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Diabetes > Non-Insulin Treatment > Flashcards

Non-Insulin Treatment Flashcards

1
Q

Do not use ____ and ____ together

A

GLP-1 and DPP-IV

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2
Q

Metformin MOA

A

decreases hepatic production of glucose
increases intestinal glucose utilization and decreases glucose uptake into circulation
can increase GLP-1 secretion
modest effect on increasing tissue uptake and utilization of glucose by muscle

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3
Q

Metformin clinical applications

A

adjunct to diet in T2 pts that are uncontrolled
in combo with insulin/non-insulin agents in T2
consider for use in all T2 pts: reduce risk of mortality and CV death, efficacious with minimal hypoglycemia, positive effects on weight
off label: PCOS and being used in T1 pts who are overweight and have low risk of ketoacidosis

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4
Q

Metformin efficacy

A

A1C: decrease 1.5-2%
FBG: decrease 60-80 mg/dL
Weight: no weight gain, often weight loss

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5
Q

Metformin PK

A

excreted unchanged in the urine

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6
Q

Metformin Advantages

A

a. Less risk of hypoglycemia due to no insulin release

b. Benefit on lipids: ↓ TG and LDL by 8-15%

c. Weight loss or at least weight neutral

d. Cost-effective

e. ↑ fibrinolysis = CV protection

f. Has been shown to ↓ macrovascular complications and the risk of total mortality in clinical trials

g. ↓ risk of stroke and all-cause mortality when compared to insulin and sulfonylureas

h. ↓ diabetes-related death and myocardial infarctions vs. conventional treatment in UKPDS trial

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7
Q

Metformin disadvantages

A

lactic acidosis

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8
Q

Metformin cautions/contraindications

A

renal dysfunction
anyone with HF who isn’t stable = avoid
alcoholics - avoid use with heavy intake
avoid use in pt at risk for lactice acidosis: post MI, COPD, shock, hepatic failure, surgery procedure with contrast dye
GI effects
vitamin B12 malabsorption/deficiency
dementia risk

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9
Q

Metformin dosing

A

500 mg po BID or 850 mg po daily w/ meals to decrease SEs
titrate dose weekly or bi-monthly and increase by 250-500 mg/day
max dose: 2 gm/day (package insert: 2.55 gm/day)

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10
Q

Metformin dosing in renal insufficiency

A

≥ 60: No renal contraindication to metformin; Monitor SCr annually
<60 and ≥ 45: Safe to start therapy; Continue use if already taking; Monitor SCr every 3-6 months
<45 and ≥ 30: Starting metformin not recommended; Reduce metformin dose by 50% if already taking; Monitor SCr every 3 months
< 30: Do not start metformin; Stop metformin, if currently taking

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11
Q

SGLT2 inhibitors

A

canagliflozin (invokana)
dapagliflozin (farxiga)
empagliflozin (jardiance)
ertugliflozin (steglatro)

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12
Q

SGLT2 inhibitors MOA

A

SGLT2 is the major transporter of renal glucose to assist in glucose reabsorption
Inhibition of SGLT2 leads to renal glucose excretion

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13
Q

SGLT2 inhibitors clinical application

A

adjunct to diet + exercise in T2D
initial therapy for individuals with type 2 diabetes with or at high risk for atherosclerotic cardiovascular disease, heart failure, and/or chronic kidney disease

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14
Q

SGLT2 inhibitors efficacy

A

a. A1C: ↓ 0.5-1.0%
b. FBG: ↓ 25-35 mg/dL
c. PPG: ↓ 40-60 mg/dL
d. Weight: ↓ 1-5 kg
e. BP: ↓ SBP 3-6 mmHg and DBP 2-3 mmHg

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15
Q

SGLT2 inhibitors PK

A

Undergoes glucuronidation by UGT1A9 and UGT2B4 to inactive metabolites; UGT = UDP-glucuronosyl transferase
CYP3A4 metabolism is minimal
Excreted mostly in feces, but 1/3 in urine

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16
Q

SGLT2 inhibitors adverse effects

A

Most common: UTIs, female/male genital fungal infections, increased urination
Hypotension
Hyperkalemia
Increased cholesterol
DKA: now recommended to hold SGLT2 3 days before surgery (4 if on ertugliflozin), may restart therapy once oral intake is back to baseline and other risk factors for ketoacidosis have resolved
Bone fractures and decreased BMD (canagliflozin)
AKI (canagliflozin and dapagliflozin)
Increased risk of leg and foot amputations (canagliflozin)
Serious genital infections

