Diabetes Flashcards
Short term meds for weight loss
Phentermine(Lomaira)
Long term meds for weight loss
Orlistat (Alli or Xenical), Lorcaserin (Belviq), phenetermine/topiramate ER (Qysymia), Naltrexone/bupropion (Contrave), Liraglutide (Saxenda)
Surgery for weight loss requirements
Considered in BMI > 40 kg/m2 regardless of control or
BMI 30-34.9 kg/m2 if hyperglycemia is inadequately control despite optimal medical care
Biguanide Drug name and MOA
1st line for T2DM
Metformin
MOA:
Primary – dec. hepatic glucose output
Secondary – inc. peripheral glucose uptake and utilization
Mild anorexia effect may promote weight loss
Does NOT affect insulin secretion
Biguanides Efficacy and Pharmacokinetics
Efficacy
- dec. fasting blood glucose by 50-70 mg/dL
- dec. A1c by 1-2%
- dec. LDL, dec. TG, inc. HDL
- Weight loss
- Only oral agent shown to improve mortality
Pharmacokinetics:
Eliminated entirely by the kidney
Biguanides ADE
Anorexia and nausea on initiation (20-30%)
Abdominal discomfort and diarrhea
Decreased serum vitamin B12 levels over time- risk for peripheral neuropathy
Metallic taste (3%)
BBW for Lactic acidosis – (Rare) occurs in 3 per 100,000 patients/year:
- Fatal in approximately 50% of cases
- Signs and symptoms are nausea, shallow/labored breathing, mental confusion
Biguanides Contraindications/Precautions
Renal impairment:
- CrCl < 30 ml/min
- Starting NOT recommended if CrCl between 30-45 ml/min
Biguanides Drug-Drug Interactions
Alcohol
Iodinated contrast agents (Discontinue metformin prior to exposure and withhold for 48 hours after, SCr should be checked prior to restarting)
Cimetidine may increase metformin levels
Biguanides Dosing
Initial IR dose: 500 mg BID or 850 mg daily
Titrate in increments of 500 mg weekly or 850 mg every other week
IR: 500 mg to 850 mg TID with meals
To minimize GI effects
Max dose:
Immediate Release: 2,550 mg/day
Extended Release: 2,000 mg once daily
Sulfonylureas Drugs
Glipizide (Glucotrol®, Glucotrol® XL)
Glimepiride (Amaryl®)
Glyburide (Micronase®, Diabeta®, Glynase®) - No longer recommended by guidelines, increased risk of hypoglycemia especially in elderly. However, still used for gestational diabetes.
Sulfonylureas MOA
stimulate insulin secretion from beta cells of pancreas
Sulfonylurease Pharmacokinetics
Glipizide, glimepiride: Metabolized in liver to inactive or mildly active metabolites
Glyburide: 50% of metabolites eliminated in kidney, 50% feces
Sulfonylureas ADE
Hypoglycemia – most common
Weight gain (5-20 lb)
Gastrointestinal disturbances: Nausea, dyspepsia, vomiting, abnormal liver function tests
Dermatologic reactions: Rash, photosensitivity reactions, pruritus, hypersensitivity reactions
Sulfonylurea Contraindications/Precautions
Pregnancy Renal Insufficiency (Glyburide)
Sulfonylurea Drug-Drug Interactions
↑ SU effect: antacids, fluconazole, gemfibrozil, salicylates
↓ SU effect: rifampin (glyburide), cyclosporine
Sulfonylureas place in therapy
Fasting BG < 200 mg/dL
Patients who develop diabetes after the age of 40
Have diabetes < 5 years
No previous treatment with insulin
Glipizide and glimepiride preferred with CrCl < 50 mL/min
Meglitinides Drugs and MOA
Repaglinide (Prandin®)
Nateglinide (Starlix®)
Mechanism of action:
Stimulates insulin secretion in glucose dependent manner -> less hypoglycemia
Lowers PPBG*
Do not take if miss a meal
Meglitinides Pharmacokinetics
Onset of action: 15 minutes
Peak response: 60-90 min
Duration of action: <4 hrs
Metabolism: via cytochrome P450 enzymes (CYP 3A4)
Meglitinides ADE (less than SU)
Hypoglycemia (repaglinide > nateglinide)
Weight gain
Meglitinides Contraindications/Precautions
Use with caution in patients w/ hepatic dysfunction
Pregnancy Category C
Meglitinides Drug Interactions
Dec. hypoglycemic effect
Cytochrome P3A4 inducers: Rifampin, Carbamazepine, Phenobarbital
Inc. hypoglycemic effect:
Cytochrome P3A4 inhibitors
Erythromycin
Azole antifungals (ketoconazole, fluconazole, itraconazole)
Gemfibrozil – severe hypoglycemia w/ repaglinide (KNOW)
Thiazolidinediones (TZD) Drugs and MOA
Pioglitazone (Actos®)
Rosiglitazone (Avandia®)
MOA: Peroxisome proliferator activated receptor (PPAR) agonist to promote glucose uptake into target cells: - Increase insulin sensitivity - Decrease hepatic glucose output - No effect on insulin secretion
TZDs Safety Concerns
TZDs are contraindicated in patients with NYHA Stage III-IV CHF and should be avoided in patients with symptomatic CHF on nitrates.
