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Diabetes Therapeutics > Type-2 Diabetes Management > Flashcards

Type-2 Diabetes Management Flashcards

1
Q

How should therapy be chosen for T2DM?

A

Study Flow Chart

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2
Q

What is important for pharmacists and pt’s to know about Type-2 diabetes?

A

T2DM is a progressive disease – where you start is rarely where you will end

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3
Q

What is an example of a biguanides?

A

Metformin (Glucophage)

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4
Q

How does metformin work?

A

↓’s hepatic glucose production
Can also enhance sensitivity to insulin
Increases glucose utilization via action in the gut (interaction with incretins)
Has effects on the gut microbiome which may explain some anti-inflammatory effects

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5
Q

What is the dose for metformin? Does it require titration?

A

Start slow: Initiate at 250mg - 500mg od

Titrate up by 500mg weekly if no GI side effects

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6
Q

What is the desired usual dose of metformin?

A

Desired usual dose: 850 - 1000mg bid. Max dose of 850mg TID

  • ADJUST in RENAL FAILURE
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7
Q

What is the efficacy of metformin?

A
  • Decrease A1C by 1 to 1.5%
  • Decreases TG and LDL, and slightly increases HDL

↓ MI & mortality in T2 patients with obesity (No definite evidence that metformin is cardio protective)

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8
Q

What are some drug interactions of metformin?

A

Cimetidine: competes for renal tubular secretion; ↑’s metformin levels by 60%
Dolutegravir: can increase metformin concentration
Alcohol: potentiates metformin’s effect on lactate metabolism; enhanced hypoglycemic effect
Contrast media: hold for 48hrs after imaging

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9
Q

Adverse Effects of Metformin. Common and Less Common

A

GI*: (up to 30% will experience, and about 5% will d/c)
Diarrhea, nausea, abdominal discomfort

Less common:
Metallic taste: if occurs, generally only lasts a few weeks
Vitamin B12 deficiency with long-term use (>5yrs)

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10
Q

Metformin Weight Loss?

A

Weight neutral to modest weight loss

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11
Q

Precaution of Metformin

A

Lactic acidosis: A ↓ in arterial pH & an accumulation of serum lactate (medical emergency)
Sx’s: weakness, malaise, myalgias, heavy laboured breathing

Metformin, in part, inhibits the conversion of lactate into glucose in the liver
Since it is eliminated unchanged by the kidneys, those with reduced eGFR will have reduced elimination. The concern is an accumulation of lactate

  • Rare
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12
Q

Does metformin dose need to be educed in renal impairement?

A

Yes

Decrease dose if Clcr <60ml/min
eGFR 45-59: 1500mg/d (divided doses)
eGFR 30-44: 1000mg/d (divided doses) – check eGFR q3mos
CI when eGFR<30ml/min (majority of cases)

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13
Q

What are some risk factors for lactic acidosis?

A
  • Effects on Kidney or Liver Function

History of lactic acidosis
Severe liver disease
Alcohol abuse
Radiologic procedures (iodinated contrast)
Acute illness (severe infection, trauma)
Severe dehydration

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14
Q

Why is metformin used first line?

A

Efficacy

Mild side effect profile

Long-term safety

Neutral effect on weight

Low hypoglycemia

Cost

Cardiac outcomes in overweight

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15
Q

Sulfonureas MOA

A

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

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16
Q

Sulfonureas are also known as

A

Insulin Secretagoues

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17
Q

What are examples of sulfonureas?

A

2nd generation: glyburide, gliclazide, glimepiride

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18
Q

Glyburide Dose? GFR?

A

Glyburide: 5mg–20mg/d (once or twice daily)
Usual dose is 5mg BID; may ↑ to 10mg BID
CI in eGFR<60ml/min

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19
Q

Gliclazide Dose. GFR?

A

Gliclazide: 80mg-160mg (80mg od or 80mg BID)
Gliclazide MR 30mg -120mg od
Caution in eGFR 30-60ml/min. CI in eGFR<30ml/min

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20
Q

Glimepiride Dose GFR?

A

Glimepiride: 1mg - 8mg/d
Caution in eGFR 30-60ml/min. CI in eGFR<30ml/min

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21
Q

Sulfonurea Taking Med Info

A

Take with food
Take in am
Start at lower doses and increase prn

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22
Q

Sulfonurea Efficacy. Better Response? renal Impairement?