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17
Q

Canagliflozin dosing

A

eGFR > 60 mL/min/1.73m2: 100 mg daily, Max: 300 mg daily
eGFR 30-60 mL/min/1.73m2 Max: 100 mg daily if no albuminuria
eGFR < 30 mL/min/1.73m2 Do not start, but if already taking, may use 100 mg daily if albuminuria > 300 mg/d
ESRD on HD Do not use

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18
Q

Dapagliflozin dosing

A

eGFR > 45
mL/min/1.73m2: 5 mg daily
Max: 10 mg daily
eGFR < 25: Do not start; if on therapy, may continue and monitor
ESRD on HD Do not use

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19
Q

Empagliflozin dosing

A

eGFR > 30 mL/min/1.73m2 10 mg daily; Max: 25 mg daily
eGFR < 30 mL/min/1.73m2 Do not start; if on therapy, may continue and monitor
ESRD on HD Do not use

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20
Q

Ertugliflozin

A

eGFR > 60 mL/min/1.73m2 5 mg daily
Max: 15 mg daily
eGFR < 45 mL/min/1.73m2 Do not start; if on therapy, monitor; if eGFR persistently low, may discontinue
ESRD on HD Do not use

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21
Q

SGLT2 benefits

A

CV benefits
renal benefits

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22
Q

GLP-1 Agonists

A

liraglutide (victoza)
dulaglutide (trulicity)
semaglutide (ozempic and rybelsus)
exenatide (byetta, bydureon)
lixisenatide (adylyxin)

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23
Q

GLP-1 agonists MOA

A
  • Glucagon-Like Peptide-1 (GLP-1) agonists/analogs from salivary gland of the lizard Heloderma suspectum (exenatide) and through recombinant DNA technology (others)
  • GLP-1 potentiates glucose-dependent insulin secretion by stimulating beta-cell growth and differentiation and insulin gene expression
  • Has been shown to inhibit beta-cell death
  • Inhibits glucagon secretion, delays gastric emptying, and decreases appetite
  • GLP-1 agonist medications are resistant to dipeptidyl peptidase IV, the enzyme that rapidly inactivates natural GLP-1
  • Increases in both first and second-phase insulin secretion after meals occur
  • Leads to insulin release only in presence of elevated BS
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23
Q

GLP-1 agonsits clinical applications

A
  • Recommended with or without metformin as an appropriate INITIAL therapy for individuals with type 2 diabetes with or at high risk for atherosclerotic cardiovascular disease, heart failure, and/or chronic kidney disease
  • In T2DM, a GLP-1 RA is preferred to insulin when possible
  • If insulin is used, combination therapy with a GLP-1 RA is recommended for greater efficacy and durability of treatment effect
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24
Q

GLP-1 agonists efficacy

A
  • A1C: ↓ ~0.7-1.6%
  • Short-acting GLP-1s (exenatide and lixisenatide) have more effect on PPG vs. long-acting GLP-1s, which control FBG more
  • Weight: ↓ 1.5-3 kg (may be up to 6 kg for some depending upon dosing)
  • Short-acting GLP-1s eliminated by kidneys and are contraindicated with severe renal disease
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25
Q

GLP-1 agonists adverse effects

A

nausea, vomiting, diarrhea
acute pancreatitis
black box warning for thyroid c-cell tumors
gall bladder disease
gastroparesis
retinopathy

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26
Q

dulaglutide (trulicity) dosing

A

once weekly
0.75 mg up to 4.5 mg
use caution in ESRD

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27
Q

semaglutide (ozempic)

A

once weekly
0.25 mg x 4 weeks then 0.5 mg up to 2 mg

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28
Q

liraglutide (victoza)

A

daily
0.6 mg x 7 days then 1.2 mg up to 1.8 mg

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29
Q

exenatide (byetta)

A

BID
5 mcg x one month then 10 mcg
avoid CrCl < 30

30
Q

exenatide (bydureon)

A

once weekly
2 mg
avoid CrCl < 30

31
Q

lixisenatide (adylyxin)

A

daily
10 mcg x 14 days then 20 mcg
avoid eGFR < 15

32
Q

oral semaglutide (rybelsus)

A

3 mg po daily x 30 days then increase to 7 mg daily; can increase to 14 mg daily if needed for glucose control
take 30 min before 1st food/beverage/other oral meds

33
Q

cardiovascular benefits in GLP-1s

A

LEADER trial: primary composite outcome was almost the same in liraglutide and placebo; same with death from CV causes
SUSTAIN-6: primary composite outcome was almost the same in semaglutide and placebo; same with nonfatal MI and nonfatal stroke
REWIND: primary outcome for dulaglutide - HR 0.88; hazard ratio similar for the pts with CV disease at baseline and those without CV disease; non-fatal stroke - HR 0.76

