal fractures in postmenopausal women
rare:
-macular edema
-anemia
-pio: possible increased bladder cancer risk
-rosi: possible increased MI risk

57
Q

What is a CI of the thiazolidinediones?

A

heart failure

58
Q

True or false: rosiglitazone has restricted access and informed consent is required

A

true

59
Q

What must all diabetes medications show during trials due to the TZD data?

A

must show they are not bad for the heart

60
Q

What are some GLP-1 agonists?

A

exenatide
liraglutide
dulaglutide (Trulicity)
exenatide weekly
lixisenatide
semaglutide (Ozempic)

61
Q

What are some DPP-4 inhibitors?

A

linagliptin (Trajenta)
sitagliptin (Januvia)
saxagliptin
alogliptin

62
Q

What are the drugs in Janumet?

A

sitagliptin and metformin

63
Q

What are the incretin hormones?

A

GLP-1 and GIP
-secreted from gut in response to ingestion of nutrients
-augment insulin secretion
-people with T2 have reduced incretin effect

64
Q

What does activation of the GLP-1 receptor result in?

A

potent inhibition of gastric emptying
potent inhibition of glucagon secretion
reduction of food intake and body weight

65
Q

What is the MOA of DPP4-inhibitors?

A

block the enzyme DPP4 which rapidly hydrolyzes incretins, thus enhancing the action of endogenous incretins
-as a result they increase insulin release and decrease
glucagon in a dose-dependent manner

66
Q

Describe the efficacy of DPP4 inhibitors.

A

decrease A1C ~0.7% (ranges, but typically ~1%)
work quickly-can see effects within weeks

67
Q

Which DPP4 inhibitor is not EDS? What is the EDS criteria of DPP4 inhibitors?

A

alogliptin
those uncontrolled after metformin and a SU

68
Q

What are the adverse effects of DPP4 inhibitors?

A

overall, well tolerated (no hypo on their own, weight neutral)
more common: headache, nasopharyngitis, URTI
less common/rare:
-hypersensitivity
-bullous pemphigoid
-joint pain
-pancreatitis

69
Q

What are some drug interactions with DPP4 inhibitors?

A

combined with insulin or SU–>risk of hypoglycemia
saxagliptin: clearance is reduced/enhanced with 3A4 inhibitors and inducers
linagliptin: clearance enhanced with strong 3A4 inducers
all: avoid with GLP1A (similar MOA and risk of pancreatitis)

70
Q

What are the results of DPP4 inhibitors and CV safety?

A

safe but not cardioprotective

71
Q

Why are DPP4 inhibitors a good option for the elderly?

A

weight neutral to modest weight loss
low risk of hypo
well tolerated
OD
no titration
less A1C lowering than other antihyperglycemics

72
Q

Which GLP1RAs are covered under EDS? What are their EDS criterias?

A

lixisenatide: tx of T2 combined with a basal insulin when control is not adequate with a SU and metformin
semaglutide: tx of T2 when combined with metformin and a SU when control is not adequate with a SU and metformin

73
Q

What is the MOA of GLP1RAs?

A

stimulate insulin secretion in a glucose-dependent manner
-decreased glucagon
-slow gastric emptying
-increase satiety
-decreased hepatic glucose production

74
Q

How should GLP1RAs be stored when not in use? What about when in use?

A

not in use: fridge
in use: room temp or fridge (oral semaglutide: room temp)

75
Q

What do you do if you miss a dose of a short-acting GLP1RA?

A

exenatide: skip
lixisenatide: within the hour prior to the next meal

76
Q

What is the dosing of long-acting GLP1RAs?

A

liraglutide: 0.6mg OD x 1 week, then 1.2-1.8mg OD
exenatide QW: 2mg SC q week
dulaglutide: 0.75mg SC weekly; can increase to 1.5mg q week
semaglutide: 0.25mg SC weekly; increase to 0.5mg after 4 weeks then 1mg

77
Q

What do you do if you miss a dose of a long-acting GLP1RA?

A

administer ASAP if at least 3 days until next dose
-5 days for semaglutide

78
Q

How is oral semaglutide dosed?

A

3mg OD for 30 days
increase to 7mg OD for at least 30 days
may increase 14mg OD
empty stomach after waking up, with sip of water, wait 30 minutes before eating/drinking/other meds

79
Q

How is oral semaglutide formulated?

A

to make po bioavailable, it is co-formulated with SNAC
this creates a bubble around it and prevents degradation from stomach acid so it can be absorbed
-1% makes the journey
-keep in original packaging

80
Q

What do you do if you miss a dose of oral semaglutide?

A

skip and take the next day

81
Q

Describe the efficacy of GLP1RAs.

A

decreases A1C 1-1.5%
-semaglutide SC appears to be more potent than dulaglutide
long-acting GLPs more potent than short-acting
work on both FPG and PPG, however, short-acting GLPs have more effect on PPG, & long-acting have more effect on FPG
modest decrease in bp (within 3 weeks)
benefits on BG are dose-dependent

82
Q

What are common adverse effects of GLP1RAs?

A

GI: N/V/D (up to 40%); especially nausea (20-50%)
-nausea and vomiting are generally mild and transient and
resolve after 4-8 weeks (longer with exenatide BID and
lixisenatide)

83
Q

How can you minimize nausea with GLP1RAs?

A

appreciate the feeling of fullness: stop eating when full
eat smaller portions and eat slowly
titrate slowly; stay on low dose until nausea improves
avoid fatty, spicy, and high-fibre foods
consider using on an empty stomach-dont administer close to a large meal
consider end of day dosing
stay hydrated and drink cold water when nauseous

84
Q

What are the effects of GLP1RAs on weight & hypoglycemia?

A

weight loss
-varies but on average ~3kg
-not due to N/V/D
-weight loss is dose dependent and will plateau
low risk of hypoglycemia
-when initiating may either stop or decrease dose of SU and
perhaps decrease insulin dose

85
Q

What are drug interactions with GLP1RAs?

A

these drugs decrease gastric emptying, space out drugs that require rapid GI absorption (>1hr before GLP1RA):
-oral contraceptives
-antibiotics
-narrow TI drugs
-increases levothyroxine by 33%

86
Q

What are contraindications of GLR1RAs?

A

family history of MTC (medullary thyroid cancer) or MEN2
family history of pancreatic cancer

87
Q

How do GLP1RAs exert cardioprotective and renal benefits?

A

effects on BP, LDL/TG (although modest)
effects on weight
effects on BG
may help modulate vascular inflammation (inhibit atherogenesis)
combination of metabolic, CV, and anti-inflammatory effects

88
Q

True or false: lixisenatide, semaglutide po, and exenatide have not been shown to be CV protective but are CV safe

A

true
the trials for CV protective were done on liraglutide, semaglutide sc, and dulaglutide

89
Q

What are the CV outcomes with repaglinide?

A

absence of CV outcome data

90
Q

What are rare adverse effects of GLP1RAs?

A

acute gallstone disease
acute pancreatitis
increased cancer risk
retinopathy

PHAR152 (21 decks)

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