A

↓ A1C 1 to 1.5% (up to 2% in drug naïve and elevated A1C)

May get a better response if initiated early in diagnosis; long-term durability is poor
Must dose adjust in renal impairment

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23
Q

Sulfonurea Onset of Action. Titration?

A

Work quickly: can start titrating dose after 2 weeks based on fasting BG, then can titrate every 1-2 weeks
Get bang for buck at lower doses (effective at ½ max dose and max effective dose is about 60-75% of the max dose)

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24
Q

Are sulfon ureas cardio-protective?

A

neutral CV outcomes –> No harm, no benefit

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25
Q

Adverse Effects of sulfonureas

A

Hypoglycemia (2-30%)
–> glyburide > glimepiride > gliclazide

Weight Gain

Less Frequent:
Less frequent (<2%):
nausea, skin reaction: rash, photosensitivity
Cross-sensitivity with those with a sulfa allergy is very rare (no C.I. with sulfa antibiotics, but cation with severe anaphylaxis)

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26
Q

Sulfonurea Precautions and C.I.’s

A

Pregnancy/breast-feeding (all cross placenta except glyburide)
Metabolized in the liver and excreted through kidneys. CI in severe hepatic and renal impairment
Hold in acute illness

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27
Q

Drug Interactions of Sulfonureas

A

When these drugs are used along with SU’s, there may be an increased risk of hypoglycemia:
Sulfonamides, salicylates, warfarin (via displacement from albumin binding sites)
Alcohol
Cimetidine, clarithromycin, fluconazole, NSAIDs, beta-blockers, MAOIs

Some drugs when combined may lead to lessened effects and increased blood sugar:
Phenytoin
Rifampin
Colesevelam (binding, separate by 4hrs)

Bosentan: glyburide can enhance its hepatoxic effects

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28
Q

Meglitinide Example and MOA

A

Repaglinide

Binds to a site adjacent to the SU receptor, resulting in stimulation of the secretion of insulin from the pancreas

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29
Q

Difference between meglinides and SU’s

A

Similar to SUs but have a faster onset and shorter D of A
Peak levels within 1 hour and half-life is 1 hour

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30
Q

Efficacy of Meglinides. Works primarily to….

A

↓ A1C 1 to 1.5% (similar to SUs)
Works primarily to decrease PPG: Is intended to be taken before meals to improve early phase meal-induced insulin secretion

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31
Q

Dosing of Repaglinide. Titration?

A

A1C <8%: initiate at 0.5mg (lower dose) before each meal + titrate up
A1C >8%. Initiate at 1-2mg (higher dose) before each meal + titrate up Max dose: 4mg before each meal (max dose 16mg/d)
Start at a low dose and titrate up every 1-2 weeks until target BG achieved

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32
Q

When does repalginlide need to be adminstered?

A

Due to its short D of A, it needs to be administered right before a meal (within 30 minutes)

Provides some flexibility:
skip a meal, skip a dose, add a meal, add a dose

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33
Q

repaglinide GFR

A

Use with caution if eGFR <30ml/min

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34
Q

Adverse Effects of repaglinide

A

Hypoglycemia (more so when combined with other agents)
Weight gain (~0.3 to 1kg)
Similar to SUs, but to a lesser extent

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35
Q

Precautions and C.I.’s of Repaglinide

A

Metabolized in the liver: CYP 450. Clearance significantly reduced in hepatic impairment. Hence, precaution with moderate hepatic impairment and CI with severe liver disease

Increased repaglinide with:
3A4 inhibitors (cyclosporine, clarithromycin, grapefruit, azoles
2C8 ( gemfibrozil, clopidogrel; these are CI)

Decreased repaglinide with 3A4 inducers (e.g. carbamazepine, rifampin)  HIV medications

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36
Q

Alpha-Glucosidase Inhibitor Example and MAO. Net result?

A

Acarbose

α-Glucosidase enzymes in the small intestine are responsible for the breakdown of polysaccharides into absorbable glucose
Acarbose inhibits these enzymes, hence there is a delay in the rate of digestion of CHO’s and glucose absorption

Net effect is reduction in PPG levels

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37
Q

Efficacy of Acarbose. Effect other things?

A

A1C: ↓ 0.5-0.8%
Does not affect body weight or lipids

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38
Q

Dose of Acarbose. When is it adminstered?

A

Initial: 25-50mg od. Titrate up every couple of weeks to 50mg tid
Assess for efficacy q 4-8 weeks to a max dose of 100mg tid
Take with the first bite of each main meal

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39
Q

Acarbose Adverse Effects. Effect on weight? How should hypo be tx?