TZDs Efficacy
Dec A1c approximately 0.6-1.3%, FBG by 30-60 mg/dL
Rosiglitazone: inc HDL and LDL cholesterol
Pioglitazone: Dec. triglyceride levels 10%
TZDs Pharmacokinetics
Hepatic metabolism
Onset of action is slow:
Several weeks
4 months - maximum effect
TZDs ADE
Weight gain (>2-6 kg)
Hepatotoxicity :
Baseline liver function tests
Do not initiate therapy if ALT >2.5 times ULN
ALT >3x ULN, discontinue therapy
ALT >1.5 but <2x ULN, repeat and weekly until normal
Peripheral Edema (5%): Worse if combined with insulin (risk of CHF)
Mild anemia (1-2%)
Macular Edema (3-6 times more likely to develop)
Risk of proximal fractures
TZDs Contraindications/Precautions
Do not use in NYHA Class III or IV heart failure (KNOW)
Contraindicated in pregnancy
Avoid in patients with active liver disease
Caution in patients with anemia, edema
MI (Rosi) – although FDA restrictions removed
Bladder cancer (Pio)
Mild fracture risk
TZDs Drug Interactions
Pioglitazone (induces CYP3A4)–↓ effect:
- Cyclosporine, tacrolimus, HMG-CoA reductase inhibitors, oral contraceptives containing ethinyl estradiol and norethindrone
Ketoconazole-inhibits pio metabolism
Rosiglitazone:
- Does not affect PK of oral contraceptives
DPP-4 Inhibitors MOA
Inhibits dipeptidyl peptidase-4 enzyme (DPP-4), which inactivates the incretin hormones, glucagon-like peptide-1 (GLP-1) and glucose dependent insulinotropic polypeptide (GIP)
↑insulin release and ↓ glucagon levels in a glucose- dependent manner in patients with T2DM
DPP-4 Inhibitors Pharmacokinetics
Pharmacokinetics:
Primarily renal elimination
Half-life = 12.4 hours
DPP-4 Inhibitors ADE
Headache
Acute pancreatitis
Upper Respiratory Tract Infections
Severe Joint Pain (FDA warning, most w/ Sita)
Saxagliptin ADE
Urinary Tract Infections
Skin reactions
Linagliptin ADE
Hypoglycemia, arthralgia and back pain
Saxagliptin FDA Warning
Increased rate of heart failure hospitalizations, still being reviewed.
Patients should not stop taking saxagliptin
Health care professionals should continue to follow the prescribing recommendations
DPP-4 Inhibitors Contraindications/precautions
Sita:
Cases of acute Pancreatitis reported, caution in starting in patients with history of or active pancreatitis (FDA warning)
Saxa:
Caution in patients with heart failure and concurrent elevation in BNP, CKD.
Alo:
Post-marketing reports of hepatic failure
Alo,sita,saxa:
Dose adjustment in renal dysfunction
DPP-4 Inhibitors Drug Interactions
Digoxin: oral sitagliptin caused small (11%) increase in AUC and plasma Cmax (18%) of digoxin at 0.25 mg/day. Dose adjustment of digoxin not recommended, but monitor closely.
SGLT-2 Inhibitors MOA
Inhibits glucose and sodium reabsorption in renal proximal tubule
SGLT2: ~90% of renal glucose reabsorption
Increases urinary glucose excretion
SGLT-2 Inhibitors Efficacy
decrease A1c 0.6-1.2%
decrease FBG and PPG
Reduction in weight (1.6-3.8%) and BP
SGLT-2 Inhibitors Pharmacokinetics
Hepatic metabolism
Excretion: fecal and renal
Renal: Dapagliflozin > Canagliflozin
SGLT-2 Inhibitors ADE
Polyuria (4-5%) UTI (4-6%) Genital mycosis: Female (10-11%), Male (3-4%) Hypotension (2-3%) Dapaglifozin: Nasopharyngitis (6-7%)
SGLT-2 Inhibitors Contraindications/Precautions
Renal impairment (eGFR < 30mL/min) or ESRD
Dialysis
Caution in the elderly or hepatic impairment
SGLT-2 Inhibitors Drug interactions
Rifampin, phenytoin, phenobarbital, and ritonavir decrease canagliflozin concentration
Canagliflozin increase digoxin concentration
What is an important health benefit of SGLT-2 Inhibitors
decreasing ASCVD/CHF risks
Empagliflozin received FDA approval for this!
