Diabetes Therapeutics Flashcards
When we consider insulin in a new diagnosis (ADA)
Symptomatic and/or have an AIC of 10% or more and/or CBGs 300 of higher
Insulin should always be considered if A1C is around 9-10% (this doesn’t mean the patient will be on it forever!)
Guideline recommendations for patient with long-standing suboptimally controlled T2DM and ASCVD
Empagliflozin or liraglutide (shown to reduce CV and all-cause mortality in combo with standard care)
Considerations for treating diabetes in older adults
Reduced life expectancy, higher CVD burden, reduced GFR, at risk for adverse events from polypharmacy, more likely to be compromised from hypoglycemia
Consider less ambitious targets (<7.5-8% if tighter targets not easily achieved)
Recommendations for reasonable A1C treatment goals in older adults based on level of health
Healthy (<7.5%)
Comorbidities (<8%)
Very complex/poor health (<8.5%)
*the key is to individualize
Considerations in treating a diabetic with renal disease
Increased risk of hypoglycemia
Avoid glyburide, use other insulin secretagogues cautiously
Reduce metformin dose when eGFR <45 and avoid if less than 30
Most DPP4 inhibitors require dose adjustment
avoid exenatide if CrCl <30 ml/min
avoid SGLT2 inhibitors for eGFR <45-60 (agent specific)
Which agents have minimal hypoglycemia risk?
Thiazolidinediones, DPP4s, SGLT2s and GLP-1s
Insulin and sulfonylureas should be avoided
Considerations for those with coronary disease
Avoid hypoglycemia
Empagliflozin reduces CV events in high-risk patients
Liraglutide reduces CV events in high-risk patients
Considerations for those with heart failure
Metformin is ok unless HF is severe or unstable
Avoid thiazolidinediones
Warning with DPP4i saxagliptin
Potential benefit with SGLT2 inhibitors based on diuretic effect
Liraglutide reduced CV outcomes in high-risk patients
EMPA-REG outcome(s)
Reduction in CV death, death from any cause and HF hospitalizations (with Empagliflozin compared with placebo)
LEADER outcome(s)
Reduction in CV death, death from any cause and microvascular outcomes
No reduction in HF hospitalizations, nonfatal MI or nonfatal stroke
LEADER vs EMPA-REG
The time to effect was delayed in the LEADER trial (Liraglutide, > 12-18 months) compared with EMPA-REG (< 3 months)
Considerations for those with liver dysfunction
Most drugs not tested in advanced liver disease
Pioglitazone and metformin may be beneficial for NAFLD but should be avoided in active or advanced liver disease
Insulin best option for patients with advanced disease
Considerations for those with obesity
Obesity can contribute to insulin resistance
Preference for or weight neutral or weight loss agents
Diet, physical activity and behavior changes (goal at least 5% weight loss)
Consider weight loss medications as adjunct to lifestyle
Consider or recommend metabolic surgery (if BMI > 30)
Which medications are ideal if patient wants to avoid weight gain?
DPP4, SGLT2 and GLP-1 agonist, metformin
Sulfonylureas, thiazolidinediones and insulin should be avoided
What medications are ideal if the patient wants to minimize cost?
Sulfonylureas, thiazoidinediones, metformin
DPP4, SGLT2, GLP1 and Insulin should all be avoided (except for insulin N/R 70/30 which is cheap at walmart)
Initial daily dose of insulin for T1DM
0.3-0.5 units/kg/day
Diabetes in pregnancy
Metformin + insulin preferred (glyburide now inferior)
Levemir, Humalog and Novolog (category B); Lantus (category C)
Tighter glycemic control indicated (especially for those with pre-existing T2/T1DM): bedtime 60-99, postprandial 100-129, A1C <6%
General guidelines for initiating/titrating insulin in T2DM
Start 10 U/day or 0.1-0.2 U/kg/day
Adjust 10-15% or 2-4 units once or twice weekly to reach FBG target
For hypo, do the opposite of the increase dose adjustment
Initiating basal insulin algorithm
Bedtime NPH, detemir glargine (start with 10 units or 0.1-0.2 U/kg and increase weekly/bi-weekly by 10-15% or 2-4 units)
If hypoglycemia then decrease by 10-20% or 4 units
If A1C not controlled after FBG reached and basal dose >0.5 U/kg/day add post-prandial insulin or consider GLP-1 agonist
Dosing consideration for insulin detemir
Dose dependent duration of action (6 hours at low doses-23 hours at high doses)
Appropriate to start with qd dosing and split later on if insulin appears to be wearing off
Dosing considerations for insulin degludenc
Can be injected at variable times so could be advantageous in patients with poor adherence
When is it time to consider adding on bolus or meal-time insulin?