A

GI: flatulence (40-80%), diarrhea (30%) –> bloating, abdominal pain

May elevate ALT: monitor LFT’s first 6-12 months

Hypoglycemia: only negligible risk; may be ↑ with concomitant use of SU’s
Weight neutral
→ the digestion of sucrose is impaired by acarbose, hence hypo should be treated with glucose rather than sucrose

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40
Q

Acarbose D.I’s

A

Digestive enzyme preparations
May decrease digoxin effect

41
Q

Cautions of Acarbose

A

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

42
Q

Thiazolidines Examples

A

Rosiglitazone
Pioglitazone

43
Q

Thiazolidines MOA

A

Bind to PPAR-γ 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 ↓ insulin resistance
↓ hepatic glucose production
Convert small, dense LDL particles to large, fluffy LDL’s that are less dense and less atherogenic

44
Q

Efficacy of Thiazolidines –> A1C, TG, LDL, HDL?

A

↓ A1C 1 – 1.5%

Effects on TG: PIO ↓’s by 10-20%, Rosi neutral
Effects on LDL: Rosi ↑’s LDL 5-15%, Pio is neutral
Effects on HDL: Both may ↑ HDL to some degree

45
Q

Thiazolidines Rosi Dose

A

Rosi: initiate at 2-4mg od; may ↑ to 4mg bid or 8mg od (greater effects seen bid)

46
Q

Thiazolidine Pio Dose

A

initiate at 15mg od; titrate up to 30 - 45mg od

47
Q

Thiazolidines Onset of Action

A

Have a delayed onset: wait 4-8 weeks for dose adjustments (max effects 3mos)
Larger people will generally require a larger dose

A to Z –> Long time

48
Q

Thiazolidines GFR

A

Caution in eGFR <60ml/min (no dose adjustment required)

49
Q

Thiazolidne Cautions

A

Mainly metabolized by liver: use with caution or use an alternative in severe liver disease (monitor LFT at baseline and periodically)

50
Q

D.I.’s of Thiazolidines

A

Metabolized by CYP 2C8:
↑ effects with inhibitors (e.g. gemfibrizol, TMP)
↓ effects with inducers (rifampicin)

51
Q

A/E of Thiazolidines

A

Peripheral edema(~5%); combined with insulin (~15%)
Hence, do not use with insulin
New-onset / worsening of HF
Weight gain (2.5 to 4.8kg; dose related)
↑ distal fractures in postmenopausal women
Caution in those at risk of fracture /elderly

Rare:
Macular edema: report any blurred vision, loss of sight
Anemia: not very common; long-term side effect

52
Q

Pio Caution?

A

Bladder Cancer

53
Q

Rosi caution?

A

Possible MI

54
Q

Thiazolidines and HF

A

Heart failure: Both rosiglitazone and pioglitazone can promote fluid retention and edema & increase risk of HF → both are CI in heart failure

55
Q

What are the two types of incretin based tx?

A

1) GLP-1 receptor Agonists (glucagon-lik peptide)
2) DPP-4 (dipeptidyl peptidase) inhibitors

56
Q

GLP-1 receptor Agonists (glucagon-lik peptide) Examples

A

Exenatide
Liraglutide
Dulaglutide
Exenatide weekly
Lixisenatide
Semaglutide

“TIDES”

57
Q

DPP-4 Inhibitor Examples

A

Linagliptin
Sitagliptin
Saxagliptin
Alogliptin

“LIPTINS”

58
Q

What are incretin hormones? Type-2?

A

Are secreted from the gut in response to ingestion of nutrients
Main role is to augment (increase) insulin secretion
People with T2 have a reduced incretin effect

59
Q

Activation of GLP-1 receptor results in:

A

Potent inhibition of gastric emptying
Potent inhibition of glucagon secretion
Reduction of food intake and body weight

60
Q

What is the role of GLP-1? How does it breakdown?

A

Decreased gastric emptying, food intake and glucagon secretion

  • Enzyme DPP-4 breaks it down
61
Q

How do DPP4-i work?
Efficacy?
Onset of Action?

A

MOA: block the enzyme DPP4 (dipeptidyl peptidase-4) which rapidly hydrolyzes incretins, thus enhancing the action of endogenous incretins
As a result, they increase insulin release and decrease glucagon in a dose-dependant manner

Efficacy: A1C ↓ ~ 0.7 (ranges, but typically < 1%)
Work quickly – can see effects within a couple of weeks

62
Q

Sitagliptin Dose. Renal Impairement?

