Block 3: Diabetes II Flashcards
How does metformin work?
Lowers glucose level by:
1. Decreasing hepatic glucose production
2. Decreases intestinal absoprtion of glucose
3. Increasing peripheral insulin sensitivity
Liver»_space; Muscle
Does NOT directly effect beta-cells
Eliminated by kidneys
CI for metformin?
- T1DM/Ketoacidosis
- Hyperssensitivity
- Renal impairment requires a dosage adjustment
- Unstable HF
- Metabolic acidosis
- Hx of lactic acidosis
Metformin place in therapy?
- Highly effective: Decreases A1c 1-1.5%
- Lower risk of hypoglycemia
- Modest to neutral weight
- Low cost
- Avoid renal insufficiency
- Approved for pediatrics as young as 10
Metformin
Brand, ADR, DDI, Dosing, Monitoring
Glucophage, Glucophage XR
ADR:
1. GI upset stomach, diarrhea
2. Decreased B12 absorption
3. Induction of ovulation
4. Lactic acidosis
CI: Alcohol, Cimetidine, Constrast dye (hold metformin 48 hrs after procedure)
Dosing: Take with food and titrate slowly (weekly) to minimize GI problems
Monitoring: Srcr, hepatic function, B12 levels, H&H yearly
Pharmacology of TZDs (Piaglitazone)
PPAR agonist that increases glucose uptake by muscle and fat
Insulin sensitizer in muscle, fat»_space; liver
Hepatically metabolized
CI of Pioglitazone?
- T1DM or Ketoacidosis
- Hypersensitivity
- Hepatic Impairment* (Baseline ALT >2.5 X NL) or Cirrhosis
- Severe CHF (NYHA Class III and IV)
- Premenopausal Anovulatory Woman
- ACS
- Monitor Mucular edema
- Increased risk of fractures in women
Place in therapy TZDs?
- High effectiveness for glucose lowering: Decreases A1c 1.0-1.5%
- alternative to metformin
- Low risk of hypoglycemia
- Risk reduction in patients with ASCVD: add-on to SGLT2 and/or GLP-1
- Weight gain/edema
- Low cost
- Avoid in patients with ALT > 2.5 times normal at baseline; STOP if ALT 3 times normal while on therapy
Pioglitazone
Brand, ADR, DDI, DOsing, Monitoring
Actos
ADRs: Hepatotoxicity, macular edema, fluid retention, weight gain, Resumption of ovulation in premenopausal anovulatory women, fracture risk in women, bladder cancer
DDI: Strong CYP2C8 inhibitor, Pioglitazone induces CYP3A4, oral contraceptives
Dosing: Take with or without food
Monitoring: Hepatic function, ADRs, may take 4-8 weeks to see effect
Types of sulfonylurea?
Glimepiride (Amaryl)
Glipizide (Glucotrol, Glucotrol XL)
Glyburide (Diabeta, Micronase)
Glyburide micronized (Glynase)
Pharmacology and PK of sulfonylurea?
Lowers glucose levels by:
1. Increasing insulin secretion from beta cell (Requires functioning B cells)
2. Normalizing hepatic glucose production
3. Partially reversing insulin resistance in the peripheral tissues
Dose adjust in renal insufficiency
Increased half-life -> increased accumulation -> increased risk of hypoglycemia
CI of sulfonylurea?
- T1DM or Ketoacidosis*
- Hypersensitivity*
- Severe hepatic or renal impairment
- G6PD deficiency
- Illness that affect blood glucose levels
Place in therapy for sulfonylurea?
- High effectiveness for glucose lowering: Decreases A1c 1.0-1.5%
- High risk of hypoglycemia
- Weight gain
- Low cost
- Avoid in patients with significant renal insufficiency
- More useful in long standing DM
- Avoid in patients where hypoglycemia is a problem (i.e., elderly)
* Especially glyburide (long ½ life)
Sulfonylurea
ADR, DDI, Dosing,
ADR: Hypoglycemia, weight gain
DDI: Warfarin, cimetidine
Dosing: QD w/ breakfast
Types of Short-acting Insulin Secretagogues?