When fasting glucose is under control but A1C remains greater than goal after 3-6 months of basal insulin
If titration of basal insulin leads to nocturnal hypoglycemia
When basal doses exceed 0.5 U/kg/day
General dosing of adding mealtime insulin before patients largest meal
Start with 4, adjust by 2 units every 3 days until CBG within range
What is an insulin sliding scale
Catching up
Uses a correction factor which refers to use of additional short or rapid-acting insulin in addition to scheduled insulin doses
Calculating ISF
1500 for regular/TDD
1800 for rapid/TDD
Target BG - Actual BG/ISF = # of units needed to correct
Usually want to skip or decrease correction dose by 1/2 at bedtime to avoid hypoglycemia
Insulin Carbohydrate ratio
In general, approximately 1 unit per 10-15 g CHO
500/TDD = grams of carbs covered
Lab values that define normal range (not diabetic)
FPG 70-99
2-hour Plasma Glucose 100-139
A1C 4.5-5.6%
Lab values that define pre-diabetes
FPG 100-125
2-hour Plasma Glucose 140-199
A1C 5.6-6.4%
Lab values that define diabetes
FPG 126 or higher
2-hour Plasma glucose 200 or higher
A1C 6.5% or higher
Diagnosis should be confirmed by repeat testing unless RBG 200 or more with overt symptoms of hyperglycemia
Gestational diabetes risk factors
Ethnicity (African-American, Native American, Asian), obesity, age over 25, family history of T2DM, signs of insulin resistance (PCOS, lipids), maternal history of gestational diabetes, prior delivery of baby exceeding 9 pounds
*screen all with risk factors or at the 24-28 week mark
Frequency all adults should be tested for T2DM
All adults 45 or over should be tested every 3 years (if normal)
How often is urinary albumin excretion assessed?
Annually
Vaccine recommendations in diabetics
Influenza (annually)
Pneumococcal (PPSV23 x 1; PPSV23 & PCV12 for those 65 or older)
HepB vaccine series recommended for adults 19-59
General blood pressure goal in diabetics
under 140/90
130/80 could be used in patients that can handle a stricter goal
Lipid management in diabetes
Statin therapy often recommended
In adults not taking a statin, check lipid profile at diagnosis and then at least every 5 years
When taking a statin, lipids should be checked periodically to assess response to therapy and adherence
Therapy recommendation for patient (age >40) with ASCVD who cannot tolerate high-intensity statin therapy
Moderate intensity statin + ezetimibe
Also used in those with ACS and LDL of 50 or more (IMPROVE-IT trial)
Which STATINs are high-intensity? What are their dosage strengths?
Rosuvastatin 20-40mg
Atorvastatin 40-80mg
Recommended anti-platelet therapy in diabetes
Low-dose aspirin (75-162 mg/day) indicated for primary prevention in those with increased CV risk (10-year risk >10%) - includes most men/women 50+ years of age with at least 1 additional risk factor
Aspirin not recommended for those with 10-year risk <5% (between 5-10%, use clinical judgement)
Use aspirin as a secondary prevention in those with diabetes and a history of ASCVD (clopidogrel 75mg if aspirin allergy)
Dual therapy acceptable up to 1 year after ACS
Nephropathy treatment recommendations (general)
Assess urinary albumin annually in those with T2DM and in those with T1DM for 5 or more years
Optimize glycemic control and BP
ACEi or ARB recommended for all with abnormal albuminuria (>29) or eGFR <60
Eye exams in T1/T2DM
Done in those with T1 within 5 years of diagnosis, shortly after diagnosis in T2
If no retinopathy, repeat every 2 years; if present, every year
Foot exams in diabetes
screen for diabetic peripheral neuropathy annually
Feet inspection at every visit
Agents for diabetic neuropathy
FDA approved (Duloxetine, Pregabalin, Tapentadol)
Off-label (TCAs - amitriptyline, nortriptyline; Gabapentin, Valproate)
Minimum recommendation for exercise in diabetic patients
150 minutes or more of moderate physical activity a week (or 75 minutes of vigorous exercise)
Recommended to perform resistance training at least twice per week
Prolonged sitting should be interrupted every 30 minutes for blood glucose benefits
When should metabolic surgery be recommended?