A

100 mg po od

Decrease dose

63
Q

Saxagliptin Dose. Renal?

A

5 mg po od

Decrese Dose

64
Q

Linagliptin Dose. Renal?

A

5 mg po od

No dose adjustment for renal impairement

65
Q

Alogliptin dose Renal?

A

25 mg po od

Dose adjustment

66
Q

Is titration required for dpp4-i?

A

No

67
Q

A/e of dpp4-i

A

Overall, well tolerated medications
No hypo on their own
Weight neutral

More common: headache, nasopharyngitis, URTI

Less common/Rare:
Hypersensitivity reactions
Bullous pemphigoid: An autoimmune disease presenting with urticarial plaques, subepidermal bullae, and pruritis. D/c if any new-onset diffuse itchiness, lesions/blisters
Joint Pain: case reports. If symptoms appear, contact HCP
Pancreatitis: case reports, but no causal relationships
Caution in those with a history of pancreatitis; report signs of acute pancreatitis to physician

68
Q

Dpp4-i D.I.

A

When combined with a SU or insulin, may increase the risk of hypoglycemia (rates are still low)

Saxagliptin: clearance is reduced / enhanced with strong CYP 3A4 inhibitors and inducers

Linagliptin: clearance is enhanced with strong 3A4 inducers

All: avoid with GLP1RA: similar MOA and increased risk of pancreatitis (similar MOA)

69
Q

GLP-1 receptor agonist MOA

A

stimulate insulin secretion in a glucose-dependent manner; ↓ glucagon, slow gastric emptying, increase satiety
- work all over the body

70
Q

Where are GLP-1 recptor agonists stored? Exception?

A

At the pharmacy or at home and not in-use: in the fridge

Semaglutide oral (Rybelsus): room temp always

71
Q

GLP-RA’s Short Acting

A

Exenatide

Lixsenatide

  • Take with meals
72
Q

Long-acting GLP-1 RA’s

A

Liraglutide
Exenatide
Dulaglutide
Semaglutide

Can take any time of day, irrespective of meals

73
Q

Oral semaglutide Dose and Administration

A
  • Low dose and titrate up 3–> 7–> 14 mg
    empty stomach upon waking
  • take tab with sip of water
  • wait 30 mins before eating, drinking, or taking other oral meds
74
Q

GLP1RA’s Efficacy A1C Other Effects

A

↓ A1C by about 1 - 1.5%

Long-acting GLP’s more potent on A1C than short-acting
Work on both FPG and PPG, however, short-acting GLP’s have more effect on PPG, & long-acting have more effect on FPG

Modest decrease in blood pressure (within 3 weeks)

75
Q

A/E’s of GLP1RA’s

A

Nauseau, vomitting, diarhhea

  • Particularily Nauseau

GLP-1’s may increase the risk of retinopathy –> rapid glucose lowering can increase retinopathy

CI in personal/family history of MTC (medullary thyroid cancer) or MEN2 (multiple endocrine neoplasia syndrome type 2) –> Rare –> Never shown in humans; rat studies

76
Q

GLP1RA’s Weight

A

GLP1RAs cause weight loss
Amount varies across clinical trials, but on average it is ~3kg weight loss

Weight loss is not due to N/V/D
GLP1RAs slow gastric emptying and cause a sense of satiety – leading to reduced food intake and weight loss

77
Q

GLP1RA’s Hypo?

A

Low risk of hypoglycemia
When initiate a GLP1RA, depending on baseline BG, may either stop or decrease dose of SU, and perhaps ↓ insulin dose

78
Q

D.I. GLP1RA’s

A

If a drug requires rapid GI absorption, space these oral agents out (≥ 1hr before the GLP1RA)
Oral contraceptives
Antibiotics
Narrow TI drugs
↑ levothyroxine by 33%

79
Q

GLP1RA’s are _____ and ______ because

A

Have effects on CVD parameters such as BP, LDL/TG (although modest)
Have effects on weight (on average – modest reduction)
Have effects on BG, but ACCORD, VADT, ADVANCE only show modest decrease in non-fatal MI, not all-cause mortality
May help modulate vascular inflammation (inhibit atherogenesis)
Most likely due to a combination of metabolic, CV, and anti-inflammatory effects

80
Q

Examples of SGLT2 Inhibitors

A

Dapaglifozin
Canaglifozin
Empaglifozin

81
Q

SGLT2 Ihibitor MOA. Hypoglycemia?