Nateglinide (Starlix) and Repaglinide (Prandin)
Pharmacology of Short-acting Insulin Secretagogues?
- Lowers glucose levels
- Increasing insulin secretion from the beta cells in the pancreas in the presence of glucose
- Requires functioning B cells
Short half-life
CI of Short-acting Insulin Secretagogues?
- T1DM or Ketoacidosis*
- Hypersensitivity*
- Use with caution in severe hepatic or renal impairment
Short-acting Insulin Secretagogues Place in therapy?
Less effective for glucose lowering than sulfonylureas: Decreases A1c 1%
* post-prandial glucose levels (taken with meals: “oral insulin”)
May be used as an alternative to sulfonylureas in patients with renal insufficiency
* Do NOT use with sulfonylureas
Low cost
Short-acting Insulin Secretagogues
ADR, Dosing, DDI
ADR: hypoglycemia, weight gain
Dosing: Take 30 minutes prior to each meal
DDI: Repaglinide/gemfibrozil
What is secondary b cell failure?
Oral secretagogues, i.e., sulfonylureas, which increase insulin secretion are effective initially
Over time:
1. ß cell failure
2. Insulin secretion declines
3. Secondary failure of oral secretagogues and increased blood glucose levels
Types of Alpha-glucosidase Inhibitors?
Acarbose (Precose) and Miglitol (Glyset)
Pharmacology of a-glucosidase inhibitors?
Delays digestion of carbs
Acarbose is metabolized by amylases to inactive metabolites
Miglitol is excreted uncahnged in urine
CI of a-glucosidase inhibitor?
- T1DM or Ketoacidosis*
- Hypersensitivity*
- Hypoglycemia
- Severe renal impairment
- Cirrhosis
- GI conditions
a-glucosidase inhibitor place in therapy?
Adjunctive therapy:
1. Low effectiveness: A1c 0.5-1%
2. Low risk of hypoglycemia
3. Weight neutral
4. Avoid in patients with GI problems
ADRs of a-glucosidase inhibitors?
- Flatulense, diarrhea, abdominal pain
- Treat hypoglycemia with PO glucose or lactose NOT sucrose
How do you dose a-glucosidase inhibitors?
Start low, go slow
At the beginning of each meal
What are the types of BAS?
Colesevelam (Welchol)
What is the caution using Welchol?
CI:
1. Bowel obstruction
2. TG >500, precation >300
3. High TG
4. T1DM
5. Hypersensitivity
6. ADEK def
BAS place in therapy?
- Lower effectiveness: <0.5%
- Not used in T2DM except in specific situations
- Lower LDL, increase TG
ADR and DDI of Colesevelam?
ADR: GI effects, hyperTG, pancreatitis
DDI:
* Separate by 4 hours from drugs with narrow therapeutic index i.e., warfarin, phenytoin, digoxin
* Decreases levels of many drugs (levothyroxine, phenytoin, OC, warfarin, ADEK, glyburide
Dosing and monitoring of BAS?
Take with food and water
- Lipid panel
- May take 4-6 weeks to see effect
Types of dopamine agonists?
Bromocriptine (Cycloset)
Place in therapy and CI of Bromocriptine?
CI:
1. Hypersensitivity to ergots and drug
2. T1DM
3. Don’t use in lactating mothers (decreases lactation)
4. Renal and hepatic impairment
Lower effectiveness decreases A1C 0.5%
Bromocriptine
ADR, Monitoring Dosing
ADR:
1. Somnolence
2. Hypotension
3. Syncope
DOsing:
1. Take first thing in the morning with food, within two hours of rising
2. Use of ergots within 6 hours of bromocriptine is NOT recommended
Monitoring:
1. BP and HR
2. Vision
3. Melanoma skin exam
4. Prolactin levels
Type of SGLT2 inhibitor?
Canagliflozin (Invokana)
Dapagliflozin (Forxiga)
Empagliflozin (Jardiance)
Ertugliflozin (Steglatro)
Bexaglifozin (Brenzavvy)*
SGLT2 inhibitor MOA and PK?
Lowers glucose levels by:
1. Reduces glucose reabsopriton
2. Increases urinary glucose excretion
3. Lowers blood glucose levels
Urine and feces
CI of SGLT2i?