34
Q

Dual GLP-1 and GIP receptor agonist

A

tirzepatide (mounjaro)

35
Q

Dual GLP-1 and GIP receptor agonist MOA and clinical use

A
  • Dual action as a GLP-1 RA and a GIP RA
  • Enhances first- and second-phase insulin secretion
  • Reduces glucagon levels, in a glucose-dependent manner
  • Delays gastric emptying
  • increases satiety
  • CV outcomes expected in 2025
  • Being marketed especially for weight loss
36
Q

Dual GLP-1 and GIP receptor agonist efficacy

A
  • A1C: decrease 1.5-2.3%
  • FBS: decrease 40-60 mg/dL
  • PPG: decrease 20-40 mg/dL
  • Weight: decrease 6-11kg
37
Q

Dual GLP-1 and GIP receptor agonist adverse effects

A
  • Similar to GLP-1 RAs
    o N, V, D
    o Warnings for pancreatitis thyroid tumors, and gallbladder disease
  • Tachycardia (10-20% of patients)
38
Q

Dual GLP-1 and GIP receptor agonist dosing

A

2.5 mg SQ weekly
up to 15 mg weekly

39
Q

DPP-4 inhibitors

A

sitagliptin (januvia)
saxagliptin (ongylza)
linagliptin (tradjenta)
alogliptin (nesina)

40
Q

DPP-4 inhibitors MOA

A
  • Dipeptidyl peptidase-4 (DPP-4) inhibitors
  • Increases the activity of endogenous incretin hormones (GLP-1 & GIP): Gut hormones that enhance insulin secretion in response to food

Glucagon-like peptide 1
* Released from cells in ileum and colon after eating and is normally degraded quickly by DPP-4
* Studies have shown significant reductions in levels of GLP-1 after meals in type 2 diabetics
* Stimulates insulin response from beta cells in a glucose dependent manner—helps prevent hypoglycemia
* Inhibits glucagon secretion from alpha cells in a glucose-dependent manner
* Inhibits gastric emptying (less than GLP-1 agonists)
* Reduces food intake and body weight (less than GLP-1 agonists)

  • GLP-1 is degraded by the DPP-4 enzyme; therefore DPP-4 inhibitors prevent the breakdown of endogenous GLP-1
41
Q

DPP-4 inhibitors efficacy

A
  • A1C: ↓ 0.5-1%
  • FBS: ↓ 20 mg/dL
  • PPG: ↓ 20-40 mg/dL
  • Weight: ↓ 0-0.5 kg – “weight neutral”
42
Q

DPP-4 inhibitors PK

A

excreted unchanged in urine
adjust dose for renal function (except linagliptin)

43
Q

DPP-4 inhibitors adverse effects

A

nasopharyngitis
upper respiratory tract infections
headache
acute pancreatitis
joint pain
heart failure risk

44
Q

sitagliptin dosing

A

100 mg daily for CrCl > 50 mL/min
50 mg daily for CrCl 30-50 mL/min
25 mg daily for CrCl < 30 mL/min or with ESRD on dialysis

45
Q

saxagliptin dosing

A

2.5-5.0 mg once daily
2.5 mg daily for CrCl < 50 mL

46
Q

linagliptin dosing

A

5 mg once daily

47
Q

alogliptin

A

25 mg daily
12.5 mg CrCl 30-60
6.25 mg CrCl < 30 or ESRD on dialysis

48
Q

Sulfonylureas MOA

A
  • Stimulate insulin release from pancreatic beta cells
  • May ↑ binding between insulin and receptors or ↑ # of receptors
49
Q

Sulfonylureas clinical applications

A
  • Adjunct to diet and exercise in type 2 patients
  • Used in combination therapy with insulin and other non-insulin agents
50
Q

Sulfonylureas efficacy

A
  • A1C: ↓ 1-2%
  • FBG: ↓ 60-70 mg/dL
51
Q

Types of sulfonylureas

A

a. First generation
* Acetohexamide, chlorpropamide, tolazamide, and tolbutamide; Not used due to increased adverse effects, active metabolites, prolonged half-lives, and increased drug interactions

b. Second generation

  • Glyburide (Diabeta®, Micronase®, Glynase®)
  • Glipizide (Glucotrol®, Glucotrol XL®)
  • Glimepiride (Amaryl®)
52
Q