Alpha-Glucosidase Inhibitors MOA
Potent competitive inhibitor of brush border alpha-glucosidases necessary for the breakdown of complex carbohydrates
Slows intestinal carbohydrate digestion/absorption
Alpha-Glucosidase Inhibitors Efficacy
Decrease postprandial hyperglycemia 30-60mg/dL
Not effective in lowering blood glucose levels throughout the rest of the day
Small improvements in A1c
Alpha-Glucosidase Inhibitors ADE
Gastrointestinal side effects (up to 70%)
Acarbose – increased LFTs at doses >100 mg TID
No hypoglycemia as monotherapy
Alpha-Glucosidase Inhibitors Contraindications/precautions
GI disorders including inflammatory bowel disease, chronic ulceration, and partial obstruction
Renal impairment: avoid acarbose if Scr > 2 mg/dL; not studied
Hypoglycemia -Treat with glucose ,dextrose, lactose only ( why?…MOA prevents breakdown of table sugar)
Contraindicated in pregnancy
Alpha-Glucosidase Inhibitors Drug interactions
Acarbose and miglitol may decrease digoxin levels
Miglitol may decrease propranolol and ranitidine concentrations
Bile Acid Sequestrant (BAS) MOA
Thought to be an antagonist to the farnesoid X receptor (FXR), which subsequently reduces hepatic gluconeogenesis
Used in conjunction with insulin or oral DM medications
Bile Acid Sequestrant (BAS) Adverse Effects:
Constipation, dyspepsia, nausea, myalgia
Bile Acid Sequestrant (BAS) Contraindications and precautions
Contraindicated in patients with a history of bowel obstruction, serum TG concentration greater than 500 mg/dL
Caution in patients with swallowing disorders (large pill), dysphasia, gastric mobility disor- ders, and serum TG concentrations greater than 300 mg/dL
Are GLP-1 Receptor Agonists monotherapy?
This injectable agent is not indicated as monotherapy!
GLP-1 Receptor Agonists MOA
Mimics the effects of an incretin hormone called glucagon-like peptide-1 (GLP-1):
Stress response to high BG levels
Inhibits release of glucagon after meals
Slows the rate of gastric emptying-> DDIs
Promotes satiety -> less intake -> weight loss
stimulates production of insulin
GLP-1 Receptor Agonists ADE
Mild to moderate: Hypoglycemia (14–36%)-more commonly in patients receiving a sulfonylurea Nausea (40-50%) Vomiting (13%) Diarrhea (13%) Dizziness (9%) Immunogenicity may occur – exenatide is a protein Injection-site reactions
GLP-1 Receptor Agonists Black Box Warning
Can cause dose-dependent and treatment duration–dependent thyroid C-cell tumors at clinically relevant exposures in rodents.
Unknown in humans
GLP-1 Receptor Agonists Drug Interactions
Slows gastric emptying – may alter rate and extent of absorption of oral drugs
Take oral meds at least one hour before injecting a GLP-1 RA
GLP-1 Receptor Agonists Precautions
Should not be used in patients with severe renal impairment (CrCl < 30 mL/min) or those with ESRD (Exenatide ONLY)
Should not be used in patients with severe GI disease including gastroparesis
Cases of acute pancreatitis have been reported. Consider alternatives in patients w/ history of pancreatitis
GLP-1 Receptor Agonists Indication
Adjunctive therapy to improve glycemic control in patients with T2DM who are not adequately controlled with metformin, a sulfonylurea, or a combination of both
Pramlintide (Symlin®) MOA
Synthetic analog of amylin, an endogenous hormone produced in the pancreas to assist in postprandial glucose control
Decrease glucagon secretion
Delays gastric emptying, increases the feeling of satiety
Pramlintide (Symlin) Indications
Approved for use in patients with either type 1 or type 2 diabetes
Type 1 diabetes:
Approved as an adjunctive treatment in patients who use mealtime insulin and who have failed to achieve glucose control despite optimal insulin therapy
Type 2 diabetes:
Approved as an adjunct to mealtime insulin in patients who have failed to achieve optimal glucose control with insulin therapy, with or without concurrent sulfonylureas and/or metformin
Pramlintide (Symlin) ADE
Does not cause hypoglycemia when used alone
Can cause severe, insulin-induced hypoglycemia when used in combination with insulin:
Type 1 diabetes
Occurs within 3 hours after a dose
Gastrointestinal: Nausea especially upon initiation of therapy (28-48%) Loss of appetite Vomiting Headache
Pramlintide (Symlin) has a REMS for what?
risk for severe hypoglycemia with concurrent use of pramlintide and insulin.
