Type-2 Diabetes Management Flashcards
How should therapy be chosen for T2DM?
Study Flow Chart
What is important for pharmacists and pt’s to know about Type-2 diabetes?
T2DM is a progressive disease – where you start is rarely where you will end
What is an example of a biguanides?
Metformin (Glucophage)
How does metformin work?
↓’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
What is the dose for metformin? Does it require titration?
Start slow: Initiate at 250mg - 500mg od
Titrate up by 500mg weekly if no GI side effects
What is the desired usual dose of metformin?
Desired usual dose: 850 - 1000mg bid. Max dose of 850mg TID
- ADJUST in RENAL FAILURE
What is the efficacy of metformin?
- 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)
What are some drug interactions of metformin?
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
Adverse Effects of Metformin. Common and Less Common
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)
Metformin Weight Loss?
Weight neutral to modest weight loss
Precaution of Metformin
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
Does metformin dose need to be educed in renal impairement?
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)
What are some risk factors for lactic acidosis?
- 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
Why is metformin used first line?
Efficacy
Mild side effect profile
Long-term safety
Neutral effect on weight
Low hypoglycemia
Cost
Cardiac outcomes in overweight
Sulfonureas MOA
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
Sulfonureas are also known as
Insulin Secretagoues
What are examples of sulfonureas?
2nd generation: glyburide, gliclazide, glimepiride
Glyburide Dose? GFR?
Glyburide: 5mg–20mg/d (once or twice daily)
Usual dose is 5mg BID; may ↑ to 10mg BID
CI in eGFR<60ml/min
Gliclazide Dose. GFR?
Gliclazide: 80mg-160mg (80mg od or 80mg BID)
Gliclazide MR 30mg -120mg od
Caution in eGFR 30-60ml/min. CI in eGFR<30ml/min
Glimepiride Dose GFR?
Glimepiride: 1mg - 8mg/d
Caution in eGFR 30-60ml/min. CI in eGFR<30ml/min
Sulfonurea Taking Med Info
Take with food
Take in am
Start at lower doses and increase prn
Sulfonurea Efficacy. Better Response? renal Impairement?
↓ 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
Sulfonurea Onset of Action. Titration?
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)
Are sulfon ureas cardio-protective?
neutral CV outcomes –> No harm, no benefit
Adverse Effects of sulfonureas
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)
Sulfonurea Precautions and C.I.’s
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
Drug Interactions of Sulfonureas
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
Meglitinide Example and MOA
Repaglinide
Binds to a site adjacent to the SU receptor, resulting in stimulation of the secretion of insulin from the pancreas
Difference between meglinides and SU’s
Similar to SUs but have a faster onset and shorter D of A
Peak levels within 1 hour and half-life is 1 hour
Efficacy of Meglinides. Works primarily to….
↓ 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
Dosing of Repaglinide. Titration?
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
When does repalginlide need to be adminstered?
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
repaglinide GFR
Use with caution if eGFR <30ml/min
Adverse Effects of repaglinide
Hypoglycemia (more so when combined with other agents)
Weight gain (~0.3 to 1kg)
Similar to SUs, but to a lesser extent
Precautions and C.I.’s of Repaglinide
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
Alpha-Glucosidase Inhibitor Example and MAO. Net result?
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
Efficacy of Acarbose. Effect other things?
A1C: ↓ 0.5-0.8%
Does not affect body weight or lipids
Dose of Acarbose. When is it adminstered?
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
Acarbose Adverse Effects. Effect on weight? How should hypo be tx?
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