- T1 DM or Ketoacidosis*
- Hypersensitivity*
- Avoid in patients with significant renal insufficiency
- Use with caution in patients with a history of bladder CA
- Ensure patients are NOT volume depleted before initiating therapy
SGLT2 place in therapy?
- Intermediate: A1c 0.5-1%
- Low risk of hypoglycemia
- Risk reduction in ASCVD, HF, CKD
- Weight loss
- High cost
- Avoid renal insufficiency
- Empaglifozin is approved in pediatric patients as young as 10 years of age
SGLT2I indication
Indications, DDI, ADR
Indication: ASCVD, HF, DKD, T2DM (Canagliflozin, Empagliflozin)
DDI: UGT inducer, digoxin
ADR: Fungal infection, UTI, Polyuria (hypovolemia), Hypotension w/ elederly, diuretics, ACEIs or ARBs, Hetoacidosis, Increased risk of lower limb amputations
Dosing: Take in morning with or without food
* Canagliflozin: CI in eGFR < 30
* Dapagliflozin: CI in eGFR < 45
DPP4 inhibitor types?
Sitagliptin (Januvia)
Saxagliptin (Onglyza)
Linagliptin (Tradjenta)
Alogliptin (Nesina)
MOA and PK of DPP inhibitors?
MOA: Decreases the breakdown of incretins by DDP4
PK: Excreted in feces and urine
DPP4 inhibitors CI
- T1DM or Ketoacidosis*
- Hypersensitivity*
- Hx of pancreatitis
- Adjust doses in renal impairment (not linagliptin)
Place in therapy DPP4 inhibitors?
- Intermediate: A1C 0.5-1%
- Low risk of hypoglycemia
- Risk of HF with saxagliptin
- Weight neutral
- High cost
- MAY be used in renal impairment
- No GI effects
DPP4 inhibitors?
ADR, DDI, Dosing, Monitoring
ADR: Pancreatitis, bullous pemphigoid
DDI: GLP1 inhibitors
Dosing:
* Sitagliptin: 100 mg QD: Reduce dose in moderate to severe renal insufficiency (50 mg: GFR <45, 25 mg: <30
* Saxagliptin: Moderate to severe renal insufficiency (eGFR < 45 ml/min/1.73 m2)
* Alogliptin: Reduce dose in renal insufficiency (CrCl 30 to 59 ml/min: 12.5 mg daily, CrCl < 30 ml/min: 6.25 mg daily)
Monitoring:
* Renal function
* HF sx (saxagliptin)
* Pancreatitis
* Dermatological conditions
Injectable meds?
Incretin Mimetics (GLP-1 Agonists) (Type 2 DM)
GIP-GLP-1 Agonists (Type 2 DM)
Amylin Analogs (Type 1 & 2 DM)
Insulin (Type 1 & 2 DM)
Incretin mimetics types?
Semaglutide (Ozempic [SC]; Rybelsus [PO])
Liraglutide (Victoza)
Dulaglutide (Trulicity)
Lixisenatide (Adlyxin)
Exenatide (Byetta, Bydureon BCise)
MOA and PK of GLI agonists?
Activates glucsgon-like-peptide-1 (GLP-1) receptors:
1. Enhances glucose-dependent insulin secretion by the pancreatic beta-cell
2. Suppresses inappropriately elevated glucagon secretion
3. Slows gastric emptying
4. Improves glycemic control by reducing fasting and postprandial glucose concentrations
PK: feces and urine
CI GLP1 agonists?
- T1DM
- Hypersensitivity
- Pregnancy, lactation
- GI dx
- Pancreatitis
- Thyroid C-cel tumors, MTC, MENS2
Place in therapy GLP1 agonists?