*Need to reduce insulin doses when initiating pramlintide
Pramlintide (Symlin) Contraindications
Patients with confirmed diagnosis of gastroparesis or hypoglycemia awareness
Should not be used in patients who have had recurrent severe hypoglycemia, have poor compliance with insulin regimens or SMBG instructions
Pramlintide (Symlin) Drug interactions
Should not be used in patients who are taking medications that affect gastric motility such as anticholinergic medications or agents that slow intestinal absorption of nutrients such as the alpha-glucosidase inhibitors
May slow the absorption of drugs taken orally
Take oral medication 1 hour before pramlintide
What are the Insulin Indications for T2DM
Severe Hyperglycemia at Dx
Overcoming glucose toxicity
A1c> goal despite max doses of 2 oral agents
Pregnancy, surgery
Insulin Pharmacokinetics
Route of administration: IV > IM > SC
Clearance:
Renal Function (failure decreases clearance)
Insulin antibodies – IgG antibodies bind insulin and release it slowly
Absorption:
Injection site, exercise, temperature, massage, dose
How does thyroid function effect insulin clearance?
Hyperthyroidism increases insulin clearance but also delays action
Basal Insulin Characteristics
Suppresses hepatic glucose production b/w meals and overnight
Stimulates lipid and protein synthesis
Use intermediate or long-acting insulin
50 % of daily needs
Bolus Insulin Characteristics
Controls hyperglycemia after meals (stores nutrients)
Use rapid (best) or regular insulin
10-20 % of daily insulin requirement for each meal
Basal Insulin Long Acting Drugs
Insulin Glargine (Lantus®) Insulin Detemir (Levemir®) Insulin Degludec (Tresiba®)
Bolus Insulin Rapid Acting Drugs and how to use
Insulin lispro (Humalog®) Aspart insulin (Novolog®) Insulin glulisine (Apidra®)
Inject just before meals (15 min)
Bolus Insulin Short Acting Drugs and how to use
Regular insulin (Humulin R)
Must be administered 30-45 minutes before meals
Afrezza Administration and Contraindication
Shorting acting and
Regular Inhaled Insulin
Contraindicated in patients w/ chronic lung disease such as asthma or COPD
What is a problem with premixed insulin?
Problematic for hospitalized patients
Inflexible dosing
What is the recommended initial insulin dosing therapy for T1DM
Initially, start total daily insulin at 0.4-0.5 units/kg/day
Steps for Initiating Insulin in T2DM
Step 1: ODA + Basal Insulin
After 3 months, if target A1C is not reached…
Step 2: Consider GLP-1 OR Add prandial (bolus) insulin
After 3 months, if target A1C is not reached…
Step 3: Add prandial (Bolus) insulin to the next meal
After 3 months, if target A1C is not reached…
Step 4: Add prandial (Bolus) insulin to the last meal
What are the BG goals for pre-meal, bedtime, and post-meal for T2DM?
Pre-meal & bedtime glucose = 80-130 mg/dL
1-2 hour post-prandial = <180 mg/dL
Patients on multiple-dose insulin or insulin pump therapy should perform SMBG when?
Prior to meals and snacks Occasionally post-prandially At bedtime Prior to exercise When they suspect hypoglycemia Prior to critical tasks such as driving
When should A1C testing be done?
At least two times a year in patients who are meeting treatment goals (and who have stable glycemic control)
OR
Test quarterly in patients whose therapy has changed or who are not meeting glycemic goals
Insulin ADE
Hypoglycemia
Weight gain
Injection site discomfort or redness:
Lipohypertrophy- Repeated injection in the same site causing fatty build up. Stress importance of rotating injection sites
Lipoatrophy- Pitting of skin (immune response to impure insulin)
Local allergic reactions & hypersensitivity
Hypoglycemia Types (Levels) and General Tx
< 70mg/dL = Hypoglycemia alert value (level 1)
-Treat w/ fast acting carbohydrate, dose adjustment
<54mg/dL = Clinically significant hypoglycemia (level 2)
-Give Glucagon
No level but severe cognitive impairment = Severe (level 3)
-Requires assistance from another person for recovery
Values associated with Symptoms
BG < 50 mg/dL; patient may or may not be symptomatic
BG < 40 mg/dL; patient generally symptomatic
BG < 20 mg/dL; can be associated with seizures and coma
Hypoglycemia Clinical Considerations
Irregular eating patterns
Increased physical exercise
Gastroparesis (delayed gastric emptying time)
Medications (including oral sulfonylureas)
Hypoglycemia Tx
15-20 g rapidly absorbed carbohydrate
Repeat in 15-20 min of glucose concentration <60 mg/dl or if patient symptomatic
Follow with complex carbohydrate/protein snack
15-15-15 Rule
What do you use to treat a patient who is unconscious as a result of hypoglycemia?
Glucagon 1 mg SC, IM, or IV – mean response time 6.5 minutes – must reconstitute