PK of second generations

A
  • Glyburide and glipizide more effective when taken 30 minutes AC
  • Metabolized by the liver
  • Some excreted in the urine
  • Glipizide metabolized without the formation of active metabolites, so therefore it is preferred in renal disease
53
Q

Sulfonylureas adverse effects

A

a. Hypoglycemia: Renal/hepatic insufficiency patients; Elderly or malnourished patients; Concurrent hypoglycemic drugs

b. Weight gain (up to 3 kg) and GI upset

c. Hematologic: leukopenia, thrombocytopenia, aplastic anemia

d. Allergic skin reactions/photosensitivity

54
Q

Sulfonylureas

A

exceeding max dose increases SEs but does not decrease BG

55
Q

Glipizide (Glucotrol) dosing

A

2.5-5 mg daily
max dose: 40 mg

56
Q

Glipizide (Glucotrol XL) dosing

A

2.5-5 mg daily
max dose: 20 mg

57
Q

Glyburide (Micronase/Diabeta)

A

1.25-5 mg daily
max dose: 20 mg

58
Q

Glyburide micronized (Glynase) dosing

A

1.5-3 mg daily
max dose: 12 mg

59
Q

Use cautiously in the following patients due to increased risk of hypoglycemia:

A
  • Elderly or patients with renal/hepatic disease
  • Irregular dietary intake
  • Alcoholics
  • Patients taking concomitant hypoglycemic agents
60
Q

Best candidates for sulfonylureas

A
  • No type 1 patients
  • Short duration of diabetes
  • FBS < 250 mg/dL
  • High fasting C-peptide levels
61
Q

Sulfonylureas treatment failure

A

25% will have primary failure (poor BS control)
50-75% experience secondary failure (fail after 6-12 months)

62
Q

Thiazolidinediones

A

pioglitazone (actos)
rosiglitazone (avandia)

63
Q

Thiazolidinediones MOA

A
  • Bind to peroxisome proliferator activator receptor-γ (PPAR-γ) on fat cells and vascular cells
  • Improves cellular response to insulin w/o increasing pancreatic insulin
    secretion
  • Decreases insulin resistance
  • Decreases hepatic glucose production
64
Q

Thiazolidinediones benefits

A

 Pioglitazone can ↓ TG by 10-20%

 LDL remains unchanged on pioglitazone
–Some rosiglitazone studies have shown ↑ in LDL

 Both meds convert small atherogenic LDL particles to large fluffy ones

 Both medications ↑ HDL by 3-9 mg/dL

 Endothelial function has improved and blood pressure may decrease slightly

65
Q

Thiazolidinediones efficacy

A

a. A1C: ↓0.5-1.5%

b. FBG: ↓60-70 mg/dL

66
Q

Thiazolidinediones adverse effects

A

hepatotoxicity: do not start therapy in pts with baseline LFTs > 2.5x normal; D/C med if LFTs > 3x normal
resumption of ovulation
exacerbations of HF
macular edema
increased fracture risk

67
Q

Controversial studies on CV benefits

A

 DREAM study showed MI rates of 0.6% for rosiglitazone group vs 0.3% for controls, and the MI/stroke/cardiovascular composite occurred in 1.2% of rosiglitazone vs 0.9% of control patients, with neither result reaching
 The ADOPT trial showed a statistically significant excess of congestive heart failure episodes for rosiglitazone-treated patients compared with glyburide (22 vs 9 events)
 The RECORD trial showed no statistical difference in actual occurrence of CV death and time to first fatal and nonfatal MI or stroke when rosiglitazone was compared to metformin/sulfonylurea
Pioglitazone has shown some anti-atherogenic potential

68
Q

Pioglitazone dosing

A

intitial dose: 15-30 mg daily
max dose: 30-45 mg daily
titrate dose every 12 weeks

69
Q

In patients with established/high risk of atherosclerotic cardiovascular disease, heart failure, and/or chronic kidney disease, the treatment regimen should include agents that reduce cardiorenal risk.

A
  • SGLT2Is and GLP1RAs are recommended independent of A1C, but with consideration for person-specific factors
70
Q

Start dual therapy if

A

A1C > 9% (ADA guidelines) or > 7.5-9% (AACE guidelines)

71
Q

In pts with T2DM, _____ is preferred to insulin when possible

A

GLP-1 RA

72
Q

Insulin should be used if

A

there is evidence of ongoing catabolism (weight loss), if s/s of hyperglycemia are present, or if A1C is > 10% or blood glucose readings are > 300 mg/dL.

Diabetes (6 decks)

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