BMI 40+ (regardless of glycemic control)
BMI 35-39.9 (glycemic control not adequate)
BMI 30-34.9 (poor glycemic control)
Medications/drug abuse that could result in DKA
Cocaine, Meth
Clozapine, olanzapine, steroids
Caloric intake recommendation during sick day to avoid DKA
45 g carbs every 4 hours and drink plenty of fluid
Signs/symptoms of DKA
NV, thirst, polyuria, abdominal pain, vision blurring
Tachycardia, hypotension, dehydration, warm dry skin, Kussmail respiration, fruity breath, mental status change
Describe HHS
Hyperglycemic Hyperosmolar State
Usually seen in older individuals with predisposing factors
No absolute insulin deficiency so little ketogenesis (hyperglycemia usually worse but little acidosis)
Much more dehydration secondary to worsening hyperglycemia
Blood glucose level for clinically significant hypoglycemia
< 54 mg/dL
Glucose utilization is ___________ during exercise; insulin sensitivity is __________ during/following exercise
Increased
Increased
Alcohol impairs __________
Gluconeogenesis
What hormones/molecules are released when BG drops to 60 mg/dL or lower
Catecholamines
Growth hormone and corisol (both antagonize insulin)
Contributing factors to hypoglycemia unawareness
Often occurs in those with frequent hypoglycemia
Reduction in epinephrine response to low BG, increased expression of glucose transporters in brain (GLUT1, GLUT3), suppression of autonomic responses secondary to cortisol
Treatment of hypoglycemia
MILD (rule of 15) - ingest 15 grams of rapid acting carb, re-check in 15 minutes (5 lifesavers, 3-4 glucose tabs, 4 oz juice/soda, 8oz milk, avoid high-fat foods, follow with a snack or small meal within 1-2 hours)
SEVERE - glucagon kit (adults = 1.0 mg, children <5 = 0.5 mg, infants = 0.25 mg)
Fructosamine levels
Measure of glycated albumin, reflecting the average glucose over 2-3 weeks
Indicated for pregnancy and hemoglobinopathies; could be useful in patient with discordant A1C and CBGs
Not well standardized and not to be used for diagnosis
Benefit of A1C goal
Lowering below or around 7% associated with microvascular complication reduction; if implemented soon after diagnosis, has been reduction in macrovascular disease
Factors leading to less stringent A1C goals?
High risk of hypoglycemia or AEs, long-standing disease duration, short life-expectancy, many comorbidities, severe established vascular complications, less motivated patient, limited resources/support
Benefit of intensive therapy in diabetes (summary of major clinical trials)
Decrease in microvascular complications (long and short term)
CVD reduction long-term, not short
Relatively no change in mortality (some increase in mortality - ACCORD trial)
How does hypoglycemia increase CVD risk
Cardiac arrhythmias due to abnormal cardiac repolarization
Increased thrombotic tendency/decreased thrombolysis
CV changes induced by catecholamines (increased HR, silent myocardial ischemia, angina/MI)
Metformin advantages
A1C reduction by 1-2%
Decrease in micro and macro-vascular complications (UKPDS)
Weight neutral
Low-cost
Metformin contraindications
eGFR <30, hepatic disease, excessive alcohol intake, 80+ y.o., acute illness/major surgery/infection, hypoxic states, dehydration and iodinated constrast media
Lactic acidosis signs/symptoms
SOB, muscle aches, weakness, ataxia, altered mental status, palpitations, slurred speech, tachypnea
Metformin recommendations based on eGFR
60+ (continue)
45-59 (monitoring every 3-6 months)
30-44 (prescribe with caution, use lower dose such as 50% max, monitor renal function every 3 months, avoid starting in new patients)
< 30 (DO NOT START/STOP)
Sulfonylurea advantages
Decrease A1C by 1-1.5%
Low-cost generics
Well-tolerated
Decease microvascular complications
Sulfonylurea disadvantages
Hypoglycemia (mostly in elderly) - greater risk with glyburide due to active metabolites (medicare won’t pay for glyburide as result)
Weight gain (1-3 kg)
Low durability
*glimepiride is the only other 2nd generation with active metabolites but they have minimal activity
Glyburide dosing consideration
If CrCl <50 avoid use
Sulfonylurea dosing consideration (general)
In general, the max effective dose is about 1/2 of the max approved dose
Glipizide 20mg/day (ER 10mg/day)
Glimepiride 4mg/day
Glyburide 10mg/day
Rare ADRs with sulfonylureas
Syndrome of inappropriate Antidiuretic Hormone (SIADH; Chlorpropamide and tolbutamide may increase release of ADH)
Disulfiram reactions (chlorpropamide)
Hepatotoxicity
Hemolytic anemia
Meglitinides disadvantages
Frequent dosing schedule
Decrease A1C only by 0.5-1%