- HIGH effectiveness for glucose lowering: Decreases A1c by 1.0% to 1.5%
- Low risk of hypoglycemia
- Weight loss
- Avoid in patients with significant renal insufficiency
- Do NOT use with DPP-4s
GLP1 agonist
Indications,
Indications: ASCVD, DKD, T2DM (Dulagutide, Liraglutide, Semaglutide)
ADR: GI, weight loss, pancreatitis, AKI, acute gallbladder disease
DI: Medications that may be affected by delay in gastric emptying (OC)
Dosing:
* DO NOT mix with insulin or inject into an area adjacent to insulin
* SubQ injection: thigh, abdomen, or upper arm
* Give daily injections WITH food; weekly injections may be given WITH or WITHOUT food
* Exenatide (Bydueron BCise): injected immediately after mixing
* Exenatide (Byetta): Increase dose after 1 month, 60 minutes before 2 main meals, not after meals
* Lixisenatide: 60 minutes before meal
How do you administer Rybelsus?
- Take at least 30 minutes BEFORE first food, beverage, or other oral medications of the day
- Take with a sip (no more than 4 ounces) of PLAIN Water only
Tizepatide MOA
GIP/GLP1 receptor agonists:
1. Enhances glucose-dependent insulin secretion by the pancreatic beta-cell
2. Suppresses inappropriately elevated glucagon secretion
3. Slows gastric emptying
4. Improves glycemic control by reducing fasting and postprandial glucose concentrations
CI of Mounjaro?
- Severe GI disease (i.e., Crohn’s disease, gastroparesis)
- Hx of pancreatitis
- T c-cell tumor, MTC, MENS2
- Caution with gallbladder dx and diabetic retinopathy
- T1DM, Hypersensitivity
- Pregnancy and lactation
- Renal insufficiency
Mounjaro place in therapy?
- High effectivenss: 1.5%
- Low risk of hypoglycemia
- Weight loss
- High cose
- Avoid patients with renal insufficiency
Mounjaro
ADR, DDI,
ADR: GI, weight loss, pancreatitis, AKI, acute gallbladder disease
DDI: Slows gastric emptyin (OC), DPP4i
Dosing:
* DO NOT mix with insulin or inject into an area adjacent to insulin
* Increase dosea fter 4 weeks (max 15 mg)
* SubQ injection: thigh, abdomen, or upper arm
* May be given with or without food
What are the amylin analogs? MOA?
Pramlintide (Symlin):
1. Slows gastric emptying
2. Suppressing glucagon secretion
3. Satiety
CI with Symlin?
- Hypoglycemia unawareness
- Severe hypoglycemia in the past 6 months
- Gastroparesis
Place in therapy of Pramlinitide?
- Decreases A1c 1.0%
- Hypoglycemia risk
- Insulin dose reduction required when initiating pramlintide to avoid SEVERE HYPOglycemia
- Weight loss
- Relative high cost
Amylin analog
ADR,
ADR: Hypoglycemia
DDI: Delayed absorption
Admin:
* Take immediately before major meals containing at least 250 calories or 30 grams of carbohydrate
* Do NOT take if the meal has less than 250 calories or 30 grams of carbohydrates
* When first starting reduce the amount of mealtime insulin by 50% to reduce the risk of HYPOglycemia
* SC, don’t inject in arm
* Rotate injection site or 2 inches from
* Don’t mix with insulin
* Refrigerate, room temp (30 days)
Amylin dosing?
MOA of insulin? PK?
- Anabolic and anticatabolic hormone
- Major role in protein, carbohydrate and fat metabolism
- Lowers blood glucose levels by: Stimulating peripheral glucose uptake, Inhibits lipolysis and proteolysis, Enhances protein synthesis
PK:
Absorption:
1. Concentration
2. Insulin source
3. Additives
4. Injection site (abdomen»_space; arms»_space; thighs»_space; buttocks)
5. Blood flow to injection site
Insulin is categorized by what factors?
- Source
- Strenfth
- Onset
- Peak
- DOA
URA insulin types?
Place in therapy, Admin
U-100 Insulin Lispro-aabc (Lyumjev)
U-100 Insulin Aspart (Fiasp)
Oral Inhaled Insulin (Afreeza)
Place: Lower post-prandial glucose levels
Admin: Immediately before meals
Rapid acting insulins?