A

SGLT2 is a high capacity transporter that is responsible for glucose reabsorption (90%) from the glomerular filtrate, & is overexpressed in those with T2DM
These drugs inhibit SGLT2, thereby decreasing the reabsorption of glucose, and ↑’ing urinary glucose excretion

They have insulin-independent action
There is no insulin stimulation, hence no hypoglycemia

82
Q

SGLT-2 Efficacy. Work when?

A

↓ A1C 0.5-0.8% in clinical trials as add-on agent (same as acarbose)

Works on both FPG and PPG
Begin working quickly (FPG ↓ within 2 weeks)

83
Q

What do SGLT-2 require to work?

A

hey require functioning nephrons to work; hence blood glucose lowering ability declines with ↓ renal function

84
Q

Do SGLT-2 cause wght loss?

A

YES

85
Q

Dose of SGLT-2

A

Are oral, once daily medications
Start at low dose; effects on A1C, cardio / renal outcomes are not dose-dependant

86
Q

Do SGLT-2 require renal dose adjustments?

A

At eGFR<45, no longer effective for BG lowering (but beneficial for cardio renal protection)

87
Q

What occurs when first starting an SGLT-2?

A

When initiating, they cause a very early decrease in kidney function – about 5ml/min in eGFR
This is not kidney damage – it is a hemodynamic effect that is reversed upon d/c

88
Q

a/e of sglt-2

A

↑ urination, ↑thirst
mycotic genital infections
females (~8%) > males; usually 1 time only and rarely leads to d/c (once and done, happens once, get tx)

89
Q

SGLT-2 Cardio Effects

A

Mild ↑ in LDL & HDL, and ↓ in TGs (all about 5%)
Mild ↓ in SBP and DBP (3-5mmHg and 2mmHG) – hence maybe some postural hypotension

90
Q

C.I. of SGLT-2

A

Dehydration potential: use cautiously in patients at risk for volume depletion effects
Elderly, loop diuretics, low SBP, CKD, ACEi/ARBs

DKA risk: rare, but severe if it occurs

91
Q

DKA and SGLT-2

A

withhold SGLT2i and check ketones regardless of BG value (as it can occur at normal BG) Notify physician if symptoms are occurring

92
Q

Drug Interactions of SGLT-2

A

Concomitant use with diuretics may increase risk of hypovolemia and hypotension

SGLT2is cause diuresis and small ↓ in BP
If hypovolemia present, address before adding SGLT2i
If adding to someone on a diuretic, consider adjusting diuretic first

93
Q

How are SGLT-2 cardio-renal protetctive?

A

They cause natriuesis and glucosuria – lowers cardiac pre-load and reduces pulmonary congestion and systemic edema
Decrease BP
Sodium depletion may improve ejection fraction
Stimulates renal erythropoietin secretion leading to new RBC formation and increased hematocrit – improved oxygen delivery
Decreases oxidative stress, local inflammation

94
Q

Dose for Cardio-renal benefit

A

The dose of the SGLT2i doesn’t seem to matter (most of the time just use the lower dose

95
Q

Insulin in Type-2

A
  1. Basal Insulin + antihyperglycemic medications
    Usually initiated as 10 Units at bedtime
  2. Basal and bolus insulin
  3. Biphasic (premixed) insulin
96
Q

Why is basal insulin to start preferred?

A

Simplicity
Minimization of weight gain and hypoglycemia
Keeping oral meds on board helps with insulin sensitization (use lower amounts of insulin to achieve BG lowering)

97
Q

What is overbasilization? When does it occur?

A

Basal insulin has a ceiling effect of about 0.5U/kg/d
If requiring >0.5U/kg/d, consider other options rather than continuing to increase the basal insulin dose –> Conversations about adding on naother insulin

98
Q

Basal-Bolus Insulin Type-2

A

If patients are only willing to do 2 injections per day, BID split-mixed insulin is an option

If patients are willing to do MDI, start by introducing 1 prandial insulin at a time
Start with largest meal; 2-4U (most folks: supper time)
Titrate by 1-2U/week until FPG and PPG at target
As insulin gets added, consider removing secretagogues
Monitor for effectiveness (BG targets) as well as hypoglycemia

Diabetes Therapeutics (4 decks)

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