Both agents cleared by liver and metabolized by CYP3A4 (Nateglinide also by 2C9 and inhibits 2C9) - interaction with gemfibrozil, itraconazole (and other 3A4 inhibitors/inducers)
If patient skips a meal, the (sulfonylurea/meglitinide) should be skipped
Meglitinide
Thiazolidinediones advantages
No hypolgycemia, durable, increase HDL, lower TG, lower CVD
Thiazolidinediones disadvantages
Weight gain, edema/HF, bladder cancer, increased risk of fractures, decrease A1C only by 0.5-1.4%
Alpha-glucosidase inhibitors disadvantages
Modest efficacy (decrease A1C 0.5-0.9%)
Alpha-glucosidase inhibitors contraindications
IBD, intestinal obstruction, GI disorders
Cirrhosis of liver
Avoid use if Scr > 2mg/dl
What to use if patient has low blood sugary while taking alpha-glucosidase inhibitor
Sucrose won’t work, must use glucose
DPP4 inhibitors MOA
Increase insulin secretion, decrease glucagon secretion by inhibiting DPP4 (which increases postprandial GLP-1,GIP)
DPP-4 Inhibitor Disadvantages
Only decrease A1C by 0.5-0.8%
High cost
Increased risk of pancreatitis (counsel on nausea, vomiting, anorexia and persistent abdominal pain)
FDA warning for joint pain (went away with removal of agent)
HF risk with saxagliptin and alogliptin
All require renal adjustment (except Linagliptin)
SGLT2 inhibitors disadvantages
4-7 fold increase in genital mycotic infections, increased risk of UTIs
Increased risk of euglycemic ketoacidosis
Increased urination, fluid loss
Hyperkalemia/serum creatinine bump
Relatively modest efficacy (decreases A1c by 0.5-1%)
High cost
FDA safety alert for Canagliflozin
Bone fractures can occur more frequently (as early as 12 weeks after start)
Colesevelam
Bile acid sequestrant (decreases hepatic glucose production, increases incretin levels)
Decreases A1C by 0.3-0.4%
GI side effects, high cost
Bromocriptine
Ergot derived dopamine agonist (modulates hypothalamic regulation of metabolism, increases insulin sensitivity)
Decreases A1C by 0.4-0.5%
GI side effects, dizziness, nausea, fatigue, rhinitis
GLP-1 Agonists advantages
Decrease A1C by 0.5-1.5%, no hypoglycemia, weight reduction through increased satiety, potential beta-cell proliferation/increase in function, CVD benefit (liraglutide)
GLP-1 agonists disadvantages
GI side effects, increased risk of pancreatitis, high cost
BLACK BOX WARNING (all but byetta) for thyroid-C cell tumors
Special considerations for GLP-1 agonist formulations
Albiglutide (requires mixing)
Dulaglutide (auto-injector)
Exenatide (timing with meals)
Exenatide ER (both kit and pen require mixing)
Liraglutide (FDA approval for weight loss)
Adverse reaction associated with qweek GLP-1 agonists
injection site reaction more common
Of GLP-1 agonists an DPP4 inhibitors, which have a higher incidence of SEs?
GLP-1 agonists (have improvement in CV markers though!)
Amylin analog MOA
Slows gastric emptying, decreasing glucagon secretion
Advantages of Pramlintide
Decrease postprandial glucose, weight loss
Disadvantages of Pramlintide
A1C reduction 0.5-1%, GI effects, frequent dosing, increases daily injection burden, potential for hypoglycemia with insulin use, spendy
Pramlintide Black Box Warning
Can contribute to episodes of severe hypoglycemia
When initiating, prandial insulin dose needs to be reduced by 50% with subsequent re-titration
Pramlintide adverse effects
Severe hypoglycemia, nausea, decreased appetite, anorexia, vomiting, headache
Pramlintide contraindications
Poor compliance with insulin regimen or with blood glucose monitoring, A1C >9%, recurrent severe hypoglycemia requiring assistance in past 6 months, hypoglycemia unawareness, confirmed gastroparesis, use of drugs that stimulate GI motility, pediatric patients
Pramlintide patient education
Refrigerate unopened pens
Discard opened pens or vials after 30 days
Can NOT be mixed with insulin
Inject SubQ in abdomen or thigh
Separate pramlintide and insulin injections by at least 2 inches
Only take before meals of more than 250 calories (or >30 grams of carbs)
Do not take if pre-meal BG is low or if meal contains insufficient carbs or calories
Special consideration about appearance of NPH
Cloudy
Special consideration about administration of NPH
Can be rolled/mixed (only basal insulin that can be)
Afrezza disadvantages
Boxed warning for acute bronchospasm in patients with chronic lung disease
Contraindicated in asthma and COPD
Not a replacement of long-acting
Not recommended for DKA
Not recommended for patients who smoke or recently stopped
Costly
Complicated dosing, expiration and storage
How is Afrezza supplied?
4 units, 8 units or 12 units
Cartridge loaded into small inhaler