Types, Place in therapy, Admin
U-100 Insulin Lispro (Humalog)
U-200 Insulin Lispro (Humalog)
U-100 Insulin Aspart (Novolog)
U-100 Insulin Glulisine (Apidra)
Place: Lower post-prandial glucose levels
Admin: 15 minutes to immediately before meals
SA insulin
Types, Place in therapy, Admin
U-100 Humulin R
U-100 Novolin R
U-500 Humulin R (Concentrated)
Place: Lower post-prandial glucose levels
Admin: 30 minutes prior to meals
Intermediate acting insulins?
Type, Place in therapy, admin
NPH:
U-100 Humulin N
U-100 Novolin N
Place: basal or bolus
Admin: Given once or twice daily, Can be used alone or in combination with rapid or short acting insulin
Long acting insulins?
Types, place in therapy, admin
U-100 Insulin Glargine (Lantus, Toujeo)
U-100 Insulin Glargine Equivalent (Basaglar)
U-100 Insulin Detemir (Levemir)
U-100 Insulin Degludec (Tresiba)
U-200 Insulin Degludec (Tresiba)
U-300 Insulin Glargine (Toujeo Max)
Place: Basal
Admin: QHS, Lantus and Levemir CANNOT be mixed with other insulin products
Insulin
CI, ADR
CI: hypoglycemia, hypersensitivity
ADR: hypoglycemia, weight gain, hypokalemia, lipodystrophy
RF of lipodystrophy? Types?
- Reusing needles
- Not rotating injection site
Lipohypertrophy: increased mass, Caused by repeat injections of insulin
Lipoatrophy: decreased mass from insulin antibodies
DDI of insulin?
Drugs that affect glucose control:
1. Steroids
2. Diuretics
3. Beta-blockers
4. Alcohol
What is the initial insulin dose for T1DM?
Initial dose: 0.5-0.6 units/kg/day in divided doses
Honeymoon phase: lower dose
Ketosis, growth, illness: higher dodes
Basal insulin is about ___ of the total daily requirements?
50%
What is the initial dose for T2DM?
Start with low doses of basal insulin and titrate up based on response
* 10 units of intermediate or long acting at bedtime
Types of insulin admin devices?
- Insulin syringe
- Insulin pen
- I-Port
- Insulin pump
- Inhaler
What is the least expensive insulin admin device?
Syringe:
Requires more visual acuity and physical manipulation
Pros and cons of insulin pens?
- Disposible
- Convenient and portable
- Accurate
More expensive than syringe and vial
Pros of I port?
- Device for multiple insulin injections
- Can be worn for up to 72 hours (75 injections)
- Good for patients with needle phobia
- Comes with inserter
Pros and Cons of insulin pump?
Use rapid or ultra rapid acting insulin in pumps:
* Program pump for basal and bolus
Afreeza
Indications, CI, ADR, Admin, Storage
Indications: Lowers postprandial BG
CI: COPD, asthma
ADR: Less weight gain
Admin: Administered at the start of a meal, and dissolves immediately upon inhalation delivering insulin to the blood stream.
Storage: Sealed foil package (10 days room temp), opened (used within 3 days)
How do you dose Afrezza?
Insulin naive: 4 units/meal
Conversion from SubQ pre-meal rapid acting insulin: # units SubQ injected with each meal = # units inhaled with each meal
Conversion from SubQ BID premixed insulin:
* Estimate the mealtime injected dose by dividing ½ of the total daily injected premixed dose equally among the three meals of the day.
* Convert each injected mealtime dose to a mealtime inhalation dose using the scale above.
* Administer ½ of the injected premixed dose as an injected basal insulin dose.
What is the goals of intensive insulin therapy?
- Goal of tight glycemic control
- Multiple insulin injections or pump
- Frequent FSBS monitoring or CGM
- Alternation of insulin therapy based on BS results
What dis Diabetes Control and Complications Trial (DCCT) reveal?
Intensive therapy:
1. Reduces microvascular complications in T1DM (retinopathy, neuropathy, nephropathy)
2. Increases risk of hypoglycemia and weight gain
What did United Kingdom Prospective Diabetes Study (UKPDS) reveal?
- Tight glycemic control in T2DM helps microvascular complications
- Sulfonylurea/insulin does not increase macrovascular risk
- Metformin reduces macrovascular risk in obese patients
- Aggressive blood pressure control reduces microvascular and macrovascular events
